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Temodal (temozolomide) – Summary of product characteristics - L01AX03

Updated on site: 10-Oct-2017

Medication nameTemodal
ATC CodeL01AX03
Substancetemozolomide
ManufacturerMerck Sharp

1.NAME OF THE MEDICINAL PRODUCT

Temodal 5 mg hard capsules

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 5 mg temozolomide.

Excipient with known effect:

Each hard capsule contains 132.8 mg of anhydrous lactose.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Hard capsule (capsule).

The hard capsules have an opaque white body, an opaque green cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with "5 mg", the Schering-Plough logo and two stripes.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Temodal is indicated for the treatment of:

-adult patients with newly-diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment.

-children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

4.2Posology and method of administration

Temodal should only be prescribed by physicians experienced in the oncological treatment of brain tumours.

Anti-emetic therapy may be administered (see section 4.4).

Posology

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant phase

TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met:

-absolute neutrophil count (ANC) ≥ 1.5 x 109/l

-thrombocyte count ≥ 100 x 109/l

-common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).

During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.

Table 1. TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ

Toxicity

TMZ interruptiona

TMZ discontinuation

Absolute neutrophil count

0.5 and < 1.5 x 109/l

< 0.5 x 109/l

Thrombocyte count

10 and < 100 x 109/l

< 10 x 109/l

CTC non-haematological toxicity

CTC Grade 2

CTC Grade 3 or 4

(except for alopecia, nausea, vomiting)

 

 

a:Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count 1.5 x 109/l; thrombocyte count 100 x 109/l; CTC non-haematological toxicity Grade 1 (except for alopecia, nausea, vomiting).

Monotherapy phase

Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia,

nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/l, and the thrombocyte count is ≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase should be applied according to Tables 2 and 3.

During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TMZ). The dose should be reduced or administration discontinued according to Table 3.

Table 2. TMZ dose levels for monotherapy treatment

Dose level

TMZ dose

Remarks

 

(mg/m2/day)

 

–1

Reduction for prior toxicity

Dose during Cycle 1

Dose during Cycles 2-6 in absence of toxicity

Table 3. TMZ dose reduction or discontinuation during monotherapy treatment

Toxicity

Reduce TMZ by 1 dose levela

Discontinue TMZ

Absolute neutrophil count

< 1.0 x 109/l

See footnote b

Thrombocyte count

< 50 x 109/l

See footnote b

CTC non-haematological Toxicity

CTC Grade 3

CTC Grade 4b

(except for alopecia, nausea, vomiting)

a:TMZ dose levels are listed in Table 2.

b:TMZ is to be discontinued if:

dose level -1 (100 mg/m2) still results in unacceptable toxicity

the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:

A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is no haematological toxicity (see section 4.4)

Special populations

Paediatric population

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in children under the age of 3 years have not been established. No data are available.

Patients with hepatic or renal impairment

The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TMZ is administered in these patients.

Elderly patients

Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia (see section 4.4).

Method of administration

Temodal hard capsules should be administered in the fasting state.

The capsules must be swallowed whole with a glass of water and must not be opened or chewed.

If vomiting occurs after the dose is administered, a second dose should not be administered that day.

4.3Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression (see section 4.4).

4.4Special warnings and precautions for use

Opportunistic infections and reactivation of infections

Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8).

Meningoencephalitis herpetic

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids administration.

Pneumocystis jirovecii pneumonia

Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.

There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids.

HBV

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately.

Hepatotoxicity

Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely (see section 4.8).

Anti-emetic therapy

Nausea and vomiting are very commonly associated with TMZ.

Anti-emetic therapy may be administered prior to or following administration of TMZ.

Adult patients with newly-diagnosed glioblastoma multiforme

Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is strongly recommended during the monotherapy phase.

Patients with recurrent or progressive malignant glioma

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.

Laboratory parameters

Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: ANC 1.5 x 109/l and platelet count

100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and

200 mg/m2. The lowest recommended dose is 100 mg/m2.

Paediatric population

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).

Elderly patients (> 70 years of age)

Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.

Male patients

Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5Interaction with other medicinal products and other forms of interaction

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC).

Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under the curve (AUC).

As it cannot be excluded that the change in Cmax is clinically significant, Temodal should be administered without food.

Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ.

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2).

Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.

Paediatric population

Interaction studies have only been performed in adults.

4.6Fertility, pregnancy and lactation

Pregnancy

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.

Breast-feeding

It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.

Male fertility

TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.

4.7Effects on ability to drive and use machines

TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see section 4.8).

4.8Undesirable effects

Clinical trial experience

In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions were reported commonly or very commonly in both indications (Tables 4 and 5); the frequency of grade 3-4 laboratory findings is presented after each table.

In the tables undesirable effects are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Newly-diagnosed glioblastoma multiforme

Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma multiforme during the concomitant and monotherapy phases of treatment.

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Infections and infestations

 

 

 

 

Common:

Infection, Herpes simplex, wound

Infection, candidiasis oral

 

infection, pharyngitis, candidiasis oral

 

Uncommon:

 

Herpes simplex, herpes zoster,

 

 

influenza–like symptoms

Blood and lymphatic system disorders

 

 

 

 

Common:

Neutropenia, thrombocytopenia,

Febrile neutropenia,

 

lymphopenia, leukopenia

thrombocytopenia, anaemia,

 

 

leukopenia

Uncommon:

Febrile neutropenia, anaemia

Lymphopenia, petechiae

 

 

 

Endocrine disorders

 

 

 

 

 

Uncommon:

Cushingoid

Cushingoid

 

 

 

Metabolism and nutrition disorders

 

 

 

 

Very common:

Anorexia

Anorexia

 

 

 

Common:

Hyperglycaemia, weight decreased

Weight decreased

 

 

 

Uncommon:

Hypokalemia, alkaline phosphatase

Hyperglycaemia, weight increased

 

increased, weight increased

 

Psychiatric disorders

 

 

 

 

 

Common:

Anxiety, emotional lability, insomnia

Anxiety, depression, emotional

 

 

lability, insomnia

Uncommon:

Agitation, apathy, behaviour disorder,

Hallucination, amnesia

 

depression, hallucination

 

Nervous system disorders

 

 

 

 

Very common:

Headache

Convulsions, headache

 

 

 

Common:

Convulsions, consciousness decreased,

Hemiparesis, aphasia, balance

 

somnolence, aphasia, balance impaired,

impaired, somnolence, confusion,

 

dizziness, confusion, memory

dizziness, memory impairment,

 

impairment, concentration impaired,

concentration impaired, dysphasia,

 

neuropathy, paresthesia, speech

neurological disorder (NOS),

 

disorder, tremor

neuropathy, peripheral neuropathy,

 

 

paresthesia, speech disorder, tremor

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Uncommon:

Status epilepticus, extrapyramidal

Hemiplegia, ataxia, coordination

 

disorder, hemiparesis, ataxia, cognition

abnormal, gait abnormal,

 

impaired, dysphasia, gait abnormal,

hyperesthesia, sensory disturbance

 

hyperesthesia, hypoesthesia,

 

 

neurological disorder (NOS), peripheral

 

 

neuropathy

 

Eye disorders

 

 

 

 

 

Common:

Vision blurred

Visual field defect, vision blurred,

 

 

diplopia

Uncommon:

Hemianopia, visual acuity reduced,

Visual acuity reduced, eye pain,

 

vision disorder, visual field defect, eye

eyes dry

 

pain

 

Ear and labyrinth disorders

 

 

 

 

Common:

Hearing impairment

Hearing impairment, tinnitus

 

 

 

Uncommon:

Otitis media, tinnitus, hyperacusis,

Deafness, vertigo, earache

 

earache

 

Cardiac disorders

 

 

 

 

 

Uncommon:

Palpitation

 

 

 

 

Vascular disorders

 

 

 

 

 

Common:

Haemorrhage, oedema, oedema leg

Haemorrhage, deep venous

 

 

thrombosis, oedema leg

Uncommon:

Cerebral haemorrhage, hypertension

Embolism pulmonary, oedema,

 

 

oedema peripheral

Respiratory, thoracic and mediastinal disorders

 

 

 

 

Common:

Dyspnoea, coughing

Dyspnoea, coughing

 

 

 

Uncommon:

Pneumonia, upper respiratory infection,

Pneumonia, sinusitis, upper

 

nasal congestion

respiratory infection, bronchitis

Gastrointestinal disorders

 

 

 

 

Very common:

Constipation, nausea, vomiting

Constipation, nausea, vomiting

 

 

 

Common:

Stomatitis, diarrhoea, abdominal pain,

Stomatitis, diarrhoea, dyspepsia,

 

dyspepsia, dysphagia

dysphagia, mouth dry

Uncommon:

 

Abdominal distension, fecal

 

 

incontinence, gastrointestinal

 

 

disorder (NOS), gastroenteritis,

 

 

haemorrhoids

Skin and subcutaneous tissue disorders

 

 

 

 

Very common:

Rash, alopecia

Rash, alopecia

 

 

 

Common:

Dermatitis, dry skin, erythema, pruritus

Dry skin, pruritus

 

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Uncommon:

Skin exfoliation, photosensitivity

Erythema, pigmentation abnormal,

 

reaction, pigmentation abnormal

sweating increased

Musculoskeletal and connective tissue disorders

 

 

 

 

Common:

Muscle weakness, arthralgia

Muscle weakness, arthralgia,

 

 

musculoskeletal pain, myalgia

Uncommon:

Myopathy, back pain, musculoskeletal

Myopathy, back pain

 

pain, myalgia

 

Renal and urinary disorders

 

 

 

 

Common:

Micturition frequency, urinary

Urinary incontinence

 

incontinence

 

Uncommon:

 

Dysuria

 

 

 

Reproductive system and breast disorders

 

 

 

 

Uncommon:

Impotence

Vaginal haemorrhage, menorrhagia,

 

 

amenorrhea, vaginitis, breast pain

General disorders and administration site conditions

 

 

 

 

Very common:

Fatigue

Fatigue

 

 

 

Common:

Allergic reaction, fever, radiation

Allergic reaction, fever, radiation

 

injury, face oedema, pain, taste

injury, pain, taste perversion

 

perversion

 

Uncommon:

Asthenia, flushing, hot flushes,

Asthenia, face oedema, pain,

 

condition aggravated, rigors, tongue

condition aggravated, rigors, tooth

 

discolouration, parosmia, thirst

disorder

Investigations

 

 

 

 

 

Common:

ALT increased

ALT increased

 

 

 

Uncommon:

Hepatic enzymes increased, Gamma GT

 

 

increased, AST increased

 

*A patient who was randomised to the RT arm only, received TMZ + RT.

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the patients who received TMZ.

Recurrent or progressive malignant glioma

In clinical trials, the most frequently occurring treatment-related undesirable effects were gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of Temodal.

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma

Infections and infestations

Rare:

Opportunistic infections, including PCP

 

 

Blood and lymphatic system disorders

 

 

 

Very common:

Neutropenia or lymphopenia (grade 3-4),

 

thrombocytopenia (grade 3-4)

Uncommon:

Pancytopenia, anaemia (grade 3-4), leukopenia

Metabolism and nutrition disorders

 

Very common:

Anorexia

Common:

Weight decrease

 

 

Nervous system disorders

 

 

 

Very common:

Headache

Common:

Somnolence, dizziness, paresthesia

 

 

Respiratory, thoracic and mediastinal disorders

 

 

Common:

Dyspnoea

Gastrointestinal disorders

 

 

 

Very common:

Vomiting, nausea, constipation

Common:

Diarrhoea, abdominal pain, dyspepsia

 

 

Skin and subcutaneous tissue disorders

 

 

 

Common:

Rash, pruritus, alopecia

Very rare:

Erythema multiforme, erythroderma, urticaria,

 

exanthema

 

 

General disorders and administration site conditions

 

 

Very common:

Fatigue

Common:

Fever, asthenia, rigors, malaise, pain, taste perversion

Very rare:

Allergic reactions, including anaphylaxis, angioedema

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the

nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4

neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with newly-

diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle of therapy.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in children under the age of 3 years has not been established.

Post-Marketing Experience

The following additional serious adverse reactions have been identified during post-marketing exposure:

Table 6. Summary of events reported with temozolomide in the post-marketing setting

Infections and infestations*

Uncommon:

 

cytomegalovirus infection, infection reactivation such as

 

 

cytomegalovirus, hepatitis B virus,

 

 

meningoencephalitis herpetic

Blood and lymphatic system disorders

 

 

 

 

 

Very rare:

 

prolonged pancytopenia, aplastic anaemia

Neoplasm benign, malignant and unspecified

Very rare:

 

myelodysplastic syndrome (MDS), secondary

 

 

malignancies, including myeloid leukaemia

Endocrine disorders*

 

Uncommon:

 

diabetes insipidus

Respiratory, thoracic and mediastinal disorders

Very rare:

 

interstitial pneumonitis/pneumonitis, pulmonary

 

 

fibrosis, respiratory failure

Hepatobiliary disorders*

 

Common:

 

liver enzymes elevations

 

 

 

Uncommon:

 

hyperbilirubinemia, cholestasis, hepatitis, hepatic

 

 

injury, hepatic failure

Skin and subcutaneous tissue disorders

 

 

 

Very rare:

 

toxic epidermal necrolysis, Stevens-Johnson syndrome

Including cases with fatal outcome

 

 

* Frequencies estimated based on relevant clinical trials.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle,

over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure and death. There are reports of patients who have taken the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03

Mechanism of action

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Clinical efficacy and safety

Newly-diagnosed glioblastoma multiforme

A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by monotherapy TMZ (150 - 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.

TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm.

The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33 -1.91) with a log-rank

p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).

H R (95 % C .I.) = 1 .59 (1 .33 – 1 .9 1 ) lo g -rank p -valu e < .0 001

26%

R T + T M Z

10%

R T O n ly

12 .114 .6

Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population)

The results from the trial were not consistent in the subgroup of patients with a poor performance status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, no unacceptable risks appear to be present in this patient group.

Recurrent or progressive malignant glioma

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the non- comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was

2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8 %.

In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) (chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS 80.

Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT)

n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT population was 44 % with a median event-free survival of 4.6 months, which was similar to the results for the progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression-free status was strongly associated with maintained or improved quality of life.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to TMZ is similar to adults.

5.2Pharmacokinetic properties

TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl- (triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino- imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.

Absorption

After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % indicating complete absorption.

Distribution

TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with highly protein-bound substances.

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data.

Elimination

The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4- carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.

Special populations

Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.

5.3Preclinical safety data

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.

TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome aberration tests showed a positive mutagenicity response.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Capsule content: anhydrous lactose, colloidal anhydrous silica,

sodium starch glycolate type A, tartaric acid,

stearic acid.

Capsule shell: gelatin,

titanium dioxide (E 171), sodium laurilsulfate, yellow iron oxide (E 172), indigo carmine (E 132),

Printing ink: shellac, propylene glycol, purified water,

ammonium hydroxide, potassium hydroxide, black iron oxide (E 172).

6.2Incompatibilities

Not applicable.

6.3Shelf life

3 years

6.4Special precautions for storage

Bottle presentation

Do not store above 30 C.

Store in the original bottle in order to protect from moisture.

Keep the bottle tightly closed.

Sachet presentation

Do not store above 30 C.

6.5Nature and contents of container

Bottle presentation

Type I amber glass bottles with polypropylene child-resistant closures containing 5 or 20 hard capsules.

The carton contains one bottle.

Sachet presentation

Sachets are composed of linear low density polyethylene (innermost layer), aluminium and polyethylene terephthalate.

Each sachet contains 1 hard capsule and is dispensed in a cardboard carton. The carton contains 5 or 20 hard capsules, individually sealed in sachets.

Not all pack sizes may be marketed.

6.6Special precautions for disposal and other handling

Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin or mucous membrane must be avoided. If Temodal comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Patients should be advised to keep capsules out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7.MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/98/096/001

EU/1/98/096/002

EU/1/98/096/024

EU/1/98/096/025

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 January 1999

Date of latest renewal: 26 January 2009

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1. NAME OF THE MEDICINAL PRODUCT

Temodal 20 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 20 mg temozolomide.

Excipient with known effect:

Each hard capsule contains 182.2 mg of anhydrous lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule (capsule).

The hard capsules have an opaque white body, an opaque yellow cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with "20 mg", the Schering-Plough logo and two stripes.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Temodal is indicated for the treatment of:

-adult patients with newly-diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment.

-children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

4.2 Posology and method of administration

Temodal should only be prescribed by physicians experienced in the oncological treatment of brain tumours.

Anti-emetic therapy may be administered (see section 4.4).

Posology

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant phase

TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met:

-absolute neutrophil count (ANC) ≥ 1.5 x 109/l

-thrombocyte count ≥ 100 x 109/l

-common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).

During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.

Table 1. TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ

Toxicity

TMZ interruptiona

TMZ discontinuation

Absolute neutrophil count

0.5 and < 1.5 x 109/l

< 0.5 x 109/l

Thrombocyte count

10 and < 100 x 109/l

< 10 x 109/l

CTC non-haematological toxicity

CTC Grade 2

CTC Grade 3 or 4

(except for alopecia, nausea, vomiting)

 

 

a:Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count 1.5 x 109/l; thrombocyte count 100 x 109/l; CTC non-haematological toxicity Grade 1 (except for alopecia, nausea, vomiting).

Monotherapy phase

Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia,

nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/l, and the thrombocyte count is ≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase should be applied according to Tables 2 and 3.

During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TMZ). The dose should be reduced or administration discontinued according to Table 3.

Table 2. TMZ dose levels for monotherapy treatment

Dose level

TMZ dose

Remarks

 

(mg/m2/day)

 

–1

Reduction for prior toxicity

Dose during Cycle 1

Dose during Cycles 2-6 in absence of toxicity

Table 3. TMZ dose reduction or discontinuation during monotherapy treatment

Toxicity

Reduce TMZ by 1 dose levela

Discontinue TMZ

Absolute neutrophil count

< 1.0 x 109/l

See footnote b

Thrombocyte count

< 50 x 109/l

See footnote b

CTC non-haematological Toxicity

CTC Grade 3

CTC Grade 4b

(except for alopecia, nausea, vomiting)

a:TMZ dose levels are listed in Table 2.

b:TMZ is to be discontinued if:

dose level -1 (100 mg/m2) still results in unacceptable toxicity

the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:

A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is no haematological toxicity (see section 4.4)

Special populations

Paediatric population

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in children under the age of 3 years have not been established. No data are available.

Patients with hepatic or renal impairment

The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TMZ is administered in these patients.

Elderly patients

Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia (see section 4.4).

Method of administration

Temodal hard capsules should be administered in the fasting state.

The capsules must be swallowed whole with a glass of water and must not be opened or chewed.

If vomiting occurs after the dose is administered, a second dose should not be administered that day.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression (see section 4.4).

4.4 Special warnings and precautions for use

Opportunistic infections and reactivation of infections

Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8).

Meningoencephalitis herpetic

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids administration.

Pneumocystis jirovecii pneumonia

Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.

There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids.

HBV

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately.

Hepatotoxicity

Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely (see section 4.8).

Anti-emetic therapy

Nausea and vomiting are very commonly associated with TMZ.

Anti-emetic therapy may be administered prior to or following administration of TMZ.

Adult patients with newly-diagnosed glioblastoma multiforme

Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is strongly recommended during the monotherapy phase.

Patients with recurrent or progressive malignant glioma

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.

Laboratory parameters

Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: ANC 1.5 x 109/l and platelet count

100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and

200 mg/m2. The lowest recommended dose is 100 mg/m2.

Paediatric population

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).

Elderly patients (> 70 years of age)

Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.

Male patients

Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC).

Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under the curve (AUC).

As it cannot be excluded that the change in Cmax is clinically significant, Temodal should be administered without food.

Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ.

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2).

Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.

Breast-feeding

It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.

Male fertility

TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.

4.7 Effects on ability to drive and use machines

TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see section 4.8).

4.8 Undesirable effects

Clinical trial experience

In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions were reported commonly or very commonly in both indications (Tables 4 and 5); the frequency of grade 3-4 laboratory findings is presented after each table.

In the tables undesirable effects are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Newly-diagnosed glioblastoma multiforme

Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma multiforme during the concomitant and monotherapy phases of treatment.

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Infections and infestations

 

 

 

 

Common:

Infection, Herpes simplex, wound

Infection, candidiasis oral

 

infection, pharyngitis, candidiasis oral

 

Uncommon:

 

Herpes simplex, herpes zoster,

 

 

influenza–like symptoms

Blood and lymphatic system disorders

 

 

 

 

Common:

Neutropenia, thrombocytopenia,

Febrile neutropenia,

 

lymphopenia, leukopenia

thrombocytopenia, anaemia,

 

 

leukopenia

 

 

 

Uncommon:

Febrile neutropenia, anaemia

Lymphopenia, petechiae

Endocrine disorders

 

 

 

 

 

Uncommon:

Cushingoid

Cushingoid

Metabolism and nutrition disorders

 

 

 

 

Very common:

Anorexia

Anorexia

 

 

 

Common:

Hyperglycaemia, weight decreased

Weight decreased

Uncommon:

Hypokalemia, alkaline phosphatase

Hyperglycaemia, weight increased

 

increased, weight increased

 

 

 

 

Psychiatric disorders

 

 

 

 

 

Common:

Anxiety, emotional lability, insomnia

Anxiety, depression, emotional

 

 

lability, insomnia

Uncommon:

Agitation, apathy, behaviour disorder,

Hallucination, amnesia

 

depression, hallucination

 

 

 

 

Nervous system disorders

 

 

 

 

Very common:

Headache

Convulsions, headache

 

 

 

Common:

Convulsions, consciousness decreased,

Hemiparesis, aphasia, balance

 

somnolence, aphasia, balance impaired,

impaired, somnolence, confusion,

 

dizziness, confusion, memory

dizziness, memory impairment,

 

impairment, concentration impaired,

concentration impaired, dysphasia,

 

neuropathy, paresthesia, speech

neurological disorder (NOS),

 

disorder, tremor

neuropathy, peripheral neuropathy,

 

 

paresthesia, speech disorder, tremor

 

 

 

Uncommon:

Status epilepticus, extrapyramidal

Hemiplegia, ataxia, coordination

 

disorder, hemiparesis, ataxia, cognition

abnormal, gait abnormal,

 

impaired, dysphasia, gait abnormal,

hyperesthesia, sensory disturbance

 

hyperesthesia, hypoesthesia,

 

 

neurological disorder (NOS), peripheral

 

 

neuropathy

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Eye disorders

 

 

 

 

 

Common:

Vision blurred

Visual field defect, vision blurred,

 

 

diplopia

Uncommon:

Hemianopia, visual acuity reduced,

Visual acuity reduced, eye pain,

 

vision disorder, visual field defect, eye

eyes dry

 

pain

 

Ear and labyrinth disorders

 

 

 

 

Common:

Hearing impairment

Hearing impairment, tinnitus

 

 

 

Uncommon:

Otitis media, tinnitus, hyperacusis,

Deafness, vertigo, earache

 

earache

 

 

 

 

Cardiac disorders

 

 

 

 

 

Uncommon:

Palpitation

 

Vascular disorders

 

 

 

 

 

Common:

Haemorrhage, oedema, oedema leg

Haemorrhage, deep venous

 

 

thrombosis, oedema leg

 

 

 

Uncommon:

Cerebral haemorrhage, hypertension

Embolism pulmonary, oedema,

 

 

oedema peripheral

Respiratory, thoracic and mediastinal disorders

 

 

 

 

Common:

Dyspnoea, coughing

Dyspnoea, coughing

 

 

 

Uncommon:

Pneumonia, upper respiratory infection,

Pneumonia, sinusitis, upper

 

nasal congestion

respiratory infection, bronchitis

 

 

 

Gastrointestinal disorders

 

 

 

 

Very common:

Constipation, nausea, vomiting

Constipation, nausea, vomiting

 

 

 

Common:

Stomatitis, diarrhoea, abdominal pain,

Stomatitis, diarrhoea, dyspepsia,

 

dyspepsia, dysphagia

dysphagia, mouth dry

 

 

 

Uncommon:

 

Abdominal distension, fecal

 

 

incontinence, gastrointestinal

 

 

disorder (NOS), gastroenteritis,

 

 

haemorrhoids

Skin and subcutaneous tissue disorders

 

 

 

 

Very common:

Rash, alopecia

Rash, alopecia

 

 

 

Common:

Dermatitis, dry skin, erythema, pruritus

Dry skin, pruritus

 

 

 

Uncommon:

Skin exfoliation, photosensitivity

Erythema, pigmentation abnormal,

 

reaction, pigmentation abnormal

sweating increased

 

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Musculoskeletal and connective tissue disorders

 

 

 

 

Common:

Muscle weakness, arthralgia

Muscle weakness, arthralgia,

 

 

musculoskeletal pain, myalgia

 

 

 

Uncommon:

Myopathy, back pain, musculoskeletal

Myopathy, back pain

 

pain, myalgia

 

 

 

 

Renal and urinary disorders

 

 

 

 

Common:

Micturition frequency, urinary

Urinary incontinence

 

incontinence

 

Uncommon:

 

Dysuria

 

 

 

Reproductive system and breast disorders

 

 

 

 

Uncommon:

Impotence

Vaginal haemorrhage, menorrhagia,

 

 

amenorrhea, vaginitis, breast pain

General disorders and administration site conditions

 

 

 

 

Very common:

Fatigue

Fatigue

 

 

 

Common:

Allergic reaction, fever, radiation

Allergic reaction, fever, radiation

 

injury, face oedema, pain, taste

injury, pain, taste perversion

 

perversion

 

Uncommon:

Asthenia, flushing, hot flushes,

Asthenia, face oedema, pain,

 

condition aggravated, rigors, tongue

condition aggravated, rigors, tooth

 

discolouration, parosmia, thirst

disorder

 

 

 

Investigations

 

 

 

 

 

Common:

ALT increased

ALT increased

 

 

 

Uncommon:

Hepatic enzymes increased, Gamma GT

 

 

increased, AST increased

 

*A patient who was randomised to the RT arm only, received TMZ + RT.

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the patients who received TMZ.

Recurrent or progressive malignant glioma

In clinical trials, the most frequently occurring treatment-related undesirable effects were gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of Temodal.

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma

Infections and infestations

Rare:

Opportunistic infections, including PCP

 

 

Blood and lymphatic system disorders

 

 

 

Very common:

Neutropenia or lymphopenia (grade 3-4),

 

thrombocytopenia (grade 3-4)

Uncommon:

Pancytopenia, anaemia (grade 3-4), leukopenia

Metabolism and nutrition disorders

 

 

 

Very common:

Anorexia

Common:

Weight decrease

 

 

Nervous system disorders

 

 

 

Very common:

Headache

Common:

Somnolence, dizziness, paresthesia

 

 

Respiratory, thoracic and mediastinal disorders

 

 

Common:

Dyspnoea

Gastrointestinal disorders

 

 

 

Very common:

Vomiting, nausea, constipation

Common:

Diarrhoea, abdominal pain, dyspepsia

 

 

Skin and subcutaneous tissue disorders

 

 

 

Common:

Rash, pruritus, alopecia

Very rare:

Erythema multiforme, erythroderma, urticaria,

 

exanthema

 

 

General disorders and administration site conditions

 

 

Very common:

Fatigue

Common:

Fever, asthenia, rigors, malaise, pain, taste perversion

Very rare:

Allergic reactions, including anaphylaxis, angioedema

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the

nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4

neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with newly- diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of male

subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle of therapy.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in children under the age of 3 years has not been established.

Post-Marketing Experience

The following additional serious adverse reactions have been identified during post-marketing exposure:

Table 6. Summary of events reported with temozolomide in the post-marketing setting

Infections and infestations*

Uncommon:

 

cytomegalovirus infection, infection reactivation such as

 

 

cytomegalovirus, hepatitis B virus,

 

 

meningoencephalitis herpetic

Blood and lymphatic system disorders

 

 

 

 

 

Very rare:

 

prolonged pancytopenia, aplastic anaemia

Neoplasm benign, malignant and unspecified

 

 

Very rare:

 

myelodysplastic syndrome (MDS), secondary

 

 

malignancies, including myeloid leukaemia

Endocrine disorders*

 

Uncommon:

 

diabetes insipidus

Respiratory, thoracic and mediastinal disorders

 

 

Very rare:

 

interstitial pneumonitis/pneumonitis, pulmonary

 

 

fibrosis, respiratory failure

Hepatobiliary disorders*

 

Common:

 

liver enzymes elevations

 

 

 

Uncommon:

 

hyperbilirubinemia, cholestasis, hepatitis, hepatic

 

 

injury, hepatic failure

Skin and subcutaneous tissue disorders

 

 

 

Very rare:

 

toxic epidermal necrolysis, Stevens-Johnson syndrome

Including cases with fatal outcome

 

 

* Frequencies estimated based on relevant clinical trials.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia,

multi-organ failure and death. There are reports of patients who have taken the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03

Mechanism of action

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Clinical efficacy and safety

Newly-diagnosed glioblastoma multiforme

A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by monotherapy TMZ (150 - 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.

TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm.

The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33 -1.91) with a log-rank

p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).

H R (95 % C .I.) = 1 .59 (1 .33 – 1 .9 1 ) lo g -rank p -valu e < .0 001

26%

R T + T M Z

10%

R T O n ly

12 .114 .6

Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population)

The results from the trial were not consistent in the subgroup of patients with a poor performance status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, no unacceptable risks appear to be present in this patient group.

Recurrent or progressive malignant glioma

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the non- comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was

2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8 %.

In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) (chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS 80.

Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT)

n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT population was 44 % with a median event-free survival of 4.6 months, which was similar to the results for the progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression-free status was strongly associated with maintained or improved quality of life.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to TMZ is similar to adults.

5.2 Pharmacokinetic properties

TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl- (triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino- imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.

Absorption

After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % indicating complete absorption.

Distribution

TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with highly protein-bound substances.

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data.

Elimination

The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4- carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.

Special populations

Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.

5.3 Preclinical safety data

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.

TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome aberration tests showed a positive mutagenicity response.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content: anhydrous lactose, colloidal anhydrous silica,

sodium starch glycolate type A, tartaric acid,

stearic acid.

Capsule shell: gelatin,

titanium dioxide (E 171), sodium lauril sulfate, yellow iron oxide (E 172)

Printing ink: shellac, propylene glycol, purified water,

ammonium hydroxide, potassium hydroxide, black iron oxide (E 172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Bottle presentation

Do not store above 30 C.

Store in the original bottle in order to protect from moisture.

Keep the bottle tightly closed.

Sachet presentation

Do not store above 30 C.

6.5 Nature and contents of container

Bottle presentation

Type I amber glass bottles with polypropylene child-resistant closures containing 5 or 20 hard capsules.

The carton contains one bottle.

Sachet presentation

Sachets are composed of linear low density polyethylene (innermost layer), aluminium and polyethylene terephthalate.

Each sachet contains 1 hard capsule and is dispensed in a cardboard carton. The carton contains 5 or 20 hard capsules, individually sealed in sachets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin or mucous membrane must be avoided. If Temodal comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Patients should be advised to keep capsules out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/98/096/003

EU/1/98/096/004

EU/1/98/096/013

EU/1/98/096/014

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 January 1999

Date of latest renewal: 26 January 2009

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1. NAME OF THE MEDICINAL PRODUCT

Temodal 100 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 100 mg temozolomide.

Excipient with known effect:

Each hard capsule contains 175.7 mg of anhydrous lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule (capsule).

The hard capsules have an opaque white body, an opaque pink cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with "100 mg", the Schering-Plough logo and two stripes.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Temodal is indicated for the treatment of:

-adult patients with newly-diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment.

-children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

4.2 Posology and method of administration

Temodal should only be prescribed by physicians experienced in the oncological treatment of brain tumours.

Anti-emetic therapy may be administered (see section 4.4).

Posology

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant phase

TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met:

-absolute neutrophil count (ANC) ≥ 1.5 x 109/l

-thrombocyte count ≥ 100 x 109/l

-common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).

During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.

Table 1. TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ

Toxicity

TMZ interruptiona

TMZ discontinuation

Absolute neutrophil count

0.5 and < 1.5 x 109/l

< 0.5 x 109/l

Thrombocyte count

10 and < 100 x 109/l

< 10 x 109/l

CTC non-haematological toxicity

CTC Grade 2

CTC Grade 3 or 4

(except for alopecia, nausea, vomiting)

 

 

a:Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count 1.5 x 109/l; thrombocyte count 100 x 109/l; CTC non-haematological toxicity Grade 1 (except for alopecia, nausea, vomiting).

Monotherapy phase

Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia,

nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/l, and the thrombocyte count is ≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase should be applied according to Tables 2 and 3.

During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TMZ). The dose should be reduced or administration discontinued according to Table 3.

Table 2. TMZ dose levels for monotherapy treatment

Dose level

TMZ dose

Remarks

 

(mg/m2/day)

 

–1

Reduction for prior toxicity

Dose during Cycle 1

Dose during Cycles 2-6 in absence of toxicity

Table 3. TMZ dose reduction or discontinuation during monotherapy treatment

Toxicity

Reduce TMZ by 1 dose levela

Discontinue TMZ

Absolute neutrophil count

< 1.0 x 109/l

See footnote b

Thrombocyte count

< 50 x 109/l

See footnote b

CTC non-haematological Toxicity

CTC Grade 3

CTC Grade 4b

(except for alopecia, nausea, vomiting)

a:TMZ dose levels are listed in Table 2.

b:TMZ is to be discontinued if:

dose level -1 (100 mg/m2) still results in unacceptable toxicity

the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:

A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is no haematological toxicity (see section 4.4)

Special populations

Paediatric population

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in children under the age of 3 years have not been established. No data are available.

Patients with hepatic or renal impairment

The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TMZ is administered in these patients.

Elderly patients

Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia (see section 4.4).

Method of administration

Temodal hard capsules should be administered in the fasting state.

The capsules must be swallowed whole with a glass of water and must not be opened or chewed.

If vomiting occurs after the dose is administered, a second dose should not be administered that day.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression (see section 4.4).

4.4 Special warnings and precautions for use

Opportunistic infections and reactivation of infections

Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8).

Meningoencephalitis herpetic

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids administration.

Pneumocystis jirovecii pneumonia

Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.

There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids.

HBV

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately.

Hepatotoxicity

Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely (see section 4.8).

Anti-emetic therapy

Nausea and vomiting are very commonly associated with TMZ.

Anti-emetic therapy may be administered prior to or following administration of TMZ.

Adult patients with newly-diagnosed glioblastoma multiforme

Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is strongly recommended during the monotherapy phase.

Patients with recurrent or progressive malignant glioma

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.

Laboratory parameters

Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: ANC 1.5 x 109/l and platelet count

100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and

200 mg/m2. The lowest recommended dose is 100 mg/m2.

Paediatric population

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).

Elderly patients (> 70 years of age)

Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.

Male patients

Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC).

Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under the curve (AUC).

As it cannot be excluded that the change in Cmax is clinically significant, Temodal should be administered without food.

Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ.

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2).

Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.

Breast-feeding

It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.

Male fertility

TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.

4.7 Effects on ability to drive and use machines

TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see section 4.8).

4.8 Undesirable effects

Clinical trial experience

In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions were reported commonly or very commonly in both indications (Tables 4 and 5); the frequency of grade 3-4 laboratory findings is presented after each table.

In the tables undesirable effects are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Newly-diagnosed glioblastoma multiforme

Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma multiforme during the concomitant and monotherapy phases of treatment.

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Infections and infestations

 

Common:

Infection, Herpes simplex, wound

Infection, candidiasis oral

 

infection, pharyngitis, candidiasis oral

 

Uncommon:

 

Herpes simplex, herpes zoster,

 

 

influenza–like symptoms

Blood and lymphatic system disorders

 

 

 

 

Common:

Neutropenia, thrombocytopenia,

Febrile neutropenia,

 

lymphopenia, leukopenia

thrombocytopenia, anaemia,

 

 

leukopenia

 

 

 

Uncommon:

Febrile neutropenia, anaemia

Lymphopenia, petechiae

Endocrine disorders

 

 

 

 

 

Uncommon:

Cushingoid

Cushingoid

Metabolism and nutrition disorders

 

 

 

 

Very common:

Anorexia

Anorexia

Common:

Hyperglycaemia, weight decreased

Weight decreased

Uncommon:

Hypokalemia, alkaline phosphatase

Hyperglycaemia, weight increased

 

increased, weight increased

 

 

 

 

Psychiatric disorders

 

 

 

 

 

Common:

Anxiety, emotional lability, insomnia

Anxiety, depression, emotional

 

 

lability, insomnia

Uncommon:

Agitation, apathy, behaviour disorder,

Hallucination, amnesia

 

depression, hallucination

 

 

 

 

Nervous system disorders

 

 

 

 

Very common:

Headache

Convulsions, headache

 

 

 

Common:

Convulsions, consciousness decreased,

Hemiparesis, aphasia, balance

 

somnolence, aphasia, balance impaired,

impaired, somnolence, confusion,

 

dizziness, confusion, memory

dizziness, memory impairment,

 

impairment, concentration impaired,

concentration impaired, dysphasia,

 

neuropathy, paresthesia, speech

neurological disorder (NOS),

 

disorder, tremor

neuropathy, peripheral neuropathy,

 

 

paresthesia, speech disorder, tremor

 

 

 

Uncommon:

Status epilepticus, extrapyramidal

Hemiplegia, ataxia, coordination

 

disorder, hemiparesis, ataxia, cognition

abnormal, gait abnormal,

 

impaired, dysphasia, gait abnormal,

hyperesthesia, sensory disturbance

 

hyperesthesia, hypoesthesia,

 

 

neurological disorder (NOS), peripheral

 

 

neuropathy

 

Eye disorders

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Common:

Vision blurred

Visual field defect, vision blurred,

 

 

diplopia

Uncommon:

Hemianopia, visual acuity reduced,

Visual acuity reduced, eye pain,

 

vision disorder, visual field defect, eye

eyes dry

 

pain

 

Ear and labyrinth disorders

 

 

 

 

Common:

Hearing impairment

Hearing impairment, tinnitus

 

 

 

Uncommon:

Otitis media, tinnitus, hyperacusis,

Deafness, vertigo, earache

 

earache

 

 

 

 

Cardiac disorders

 

 

 

 

 

Uncommon:

Palpitation

 

Vascular disorders

 

 

 

 

 

Common:

Haemorrhage, oedema, oedema leg

Haemorrhage, deep venous

 

 

thrombosis, oedema leg

 

 

 

Uncommon:

Cerebral haemorrhage, hypertension

Embolism pulmonary, oedema,

 

 

oedema peripheral

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

Common:

Dyspnoea, coughing

Dyspnoea, coughing

 

 

 

Uncommon:

Pneumonia, upper respiratory infection,

Pneumonia, sinusitis, upper

 

nasal congestion

respiratory infection, bronchitis

 

 

 

Gastrointestinal disorders

 

 

 

 

Very common:

Constipation, nausea, vomiting

Constipation, nausea, vomiting

 

 

 

Common:

Stomatitis, diarrhoea, abdominal pain,

Stomatitis, diarrhoea, dyspepsia,

 

dyspepsia, dysphagia

dysphagia, mouth dry

 

 

 

Uncommon:

 

Abdominal distension, fecal

 

 

incontinence, gastrointestinal

 

 

disorder (NOS), gastroenteritis,

 

 

haemorrhoids

Skin and subcutaneous tissue disorders

 

 

 

 

Very common:

Rash, alopecia

Rash, alopecia

 

 

 

Common:

Dermatitis, dry skin, erythema, pruritus

Dry skin, pruritus

 

 

 

Uncommon:

Skin exfoliation, photosensitivity

Erythema, pigmentation abnormal,

 

reaction, pigmentation abnormal

sweating increased

 

 

 

Musculoskeletal and connective tissue disorders

 

 

 

 

Common:

Muscle weakness, arthralgia

Muscle weakness, arthralgia,

 

 

musculoskeletal pain, myalgia

 

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Uncommon:

Myopathy, back pain, musculoskeletal

Myopathy, back pain

 

pain, myalgia

 

 

 

 

Renal and urinary disorders

 

 

 

 

Common:

Micturition frequency, urinary

Urinary incontinence

 

incontinence

 

Uncommon:

 

Dysuria

 

 

 

Reproductive system and breast disorders

 

 

 

 

Uncommon:

Impotence

Vaginal haemorrhage, menorrhagia,

 

 

amenorrhea, vaginitis, breast pain

General disorders and administration site conditions

 

 

 

 

Very common:

Fatigue

Fatigue

 

 

 

Common:

Allergic reaction, fever, radiation

Allergic reaction, fever, radiation

 

injury, face oedema, pain, taste

injury, pain, taste perversion

 

perversion

 

Uncommon:

Asthenia, flushing, hot flushes,

Asthenia, face oedema, pain,

 

condition aggravated, rigors, tongue

condition aggravated, rigors, tooth

 

discolouration, parosmia, thirst

disorder

 

 

 

Investigations

 

 

 

 

 

Common:

ALT increased

ALT increased

 

 

 

Uncommon:

Hepatic enzymes increased, Gamma GT

 

 

increased, AST increased

 

*A patient who was randomised to the RT arm only, received TMZ + RT.

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the patients who received TMZ.

Recurrent or progressive malignant glioma

In clinical trials, the most frequently occurring treatment-related undesirable effects were gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of Temodal.

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma

Infections and infestations

Rare:

Opportunistic infections, including PCP

 

 

Blood and lymphatic system disorders

 

 

 

Very common:

Neutropenia or lymphopenia (grade 3-4),

 

thrombocytopenia (grade 3-4)

Uncommon:

Pancytopenia, anaemia (grade 3-4), leukopenia

Metabolism and nutrition disorders

 

 

 

Very common:

Anorexia

Common:

Weight decrease

 

 

Nervous system disorders

 

 

 

Very common:

Headache

Common:

Somnolence, dizziness, paresthesia

 

 

Respiratory, thoracic and mediastinal disorders

 

 

Common:

Dyspnoea

Gastrointestinal disorders

 

 

 

Very common:

Vomiting, nausea, constipation

Common:

Diarrhoea, abdominal pain, dyspepsia

 

 

Skin and subcutaneous tissue disorders

 

 

 

Common:

Rash, pruritus, alopecia

Very rare:

Erythema multiforme, erythroderma, urticaria,

 

exanthema

 

 

General disorders and administration site conditions

 

 

Very common:

Fatigue

Common:

Fever, asthenia, rigors, malaise, pain, taste perversion

Very rare:

Allergic reactions, including anaphylaxis, angioedema

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the

nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4

neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with newly- diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of male

subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle of therapy.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in children under the age of 3 years has not been established.

Post-Marketing Experience

The following additional serious adverse reactions have been identified during post-marketing exposure:

Table 6. Summary of events reported with temozolomide in the post-marketing setting

Infections and infestations*

Uncommon:

 

cytomegalovirus infection, infection reactivation such as

 

 

cytomegalovirus, hepatitis B virus,

 

 

meningoencephalitis herpetic

Blood and lymphatic system disorders

 

 

 

 

 

Very rare:

 

prolonged pancytopenia, aplastic anaemia

Neoplasm benign, malignant and unspecified

 

 

Very rare:

 

myelodysplastic syndrome (MDS), secondary

 

 

malignancies, including myeloid leukaemia

Endocrine disorders*

 

Uncommon:

 

diabetes insipidus

Respiratory, thoracic and mediastinal disorders

 

 

Very rare:

 

interstitial pneumonitis/pneumonitis, pulmonary

 

 

fibrosis, respiratory failure

Hepatobiliary disorders*

 

Common:

 

liver enzymes elevations

 

 

 

Uncommon:

 

hyperbilirubinemia, cholestasis, hepatitis, hepatic

 

 

injury, hepatic failure

Skin and subcutaneous tissue disorders

 

 

 

Very rare:

 

toxic epidermal necrolysis, Stevens-Johnson syndrome

Including cases with fatal outcome

 

 

* Frequencies estimated based on relevant clinical trials.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia,

multi-organ failure and death. There are reports of patients who have taken the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03

Mechanism of action

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Clinical efficacy and safety

Newly-diagnosed glioblastoma multiforme

A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by monotherapy TMZ (150 - 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.

TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm.

The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33 -1.91) with a log-rank

p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).

H R (9 5% C .I.) = 1 .59 (1 .3 3 – 1 .91) lo g -rank p -valu e < .0001

26%

R T + T M Z

10%

R T O n ly

1 2 .114 .6

Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population)

The results from the trial were not consistent in the subgroup of patients with a poor performance status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, no unacceptable risks appear to be present in this patient group.

Recurrent or progressive malignant glioma

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the non- comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was

2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8 %.

In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) (chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS 80.

Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the

central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT population was 44 % with a median event-free survival of 4.6 months, which was similar to the results for the progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression-free status was strongly associated with maintained or improved quality of life.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to TMZ is similar to adults.

5.2 Pharmacokinetic properties

TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl- (triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino- imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.

Absorption

After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % indicating complete absorption.

Distribution

TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with highly protein-bound substances.

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data.

Elimination

The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4- carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.

Special populations

Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.

5.3 Preclinical safety data

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.

TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome aberration tests showed a positive mutagenicity response.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content: anhydrous lactose, colloidal anhydrous silica,

sodium starch glycolate type A, tartaric acid,

stearic acid.

Capsule shell: gelatin,

titanium dioxide (E 171), sodium lauril sulfate, red iron oxide (E172).

Printing ink: shellac, propylene glycol, purified water,

ammonium hydroxide, potassium hydroxide, black iron oxide (E 172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Bottle presentation

Do not store above 30 C.

Store in the original bottle in order to protect from moisture.

Keep the bottle tightly closed.

Sachet presentation

Do not store above 30 C.

6.5 Nature and contents of container

Bottle presentation

Type I amber glass bottles with polypropylene child-resistant closures containing 5 or 20 hard capsules.

The carton contains one bottle.

Sachet presentation

Sachets are composed of linear low density polyethylene (innermost layer), aluminium and polyethylene terephthalate.

Each sachet contains 1 hard capsule and is dispensed in a cardboard carton. The carton contains 5 or 20 hard capsules, individually sealed in sachets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin or mucous membrane must be avoided. If Temodal comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Patients should be advised to keep capsules out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/98/096/005

EU/1/98/096/006

EU/1/98/096/015

EU/1/98/096/016

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 January 1999

Date of latest renewal: 26 January 2009

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1. NAME OF THE MEDICINAL PRODUCT

Temodal 140 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 140 mg temozolomide.

Excipient with known effect:

Each hard capsule contains 246 mg of anhydrous lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule (capsule).

The hard capsules have an opaque white body, a blue cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with "140 mg", the Schering-Plough logo and two stripes.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Temodal is indicated for the treatment of:

-adult patients with newly-diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment.

-children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

4.2 Posology and method of administration

Temodal should only be prescribed by physicians experienced in the oncological treatment of brain tumours.

Anti-emetic therapy may be administered (see section 4.4).

Posology

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant phase

TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met:

-absolute neutrophil count (ANC) ≥ 1.5 x 109/l

-thrombocyte count ≥ 100 x 109/l

-common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).

During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.

Table 1. TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ

Toxicity

TMZ interruptiona

TMZ discontinuation

Absolute neutrophil count

0.5 and < 1.5 x 109/l

< 0.5 x 109/l

Thrombocyte count

10 and < 100 x 109/l

< 10 x 109/l

CTC non-haematological toxicity

CTC Grade 2

CTC Grade 3 or 4

(except for alopecia, nausea, vomiting)

 

 

a:Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count 1.5 x 109/l; thrombocyte count 100 x 109/l; CTC non-haematological toxicity Grade 1 (except for alopecia, nausea, vomiting).

Monotherapy phase

Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia,

nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/l, and the thrombocyte count is ≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase should be applied according to Tables 2 and 3.

During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TMZ). The dose should be reduced or administration discontinued according to Table 3.

Table 2. TMZ dose levels for monotherapy treatment

Dose level

TMZ dose

Remarks

 

(mg/m2/day)

 

–1

Reduction for prior toxicity

Dose during Cycle 1

Dose during Cycles 2-6 in absence of toxicity

Table 3. TMZ dose reduction or discontinuation during monotherapy treatment

Toxicity

Reduce TMZ by 1 dose levela

Discontinue TMZ

Absolute neutrophil count

< 1.0 x 109/l

See footnote b

Thrombocyte count

< 50 x 109/l

See footnote b

CTC non-haematological Toxicity

CTC Grade 3

CTC Grade 4b

(except for alopecia, nausea, vomiting)

a:TMZ dose levels are listed in Table 2.

b:TMZ is to be discontinued if:

dose level -1 (100 mg/m2) still results in unacceptable toxicity

the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:

A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is no haematological toxicity (see section 4.4)

Special populations

Paediatric population

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in children under the age of 3 years have not been established. No data are available.

Patients with hepatic or renal impairment

The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TMZ is administered in these patients.

Elderly patients

Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia (see section 4.4).

Method of administration

Temodal hard capsules should be administered in the fasting state.

The capsules must be swallowed whole with a glass of water and must not be opened or chewed.

If vomiting occurs after the dose is administered, a second dose should not be administered that day.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression (see section 4.4).

4.4 Special warnings and precautions for use

Opportunistic infections and reactivation of infections

Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8).

Meningoencephalitis herpetic

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids administration.

Pneumocystis jirovecii pneumonia

Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.

There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids.

HBV

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately.

Hepatotoxicity

Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely (see section 4.8).

Anti-emetic therapy

Nausea and vomiting are very commonly associated with TMZ.

Anti-emetic therapy may be administered prior to or following administration of TMZ.

Adult patients with newly-diagnosed glioblastoma multiforme

Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is strongly recommended during the monotherapy phase.

Patients with recurrent or progressive malignant glioma

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.

Laboratory parameters

Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: ANC 1.5 x 109/l and platelet count

100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and

200 mg/m2. The lowest recommended dose is 100 mg/m2.

Paediatric population

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).

Elderly patients (> 70 years of age)

Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.

Male patients

Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC).

Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under the curve (AUC).

As it cannot be excluded that the change in Cmax is clinically significant, Temodal should be administered without food.

Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ.

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2).

Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.

Breast-feeding

It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.

Male fertility

TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.

4.7 Effects on ability to drive and use machines

TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see section 4.8).

4.8 Undesirable effects

Clinical trial experience

In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions were reported commonly or very commonly in both indications (Tables 4 and 5); the frequency of grade 3-4 laboratory findings is presented after each table.

In the tables undesirable effects are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Newly-diagnosed glioblastoma multiforme

Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma multiforme during the concomitant and monotherapy phases of treatment.

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Infections and infestations

 

Common:

Infection, Herpes simplex, wound

Infection, candidiasis oral

 

infection, pharyngitis, candidiasis oral

 

Uncommon:

 

Herpes simplex, herpes zoster,

 

 

influenza–like symptoms

Blood and lymphatic system disorders

 

 

 

 

Common:

Neutropenia, thrombocytopenia,

Febrile neutropenia,

 

lymphopenia, leukopenia

thrombocytopenia, anaemia,

 

 

leukopenia

 

 

 

Uncommon:

Febrile neutropenia, anaemia

Lymphopenia, petechiae

Endocrine disorders

 

 

 

 

 

Uncommon:

Cushingoid

Cushingoid

Metabolism and nutrition disorders

 

 

 

 

Very common:

Anorexia

Anorexia

Common:

Hyperglycaemia, weight decreased

Weight decreased

Uncommon:

Hypokalemia, alkaline phosphatase

Hyperglycaemia, weight increased

 

increased, weight increased

 

 

 

 

Psychiatric disorders

 

 

 

 

 

Common:

Anxiety, emotional lability, insomnia

Anxiety, depression, emotional

 

 

lability, insomnia

Uncommon:

Agitation, apathy, behaviour disorder,

Hallucination, amnesia

 

depression, hallucination

 

 

 

 

Nervous system disorders

 

 

 

 

Very common:

Headache

Convulsions, headache

 

 

 

Common:

Convulsions, consciousness decreased,

Hemiparesis, aphasia, balance

 

somnolence, aphasia, balance impaired,

impaired, somnolence, confusion,

 

dizziness, confusion, memory

dizziness, memory impairment,

 

impairment, concentration impaired,

concentration impaired, dysphasia,

 

neuropathy, paresthesia, speech

neurological disorder (NOS),

 

disorder, tremor

neuropathy, peripheral neuropathy,

 

 

paresthesia, speech disorder, tremor

 

 

 

Uncommon:

Status epilepticus, extrapyramidal

Hemiplegia, ataxia, coordination

 

disorder, hemiparesis, ataxia, cognition

abnormal, gait abnormal,

 

impaired, dysphasia, gait abnormal,

hyperesthesia, sensory disturbance

 

hyperesthesia, hypoesthesia,

 

 

neurological disorder (NOS), peripheral

 

 

neuropathy

 

Eye disorders

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Common:

Vision blurred

Visual field defect, vision blurred,

 

 

diplopia

Uncommon:

Hemianopia, visual acuity reduced,

Visual acuity reduced, eye pain,

 

vision disorder, visual field defect, eye

eyes dry

 

pain

 

Ear and labyrinth disorders

 

 

 

 

Common:

Hearing impairment

Hearing impairment, tinnitus

 

 

 

Uncommon:

Otitis media, tinnitus, hyperacusis,

Deafness, vertigo, earache

 

earache

 

 

 

 

Cardiac disorders

 

 

 

 

 

Uncommon:

Palpitation

 

Vascular disorders

 

 

 

 

 

Common:

Haemorrhage, oedema, oedema leg

Haemorrhage, deep venous

 

 

thrombosis, oedema leg

 

 

 

Uncommon:

Cerebral haemorrhage, hypertension

Embolism pulmonary, oedema,

 

 

oedema peripheral

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

Common:

Dyspnoea, coughing

Dyspnoea, coughing

 

 

 

Uncommon:

Pneumonia, upper respiratory infection,

Pneumonia, sinusitis, upper

 

nasal congestion

respiratory infection, bronchitis

 

 

 

Gastrointestinal disorders

 

 

 

 

Very common:

Constipation, nausea, vomiting

Constipation, nausea, vomiting

 

 

 

Common:

Stomatitis, diarrhoea, abdominal pain,

Stomatitis, diarrhoea, dyspepsia,

 

dyspepsia, dysphagia

dysphagia, mouth dry

 

 

 

Uncommon:

 

Abdominal distension, fecal

 

 

incontinence, gastrointestinal

 

 

disorder (NOS), gastroenteritis,

 

 

haemorrhoids

Skin and subcutaneous tissue disorders

 

 

 

 

Very common:

Rash, alopecia

Rash, alopecia

 

 

 

Common:

Dermatitis, dry skin, erythema, pruritus

Dry skin, pruritus

 

 

 

Uncommon:

Skin exfoliation, photosensitivity

Erythema, pigmentation abnormal,

 

reaction, pigmentation abnormal

sweating increased

 

 

 

Musculoskeletal and connective tissue disorders

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Common:

Muscle weakness, arthralgia

Muscle weakness, arthralgia,

 

 

musculoskeletal pain, myalgia

 

 

 

Uncommon:

Myopathy, back pain, musculoskeletal

Myopathy, back pain

 

pain, myalgia

 

 

 

 

Renal and urinary disorders

 

 

 

 

Common:

Micturition frequency, urinary

Urinary incontinence

 

incontinence

 

Uncommon:

 

Dysuria

 

 

 

Reproductive system and breast disorders

 

 

 

 

Uncommon:

Impotence

Vaginal haemorrhage, menorrhagia,

 

 

amenorrhea, vaginitis, breast pain

General disorders and administration site conditions

 

 

 

 

Very common:

Fatigue

Fatigue

 

 

 

Common:

Allergic reaction, fever, radiation

Allergic reaction, fever, radiation

 

injury, face oedema, pain, taste

injury, pain, taste perversion

 

perversion

 

 

 

 

Uncommon:

Asthenia, flushing, hot flushes,

Asthenia, face oedema, pain,

 

condition aggravated, rigors, tongue

condition aggravated, rigors, tooth

 

discolouration, parosmia, thirst

disorder

 

 

 

Investigations

 

 

 

 

 

Common:

ALT increased

ALT increased

 

 

 

Uncommon:

Hepatic enzymes increased, Gamma GT

 

 

increased, AST increased

 

*A patient who was randomised to the RT arm only, received TMZ + RT.

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the patients who received TMZ.

Recurrent or progressive malignant glioma

In clinical trials, the most frequently occurring treatment-related undesirable effects were gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of Temodal.

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma

Infections and infestations

Rare:

Opportunistic infections, including PCP

 

 

Blood and lymphatic system disorders

 

 

 

Very common:

Neutropenia or lymphopenia (grade 3-4),

 

thrombocytopenia (grade 3-4)

Uncommon:

Pancytopenia, anaemia (grade 3-4), leukopenia

Metabolism and nutrition disorders

 

 

 

Very common:

Anorexia

Common:

Weight decrease

 

 

Nervous system disorders

 

 

 

Very common:

Headache

Common:

Somnolence, dizziness, paresthesia

 

 

Respiratory, thoracic and mediastinal disorders

 

 

Common:

Dyspnoea

Gastrointestinal disorders

 

 

 

Very common:

Vomiting, nausea, constipation

Common:

Diarrhoea, abdominal pain, dyspepsia

 

 

Skin and subcutaneous tissue disorders

 

 

 

Common:

Rash, pruritus, alopecia

Very rare:

Erythema multiforme, erythroderma, urticaria,

 

exanthema

 

 

General disorders and administration site conditions

 

 

Very common:

Fatigue

Common:

Fever, asthenia, rigors, malaise, pain, taste perversion

Very rare:

Allergic reactions, including anaphylaxis, angioedema

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the

nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l ), 9 % vs 3 %, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4

neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with newly- diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of male

subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle of therapy.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in children under the age of 3 years has not been established.

Post-Marketing Experience

The following additional serious adverse reactions have been identified during post-marketing exposure:

Table 6. Summary of events reported with temozolomide in the post-marketing setting

Infections and infestations*

Uncommon:

 

cytomegalovirus infection, infection reactivation such as

 

 

cytomegalovirus, hepatitis B virus,

 

 

meningoencephalitis herpetic

Blood and lymphatic system disorders

 

 

 

 

 

Very rare:

 

prolonged pancytopenia, aplastic anaemia

Neoplasm benign, malignant and unspecified

 

 

Very rare:

 

myelodysplastic syndrome (MDS), secondary

 

 

malignancies, including myeloid leukaemia

Endocrine disorders*

 

Uncommon:

 

diabetes insipidus

Respiratory, thoracic and mediastinal disorders

 

 

Very rare:

 

interstitial pneumonitis/pneumonitis, pulmonary

 

 

fibrosis, respiratory failure

Hepatobiliary disorders*

 

Common:

 

liver enzymes elevations

 

 

 

Uncommon:

 

hyperbilirubinemia, cholestasis, hepatitis, hepatic

 

 

injury, hepatic failure

Skin and subcutaneous tissue disorders

 

 

 

Very rare:

 

toxic epidermal necrolysis, Stevens-Johnson syndrome

Including cases with fatal outcome

 

 

* Frequencies estimated based on relevant clinical trials.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia,

multi-organ failure and death. There are reports of patients who have taken the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03

Mechanism of action

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Clinical efficacy and safety

Newly-diagnosed glioblastoma multiforme

A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by monotherapy TMZ (150 - 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.

TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm.

The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33 -1.91) with a log-rank

p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).

H R (9 5% C .I.) = 1 .59 (1 .3 3 – 1 .91) lo g -rank p -valu e < .0001

26%

R T + T M Z

10%

R T O n ly

1 2 .114 .6

Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population)

The results from the trial were not consistent in the subgroup of patients with a poor performance status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, no unacceptable risks appear to be present in this patient group.

Recurrent or progressive malignant glioma

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the non- comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was

2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8 %.

In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) (chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS 80.

Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the

central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT population was 44 % with a median event-free survival of 4.6 months, which was similar to the results for the progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression-free status was strongly associated with maintained or improved quality of life.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to TMZ is similar to adults.

5.2 Pharmacokinetic properties

TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl- (triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino- imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.

Absorption

After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % indicating complete absorption.

Distribution

TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with highly protein-bound substances.

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data.

Elimination

The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4- carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.

Special populations

Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.

5.3 Preclinical safety data

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.

TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome aberration tests showed a positive mutagenicity response.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content: anhydrous lactose, colloidal anhydrous silica,

sodium starch glycolate type A, tartaric acid,

stearic acid.

Capsule shell: gelatin,

titanium dioxide (E 171), sodium lauril sulfate , indigo carmine (E 132),

Printing ink: shellac, propylene glycol, purified water,

ammonium hydroxide, potassium hydroxide, black iron oxide (E 172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Bottle presentation

Do not store above 30 C.

Store in the original bottle in order to protect from moisture.

Keep the bottle tightly closed.

Sachet presentation

Do not store above 30 C.

6.5 Nature and contents of container

Bottle presentation

Type I amber glass bottles with polypropylene child-resistant closures containing 5 or 20 hard capsules.

The carton contains one bottle.

Sachet presentation

Sachets are composed of linear low density polyethylene (innermost layer), aluminium and polyethylene terephthalate.

Each sachet contains 1 hard capsule and is dispensed in a cardboard carton. The carton contains 5 or 20 hard capsules, individually sealed in sachets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin or mucous membrane must be avoided. If Temodal comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Patients should be advised to keep capsules out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/98/096/009

EU/1/98/096/010

EU/1/98/096/017

EU/1/98/096/018

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 January 1999

Date of latest renewal: 26 January 2009

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1. NAME OF THE MEDICINAL PRODUCT

Temodal 180 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 180 mg temozolomide.

Excipient with known effect:

Each hard capsule contains 316.3 mg of anhydrous lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule (capsule).

The hard capsules have an opaque white body, an opaque orange cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with "180 mg", the Schering-Plough logo and two stripes.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Temodal is indicated for the treatment of:

-adult patients with newly-diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment.

-children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

4.2 Posology and method of administration

Temodal should only be prescribed by physicians experienced in the oncological treatment of brain tumours.

Anti-emetic therapy may be administered (see section 4.4).

Posology

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant phase

TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met:

-absolute neutrophil count (ANC) ≥ 1.5 x 109/l

-thrombocyte count ≥ 100 x 109/l

-common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).

During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.

Table 1. TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ

Toxicity

TMZ interruptiona

TMZ discontinuation

Absolute neutrophil count

0.5 and < 1.5 x 109/l

< 0.5 x 109/l

Thrombocyte count

10 and < 100 x 109/l

< 10 x 109/l

CTC non-haematological toxicity

CTC Grade 2

CTC Grade 3 or 4

(except for alopecia, nausea, vomiting)

 

 

a:Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count 1.5 x 109/l; thrombocyte count 100 x 109/l; CTC non-haematological toxicity Grade 1 (except for alopecia, nausea, vomiting).

Monotherapy phase

Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia,

nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/l, and the thrombocyte count is ≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase should be applied according to Tables 2 and 3.

During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TMZ). The dose should be reduced or administration discontinued according to Table 3.

Table 2. TMZ dose levels for monotherapy treatment

Dose level

TMZ dose

Remarks

 

(mg/m2/day)

 

–1

Reduction for prior toxicity

Dose during Cycle 1

Dose during Cycles 2-6 in absence of toxicity

Table 3. TMZ dose reduction or discontinuation during monotherapy treatment

Toxicity

Reduce TMZ by 1 dose levela

Discontinue TMZ

Absolute neutrophil count

< 1.0 x 109/l

See footnote b

Thrombocyte count

< 50 x 109/l

See footnote b

CTC non-haematological Toxicity

CTC Grade 3

CTC Grade 4b

(except for alopecia, nausea, vomiting)

a:TMZ dose levels are listed in Table 2.

b:TMZ is to be discontinued if:

dose level -1 (100 mg/m2) still results in unacceptable toxicity

the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:

A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is no haematological toxicity (see section 4.4)

Special populations

Paediatric population

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in children under the age of 3 years have not been established. No data are available.

Patients with hepatic or renal impairment

The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TMZ is administered in these patients.

Elderly patients

Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia (see section 4.4).

Method of administration

Temodal hard capsules should be administered in the fasting state.

The capsules must be swallowed whole with a glass of water and must not be opened or chewed.

If vomiting occurs after the dose is administered, a second dose should not be administered that day.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression (see section 4.4).

4.4 Special warnings and precautions for use

Opportunistic infections and reactivation of infections

Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8).

Meningoencephalitis herpetic

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids administration.

Pneumocystis jirovecii pneumonia

Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42- day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.

There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids.

HBV

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately.

Hepatotoxicity

Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely (see section 4.8).

Anti-emetic therapy

Nausea and vomiting are very commonly associated with TMZ.

Anti-emetic therapy may be administered prior to or following administration of TMZ.

Adult patients with newly-diagnosed glioblastoma multiforme

Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is strongly recommended during the monotherapy phase.

Patients with recurrent or progressive malignant glioma

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.

Laboratory parameters

Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: ANC 1.5 x 109/l and platelet count

100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and

200 mg/m2. The lowest recommended dose is 100 mg/m2.

Paediatric population

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).

Elderly patients (> 70 years of age)

Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.

Male patients

Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC).

Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under the curve (AUC).

As it cannot be excluded that the change in Cmax is clinically significant, Temodal should be administered without food.

Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ.

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2).

Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.

Breast-feeding

It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.

Male fertility

TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.

4.7 Effects on ability to drive and use machines

TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see section 4.8).

4.8 Undesirable effects

Clinical trial experience

In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions were reported commonly or very commonly in both indications (Tables 4 and 5); the frequency of grade 3-4 laboratory findings is presented after each table.

In the tables undesirable effects are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Newly-diagnosed glioblastoma multiforme

Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma multiforme during the concomitant and monotherapy phases of treatment.

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Infections and infestations

 

 

 

 

Common:

Infection, Herpes simplex, wound

Infection, candidiasis oral

 

infection, pharyngitis, candidiasis oral

 

Uncommon:

 

Herpes simplex, herpes zoster,

 

 

influenza–like symptoms

Blood and lymphatic system disorders

 

 

 

 

Common:

Neutropenia, thrombocytopenia,

Febrile neutropenia,

 

lymphopenia, leukopenia

thrombocytopenia, anaemia,

 

 

leukopenia

 

 

 

Uncommon:

Febrile neutropenia, anaemia

Lymphopenia, petechiae

Endocrine disorders

 

 

 

 

 

Uncommon:

Cushingoid

Cushingoid

Metabolism and nutrition disorders

 

 

 

 

Very common:

Anorexia

Anorexia

Common:

Hyperglycaemia, weight decreased

Weight decreased

Uncommon:

Hypokalemia, alkaline phosphatase

Hyperglycaemia, weight increased

 

increased, weight increased

 

 

 

 

Psychiatric disorders

 

 

 

 

 

Common:

Anxiety, emotional lability, insomnia

Anxiety, depression, emotional

 

 

lability, insomnia

Uncommon:

Agitation, apathy, behaviour disorder,

Hallucination, amnesia

 

depression, hallucination

 

 

 

 

Nervous system disorders

 

 

 

 

Very common:

Headache

Convulsions, headache

 

 

 

Common:

Convulsions, consciousness decreased,

Hemiparesis, aphasia, balance

 

somnolence, aphasia, balance impaired,

impaired, somnolence, confusion,

 

dizziness, confusion, memory

dizziness, memory impairment,

 

impairment, concentration impaired,

concentration impaired, dysphasia,

 

neuropathy, paresthesia, speech

neurological disorder (NOS),

 

disorder, tremor

neuropathy, peripheral neuropathy,

 

 

paresthesia, speech disorder, tremor

 

 

 

Uncommon:

Status epilepticus, extrapyramidal

Hemiplegia, ataxia, coordination

 

disorder, hemiparesis, ataxia, cognition

abnormal, gait abnormal,

 

impaired, dysphasia, gait abnormal,

hyperesthesia, sensory disturbance

 

hyperesthesia, hypoesthesia,

 

 

neurological disorder (NOS), peripheral

 

 

neuropathy

 

Eye disorders

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Common:

Vision blurred

Visual field defect, vision blurred,

 

 

diplopia

Uncommon:

Hemianopia, visual acuity reduced,

Visual acuity reduced, eye pain,

 

vision disorder, visual field defect, eye

eyes dry

 

pain

 

Ear and labyrinth disorders

 

 

 

 

Common:

Hearing impairment

Hearing impairment, tinnitus

 

 

 

Uncommon:

Otitis media, tinnitus, hyperacusis,

Deafness, vertigo, earache

 

earache

 

 

 

 

Cardiac disorders

 

 

 

 

 

Uncommon:

Palpitation

 

 

 

 

Vascular disorders

 

 

 

 

 

Common:

Haemorrhage, oedema, oedema leg

Haemorrhage, deep venous

 

 

thrombosis, oedema leg

 

 

 

Uncommon:

Cerebral haemorrhage, hypertension

Embolism pulmonary, oedema,

 

 

oedema peripheral

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

Common:

Dyspnoea, coughing

Dyspnoea, coughing

 

 

 

Uncommon:

Pneumonia, upper respiratory infection,

Pneumonia, sinusitis, upper

 

nasal congestion

respiratory infection, bronchitis

 

 

 

Gastrointestinal disorders

 

 

 

 

Very common:

Constipation, nausea, vomiting

Constipation, nausea, vomiting

 

 

 

Common:

Stomatitis, diarrhoea, abdominal pain,

Stomatitis, diarrhoea, dyspepsia,

 

dyspepsia, dysphagia

dysphagia, mouth dry

 

 

 

Uncommon:

 

Abdominal distension, fecal

 

 

incontinence, gastrointestinal

 

 

disorder (NOS), gastroenteritis,

 

 

haemorrhoids

Skin and subcutaneous tissue disorders

 

 

 

 

Very common:

Rash, alopecia

Rash, alopecia

 

 

 

Common:

Dermatitis, dry skin, erythema, pruritus

Dry skin, pruritus

 

 

 

Uncommon:

Skin exfoliation, photosensitivity

Erythema, pigmentation abnormal,

 

reaction, pigmentation abnormal

sweating increased

 

 

 

Musculoskeletal and connective tissue disorders

 

 

 

 

Common:

Muscle weakness, arthralgia

Muscle weakness, arthralgia,

 

 

musculoskeletal pain, myalgia

 

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Uncommon:

Myopathy, back pain, musculoskeletal

Myopathy, back pain

 

pain, myalgia

 

 

 

 

Renal and urinary disorders

 

 

 

 

Common:

Micturition frequency, urinary

Urinary incontinence

 

incontinence

 

Uncommon:

 

Dysuria

 

 

 

Reproductive system and breast disorders

 

 

 

 

Uncommon:

Impotence

Vaginal haemorrhage, menorrhagia,

 

 

amenorrhea, vaginitis, breast pain

General disorders and administration site conditions

 

 

 

 

Very common:

Fatigue

Fatigue

 

 

 

Common:

Allergic reaction, fever, radiation

Allergic reaction, fever, radiation

 

injury, face oedema, pain, taste

injury, pain, taste perversion

 

perversion

 

Uncommon:

Asthenia, flushing, hot flushes,

Asthenia, face oedema, pain,

 

condition aggravated, rigors, tongue

condition aggravated, rigors, tooth

 

discolouration, parosmia, thirst

disorder

 

 

 

Investigations

 

 

 

 

 

Common:

ALT increased

ALT increased

 

 

 

Uncommon:

Hepatic enzymes increased, Gamma GT

 

 

increased, AST increased

 

*A patient who was randomised to the RT arm only, received TMZ + RT.

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the patients who received TMZ.

Recurrent or progressive malignant glioma

In clinical trials, the most frequently occurring treatment-related undesirable effects were gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of Temodal.

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma

Infections and infestations

Rare:

Opportunistic infections, including PCP

 

 

Blood and lymphatic system disorders

 

 

 

Very common:

Neutropenia or lymphopenia (grade 3-4),

 

thrombocytopenia (grade 3-4)

Uncommon:

Pancytopenia, anaemia (grade 3-4), leukopenia

Metabolism and nutrition disorders

 

 

 

Very common:

Anorexia

Common:

Weight decrease

 

 

Nervous system disorders

 

 

 

Very common:

Headache

Common:

Somnolence, dizziness, paresthesia

 

 

Respiratory, thoracic and mediastinal disorders

 

 

Common:

Dyspnoea

Gastrointestinal disorders

 

 

 

Very common:

Vomiting, nausea, constipation

Common:

Diarrhoea, abdominal pain, dyspepsia

 

 

Skin and subcutaneous tissue disorders

 

 

 

Common:

Rash, pruritus, alopecia

Very rare:

Erythema multiforme, erythroderma, urticaria,

 

exanthema

 

 

General disorders and administration site conditions

 

 

Very common:

Fatigue

Common:

Fever, asthenia, rigors, malaise, pain, taste perversion

Very rare:

Allergic reactions, including anaphylaxis, angioedema

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the

nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4

neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with newly- diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of male

subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle of therapy.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in children under the age of 3 years has not been established.

Post-Marketing Experience

The following additional serious adverse reactions have been identified during post-marketing exposure:

Table 6. Summary of events reported with temozolomide in the post-marketing setting

Infections and infestations*

Uncommon:

 

cytomegalovirus infection, infection reactivation such as

 

 

cytomegalovirus, hepatitis B virus,

 

 

meningoencephalitis herpetic

Blood and lymphatic system disorders

 

 

 

 

 

Very rare:

 

prolonged pancytopenia, aplastic anaemia

Neoplasm benign, malignant and unspecified

 

 

Very rare:

 

myelodysplastic syndrome (MDS), secondary

 

 

malignancies, including myeloid leukaemia

Endocrine disorders*

 

Uncommon:

 

diabetes insipidus

Respiratory, thoracic and mediastinal disorders

 

 

Very rare:

 

interstitial pneumonitis/pneumonitis, pulmonary

 

 

fibrosis, respiratory failure

Hepatobiliary disorders*

 

Common:

 

liver enzymes elevations

 

 

 

Uncommon:

 

hyperbilirubinemia, cholestasis, hepatitis, hepatic

 

 

injury, hepatic failure

Skin and subcutaneous tissue disorders

 

 

 

Very rare:

 

toxic epidermal necrolysis, Stevens-Johnson syndrome

Including cases with fatal outcome

 

 

* Frequencies estimated based on relevant clinical trials.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia,

multi-organ failure and death. There are reports of patients who have taken the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03

Mechanism of action

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Clinical efficacy and safety

Newly-diagnosed glioblastoma multiforme

A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by monotherapy TMZ (150 - 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.

TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm.

The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33 -1.91) with a log-rank

p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).

H R (95 % C .I.) = 1 .59 (1 .33 – 1 .9 1 ) lo g -rank p -valu e < .0 001

26%

R T + T M Z

10%

R T O n ly

12 .114 .6

Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population)

The results from the trial were not consistent in the subgroup of patients with a poor performance status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, no unacceptable risks appear to be present in this patient group.

Recurrent or progressive malignant glioma

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the non- comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was

2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8 %.

In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) (chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS 80.

Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT)

n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT population was 44 % with a median event-free survival of 4.6 months, which was similar to the results for the progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression-free status was strongly associated with maintained or improved quality of life.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to TMZ is similar to adults.

5.2 Pharmacokinetic properties

TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl- (triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino- imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.

Absorption

After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % indicating complete absorption.

Distribution

TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with highly protein-bound substances.

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data.

Elimination

The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4- carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.

Special populations

Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.

5.3 Preclinical safety data

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.

TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome aberration tests showed a positive mutagenicity response.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content: anhydrous lactose, colloidal anhydrous silica,

sodium starch glycolate type A, tartaric acid,

stearic acid.

Capsule shell: gelatin,

titanium dioxide (E 171), sodium lauril sulfate, yellow iron oxide (E 172), red iron oxide (E 172)

Printing ink: shellac, propylene glycol, purified water,

ammonium hydroxide, potassium hydroxide, black iron oxide (E 172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Bottle presentation

Do not store above 30 C.

Store in the original bottle in order to protect from moisture.

Keep the bottle tightly closed.

Sachet presentation

Do not store above 30 C.

6.5 Nature and contents of container

Bottle presentation

Type I amber glass bottles with polypropylene child-resistant closures containing 5 or 20 hard capsules.

The carton contains one bottle.

Sachet presentation

Sachets are composed of linear low density polyethylene (innermost layer), aluminium and polyethylene terephthalate.

Each sachet contains 1 hard capsule and is dispensed in a cardboard carton. The carton contains 5 or 20 hard capsules, individually sealed in sachets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin or mucous membrane must be avoided. If Temodal comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Patients should be advised to keep capsules out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/98/096/011

EU/1/98/096/012

EU/1/98/096/019

EU/1/98/096/020

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 January 1999

Date of latest renewal: 26 January 2009

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1. NAME OF THE MEDICINAL PRODUCT

Temodal 250 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 250 mg temozolomide.

Excipient with known effect:

Each hard capsule contains 154.3 mg of anhydrous lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule (capsule).

The hard capsules have an opaque white body and cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with "250 mg", the Schering-Plough logo and two stripes.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Temodal is indicated for the treatment of:

-adult patients with newly-diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment.

-children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

4.2 Posology and method of administration

Temodal should only be prescribed by physicians experienced in the oncological treatment of brain tumours.

Anti-emetic therapy may be administered (see section 4.4).

Posology

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant phase

TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met:

-absolute neutrophil count (ANC) ≥ 1.5 x 109/l

-thrombocyte count ≥ 100 x 109/l

-common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).

During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.

Table 1. TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ

Toxicity

TMZ interruptiona

TMZ discontinuation

Absolute neutrophil count

0.5 and < 1.5 x 109/l

< 0.5 x 109/l

Thrombocyte count

10 and < 100 x 109/l

< 10 x 109/l

CTC non-haematological toxicity

CTC Grade 2

CTC Grade 3 or 4

(except for alopecia, nausea, vomiting)

 

 

a:Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count 1.5 x 109/l; thrombocyte count 100 x 109/l; CTC non-haematological toxicity Grade 1 (except for alopecia, nausea, vomiting).

Monotherapy phase

Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia,

nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/l, and the thrombocyte count is ≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase should be applied according to Tables 2 and 3.

During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TMZ). The dose should be reduced or administration discontinued according to Table 3.

Table 2. TMZ dose levels for monotherapy treatment

Dose level

TMZ dose

Remarks

 

(mg/m2/day)

 

–1

Reduction for prior toxicity

Dose during Cycle 1

Dose during Cycles 2-6 in absence of toxicity

Table 3. TMZ dose reduction or discontinuation during monotherapy treatment

Toxicity

Reduce TMZ by 1 dose levela

Discontinue TMZ

Absolute neutrophil count

< 1.0 x 109/l

See footnote b

Thrombocyte count

< 50 x 109/l

See footnote b

CTC non-haematological Toxicity

CTC Grade 3

CTC Grade 4b

(except for alopecia, nausea, vomiting)

a:TMZ dose levels are listed in Table 2.

b:TMZ is to be discontinued if:

dose level -1 (100 mg/m2) still results in unacceptable toxicity

the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:

A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is no haematological toxicity (see section 4.4)

Special populations

Paediatric population

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in children under the age of 3 years have not been established. No data are available.

Patients with hepatic or renal impairment

The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TMZ is administered in these patients.

Elderly patients

Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia (see section 4.4).

Method of administration

Temodal hard capsules should be administered in the fasting state.

The capsules must be swallowed whole with a glass of water and must not be opened or chewed.

If vomiting occurs after the dose is administered, a second dose should not be administered that day.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression (see section 4.4).

4.4 Special warnings and precautions for use

Opportunistic infections and reactivation of infections

Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8).

Meningoencephalitis herpetic

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids administration.

Pneumocystis jirovecii pneumonia

Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42- day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.

There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids.

HBV

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately.

Hepatotoxicity

Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely (see section 4.8).

Anti-emetic therapy

Nausea and vomiting are very commonly associated with TMZ.

Anti-emetic therapy may be administered prior to or following administration of TMZ.

Adult patients with newly-diagnosed glioblastoma multiforme

Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is strongly recommended during the monotherapy phase.

Patients with recurrent or progressive malignant glioma

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.

Laboratory parameters

Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: ANC 1.5 x 109/l and platelet count

100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and

200 mg/m2. The lowest recommended dose is 100 mg/m2.

Paediatric population

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).

Elderly patients (> 70 years of age)

Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.

Male patients

Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC).

Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under the curve (AUC).

As it cannot be excluded that the change in Cmax is clinically significant, Temodal should be administered without food.

Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ.

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2).

Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.

Breast-feeding

It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.

Male fertility

TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.

4.7 Effects on ability to drive and use machines

TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see section 4.8).

4.8 Undesirable effects

Clinical trial experience

In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions were reported commonly or very commonly in both indications (Tables 4 and 5); the frequency of grade 3-4 laboratory findings is presented after each table.

In the tables undesirable effects are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Newly-diagnosed glioblastoma multiforme

Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma multiforme during the concomitant and monotherapy phases of treatment.

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Infections and infestations

 

Common:

Infection, Herpes simplex, wound

Infection, candidiasis oral

 

infection, pharyngitis, candidiasis oral

 

Uncommon:

 

Herpes simplex, herpes zoster,

 

 

influenza–like symptoms

Blood and lymphatic system disorders

 

 

 

 

Common:

Neutropenia, thrombocytopenia,

Febrile neutropenia,

 

lymphopenia, leukopenia

thrombocytopenia, anaemia,

 

 

leukopenia

 

 

 

Uncommon:

Febrile neutropenia, anaemia

Lymphopenia, petechiae

Endocrine disorders

 

 

 

 

 

Uncommon:

Cushingoid

Cushingoid

Metabolism and nutrition disorders

 

 

 

 

Very common:

Anorexia

Anorexia

Common:

Hyperglycaemia, weight decreased

Weight decreased

Uncommon:

Hypokalemia, alkaline phosphatase

Hyperglycaemia, weight increased

 

increased, weight increased

 

 

 

 

Psychiatric disorders

 

 

 

 

 

Common:

Anxiety, emotional lability, insomnia

Anxiety, depression, emotional

 

 

lability, insomnia

Uncommon:

Agitation, apathy, behaviour disorder,

Hallucination, amnesia

 

depression, hallucination

 

 

 

 

Nervous system disorders

 

 

 

 

Very common:

Headache

Convulsions, headache

 

 

 

Common:

Convulsions, consciousness decreased,

Hemiparesis, aphasia, balance

 

somnolence, aphasia, balance impaired,

impaired, somnolence, confusion,

 

dizziness, confusion, memory

dizziness, memory impairment,

 

impairment, concentration impaired,

concentration impaired, dysphasia,

 

neuropathy, paresthesia, speech

neurological disorder (NOS),

 

disorder, tremor

neuropathy, peripheral neuropathy,

 

 

paresthesia, speech disorder, tremor

 

 

 

Uncommon:

Status epilepticus, extrapyramidal

Hemiplegia, ataxia, coordination

 

disorder, hemiparesis, ataxia, cognition

abnormal, gait abnormal,

 

impaired, dysphasia, gait abnormal,

hyperesthesia, sensory disturbance

 

hyperesthesia, hypoesthesia,

 

 

neurological disorder (NOS), peripheral

 

 

neuropathy

 

Eye disorders

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Common:

Vision blurred

Visual field defect, vision blurred,

 

 

diplopia

Uncommon:

Hemianopia, visual acuity reduced,

Visual acuity reduced, eye pain,

 

vision disorder, visual field defect, eye

eyes dry

 

pain

 

Ear and labyrinth disorders

 

 

 

 

Common:

Hearing impairment

Hearing impairment, tinnitus

 

 

 

Uncommon:

Otitis media, tinnitus, hyperacusis,

Deafness, vertigo, earache

 

earache

 

 

 

 

Cardiac disorders

 

 

 

 

 

Uncommon:

Palpitation

 

Vascular disorders

 

 

 

 

 

Common:

Haemorrhage, oedema, oedema leg

Haemorrhage, deep venous

 

 

thrombosis, oedema leg

 

 

 

Uncommon:

Cerebral haemorrhage, hypertension

Embolism pulmonary, oedema,

 

 

oedema peripheral

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

Common:

Dyspnoea, coughing

Dyspnoea, coughing

 

 

 

Uncommon:

Pneumonia, upper respiratory infection,

Pneumonia, sinusitis, upper

 

nasal congestion

respiratory infection, bronchitis

 

 

 

Gastrointestinal disorders

 

 

 

 

Very common:

Constipation, nausea, vomiting

Constipation, nausea, vomiting

 

 

 

Common:

Stomatitis, diarrhoea, abdominal pain,

Stomatitis, diarrhoea, dyspepsia,

 

dyspepsia, dysphagia

dysphagia, mouth dry

 

 

 

Uncommon:

 

Abdominal distension, fecal

 

 

incontinence, gastrointestinal

 

 

disorder (NOS), gastroenteritis,

 

 

haemorrhoids

Skin and subcutaneous tissue disorders

 

 

 

 

Very common:

Rash, alopecia

Rash, alopecia

 

 

 

Common:

Dermatitis, dry skin, erythema, pruritus

Dry skin, pruritus

 

 

 

Uncommon:

Skin exfoliation, photosensitivity

Erythema, pigmentation abnormal,

 

reaction, pigmentation abnormal

sweating increased

 

 

 

Musculoskeletal and connective tissue disorders

 

 

 

 

Common:

Muscle weakness, arthralgia

Muscle weakness, arthralgia,

 

 

musculoskeletal pain, myalgia

 

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Uncommon:

Myopathy, back pain, musculoskeletal

Myopathy, back pain

 

pain, myalgia

 

 

 

 

Renal and urinary disorders

 

 

 

 

Common:

Micturition frequency, urinary

Urinary incontinence

 

incontinence

 

Uncommon:

 

Dysuria

 

 

 

Reproductive system and breast disorders

 

 

 

 

Uncommon:

Impotence

Vaginal haemorrhage, menorrhagia,

 

 

amenorrhea, vaginitis, breast pain

General disorders and administration site conditions

 

 

 

 

Very common:

Fatigue

Fatigue

 

 

 

Common:

Allergic reaction, fever, radiation

Allergic reaction, fever, radiation

 

injury, face oedema, pain, taste

injury, pain, taste perversion

 

perversion

 

Uncommon:

Asthenia, flushing, hot flushes,

Asthenia, face oedema, pain,

 

condition aggravated, rigors, tongue

condition aggravated, rigors, tooth

 

discolouration, parosmia, thirst

disorder

 

 

 

Investigations

 

 

 

 

 

Common:

ALT increased

ALT increased

 

 

 

Uncommon:

Hepatic enzymes increased, Gamma GT

 

 

increased, AST increased

 

*A patient who was randomised to the RT arm only, received TMZ + RT.

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the patients who received TMZ.

Recurrent or progressive malignant glioma

In clinical trials, the most frequently occurring treatment-related undesirable effects were gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of Temodal.

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma

Infections and infestations

Rare:

Opportunistic infections, including PCP

 

 

Blood and lymphatic system disorders

 

 

 

Very common:

Neutropenia or lymphopenia (grade 3-4),

 

thrombocytopenia (grade 3-4)

Uncommon:

Pancytopenia, anaemia (grade 3-4), leukopenia

Metabolism and nutrition disorders

 

 

 

Very common:

Anorexia

Common:

Weight decrease

 

 

Nervous system disorders

 

 

 

Very common:

Headache

Common:

Somnolence, dizziness, paresthesia

 

 

Respiratory, thoracic and mediastinal disorders

 

 

Common:

Dyspnoea

Gastrointestinal disorders

 

 

 

Very common:

Vomiting, nausea, constipation

Common:

Diarrhoea, abdominal pain, dyspepsia

 

 

Skin and subcutaneous tissue disorders

 

 

 

Common:

Rash, pruritus, alopecia

Very rare:

Erythema multiforme, erythroderma, urticaria,

 

exanthema

 

 

General disorders and administration site conditions

 

 

Very common:

Fatigue

Common:

Fever, asthenia, rigors, malaise, pain, taste perversion

Very rare:

Allergic reactions, including anaphylaxis, angioedema

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the

nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4

neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with newly- diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of male

subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle of therapy.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in children under the age of 3 years has not been established.

Post-Marketing Experience

The following additional serious adverse reactions have been identified during post-marketing exposure:

Table 6. Summary of events reported with temozolomide in the post-marketing setting

Infections and infestations*

Uncommon:

 

cytomegalovirus infection, infection reactivation such as

 

 

cytomegalovirus, hepatitis B virus,

 

 

meningoencephalitis herpetic

Blood and lymphatic system disorders

 

 

 

 

 

Very rare:

 

prolonged pancytopenia, aplastic anaemia

Neoplasm benign, malignant and unspecified

 

 

Very rare:

 

myelodysplastic syndrome (MDS), secondary

 

 

malignancies, including myeloid leukaemia

Endocrine disorders*

 

Uncommon:

 

diabetes insipidus

Respiratory, thoracic and mediastinal disorders

 

 

Very rare:

 

interstitial pneumonitis/pneumonitis, pulmonary

 

 

fibrosis, respiratory failure

Hepatobiliary disorders*

 

Common:

 

liver enzymes elevations

 

 

 

Uncommon:

 

hyperbilirubinemia, cholestasis, hepatitis, hepatic

 

 

injury, hepatic failure

Skin and subcutaneous tissue disorders

 

 

 

Very rare:

 

toxic epidermal necrolysis, Stevens-Johnson syndrome

Including cases with fatal outcome

 

 

* Frequencies estimated based on relevant clinical trials.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia,

multi-organ failure and death. There are reports of patients who have taken the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03

Mechanism of action

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Clinical efficacy and safety

Newly-diagnosed glioblastoma multiforme

A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by monotherapy TMZ (150 - 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.

TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm.

The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33 -1.91) with a log-rank

p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).

H R (95 % C .I.) = 1 .59 (1 .33 – 1 .9 1 ) lo g -rank p -valu e < .0 001

26%

R T + T M Z

10%

R T O n ly

12 .114 .6

Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population)

The results from the trial were not consistent in the subgroup of patients with a poor performance status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, no unacceptable risks appear to be present in this patient group.

Recurrent or progressive malignant glioma

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the non- comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was

2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8 %.

In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) (chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS 80.

Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT)

n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT population was 44 % with a median event-free survival of 4.6 months, which was similar to the results for the progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression-free status was strongly associated with maintained or improved quality of life.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to TMZ is similar to adults.

5.2 Pharmacokinetic properties

TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl- (triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino- imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.

Absorption

After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % indicating complete absorption.

Distribution

TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with highly protein-bound substances.

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data.

Elimination

The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4- carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.

Special populations

Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.

5.3 Preclinical safety data

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.

TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome aberration tests showed a positive mutagenicity response.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content: anhydrous lactose, colloidal anhydrous silica,

sodium starch glycolate type A, tartaric acid,

stearic acid.

Capsule shell: gelatin,

titanium dioxide (E 171), sodium lauril sulfate

Printing ink: shellac, propylene glycol, purified water,

ammonium hydroxide, potassium hydroxide, black iron oxide (E 172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Bottle presentation

Do not store above 30 C.

Store in the original bottle in order to protect from moisture.

Keep the bottle tightly closed.

Sachet presentation

Do not store above 30 C.

6.5 Nature and contents of container

Bottle presentation

Type I amber glass bottles with polypropylene child-resistant closures containing 5 or 20 hard capsules.

The carton contains one bottle.

Sachet presentation

Sachets are composed of linear low density polyethylene (innermost layer), aluminium and polyethylene terephthalate.

Each sachet contains 1 hard capsule and is dispensed in a cardboard carton. The carton contains 5 or 20 hard capsules, individually sealed in sachets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin or mucous membrane must be avoided. If Temodal comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Patients should be advised to keep capsules out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/98/096/007

EU/1/98/096/008

EU/1/98/096/021

EU/1/98/096/022

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 January 1999

Date of latest renewal: 26 January 2009

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1. NAME OF THE MEDICINAL PRODUCT

Temodal 2.5 mg/ml powder for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 100 mg of temozolomide.

After reconstitution, 1 ml solution for infusion contains 2.5 mg temozolomide.

Excipient with known effect:

Each vial contains 2.4 mmol sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for infusion.

White powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Temodal is indicated for the treatment of:

-adult patients with newly-diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment.

-children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

4.2 Posology and method of administration

Temodal should only be prescribed by physicians experienced in the oncological treatment of brain tumours.

Anti-emetic therapy may be administered (see section 4.4).

Posology

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant phase

TMZ is administered at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria.

TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met:

-absolute neutrophil count (ANC) ≥ 1.5 x 109/l

-thrombocyte count ≥ 100 x 109/l

-common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).

During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.

Table 1. TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ

Toxicity

TMZ interruptiona

TMZ discontinuation

Absolute neutrophil count

0.5 and < 1.5 x 109/l

< 0.5 x 109/l

Thrombocyte count

10 and < 100 x 109/l

< 10 x 109/l

CTC non-haematological toxicity

CTC Grade 2

CTC Grade 3 or 4

(except for alopecia, nausea, vomiting)

 

 

a:Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count 1.5 x 109/l; thrombocyte count 100 x 109/l; CTC non-haematological toxicity Grade 1 (except for alopecia, nausea, vomiting).

Monotherapy phase

Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia,

nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/l, and the thrombocyte count is ≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase should be applied according to Tables 2 and 3.

During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TMZ). The dose should be reduced or administration discontinued according to Table 3.

Table 2. TMZ dose levels for monotherapy treatment

Dose level

TMZ dose

Remarks

 

(mg/m2/day)

 

–1

Reduction for prior toxicity

Dose during Cycle 1

Dose during Cycles 2-6 in absence of toxicity

Table 3. TMZ dose reduction or discontinuation during monotherapy treatment

Toxicity

Reduce TMZ by 1 dose levela

Discontinue TMZ

Absolute neutrophil count

< 1.0 x 109/l

See footnote b

Thrombocyte count

< 50 x 109/l

See footnote b

CTC non-haematological Toxicity

CTC Grade 3

CTC Grade 4b

(except for alopecia, nausea, vomiting)

 

 

a:TMZ dose levels are listed in Table 2.

b:TMZ is to be discontinued if:

dose level -1 (100 mg/m2) still results in unacceptable toxicity

the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:

A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is no haematological toxicity (see section 4.4)

Special populations

Paediatric population

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in children under the age of 3 years have not been established. No data are available.

Patients with hepatic or renal impairment

The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TMZ is administered in these patients.

Elderly patients

Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia (see section 4.4).

Method of administration

Temodal 2.5 mg/ml powder for solution for infusion must be administered only by intravenous infusion. It must not be given by other routes of administration, such as the intrathecal, intramuscular, or subcutaneous route. Temodal 2.5 mg/ml powder for solution for infusion may be administered in the same IV line with 0.9% Sodium Chloride injection. It is incompatible with dextrose solutions.

The appropriate dose of TMZ should be infused intravenously using a pump over a period of 90 minutes.

As with other similar chemotherapeutic agents, caution is recommended to avoid extravasation. Local injection site adverse reactions, which were mostly mild and short-lived were reported in patients receiving Temodal 2.5 mg/ml powder for solution for infusion. Preclinical studies did not show permanent tissue damage (see sections 4.8 and 5.3).

Temodal is also available as a hard capsule formulation (oral use). Temodal 2.5 mg/ml powder for solution for infusion, given as an intravenous infusion over 90 minutes, is bioequivalent to the hard capsule formulation (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression (see section 4.4).

4.4 Special warnings and precautions for use

Opportunistic infections and reactivation of infections

Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8).

Meningoencephalitis herpetic

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids administration.

Pneumocystis jirovecii pneumonia

Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42- day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.

There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids.

HBV

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately.

Hepatotoxicity

Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely (see section 4.8).

Anti-emetic therapy

Nausea and vomiting are very commonly associated with TMZ.

Anti-emetic therapy may be administered prior to or following administration of TMZ.

Adult patients with newly-diagnosed glioblastoma multiforme

Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is strongly recommended during the monotherapy phase.

Patients with recurrent or progressive malignant glioma

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.

Laboratory parameters

Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: ANC 1.5 x 109/l and platelet count

100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and

200 mg/m2. The lowest recommended dose is 100 mg/m2.

Paediatric population

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).

Elderly patients (> 70 years of age)

Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.

Male patients

Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6).

Sodium

This medicinal product contains 2.4 mmol sodium per vial. This should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC).

Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ.

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2).

Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3).

Temodal should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.

Breast-feeding

It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.

Male fertility

TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.

4.7 Effects on ability to drive and use machines

TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see section 4.8).

4.8 Undesirable effects

Clinical trial experience with hard capsules

In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as monotherapy, and commonly in recurrent glioma. Most haematological adverse reactions were reported commonly or very commonly in both indications (Tables 4 and 5); the frequency of grade 3-4 laboratory findings is presented after each table.

In the tables undesirable effects are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Newly-diagnosed glioblastoma multiforme

Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma multiforme during the concomitant and monotherapy phases of treatment.

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Infections and infestations

 

Common:

Infection, Herpes simplex, wound

Infection, candidiasis oral

 

infection, pharyngitis, candidiasis oral

 

Uncommon:

 

Herpes simplex, herpes zoster,

 

 

influenza–like symptoms

Blood and lymphatic system disorders

 

 

 

 

Common:

Neutropenia, thrombocytopenia,

Febrile neutropenia,

 

lymphopenia, leukopenia

thrombocytopenia, anaemia,

 

 

leukopenia

 

 

 

Uncommon:

Febrile neutropenia, anaemia

Lymphopenia, petechiae

Endocrine disorders

 

 

 

 

 

Uncommon:

Cushingoid

Cushingoid

Metabolism and nutrition disorders

 

 

 

 

Very common:

Anorexia

Anorexia

 

 

 

Common:

Hyperglycaemia, weight decreased

Weight decreased

Uncommon:

Hypokalemia, alkaline phosphatase

Hyperglycaemia, weight increased

 

increased, weight increased

 

 

 

 

Psychiatric disorders

 

 

 

 

 

Common:

Anxiety, emotional lability, insomnia

Anxiety, depression, emotional

 

 

lability, insomnia

Uncommon:

Agitation, apathy, behaviour disorder,

Hallucination, amnesia

 

depression, hallucination

 

 

 

 

Nervous system disorders

 

 

 

 

Very common:

Headache

Convulsions, headache

 

 

 

Common:

Convulsions, consciousness decreased,

Hemiparesis, aphasia, balance

 

somnolence, aphasia, balance impaired,

impaired, somnolence, confusion,

 

dizziness, confusion, memory

dizziness, memory impairment,

 

impairment, concentration impaired,

concentration impaired, dysphasia,

 

neuropathy, paresthesia, speech

neurological disorder (NOS),

 

disorder, tremor

neuropathy, peripheral neuropathy,

 

 

paresthesia, speech disorder, tremor

 

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Uncommon:

Status epilepticus, extrapyramidal

Hemiplegia, ataxia, coordination

 

disorder, hemiparesis, ataxia, cognition

abnormal, gait abnormal,

 

impaired, dysphasia, gait abnormal,

hyperesthesia, sensory disturbance

 

hyperesthesia, hypoesthesia,

 

 

neurological disorder (NOS), peripheral

 

 

neuropathy

 

Eye disorders

 

 

 

 

 

Common:

Vision blurred

Visual field defect, vision blurred,

 

 

diplopia

Uncommon:

Hemianopia, visual acuity reduced,

Visual acuity reduced, eye pain,

 

vision disorder, visual field defect, eye

eyes dry

 

pain

 

Ear and labyrinth disorders

 

 

 

 

Common:

Hearing impairment

Hearing impairment, tinnitus

 

 

 

Uncommon:

Otitis media, tinnitus, hyperacusis,

Deafness, vertigo, earache

 

earache

 

 

 

 

Cardiac disorders

 

 

 

 

 

Uncommon:

Palpitation

 

Vascular disorders

 

 

 

 

 

Common:

Haemorrhage, oedema, oedema leg

Haemorrhage, deep venous

 

 

thrombosis, oedema leg

 

 

 

Uncommon:

Cerebral haemorrhage, hypertension

Embolism pulmonary, oedema,

 

 

oedema peripheral

Respiratory, thoracic and mediastinal disorders

 

 

 

 

Common:

Dyspnoea, coughing

Dyspnoea, coughing

 

 

 

Uncommon:

Pneumonia, upper respiratory infection,

Pneumonia, sinusitis, upper

 

nasal congestion

respiratory infection, bronchitis

 

 

 

Gastrointestinal disorders

 

 

 

 

Very common:

Constipation, nausea, vomiting

Constipation, nausea, vomiting

 

 

 

Common:

Stomatitis, diarrhoea, abdominal pain,

Stomatitis, diarrhoea, dyspepsia,

 

dyspepsia, dysphagia

dysphagia, mouth dry

 

 

 

Uncommon:

 

Abdominal distension, fecal

 

 

incontinence, gastrointestinal

 

 

disorder (NOS), gastroenteritis,

 

 

haemorrhoids

Skin and subcutaneous tissue disorders

 

 

 

 

Very common:

Rash, alopecia

Rash, alopecia

 

 

 

Common:

Dermatitis, dry skin, erythema, pruritus

Dry skin, pruritus

 

 

 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

 

n=288*

n=224

Uncommon:

Skin exfoliation, photosensitivity

Erythema, pigmentation abnormal,

 

reaction, pigmentation abnormal

sweating increased

 

 

 

Musculoskeletal and connective tissue disorders

 

 

 

 

Common:

Muscle weakness, arthralgia

Muscle weakness, arthralgia,

 

 

musculoskeletal pain, myalgia

 

 

 

Uncommon:

Myopathy, back pain, musculoskeletal

Myopathy, back pain

 

pain, myalgia

 

 

 

 

Renal and urinary disorders

 

 

 

 

Common:

Micturition frequency, urinary

Urinary incontinence

 

incontinence

 

Uncommon:

 

Dysuria

 

 

 

Reproductive system and breast disorders

 

 

 

 

Uncommon:

Impotence

Vaginal haemorrhage, menorrhagia,

 

 

amenorrhea, vaginitis, breast pain

General disorders and administration site conditions

 

 

 

 

Very common:

Fatigue

Fatigue

 

 

 

Common:

Allergic reaction, fever, radiation

Allergic reaction, fever, radiation

 

injury, face oedema, pain, taste

injury, pain, taste perversion

 

perversion

 

 

 

 

Uncommon:

Asthenia, flushing, hot flushes,

Asthenia, face oedema, pain,

 

condition aggravated, rigors, tongue

condition aggravated, rigors, tooth

 

discolouration, parosmia, thirst

disorder

 

 

 

Investigations

 

 

 

 

 

Common:

ALT increased

ALT increased

 

 

 

Uncommon:

Hepatic enzymes increased, Gamma GT

 

 

increased, AST increased

 

*A patient who was randomised to the RT arm only, received TMZ + RT.

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the patients who received TMZ.

Recurrent or progressive malignant glioma

In clinical trials, the most frequently occurring treatment-related undesirable effects were gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of Temodal.

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma

Infections and infestations

Rare:

Opportunistic infections, including PCP

 

 

Blood and lymphatic system disorders

 

 

 

Very common:

Neutropenia or lymphopenia (grade 3-4),

 

thrombocytopenia (grade 3-4)

Uncommon:

Pancytopenia, anaemia (grade 3-4), leukopenia

Metabolism and nutrition disorders

 

 

 

Very common:

Anorexia

Common:

Weight decrease

 

 

Nervous system disorders

 

 

 

Very common:

Headache

Common:

Somnolence, dizziness, paresthesia

 

 

Respiratory, thoracic and mediastinal disorders

 

 

Common:

Dyspnoea

Gastrointestinal disorders

 

 

 

Very common:

Vomiting, nausea, constipation

Common:

Diarrhoea, abdominal pain, dyspepsia

 

 

Skin and subcutaneous tissue disorders

 

 

 

Common:

Rash, pruritus, alopecia

Very rare:

Erythema multiforme, erythroderma, urticaria,

 

exanthema

 

 

General disorders and administration site conditions

 

 

Very common:

Fatigue

Common:

Fever, asthenia, rigors, malaise, pain, taste perversion

Very rare:

Allergic reactions, including anaphylaxis, angioedema

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the

nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4

neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with newlydiagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle of therapy.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in children under the age of 3 years has not been established.

Clinical trial experience with IV

Temodal 2.5 mg/ml powder for solution for infusion delivers equivalent TMZ dose and exposure to both TMZ and its active metabolite MTIC as the corresponding Temodal hard capsules (see section 5.2). Adverse reactions reported during the two studies with the intravenous formulation (n=35) but not in studies using hard capsules, were infusion site reactions: pain, irritation, pruritus, warmth, swelling, and erythema, as well as haematoma.

Post-Marketing Experience

The following additional serious adverse reactions have been identified during post-marketing exposure:

Table 6. Summary of events reported with temozolomide in the post-marketing setting

Infections and infestations*

Uncommon:

cytomegalovirus infection, infection reactivation such as

 

cytomegalovirus, hepatitis B virus,

 

meningoencephalitis herpetic

Blood and lymphatic system disorders

 

 

 

Very rare:

prolonged pancytopenia, aplastic anaemia

Neoplasm benign, malignant and unspecified

Very rare:

myelodysplastic syndrome (MDS), secondary

 

malignancies, including myeloid leukaemia

Endocrine disorders*

 

Uncommon:

diabetes insipidus

Respiratory, thoracic and mediastinal disorders

Very rare:

interstitial pneumonitis/pneumonitis, pulmonary

 

fibrosis, respiratory failure

Hepatobiliary disorders*

 

Common:

liver enzymes elevations

 

 

Table 6. Summary of events reported with temozolomide in the post-marketing setting

Uncommon:

 

hyperbilirubinemia, cholestasis, hepatitis, hepatic

 

 

injury, hepatic failure

Skin and subcutaneous tissue disorders

 

 

 

Very rare:

 

toxic epidermal necrolysis, Stevens-Johnson syndrome

Including cases with fatal outcome

 

 

* Frequencies estimated based on relevant clinical trials.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure and death. There are reports of patients who have taken the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03

Mechanism of action

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Clinical efficacy and safety

Newly-diagnosed glioblastoma multiforme

A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by monotherapy TMZ (150 - 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.

TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm.

The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33 -1.91) with a log-rank

p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).

H R (9 5% C .I.) = 1 .59 (1 .3 3 – 1 .91) lo g -rank p -valu e < .0001

26%

R T + T M Z

10%

R T O n ly

1 2 .114 .6

Figure 1 Kaplan-Meier curves for overall survival (Intent to treat population)

The results from the trial were not consistent in the subgroup of patients with a poor performance status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, no unacceptable risks appear to be present in this patient group.

Recurrent or progressive malignant glioma

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the non-comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was

2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8 %.

In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) (chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS 80.

Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points).

The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT population was 44 % with a median event-free survival of 4.6 months, which was similar to the results for the progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression-free status was strongly associated with maintained or improved quality of life.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to TMZ is similar to adults.

5.2 Pharmacokinetic properties

TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species,

3- methyl(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5amino-imidazole4carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.

In an open-label, two-way crossover bioequivalence study of the pharmacokinetics of oral and intravenous TMZ in patients with primary CNS malignancies, Temodal 2.5 mg/ml powder for solution for infusion administered over 90 minutes was found to be bioequivalent for Cmax and AUC of TMZ and MTIC as compared to Temodal hard capsules, following administration of 150 mg/m2 dose. Mean Cmax values for TMZ and MTIC were 7.4 µg/ml and 320 ng/ml, respectively, following 90 minute intravenous infusion. Mean AUC (0 ) values for TMZ and MTIC were 25 µg•h/ml and 1,004 ng•h/ml, respectively.

Absorption

After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % indicating complete absorption.

Distribution

TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with highly protein-bound substances.

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data.

Elimination

The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.

Special populations

Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.

5.3 Preclinical safety data

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.

TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome aberration tests showed a positive mutagenicity response.

The intravenous formulation produced local irritation at the site of injection in both rabbits and rats. The irritation was transient and not associated with lasting tissue damage.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol (E421)

Threonine

Polysorbate 80

Sodium citrate (for pH adjustment)

Hydrochloric acid concentrated (for pH adjustment)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

Unopened vial: 4 years

Reconstituted solution: after reconstitution the chemical and physical in-use stability has been demonstrated for 14 hours at 25 C, including infusion time.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2 C – 8 C).

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

Clear type I glass vial sealed with bromobutyl rubber stopper and aluminium overseal with peach-coloured flip-off bonnet. Each vial contains 100 mg TMZ.

Temodal 2.5 mg/ml is supplied as a pack of 1 vial.

6.6 Special precautions for disposal and other handling

Caution must be exercised in handling Temodal 2.5 mg/ml powder for solution for infusion. The use of gloves and aseptic technique is required. If Temodal 2.5 mg/ml comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Each vial must be reconstituted with 41 ml sterilised water for injections. The resulting solution contains 2.5 mg/ml TMZ. The vials should be gently swirled and not shaken. The solution should be inspected and any vial containing visible particulate matter should not be used. A volume up to 40 ml reconstituted solution should be withdrawn, according to the total prescribed dose and transferred into an empty 250 ml infusion bag (PVC or polyolefin). The pump tubing should be attached to the bag, the tubing purged and then capped. Temodal 2.5 mg/ml must be administered by intravenous infusion only over a period of 90 minutes.

Temodal 2.5 mg/ml powder for solution for infusion may be administered in the same IV line with 0.9% Sodium Chloride injection. It is incompatible with dextrose solutions.

In the absence of additional data, this medicinal product must not be mixed with other medicinal products or infused simultaneously through the same intravenous line.

This medicinal product is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/98/096/023

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 January 1999

Date of latest renewal: 26 January 2009

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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