English
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

MabCampath (alemtuzumab) – Summary of product characteristics - L01XC04

Updated on site: 08-Oct-2017

Medication nameMabCampath
ATC CodeL01XC04
Substancealemtuzumab
ManufacturerGenzyme Europe B.V.
Concentrate for solution for infusion. Colourless to slightly yellow concentrate.
For a full list of excipients, see section 6.1.
One ml contains 10 mg of alemtuzumab.
Each ampoule contains 30 mg of alemtuzumab.

1. NAME OF THE MEDICINAL PRODUCT

MabCampath 10 mg/ml concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibodyauthorisedspecific for 21-28 kD lymphocyte cell surface glycoprotein (CD52). The antibody is produced in mammalian cell

(Chinese Hamster Ovary) suspension culture in a nutrient medium.

3. PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

 

no

longer

MabCampath is indicated for the treatment of patients with B-cell chronic lymphocytic leukaemia (B-

CLL) for whom fludarabine combination chem therapy is not appropriate.

12 weeks.

product

 

4.2 Posology and method of adminis ra ion

 

MabCampath should be administered under he supervision of a physician experienced in the use of cancer therapy.

Posology

During the first week f eatment, MabCampath should be administered in escalating doses: 3 mg on day 1, 10 mg on day 2 and 30 mg on day 3 assuming that each dose is well tolerated. Thereafter, the recommended dose is 30 mg daily administered 3 times weekly on alternate days up to a maximum of

MedicinalIn most p tients, dose escalation to 30 mg can be accomplished in 3-7 days. However, if acute moder te to severe adverse reactions such as hypotension, rigors, fever, shortness of breath, chills,

rashes a d bronchospasm (some of which may be due to cytokine release) occur at either the 3 mg or 10 mg dose levels, then those doses should be repeated daily until they are well tolerated before further dose escalation is attempted (see section 4.4).

Median duration of treatment was 11.7 weeks for first-line patients and 9.0 weeks for previously treated patients.

Once patient meets all laboratory and clinical criteria for a complete response, MabCampath should be discontinued and the patient monitored. If a patient improves (i.e. achieves a partial response or stable disease) and then reaches a plateau without further improvement for 4 weeks or more, then MabCampath should be discontinued and the patient monitored. Therapy should be discontinued if there is evidence of disease progression.

Concomitant medicinal products

Premedications

Prophylactic antibiotics

Patients should be premedicated with oral or intravenous steroids, an appropriate antihistamine and analgesic 30-60 minutes prior to each MabCampath infusion during dose escalationauthorisedand as clinically indicated thereafter (see section 4.4).

Antibiotics and antivirals should be administered routinely to all patients throughout and foll wing treatment (see section 4.4).

Dose modification guidelines

There are no dose modifications recommended for severe lymphopenia given the mechanism of action of MabCampath.

In the event of serious infection or severe haematological toxicity MabCampath should be interrupted until the event resolves. It is recommended that MabCampath should be int upted in patients whose

platelet count falls to < 25,000/ l or whose absolute neutrophil count (ANC) drops to < 250/ l. MabCampath may be reinstituted after the infection or toxicity has resolved. MabCampath should be

permanently discontinued if autoimmune anaemia or autoimmu thrombocytopenia appears. The

following table outlines the recommended procedure for d se m dification following the occurrence

of haematological toxicity while on therapy:

 

longer

 

 

no

 

product

 

Medicinal

 

 

 

 

 

Haematologic values

 

 

Dose modification*

 

ANC < 250/μl and/or platelet count ≤25,000/μl

 

 

 

 

 

 

For first occurrence

 

Withhold MabCampath therapy. Resume

 

 

 

MabCampath at 30 mg when ANC ≥ 500/μl and

 

 

 

platelet count ≥ 50,000/μl.

 

 

 

 

 

For second occurrence

 

Withhold MabCampath therapy. Resume

 

 

 

MabCampath at 10 mg when ANC ≥ 500/μl and

 

 

 

platelet count ≥ 50,000/μl.

 

 

 

 

 

For third occurrence

 

Discontinue MabCampath therapy.

 

 

 

 

≥ 50% decrease from baseline in patients initiating therapy with a baseline ANC ≤ 250/μl and/

 

baseline platelet count ≤ 25,000/μl

 

 

 

 

 

 

For first occurrence

 

Withhold MabCampath therapy. Res me

 

 

 

MabCampath at 30 mg upon ret rn to baseline

 

 

 

value(s).

 

 

 

 

 

 

For second occurrence

 

Withhold MabCampath the apy. Resume

 

 

 

 

 

authorised

 

 

MabCampath at 10 mg upon return to baseline

 

 

value(s).

 

 

 

 

 

 

For third occurrence

 

Discontinue MabCampath therapy.

 

 

 

*If the delay between dosing is 7 days, initiate therapy at MabCampath 3 mg and escalate to 10 mg

and then to 30 mg as tolerated

 

 

longer

Special populations

no

 

 

 

Elderly (over 65 years of age)

 

 

 

 

 

 

 

Recommendations are as stated above for adults. Patients should be monitored carefully (see

section 4.4).

 

 

 

 

 

Patients with renal or hepatic impairment

 

 

 

 

 

No studies have been nducted.

 

 

 

 

 

The safety and efficacyproductof MabCampath in children aged less than 17 years of age have not been established. No ta are available.

Paediatric population

Method of administration

The MabCampath solution must be prepared according to the instructions provided in section 6.6. All oses should be administered by intravenous infusion over approximately 2 hours.

4.3

Contraindications

-

Hypersensitivity to alemtuzumab, to murine proteins or to any of the excipients.

-

Active systemic infections.

Medicinal- HIV.

-

Active second malignancies.

-

Pregnancy.

 

4.4 Special warnings and precautions for use

Acute adverse reactions, which may occur during initial dose escalation and some of which may be due to the release of cytokines, include hypotension, chills/rigors, fever, shortness of breath and rashes. Additional reactions include nausea, urticaria, vomiting, fatigue, dyspnoea, headache, pruritus, diarrhoea and bronchospasm. The frequency of infusion reactions was highest in the first week of therapy, and declined in the second or third week of treatment, in patients treated with MabCampath both as first line therapy and in previously treated patients.

If these events are moderate to severe, then dosing should continue at the same level prior to each do e escalation, with appropriate premedication, until each dose is well tolerated. If therapy is withheld for more than 7 days, MabCampath should be reinstituted with gradual dose escalation.

Transient hypotension has occurred in patients receiving MabCampath. Caution should be used in

treating patients with ischaemic heart disease, angina and/or in patients receiving an an i

yper ensive

medicinal product. Myocardial infarction and cardiac arrest have been observed in associa ion with

MabCampath infusion in this patient population.

 

 

Assessment and ongoing monitoring of cardiac function (e. . echocardiog aphy, he rt

te and body

weight) should be considered in patients previously treated with potentially ca diotoxic agents.

 

authorised

be discontinued as appropriate, once dose escalation has been achieved. In addition, an oral

It is recommended that patients be premedicated with orallongeror intravenous st roids 30 - 60 minutes prior to each MabCampath infusion during dose escalati and as clinically indicated. Steroids may

antihistamine, e.g. diphenhydramine 50 mg, and an analgesic, e.g. paracetamol 500 mg, may be given. In the event that acute infusion reactions persist, the infusi n time may be extended up to 8 hours from

the time of reconstitution of MabCampath in solution f

r infusi n.

no

gical effect of MabCampath, inevitably

Profound lymphocyte depletion, an expected pharmac l

occurs and may be prolonged. CD4 and CD8 T-cell c unts begin to rise from weeks 8-12 during

treatment and continue to recover for several mo ths following the discontinuation of treatment. In patients receivingproductMabCampath as first line herapy, the recovery of CD4+ counts to ≥200 cells/µl occurred by 6 months post-treatment, however, at 2 months post-treatment the median was 183

cells/ l. In previously treated patients re eiving MabCampath, the median time to reach a level of 200 cells/ l is 2 months following last inf sion with MabCampath but may take more than 12 months to approximate pretreatment levels. This may predispose patients to opportunistic infections. It is highly recommended that anti-infective prophylaxis (e.g. trimethoprim/sulfamethoxazole 1 tablet twice daily, 3 times weekly, or other phylaxis against Pneumocystis jiroveci pneumonia (PCP) and an effective oral anti-herpes agent, such as famciclovir, 250 mg twice daily) should be initiated while on therapy and for a minimum of 2 months following completion of treatment with MabCampath or until the

CD4+ count has recovered to 200 cells/ l or greater, whichever is the later. MedicinalThe pote ti l for n increased risk of infection-related complications may exist following treatment

w th multiple chemotherapeutic or biological agents.

Be ause of the potential for Transfusion Associated Graft Versus Host Disease (TAGVHD) it is re ommended that patients who have been treated with MabCampath receive irradiated blood products.

Asymptomatic laboratory positive Cytomegalovirus (CMV) viraemia should not necessarily be considered serious infection requiring interruption of therapy. Ongoing clinical assessment should be performed for symptomatic CMV infection during MabCampath treatment and for at least 2 months following completion of treatment.

Transient grade 3 or 4 neutropenia occurs very commonly by weeks 5-8 following initiation of treatment. Transient grade 3 or 4 thrombocytopenia occurs very commonly during the first 2 weeks of therapy and then begins to improve in most patients. Therefore, haematological monitoring of patients

is indicated. If a severe haematological toxicity develops, MabCampath treatment should be interrupted until the event resolves. Treatment may be reinstituted following resolution of the haematological toxicity (see section 4.2). MabCampath should be permanently discontinued if autoimmune anaemia or autoimmune thrombocytopenia appears.

Complete blood counts and platelet counts should be obtained at regular intervals during MabCampath

therapy and more frequently in patients who develop cytopenias.

authorised

 

It is not proposed that regular and systematic monitoring of CD52 expression should be carried out as routine clinical practice. However, if retreatment is considered, it may be prudent to confirm the presence of CD52 expression. In data available from first line patients treated with MabCampath, lo of CD52 expression was not observed around the time of disease progression or death.

Patients may have allergic or hypersensitivity reactions to MabCampath and to murine c imeric monoclonal antibodies.

Medicinal products for the treatment of hypersensitivity reactions, as well as preparedness to institute emergency measures in the event of reaction during administration is necessary (see section 4.2).

longer

 

Males and females of childbearing potential should use effective contraceptive measures during

treatment and for 6 months following MabCampath therapy (see sections 4.6 and 5.3).

No studies have been conducted which specifically address the effect of a

MabCampath

disposition and toxicity. In general, older patients (over 65 years of a e) tolerate cytotoxic therapy less well than younger individuals. Since CLL occurs comm nly in this older age group, these patients should be monitored carefully (see section 4.2). In the studies in first line and previously treated

patients no substantial differences in safety and efficacy re ated to age were observed; however the

sizes of the databases are limited.

no

 

4.5 Interaction with other medicinal products a d ther forms of interaction

Although no formalproductdrug interaction studies have been performed with MabCampath, there are no known clinically significant intera tions of MabCampath with other medicinal products. Because

MabCampath is a recombinant h manized protein, a P450 mediated drug-drug interaction would not be expected. However, it is recommended that MabCampath should not be given within 3 weeks of other chemotherapeutic agents.

Although it has not been studied, it is recommended that patients should not receive live viral vaccines in, at least, the 12 months following MabCampath therapy. The ability to generate a primary or anamnestic humoral res onse to any vaccine has not been studied.

Medicina4.6 Fertility, pregnancy and lactation

Preg cy

MabCampath is contraindicated during pregnancy. Human IgG is known to cross the placental barrier; MabCampath may cross the placental barrier as well and thus potentially cause foetal B and T cell lymphocyte depletion. Animal reproduction studies have not been conducted with MabCampath. It is not known if MabCampath can cause foetal harm when administered to a pregnant woman.

Males and females of childbearing capacity should use effective contraceptive measures during treatment and for 6 months following MabCampath therapy (see section 5.3).

Lactation

It is not known whether MabCampath is excreted in human milk. If treatment is needed, breast-feeding should be discontinued during treatment and for at least 4 weeks following MabCampath therapy.

4.7 Effects on ability to drive and use machines

Fertility

There are no definitive studies of MabCampath which assess its impact on fertility. It is not known if MabCampath can affect human reproductive capacity (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. However, caution should be exercised as confusion and somnolence have been reported.

4.8 Undesirable effects

 

 

authorised

The tables below report adverse reactions by MedDRA system organ classes (MedDRA SOCs). T e

frequencies are based on clinical trial data.

 

 

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and

related conditions.

 

 

The frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon

 

longer

 

(≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000). No information available for events that occur at lower frequency, due to the size of the population studied; n=147 for first line treated patients and n=149 for previously treated patients.

The most frequent adverse reactions with MabCampath are: i fusion reactions (pyrexia, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspn ea), cyt pe ias (neutropenia, lymphopenia, thrombocytopenia, anaemia), infections (CMV viraemia, CMV infection, other infections),

gastrointestinal symptoms (nausea, emesis, abdominal pain), and neurological symptoms (insomnia,

 

no

anxiety). The most frequent serious adverse reacti ns are cytopenias, infusion reactions, and

immunosuppression/infections.

 

Undesirable effects in first line patients

 

product

 

Safety data in first-line B-CLL patients are based on adverse reactions that occurred on study in 147

patients enrolled in a randomized, ontrolled study of MabCampath as a single agent administered at a dose of 30 mg intravenously three times weekly for up to 12 weeks, inclusive of dose escalation period. Approximately 97% of first-line patients experienced adverse reactions; the most commonly reported reactions in first line patients usually occurred in the first week of therapy.

Within each frequency g ouping, undesirable effects observed during treatment or within 30 days following the com letion of treatment with MabCampath are presented in order of decreasing

seriousness. Medicinal

 

 

System organ class

Very common

 

Common

Uncommon

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Infections and

 

Cytomegalovirus

 

Pneumonia

Sepsis

 

 

 

 

infestations

 

viraemia

 

Bronchitis

Staphylococcal

 

 

 

 

 

 

Cytomegalovirus

 

Pharyngitis

bacteraemia

 

 

 

 

 

 

infection

 

Oral candidiasis

authorised

 

 

 

 

 

Tuberculosis

 

 

 

 

 

 

 

Bronchopneumonia

 

 

 

 

 

 

 

Herpes ophthalmicus

 

 

 

 

 

 

 

Beta haemolytic

 

 

 

 

 

 

 

streptococcal infection

 

 

 

 

 

 

 

Candidiasis

 

 

 

 

 

 

 

Genital candidiasis

 

 

 

 

 

 

 

Urinary tract infecti n

 

 

 

 

 

 

 

Cystitis

 

 

 

 

 

 

 

Body tinea

 

 

 

 

 

 

 

N soph ryngitis

 

 

 

 

 

 

 

Rhinitis

 

 

 

 

 

 

 

 

 

 

Blood and lymphatic

 

 

Febrile neutropenia

Ag anulocytosis

 

 

system disorder

 

 

 

Neutropenia

Lymphopenia

 

 

 

 

 

 

Leukopenia

Lymphadenopathy

 

 

 

 

 

 

Thrombocytopenia

Epistaxis

 

 

 

 

 

 

Anaemia

 

 

 

 

 

Immune system

 

 

 

 

Anaphylactic reaction

 

 

 

disorders

 

 

 

 

Hypersensitivity

 

 

Metabolism and

 

 

 

Weight decreased

Tumour lysis syndrome

 

 

 

nutrition disorders

 

 

 

longer

Hyperglycaemia

 

 

 

 

 

 

 

Protein total decreased

 

 

 

 

 

 

 

Anorexia

 

 

Psychiatric disorders

 

 

Anxiety

 

 

 

 

 

 

product

no

 

 

 

 

 

Nervous system

 

 

 

Syncope

Vertigo

 

 

 

disorders

 

 

 

Dizziness

 

 

 

 

 

 

 

 

 

Tremor

 

 

 

 

 

 

 

 

 

Paraesthesia

 

 

 

 

 

 

 

 

 

Hypoesthesia

 

 

 

 

 

 

 

 

 

Headache

 

 

 

 

 

Eye disorders

 

 

 

 

Conjunctivitis

 

 

 

Cardiac disorders

 

 

 

Cyanosis

Cardiac arrest

 

 

 

 

 

 

 

Bradycardia

Myocardial infarction

Medicinal

 

 

 

Tachycardia

Angina pectoris

 

 

 

Sinus tachycardia

Atrial fibrillation

 

 

 

 

 

 

 

 

 

 

 

 

 

Arrhythmia

 

 

 

 

 

 

 

supraventricular

 

 

 

 

 

 

 

Sinus bradycardia

 

 

 

 

 

 

 

Supraventricular

 

 

 

 

 

 

 

extrasystoles

 

 

 

 

 

 

 

 

 

 

Vascular disorders

Hypotension

 

Hypertension

Orthostatic hypotension

 

 

 

 

 

 

 

Hot flush

 

 

 

 

 

 

 

Flushing

 

 

Respiratory, thoracic

 

 

Bronchospasm

Hypoxia

 

 

 

and mediastinal

 

 

 

Dyspnoea

Pleural effusion

 

 

disorders

 

 

 

 

Dysphonia

 

 

 

 

 

 

 

Rhinorrhoea

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

System organ class

Very common

 

Common

Uncommon

 

 

 

 

 

 

 

 

 

Gastrointestinal

Nausea

 

Vomiting

Ileus

 

 

disorders

 

 

Abdominal pain

Oral discomfort

 

 

 

 

 

 

 

 

Stomach discomfort

 

 

 

 

 

 

 

 

Diarrhoea

 

 

 

 

 

 

 

 

authorised

Skin and subcutaneous

Urticaria

 

Dermatitis allergic

Rash pruritic

 

tissue disorders

Rash

 

Pruritus

Rash macular

 

 

 

Hyperhidrosis

Rash erythematous

 

 

 

Erythema

Dermatitis

 

 

 

 

 

 

Musculoskeletal and

 

 

Myalgia

Bone pain

connective tissue

 

 

Musculoskeletal

Arthralgia

disorders

 

 

pain

 

Musculoskeletal c est

 

 

 

Back pain

pain

 

 

 

 

 

 

Muscle spasms

Renal and urinary

 

 

 

 

 

Urine tp decreased

 

disorders

 

 

 

 

 

Dys ria

General disorders and

Fever

 

Fatigue

Mucos l inflammation

 

administration site

Chills

 

 

longer

Infusion site erythema

 

Asthenia

conditions

 

 

 

 

 

Localised oedema

 

 

 

 

 

 

Infusion site oedema

 

 

 

 

 

 

Malaise

Acute infusion reactions including fever, chills, nausea, v

miti g, hypotension, fatigue, rash, urticaria,

dyspnoea, headache, pruritus and diarrhoea have been rep

rted. The majority of these reactions are

mild to moderate in severity. Acute infusion reactions usua y occur during the first week of therapy

 

no

 

 

 

 

 

and substantially decline thereafter. Grade 3 or 4 infusi n reactions are uncommon after the first week

of therapy.

 

 

 

 

 

 

 

 

product

s

 

 

 

 

 

Undesirable effects in previously treated pa ie

 

 

 

 

 

Safety data in previously treated B-CLL patients are based on 149 patients enrolled in single-arm studies of MabCampath (Studies 1, 2, and 3). More than 80% of previously treated patients may be expected to experience adverse reactions; the most commonly reported reactions usually occur during the first week of therapy.

Within each frequency g uping, undesirable effects are presented in order of decreasing seriousness. Medicinal

 

 

System organ class

Very common

 

Common

Uncommon

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Infections and

 

Sepsis

 

Cytomegalovirus

Bacterial infection

 

 

 

 

infestations

 

Pneumonia

 

infection

Viral infection

 

 

 

 

 

 

Herpes simplex

 

Pneumocystis jiroveci

Fungal dermatitis

 

 

 

 

malignant and

 

 

 

infection

Laryngitis

 

 

 

 

 

 

 

Pneumonitis

disorderauthorised

 

 

 

 

 

 

Rhinitis

 

 

 

 

 

 

Fungal infection

Onychomycosis

 

 

 

 

 

 

Candidiasis

 

 

 

 

 

 

 

 

 

Herpes zoster

 

 

 

 

 

 

 

 

 

Abscess

 

 

 

 

 

 

 

 

 

Urinary tract infection

 

 

 

 

 

 

 

 

 

Sinusitis

 

 

 

 

 

 

 

 

 

Bronchitis

 

 

 

 

 

 

 

 

 

Upper respiratory tract

 

 

 

 

 

 

 

 

 

infection

 

 

 

 

 

 

 

 

 

Pharyngitis

 

 

 

 

 

 

 

 

 

Infection

 

 

 

 

 

Neoplasms, benign,

 

 

 

longer

Lymphoma – like

 

 

 

unspecified (incl. cysts

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

and polyps)

 

 

 

 

 

 

 

 

 

 

Blood and lymphatic

Granulocytopenia

 

Febrile eutrope ia

Aplasia bone marrow

 

 

 

system disorder

 

Thrombocytopenia

 

Pancytope ia

Disseminated

 

 

 

 

Anaemia

 

Leuk pe ia

intravascular

 

 

 

 

 

 

Lymph penia

coagulation

 

 

 

 

 

 

Purpura

Haemolytic anaemia,

 

 

 

 

 

no

 

Decreased haptoglobin

 

 

 

 

 

 

Bone marrow

 

 

 

 

 

 

depression

 

 

 

 

 

 

Epistaxis

 

 

 

 

 

 

Gingival bleeding

 

 

 

 

 

 

 

 

Haematology test

 

 

 

 

 

 

 

 

abnormal

 

 

 

 

 

 

 

 

 

 

 

 

Immune system

 

 

 

 

 

Allergic reaction

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

 

product

 

 

 

Severe anaphylactic

 

 

 

 

 

 

 

 

and other

 

 

 

 

 

 

 

hypersensitivity

Medicinal

 

 

 

reactions

 

 

Metabolism nd

 

Anorexia

 

Hyponatraemia

Hypokalaemia

 

 

 

nutrition disorders

 

 

 

Hypocalcaemia

Diabetes mellitus

 

 

 

 

 

 

Weight decrease

aggravated

 

 

 

 

 

 

Dehydration

 

 

 

 

 

 

 

 

 

Thirst

 

 

 

 

 

 

 

 

 

 

 

 

 

Psychiatric disorders

 

 

Confusion

Depersonalisation

 

 

 

 

 

 

Anxiety

Personality disorder

 

 

 

 

 

 

Depression

Abnormal thinking

 

 

 

 

 

 

Somnolence

Impotence

 

 

 

 

 

 

Insomnia

Nervousness

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nervous system

Headache

 

Vertigo

Syncope

 

 

 

 

disorders

 

 

Dizziness

Abnormal gait

 

 

 

 

 

 

 

Tremor

Dystonia

 

 

 

 

 

 

 

Paresthesia

Hyperesthesia

 

 

 

 

 

 

 

Hypoesthesia

Neuropathy

 

 

 

 

Vascular disorders

Hypotension

 

Hyperkinesia

Taste perversion

 

 

 

 

 

Hypertension

Peauthorisedipheral ischaemia

 

 

 

 

 

Taste loss

 

 

 

 

 

Eye disorders

 

 

Conjunctivitis

Endophthalmitis

 

 

 

Ear and labyrinth

 

 

 

 

Deafness

 

 

 

disorders

 

 

 

 

Tinnitus

 

 

Cardiac disorders

 

 

Palpitation

Cardiac arrest

 

 

 

 

 

 

Tachycardia

Myocardial infarcti n

 

 

 

 

 

 

 

Atrial fibrillati n

 

 

 

 

 

 

 

Supraven ricular

 

 

 

 

 

 

 

tachycardia

 

 

 

 

 

 

 

Arrhythmia

 

 

 

 

 

 

 

Br dyc rdia

 

 

 

 

 

 

 

Abnorm l ECG

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

longer

decreased

 

 

 

 

 

Vasospasm

 

 

 

 

 

 

 

 

Flushing

 

 

 

 

 

Respiratory, thoracic

Dyspnoea

 

Hypoxia

Stridor

 

 

 

and mediastinal

 

 

Haemoptysis

Throat tightness

 

 

disorders

 

 

Br nch spasm

Pulmonary infiltration

 

 

 

 

 

Coughing

Pleural effusion

 

 

 

 

no

 

Breath sounds

 

 

 

 

 

Respiratory disorder

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gastrointestinal

Vomiting

 

Gastrointestinal

Gastroenteritis

 

 

disorders

Nausea

 

haemorrhage

Tongue ulceration

 

 

 

Diarrhoea

 

Ulcerative stomatitis

Gingivitis

 

 

 

 

 

Stomatitis

Hiccup

 

 

 

 

 

Abdominal pain

Eructation

 

 

 

 

 

Dyspepsia

Dry mouth

 

 

 

 

 

Constipation

 

 

 

 

 

 

 

 

Flatulence

 

 

 

 

 

Hepatobiliary disorde s

 

 

Hepatic function

 

 

 

 

 

 

 

 

abnormal

 

 

 

 

 

Skin and subcutaneous

Pruritus

 

Bullous eruption

Maculo-papular rash

 

Medicinal

productUrticaria

 

Erythematous rash

Skin disorder

 

 

tissue disorders

 

 

 

 

Rash

 

 

 

 

 

 

 

 

 

Hyperhidrosis

 

 

 

 

 

 

 

 

Mus uloskeletal and

 

 

Arthralgia

Leg pain

 

 

 

onne tive tissue

 

 

Myalgia

Hypertonia

 

 

sorders

 

 

Skeletal pain

 

 

 

 

 

 

 

 

Back pain

 

 

 

 

 

Renal and urinary

 

 

 

 

Haematuria

 

 

 

disorders

 

 

 

 

Urinary incontinence

 

 

 

 

 

 

 

Urine flow decreased

 

 

 

 

 

 

 

Polyuria

 

 

 

 

 

 

 

Renal function

 

 

 

 

 

 

 

abnormal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General disorders and

Chills

Chest pain

Pulmonary oedema

administration site

Fever

Influenza-like

Peripheral oedema

conditions

Fatigue

symptoms

Periorbital oedema

 

 

Mucositis

Mucosal ulceration

 

 

Oedema mouth

Infusion site bruising

 

 

Oedema

Infusion site dermatitis

 

 

Asthenia

Infusion site pain

 

 

Malaise

 

 

 

Temperature change

 

 

 

sensation

 

 

 

Infusion site reaction

 

 

 

Pain

 

been reported following MabCampath administration. Theselongersymptoms can be amelioratedauthorisedavoided if premedication and dose escalation are utilised (see section 4.4).

Undesirable effects observed during post-marketing surveillance

Infusion reactions: Serious and sometimes fatal reactions, including bronchospasm, hypoxia, syncope,

pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory rrest, myocardial infarction, arrhythmias, acute cardiac insufficiency and cardiac arrest have been observed. Severe anaphylactic and other hypersensitivity reactions, including anaphylactic shock nd ngioedema, have

Infections and infestations: Serious and sometimes fatal viral (e. . adenovirus, parainfluenza, hepatitis B, progressive multifocal leukoencephalopathy (PML)), bacterial (i cluding tuberculosis and atypical

mycobacterioses, nocardiosis), protozoan (e.g. toxoplasma

dii), a d fungal (e.g. rhinocerebral

mucormycosis) infections, including those due to reactivati n

f latent infections have occurred during

post-marketing surveillance. The recommended anti-infective prophylaxis treatment appears to be

 

no

effective in reducing the risk of PCP and herpes infecti ns (see section 4.4).

EBV-associated lymphoproliferative disorders, in some cases fatal, have been reported.

product

 

Blood and lymphatic system disorders: Severe bleeding reactions have been reported.

Immune system disorders: Serio s and sometimes fatal autoimmune phenomena including autoimmune haemolytic anaemia, a toimmune thrombocytopenia, aplastic anaemia, Guillain Barré syndrome and its chronic form, chronic inflammatory demyelinating polyradiculoneuropathy have been reported. A positive C mbs test has also been observed. Fatal Transfusion Associated Graft Versus Host Disease (TAGVHD) has also been reported.

Metabolism and nutritional disorders: Tumour lysis syndrome with fatal outcome has been reported.

MedicinalNervous system disorders: Intracranial haemorrhage has occurred with fatal outcome, in patients with thrombocytopenia.

Card ac disorders: Congestive heart failure, cardiomyopathy, and decreased ejection fraction have been reported patients previously treated with potentially cardiotoxic agents.

4.9 Overdose

Patients have received repeated unit doses of up to 240 mg of MabCampath. The frequency of grade 3 or 4 adverse events, such as fever, hypotension and anaemia, may be higher in these patients. There is no known specific antidote for MabCampath. Treatment consists of discontinuation of MabCampath and supportive therapy.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC04.

First line B-CLL patients

 

 

 

authorised

The safety and efficacy of MabCampath were evaluated in a Phase 3, op

-label, randomized

comparative trial of first line (previously untreated) Rai stage I-IV B-CLL pati nts requiring therapy

(Study 4). MabCampath was shown to be superior to chlorambucil as measured by the primary

endpoint progression free survival (PFS) (see Figure 1).

 

 

 

Figure 1: Progression free survival in first ine study (by treatment group)

 

 

no

longer

 

 

product

 

 

 

Medicinal

 

 

 

 

Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibody specific for 21-28 kD lymphocyte cell surface glycoprotein (CD52) expressed primarily on the surface of normal and malignant peripheral blood B and T cell lymphocytes. Alemtuzumab was generated by the insertion of six complementarity-determining regions from an IgG2a rat monoclonal antibody into a human IgG1 immunoglobulin molecule.

Alemtuzumab causes the lysis of lymphocytes by binding to CD52, a highly expressed, non- modulating antigen which is present on the surface of essentially all B and T cell lymphocytes as well as monocytes, thymocytes and macrophages. The antibody mediates the lysis of lymphocy es via complement fixation and antibody-dependent cell mediated cytotoxicity. The antigen has been found on a small percentage (< 5%) of granulocytes, but not on erythrocytes or platelets. Alemt z mab does not appear to damage haematopoietic stem cells or progenitor cells.

The secondary objectives included complete response (CR) and overall response (CR or partial response) rates using the 1996 NCIWG criteria, the duration of response, time to alternative treatment and safety of the two treatment arms.

Summary of first-line patient population and outcomes

 

Independent review of response rate and duration

 

 

MabCampath

 

Chlorambucil

P value

 

 

n=149

 

n=148

 

 

Median Age (Years)

 

Not Applicable

 

Rai Stage III/IV Disease

33.6%

 

33.1%

Not Applicable

 

 

 

 

 

 

 

Overall Response Rate

83.2%

 

55.4%

<0.0001*

 

Complete Response

24.2%

 

2.0%

<0.0001*

 

MRD negative****

7.4%

 

0.0%

0.0008*

 

Partial Response

59.1%

 

53.4%

Not Applicable

 

Duration of Response**, CR or

N=124

 

N=82

Not Applicable

 

PR (Months)

16.2

 

12.7

 

 

K-M median (95% Confidence

(11.5, 23.0)

 

(10.2, 14.3)

 

 

Interval)

 

 

 

 

 

Time to Alternative Treatment

23.3

 

14.7

0.0001***

 

(Months)

(20.7, 31.0)

 

(12.6, 16.8)

authorised

 

 

 

K-M median (95% Confidence

 

 

 

 

 

Interval)

 

 

 

 

 

*Pearson chi-square test or Exact test

 

longer

 

 

** Duration of best response

 

 

 

*** log-rank test stratified by Rai group (Stage I-II vs III-IV)

 

 

**** by 4-colour flow

 

 

 

Cytogenetic analyses in first line B-CLL patie ts:

 

 

 

 

 

 

The cytogenetic profile of B-CLL has been i creasi gly recognized as providing important prognostic

information and may predict response

er ainnotherapies. Of the first-line patients (n=282) in whom

baseline cytogenetic (FISH) data were available in Study 4, chromosomal aberrations were detected in

82%, while normal karyotype was dete ted in 18%. Chromosomal aberrations were categorized

according to Döhner’s hierarchical model. In first line patients, treated with either MabCampath or

chlorambucil, thereproductwere 21 patients with the 17p deletion, 54 patients with 11q deletion, 34 patients with trisomy 12, 51 patients with normal karyotype and 67 patients with sole 13q deletion.

ORR was superior in atients with any 11q deletion (87% v 29%; p<0.0001) or sole deletion 13q (91% v 62%; p=0.0087) treated with MabCampath compared to chlorambucil. A trend toward improved

ORR was observed in patients with 17p deletion treated with MabCampath (64% v 20%; p=0.0805). MedicinalComplete remissions were also superior in patients with sole 13q deletion treated with MabCampath

(27% v 0%; p=0.0009). Median PFS was superior in patients with sole 13q deletion treated with MabCampath (24.4 v 13.0 months; p=0.0170 stratified by Rai Stage). A trend towards improved PFS was observed patients with 17p deletion, trisomy 12 and normal karyotype, which did not reach

s gnifi ance due to small sample size.

Assessment of CMV by PCR:

In the randomized controlled trial in first line patients (Study 4), patients in the MabCampath arm were tested weekly for CMV using a PCR (polymerase chain reaction) assay from initiation through completion of therapy, and every 2 weeks for the first 2 months following therapy. In this study, asymptomatic positive PCR only for CMV was reported in 77/147 (52.4%) of MabCampath-treated patients; symptomatic CMV infection was reported less commonly in 23/147 MabCampath treated patients (16%). In the MabCampath arm 36/77 (46.8%) of patients with asymptomatic PCR positive CMV received antiviral therapy and 47/77 (61%) of these patients had MabCampath therapy interrupted. The presence of asymptomatic positive PCR for CMV or symptomatic PCR positive

CMV infection during treatment with MabCampath had no measurable impact on progression free survival (PFS).

Previously treated B-CLL patients:

Determination of the efficacy of MabCampath is based on overall response and survival rates. Data available from three uncontrolled B-CLL studies are summarised in the following table:

Efficacy parameters

 

Study 1

 

Study 2

 

 

Study 3

 

Number of Patients

 

 

 

 

 

 

Diagnostic Group

 

B-CLL pts who had

B-CLL pts who had

B-CLL (plus a PLL)

 

 

 

received an alkylating

failed to respond

pts who had failed to

 

 

 

agent and had failed

relapsed following

resp

nd relapsed

 

 

 

fludarabine

 

treatment with

following treatment

 

 

 

 

 

 

conventional

wi

fludarabine

 

 

 

 

 

 

chemotherapy

 

 

 

Median Age (years)

 

 

 

 

 

 

Disease Characteristics (%)

 

 

 

 

 

 

 

 

Rai Stage III/IV

 

 

 

 

 

 

B Symptoms

 

 

 

 

 

 

 

 

 

 

 

 

 

authorised

 

Prior Therapies (%):

 

 

 

 

 

 

 

 

 

Alkylating Agents

 

 

 

 

 

 

Fludarabine

 

 

 

 

 

 

Number of Prior Regimens (range)

 

3 (2-7)

 

3 (1-10)

 

 

3 (1-8)

 

Initial Dosing Regimen

 

Gradual escalati

 

Gradual escalation

Gradual escalation

 

 

 

from 3 to 10 to 30 mg

from 10 to 30 mg

from 10 to 30 mg

 

Final Dosing Regimen

 

30 mg iv 3 x week y

30 mg iv 3 x weekly

30 mg iv 3 x weekly

 

Overall Response Rate (%)

 

 

 

 

 

(95% Confidence Interval)

 

(23-43)

 

longer

 

 

(11-47)

 

 

 

(8-33)

 

 

 

Complete Response

 

 

 

 

 

 

Partial Response

 

 

 

 

 

 

 

 

no

 

 

 

 

 

 

Median Duration of Response (months)

 

 

 

 

 

(95% Confidence Interval)

 

(5-8)

 

(5-23)

 

 

(6-19)

 

Median time to Response (months)

 

 

 

 

 

(95% Confidence Interval)

 

(1-2)

 

(1-5)

 

 

(2-4)

 

Progression-Free Survival (m nths)

 

 

 

 

 

(95% Confidence Interval)

 

(3-5)

 

(3-7)

 

 

(3-9)

 

Survival (months):

 

 

 

 

 

 

 

 

 

(95% Confidence Interval)

16 (12-22)

 

26 (12-44)

 

 

28 (7-33)

 

All patients

 

 

 

 

 

Responders

 

33 (26-NR)

 

44 (28-NR)

 

36 (19-NR)

 

 

product

 

 

 

 

 

 

 

MedicinalNR = not re ched

5.2 Pharmacokinetic properties

Pharmacokinetics were characterised in MabCampath-naive patients with B-cell chronic lymphocytic leukaemia (B-CLL) who had failed previous therapy with purine analogues. MabCampath was

ministered as 2 hour intravenous infusion, at the recommended dosing schedule, starting at 3 mg and increasing to 30 mg, 3 times weekly, for up to 12 weeks. MabCampath pharmacokinetics followed 2-compartment model and displayed non-linear elimination kinetics. After the last 30 mg dose, the

median volume of distribution at steady-state was 0.15 l/kg (range: 0.1-0.4 l/kg), indicating that distribution was primarily to the extracellular fluid and plasma compartments. Systemic clearance

decreased with repeated administration due to decreased receptor-mediated clearance (i.e. loss of

CD52 receptors in the periphery). With repeated administration and consequent plasma concentration accumulation, the rate of elimination approached zero-order kinetics. As such, half-life was 8 hours (range: 2-32 hours) after the first 30 mg dose and was 6 days (range: 1-14 days) after the last 30 mg

dose. Steady-state concentrations were reached after about 6 weeks of dosing. No apparent difference in pharmacokinetics between males and females was observed nor was any apparent age effect observed.

5.3 Preclinical safety data

Preclinical evaluation of alemtuzumab in animals has been limited to the cynomolgus monkey because of the lack of expression of the CD52 antigen on non-primate species.

Lymphocytopenia was the most common treatment-related effect in this species. A slight cumulative effect on the degree of lymphocyte depletion was seen in repeated dose studies compared to single dose studies. Lymphocyte depletion was rapidly reversible after cessation of dosing. Reversible neutropenia was seen following daily intravenous or subcutaneous dosing for 30 days, but n t following single doses or daily dosing for 14 days. Histopathology results from bone marrow samples revealed no remarkable changes attributable to treatment. Single intravenous doses of 10 and 30 mg/kg produced moderate to severe dose related hypotension accompanied by a slight tachycardia.

No short or long term animal studies have been conducted with MabCampath to assess carcinogenic and mutagenic potential.

MabCampath Fab binding was observed in lymphoid tissues and the mononucle ph gocyte system.

Significant Fab binding was also observed in the male reproductive tract (epididymis, sperm, seminal

vesicle) and the skin.

 

 

authorised

No other findings, in the above toxicity studies, provide information of si

nificant relevance to clinical

use.

longer

 

 

 

6. PHARMACEUTICAL PARTICULARS

no6.1 List of excipientsDisodium edetate

Polysorbate 80

product

 

Potassium chloride

Potassium dihydrogen phosphate

Sodium chloride

 

Dibasic sodium phosphate

Water for injections

Medicinal6.2 Incompatibi ities

This medicin product must not be mixed with other medicinal products except those mentioned in sect on 6.6.

There are no known incompatibilities with other medicinal products. However, other medicinal

produ ts should not be added to the MabCampath infusion or simultaneously infused through the same ntravenous line.

6.3 Shelf life

Unopen ampoule: 3 years.

Reconstituted solution: MabCampath contains no antimicrobial preservative. MabCampath should be used within 8 hours after dilution. Solutions may be stored at 15 C-30 C or refrigerated. This can only be accepted if preparation of the solution takes place under strictly aseptic conditions and the solution is protected from light.

Clear Type I glass ampoule, containing 3 ml of concentrate. Pack size: carton of 3 ampoules.

6.4 Special precautions for storage

Store in a refrigerator (2 C-8 C). Do not freeze.
Store in the original package in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

6.6 Special precautions for disposal and other handling

 

 

authorised

The ampoule contents should be inspected for particulate matter and discolouration prior to

administration. If particulate matter is present or the concentrate is coloured, then the mpo le should

not be used.

longer

 

 

 

MabCampath contains no antimicrobial preservatives, therefore, it is comm nded that MabCampath

should be prepared for intravenous infusion using aseptic techniques and that the diluted solution for

infusion should be administered within 8 hours after preparation and protected from light. The

required amount of the ampoule contents should be added, via a sterile, low-protein binding, non-fibre

5 μm filter, to 100 ml of sodium chloride 9 mg/ml (0.9%) s luti for infusion or glucose (5%)

solution for infusion. The bag should be inverted gent y to mix the solution. Care should be taken to

ensure the sterility of the prepared solution particular y as it c ntains no antimicrobial preservatives.

 

 

 

no

Other medicinal products should not be added to the MabCampath infusion solution or simultaneously

infused through the same intravenous line (see section 4.5).

 

 

product

 

Caution should be exercised in the handling and preparation of the MabCampath solution. The use of

latex gloves and safety glasses is re ommended to avoid exposure in case of breakage of the ampoule

or other accidental spillage. Women who are pregnant or trying to become pregnant should not handle

MabCampath.

 

 

Procedures for proper han ling and isposal should be observed. Any spillage or waste material

should be disposed of by incineration.

 

7.

MARKETING AUTHORISATION HOLDER

Medicinal

 

 

Genzyme Europe BV

 

Goo meer 10

 

 

1411 DD Naarden

 

 

Netherlands

 

 

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/01/193/001

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 06/07/2001 Date of latest renewal: 10/07/2011

10. DATE OF REVISION OF THE TEXT

 

 

 

 

authorised

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: http://www.ema.europa.eu.

 

 

 

 

 

no

longer

 

 

product

 

 

Medicinal

 

 

 

 

 

 

 

Concentrate for solution for infusion. Colourless to slightly yellow concentrate.
For a full list of excipients, see section 6.1.
One ml contains 30 mg of alemtuzumab. Each vial contains 30 mg of alemtuzumab.
1. NAME OF THE MEDICINAL PRODUCT
MabCampath 30 mg/ml concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibodyauthorisedspecific for 21-28 kD lymphocyte cell surface glycoprotein (CD52). The antibody is produced in mammalian cell

(Chinese Hamster Ovary) suspension culture in a nutrient medium.

3. PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

 

no

longer

MabCampath is indicated for the treatment of patients with B-cell chronic lymphocytic leukaemia (B-

CLL) for whom fludarabine combination chem therapy is not appropriate.

12 weeks.

product

 

4.2 Posology and method of adminis ra ion

 

MabCampath should be administered under he supervision of a physician experienced in the use of cancer therapy.

Posology

During the first week f eatment, MabCampath should be administered in escalating doses: 3 mg on day 1, 10 mg on day 2 and 30 mg on day 3 assuming that each dose is well tolerated. Thereafter, the recommended dose is 30 mg daily administered 3 times weekly on alternate days up to a maximum of

MedicinalIn most p tients, dose escalation to 30 mg can be accomplished in 3-7 days. However, if acute moder te to severe adverse reactions such as hypotension, rigors, fever, shortness of breath, chills,

rashes a d bronchospasm (some of which may be due to cytokine release) occur at either the 3 mg or 10 mg dose levels, then those doses should be repeated daily until they are well tolerated before further dose escalation is attempted (see section 4.4).

Median duration of treatment was 11.7 weeks for first-line patients and 9.0 weeks for previously treated patients.

Once patient meets all laboratory and clinical criteria for a complete response, MabCampath should be discontinued and the patient monitored. If a patient improves (i.e. achieves a partial response or stable disease) and then reaches a plateau without further improvement for 4 weeks or more, then MabCampath should be discontinued and the patient monitored. Therapy should be discontinued if there is evidence of disease progression.

Concomitant medicinal products

Premedications

Prophylactic antibiotics

Patients should be premedicated with oral or intravenous steroids, an appropriate antihistamine and analgesic 30-60 minutes prior to each MabCampath infusion during dose escalationauthorisedand as clinically indicated thereafter (see section 4.4).

Antibiotics and antivirals should be administered routinely to all patients throughout and foll wing treatment (see section 4.4).

Dose modification guidelines

There are no dose modifications recommended for severe lymphopenia given the mechanism of action of MabCampath.

In the event of serious infection or severe haematological toxicity MabCampath should be interrupted until the event resolves. It is recommended that MabCampath should be int upted in patients whose

platelet count falls to < 25,000/ l or whose absolute neutrophil count (ANC) drops to < 250/ l. MabCampath may be reinstituted after the infection or toxicity has resolved. MabCampath should be

permanently discontinued if autoimmune anaemia or autoimmu thrombocytopenia appears. The

following table outlines the recommended procedure for d se m dification following the occurrence

of haematological toxicity while on therapy:

 

longer

 

 

no

 

product

 

Medicinal

 

 

 

 

 

 

Haematologic values

 

 

Dose modification*

 

 

 

ANC < 250/μl and/or platelet count ≤25,000/μl

 

 

 

 

 

 

For first occurrence

 

Withhold MabCampath therapy. Resume

 

 

 

 

 

MabCampath at 30 mg when ANC ≥ 500/μl and

 

 

 

 

 

platelet count ≥ 50,000/μl.

 

 

 

 

 

For second occurrence

 

Withhold MabCampath therapy. Resume

 

 

 

 

 

MabCampath at 10 mg when ANC ≥ 500/μl and

 

 

 

 

 

platelet count ≥ 50,000/μl.

 

 

 

 

 

For third occurrence

 

Discontinue MabCampath therapy.

 

 

 

 

≥ 50% decrease from baseline in patients initiating therapy with a baseline ANC ≤ 250/μl and/

 

 

 

baseline platelet count ≤ 25,000/μl

 

 

 

 

 

 

For first occurrence

 

Withhold MabCampath therapy. Res me

 

 

 

 

 

MabCampath at 30 mg upon ret rn to baseline

 

 

 

 

 

value(s).

 

 

 

 

 

 

For second occurrence

 

Withhold MabCampath the apy. Resume

 

 

 

 

 

 

 

authorised

 

 

 

 

MabCampath at 10 mg upon return to baseline

 

 

 

 

value(s).

 

 

 

 

 

 

For third occurrence

 

Discontinue MabCampath therapy.

 

 

 

*If the delay between dosing is 7 days, initiate therapy at MabCampath 3 mg and escalate to 10 mg

and then to 30 mg as tolerated

 

 

longer

Special populations

 

 

 

Elderly (over 65 years of age)

 

 

 

 

 

 

 

Recommendations are

as stated above for adults. Patients should be monitored carefully (see

section 4.4).

 

 

no

 

 

 

 

 

 

 

 

 

 

Patients with renal or hepatic impairment

 

 

 

 

 

No studies have been

n ucted.

 

 

 

 

 

 

product

 

 

 

 

 

Paediatric population

The safety and efficacy of MabCampath in children aged less than 17 years of age have not been established. No data are available.

Method of dministration

The MabCampath solution must be prepared according to the instructions provided in section 6.6. All doses should be administered by intravenous infusion over approximately 2 hours.

4.3

Contraindications

-

Hypersensitivity to alemtuzumab, to murine proteins or to any of the excipients.

-

Active systemic infections.

-

HIV.

Medicinal- Active second malignancies.

-

Pregnancy.

4.4 Special warnings and precautions for use

Acute adverse reactions, which may occur during initial dose escalation and some of which may be

due to the release of cytokines, include hypotension, chills/rigors, fever, shortness of breath and

rashes. Additional reactions include nausea, urticaria, vomiting, fatigue, dyspnoea, headache, pruritus,

diarrhoea and bronchospasm. The frequency of infusion reactions was highest in the first week of

therapy, and declined in the second or third week of treatment, in patients treated with MabCampath

both as first line therapy and in previously treated patients.

authorised

 

If these events are moderate to severe, then dosing should continue at the same level prior to each do e

escalation, with appropriate premedication, until each dose is well tolerated. If therapy is withheld for

more than 7 days, MabCampath should be reinstituted with gradual dose escalation.

 

Transient hypotension has occurred in patients receiving MabCampath. Caution should be used in

treating patients with ischaemic heart disease, angina and/or in patients receiving an anti

ypertensive

medicinal product. Myocardial infarction and cardiac arrest have been observed in associa ion with

MabCampath infusion in this patient population.

 

 

Assessment and ongoing monitoring of cardiac function (e.g. echocardiography, he rt

te and body

Profound lymphocyte depletion, an expected pharmac longergical effect of MabCampath, inevitably

weight) should be considered in patients previously treated with potentially c

diotoxic

gents.

It is recommended that patients be premedicated with oral or intravenous st

oids 30 - 60 minutes

prior to each MabCampath infusion during dose escalation and as clinically indicated. Steroids may be discontinued as appropriate, once dose escalation has been achieved. In addition, an oral antihistamine, e.g. diphenhydramine 50 mg, and an analgesic, e.g. paracetamol 500 m , may be given. In the event that acute infusion reactions persist, the infusion time may be exte ded up to 8 hours from the time of reconstitution of MabCampath in solution for infusion.

occurs and may be prolonged. CD4 and CD8noT-cell c unts begin to rise from weeks 8-12 during treatment and continue to recover for several m ths f ll wing the discontinuation of treatment. In patients receiving MabCampath as first line herapy, the recovery of CD4+ counts to ≥200 cells/µl occurred by 6 months post-treatment, however, at 2 months post-treatment the median was 183 cells/ l. In previously treated patients re eiving MabCampath, the median time to reach a level of 200

cells/ l is 2 months following last inf sion with MabCampath but may take more than 12 months to approximate pretreatment levels. This may predispose patients to opportunistic infections. It is highly recommended that anti-infective prophylaxis (e.g. trimethoprim/sulfamethoxazole 1 tablet twice daily,

3 times weekly, or other

phylaxis against Pneumocystis jiroveci pneumonia (PCP) and an effective

oral anti-herpes agent, such as famciclovir, 250 mg twice daily) should be initiated while on therapy

and for a minimum of 2 months following completion of treatment with MabCampath or until the

CD4+ count has recovered to 200 cells/ l or greater, whichever is the later.

The potenti

product

for n increased risk of infection-related complications may exist following treatment

with multiple chemotherapeutic or biological agents.

Medicinal

 

Be ause of the potential for Transfusion Associated Graft Versus Host Disease (TAGVHD) it is

re ommended that patients who have been treated with MabCampath receive irradiated blood

produ ts.

 

 

Asymptomatic laboratory positive Cytomegalovirus (CMV) viraemia should not necessarily be

considered

serious infection requiring interruption of therapy. Ongoing clinical assessment should be

performed for symptomatic CMV infection during MabCampath treatment and for at least 2 months following completion of treatment.

Transient grade 3 or 4 neutropenia occurs very commonly by weeks 5-8 following initiation of treatment. Transient grade 3 or 4 thrombocytopenia occurs very commonly during the first 2 weeks of therapy and then begins to improve in most patients. Therefore, haematological monitoring of patients is indicated. If a severe haematological toxicity develops, MabCampath treatment should be

interrupted until the event resolves. Treatment may be reinstituted following resolution of the haematological toxicity (see section 4.2). MabCampath should be permanently discontinued if autoimmune anaemia or autoimmune thrombocytopenia appears.

Complete blood counts and platelet counts should be obtained at regular intervals during MabCampath therapy and more frequently in patients who develop cytopenias.

It is not proposed that regular and systematic monitoring of CD52 expression should be carried out as routine clinical practice. However, if retreatment is considered, it may be prudent to confirm the presence of CD52 expression. In data available from first line patients treated with MabCampath, lo of CD52 expression was not observed around the time of disease progression or death.

Patients may have allergic or hypersensitivity reactions to MabCampath and to murine chimeric monoclonal antibodies.

Medicinal products for the treatment of hypersensitivity reactions, as well as preparedness o institute emergency measures in the event of reaction during administration is necessary (see section 4.2).

Males and females of childbearing potential should use effective contraceptive me sures during

treatment and for 6 months following MabCampath therapy (see sections 4.6 and 5.3).

 

 

authorised

No studies have been conducted which specifically address the effect of a

MabCampath

disposition and toxicity. In general, older patients (over 65 years of a e) tolerate cytotoxic therapy less

well than younger individuals. Since CLL occurs commonly in this older age group, these patients

 

longer

 

should be monitored carefully (see section 4.2). In the studies in first line and previously treated

patients no substantial differences in safety and efficacy re ated to age were observed; however the

sizes of the databases are limited.

 

 

4.5 Interaction with other medicinal products and ther forms of interaction

Although no formal drug interaction studies have been performed with MabCampath, there are no

known clinically significant interactions of MabCampath with other medicinal products. Because

 

 

 

no

MabCampath is a recombinant humanized pro ein, a P450 mediated drug-drug interaction would not

be expected. However, it is recommended that MabCampath should not be given within 3 weeks of

other chemotherapeutic agents.

 

Although it has not been stu

ie , it is recommended that patients should not receive live viral vaccines

in, at least, the 12 months f

ll wing MabCampath therapy. The ability to generate a primary or

anamnestic humoral es onse to any vaccine has not been studied.

4.6 Ferti ity, regnancy and lactation

 

Pregnancy

product

 

MedicinalLactation

 

 

MabCampath is contraindicated during pregnancy. Human IgG is known to cross the placental barrier; MabCampath may cross the placental barrier as well and thus potentially cause foetal B and T cell lymphocyte depletion. Animal reproduction studies have not been conducted with MabCampath. It is not known if MabCampath can cause foetal harm when administered to a pregnant woman.

Males and females of childbearing capacity should use effective contraceptive measures during treatment and for 6 months following MabCampath therapy (see section 5.3).

It is not known whether MabCampath is excreted in human milk. If treatment is needed, breast-feeding should be discontinued during treatment and for at least 4 weeks following MabCampath therapy.

Fertility

There are no definitive studies of MabCampath which assess its impact on fertility. It is not known if MabCampath can affect human reproductive capacity (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, caution should be exercised as confusion and somnolence have been reported.

4.8 Undesirable effects

(≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000). No authorisedinform tion available for events that occur at lower frequency, due to the size of the population studied; n=147 for

The tables below report adverse reactions by MedDRA system organ classes (MedDRA SOCs). The

frequencies are based on clinical trial data.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

The frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), ncommon

first line treated patients and n=149 for previously treated patients.

The most frequent adverse reactions with MabCampath are: infusion reactions (pyrexia, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspnoea), cytope ias (neutropenia, lymphopenia, thrombocytopenia, anaemia), infections (CMV viraemia, CMV i fection, other infections), gastrointestinal symptoms (nausea, emesis, abdominal pain), and neurological symptoms (insomnia, anxiety). The most frequent serious adverse reactions are cyt penias, infusion reactions, and

immunosuppression/infections.

longer

Undesirable effects in first line patients

Safety data in first-line B-CLL patients are basednoon adverse reactions that occurred on study in 147 patients enrolled in a randomized, on rolled s udy of MabCampath as a single agent administered at a dose of 30 mg intravenously three times weekly for up to 12 weeks, inclusive of dose escalation

period. Approximatelyproduct97% of first-line patients experienced adverse reactions; the most commonly reported reactions in first line patients usually occurred in the first week of therapy.

Within each frequency g uping, undesirable effects observed during treatment or within 30 days following the com letion of treatment with MabCampath are presented in order of decreasing seriousness.

Medicinal

 

 

System organ class

Very common

 

Common

Uncommon

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Infections and

 

Cytomegalovirus

 

Pneumonia

Sepsis

 

 

 

 

infestations

 

viraemia

 

Bronchitis

Staphylococcal

 

 

 

 

 

 

Cytomegalovirus

 

Pharyngitis

bacteraemia

 

 

 

 

 

 

infection

 

Oral candidiasis

authorised

 

 

 

 

 

Tuberculosis

 

 

 

 

 

 

 

Bronchopneumonia

 

 

 

 

 

 

 

Herpes ophthalmicus

 

 

 

 

 

 

 

Beta haemolytic

 

 

 

 

 

 

 

streptococcal infection

 

 

 

 

 

 

 

Candidiasis

 

 

 

 

 

 

 

Genital candidiasis

 

 

 

 

 

 

 

Urinary tract infecti n

 

 

 

 

 

 

 

Cystitis

 

 

 

 

 

 

 

Body tinea

 

 

 

 

 

 

 

N soph ryngitis

 

 

 

 

 

 

 

Rhinitis

 

 

 

 

 

 

 

 

 

 

Blood and lymphatic

 

 

Febrile neutropenia

Ag anulocytosis

 

 

system disorder

 

 

 

Neutropenia

Lymphopenia

 

 

 

 

 

 

Leukopenia

Lymphadenopathy

 

 

 

 

 

 

Thrombocytopenia

Epistaxis

 

 

 

 

 

 

Anaemia

 

 

 

 

 

Immune system

 

 

 

 

Anaphylactic reaction

 

 

 

disorders

 

 

 

 

Hypersensitivity

 

 

Metabolism and

 

 

 

Weight decreased

Tumour lysis syndrome

 

 

 

nutrition disorders

 

 

 

longer

Hyperglycaemia

 

 

 

 

 

 

 

Protein total decreased

 

 

 

 

 

 

 

Anorexia

 

 

Psychiatric disorders

 

 

Anxiety

 

 

 

 

 

 

product

no

 

 

 

 

 

Nervous system

 

 

 

Syncope

Vertigo

 

 

 

disorders

 

 

 

Dizziness

 

 

 

 

 

 

 

 

 

Tremor

 

 

 

 

 

 

 

 

 

Paraesthesia

 

 

 

 

 

 

 

 

 

Hypoesthesia

 

 

 

 

 

 

 

 

 

Headache

 

 

 

 

 

Eye disorders

 

 

 

 

Conjunctivitis

 

 

 

Cardiac disorders

 

 

 

Cyanosis

Cardiac arrest

 

 

 

 

 

 

 

Bradycardia

Myocardial infarction

Medicinal

 

 

 

Tachycardia

Angina pectoris

 

 

 

Sinus tachycardia

Atrial fibrillation

 

 

 

 

 

 

 

 

 

 

 

 

 

Arrhythmia

 

 

 

 

 

 

 

supraventricular

 

 

 

 

 

 

 

Sinus bradycardia

 

 

 

 

 

 

 

Supraventricular

 

 

 

 

 

 

 

extrasystoles

 

 

 

 

 

 

 

 

 

 

Vascular disorders

Hypotension

 

Hypertension

Orthostatic hypotension

 

 

 

 

 

 

 

Hot flush

 

 

 

 

 

 

 

Flushing

 

 

Respiratory, thoracic

 

 

Bronchospasm

Hypoxia

 

 

 

and mediastinal

 

 

 

Dyspnoea

Pleural effusion

 

 

disorders

 

 

 

 

Dysphonia

 

 

 

 

 

 

 

Rhinorrhoea

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

System organ class

Very common

 

Common

Uncommon

 

 

 

 

 

 

 

 

 

Gastrointestinal

Nausea

 

Vomiting

Ileus

 

 

disorders

 

 

Abdominal pain

Oral discomfort

 

 

 

 

 

 

 

 

Stomach discomfort

 

 

 

 

 

 

 

 

Diarrhoea

 

 

 

 

 

 

 

 

authorised

Skin and subcutaneous

Urticaria

 

Dermatitis allergic

Rash pruritic

 

tissue disorders

Rash

 

Pruritus

Rash macular

 

 

 

Hyperhidrosis

Rash erythematous

 

 

 

Erythema

Dermatitis

 

 

 

 

 

 

Musculoskeletal and

 

 

Myalgia

Bone pain

connective tissue

 

 

Musculoskeletal

Arthralgia

disorders

 

 

pain

 

Musculoskeletal c est

 

 

 

Back pain

pain

 

 

 

 

 

 

Muscle spasms

Renal and urinary

 

 

 

 

 

Urine tp decreased

 

disorders

 

 

 

 

 

Dys ria

General disorders and

Fever

 

Fatigue

Mucos l inflammation

 

administration site

Chills

 

 

longer

Infusion site erythema

 

Asthenia

conditions

 

 

 

 

 

Localised oedema

 

 

 

 

 

 

Infusion site oedema

 

 

 

 

 

 

Malaise

Acute infusion reactions including fever, chills, nausea, v

miti g, hypotension, fatigue, rash, urticaria,

dyspnoea, headache, pruritus and diarrhoea have been rep

rted. The majority of these reactions are

mild to moderate in severity. Acute infusion reactions usua y occur during the first week of therapy

 

no

 

 

 

 

 

and substantially decline thereafter. Grade 3 or 4 infusi n reactions are uncommon after the first week

of therapy.

 

 

 

 

 

 

 

 

product

s

 

 

 

 

 

Undesirable effects in previously treated pa ie

 

 

 

 

 

Safety data in previously treated B-CLL patients are based on 149 patients enrolled in single-arm studies of MabCampath (Studies 1, 2, and 3). More than 80% of previously treated patients may be expected to experience adverse reactions; the most commonly reported reactions usually occur during the first week of therapy.

Within each frequency g uping, undesirable effects are presented in order of decreasing seriousness. Medicinal

 

 

System organ class

Very common

 

Common

Uncommon

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Infections and

 

Sepsis

 

Cytomegalovirus

Bacterial infection

 

 

 

 

infestations

 

Pneumonia

 

infection

Viral infection

 

 

 

 

 

 

Herpes simplex

 

Pneumocystis jiroveci

Fungal dermatitis

 

 

 

 

malignant and

 

 

 

infection

Laryngitis

 

 

 

 

 

 

 

Pneumonitis

disorderauthorised

 

 

 

 

 

 

Rhinitis

 

 

 

 

 

 

Fungal infection

Onychomycosis

 

 

 

 

 

 

Candidiasis

 

 

 

 

 

 

 

 

 

Herpes zoster

 

 

 

 

 

 

 

 

 

Abscess

 

 

 

 

 

 

 

 

 

Urinary tract infection

 

 

 

 

 

 

 

 

 

Sinusitis

 

 

 

 

 

 

 

 

 

Bronchitis

 

 

 

 

 

 

 

 

 

Upper respiratory tract

 

 

 

 

 

 

 

 

 

infection

 

 

 

 

 

 

 

 

 

Pharyngitis

 

 

 

 

 

 

 

 

 

Infection

 

 

 

 

 

Neoplasms, benign,

 

 

 

longer

Lymphoma – like

 

 

 

unspecified (incl. cysts

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

and polyps)

 

 

 

 

 

 

 

 

 

 

Blood and lymphatic

Granulocytopenia

 

Febrile eutrope ia

Aplasia bone marrow

 

 

 

system disorder

 

Thrombocytopenia

 

Pancytope ia

Disseminated

 

 

 

 

Anaemia

 

Leuk pe ia

intravascular

 

 

 

 

 

 

Lymph penia

coagulation

 

 

 

 

 

 

Purpura

Haemolytic anaemia,

 

 

 

 

 

no

 

Decreased haptoglobin

 

 

 

 

 

 

Bone marrow

 

 

 

 

 

 

depression

 

 

 

 

 

 

Epistaxis

 

 

 

 

 

 

Gingival bleeding

 

 

 

 

 

 

 

 

Haematology test

 

 

 

 

 

 

 

 

abnormal

 

 

 

 

 

 

 

 

 

 

 

 

Immune system

 

 

 

 

 

Allergic reaction

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

 

product

 

 

 

Severe anaphylactic

 

 

 

 

 

 

 

 

and other

 

 

 

 

 

 

 

hypersensitivity

Medicinal

 

 

 

reactions

 

 

Metabolism nd

 

Anorexia

 

Hyponatraemia

Hypokalaemia

 

 

 

nutrition disorders

 

 

 

Hypocalcaemia

Diabetes mellitus

 

 

 

 

 

 

Weight decrease

aggravated

 

 

 

 

 

 

Dehydration

 

 

 

 

 

 

 

 

 

Thirst

 

 

 

 

 

 

 

 

 

 

 

 

 

Psychiatric disorders

 

 

Confusion

Depersonalisation

 

 

 

 

 

 

Anxiety

Personality disorder

 

 

 

 

 

 

Depression

Abnormal thinking

 

 

 

 

 

 

Somnolence

Impotence

 

 

 

 

 

 

Insomnia

Nervousness

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nervous system

Headache

 

Vertigo

Syncope

 

 

 

 

disorders

 

 

Dizziness

Abnormal gait

 

 

 

 

 

 

 

Tremor

Dystonia

 

 

 

 

 

 

 

Paresthesia

Hyperesthesia

 

 

 

 

 

 

 

Hypoesthesia

Neuropathy

 

 

 

 

Vascular disorders

Hypotension

 

Hyperkinesia

Taste perversion

 

 

 

 

 

Hypertension

Peauthorisedipheral ischaemia

 

 

 

 

 

Taste loss

 

 

 

 

 

Eye disorders

 

 

Conjunctivitis

Endophthalmitis

 

 

 

Ear and labyrinth

 

 

 

 

Deafness

 

 

 

disorders

 

 

 

 

Tinnitus

 

 

Cardiac disorders

 

 

Palpitation

Cardiac arrest

 

 

 

 

 

 

Tachycardia

Myocardial infarcti n

 

 

 

 

 

 

 

Atrial fibrillati n

 

 

 

 

 

 

 

Supraven ricular

 

 

 

 

 

 

 

tachycardia

 

 

 

 

 

 

 

Arrhythmia

 

 

 

 

 

 

 

Br dyc rdia

 

 

 

 

 

 

 

Abnorm l ECG

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

longer

decreased

 

 

 

 

 

Vasospasm

 

 

 

 

 

 

 

 

Flushing

 

 

 

 

 

Respiratory, thoracic

Dyspnoea

 

Hypoxia

Stridor

 

 

 

and mediastinal

 

 

Haemoptysis

Throat tightness

 

 

disorders

 

 

Br nch spasm

Pulmonary infiltration

 

 

 

 

 

Coughing

Pleural effusion

 

 

 

 

no

 

Breath sounds

 

 

 

 

 

Respiratory disorder

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gastrointestinal

Vomiting

 

Gastrointestinal

Gastroenteritis

 

 

disorders

Nausea

 

haemorrhage

Tongue ulceration

 

 

 

Diarrhoea

 

Ulcerative stomatitis

Gingivitis

 

 

 

 

 

Stomatitis

Hiccup

 

 

 

 

 

Abdominal pain

Eructation

 

 

 

 

 

Dyspepsia

Dry mouth

 

 

 

 

 

Constipation

 

 

 

 

 

 

 

 

Flatulence

 

 

 

 

 

Hepatobiliary disorde s

 

 

Hepatic function

 

 

 

 

 

 

 

 

abnormal

 

 

 

 

 

Skin and subcutaneous

Pruritus

 

Bullous eruption

Maculo-papular rash

 

Medicinal

productUrticaria

 

Erythematous rash

Skin disorder

 

 

tissue disorders

 

 

 

 

Rash

 

 

 

 

 

 

 

 

 

Hyperhidrosis

 

 

 

 

 

 

 

 

Mus uloskeletal and

 

 

Arthralgia

Leg pain

 

 

 

onne tive tissue

 

 

Myalgia

Hypertonia

 

 

sorders

 

 

Skeletal pain

 

 

 

 

 

 

 

 

Back pain

 

 

 

 

 

Renal and urinary

 

 

 

 

Haematuria

 

 

 

disorders

 

 

 

 

Urinary incontinence

 

 

 

 

 

 

 

Urine flow decreased

 

 

 

 

 

 

 

Polyuria

 

 

 

 

 

 

 

Renal function

 

 

 

 

 

 

 

abnormal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General disorders and

Chills

Chest pain

Pulmonary oedema

administration site

Fever

Influenza-like

Peripheral oedema

conditions

Fatigue

symptoms

Periorbital oedema

 

 

Mucositis

Mucosal ulceration

 

 

Oedema mouth

Infusion site bruising

 

 

Oedema

Infusion site dermatitis

 

 

Asthenia

Infusion site pain

 

 

Malaise

 

 

 

Temperature change

 

 

 

sensation

 

 

 

Infusion site reaction

 

 

 

Pain

 

been reported following MabCampath administration. Theselongersymptoms can be amelioratedauthorisedavoided if premedication and dose escalation are utilised (see section 4.4).

Undesirable effects observed during post-marketing surveillance

Infusion reactions: Serious and sometimes fatal reactions, including bronchospasm, hypoxia, syncope,

pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory rrest, myocardial infarction, arrhythmias, acute cardiac insufficiency and cardiac arrest have been observed. Severe anaphylactic and other hypersensitivity reactions, including anaphylactic shock nd ngioedema, have

Infections and infestations: Serious and sometimes fatal viral (e. . adenovirus, parainfluenza, hepatitis B, progressive multifocal leukoencephalopathy (PML)), bacterial (i cluding tuberculosis and atypical

mycobacterioses, nocardiosis), protozoan (e.g. toxoplasma

dii), a d fungal (e.g. rhinocerebral

mucormycosis) infections, including those due to reactivati n

f latent infections have occurred during

post-marketing surveillance. The recommended anti-infective prophylaxis treatment appears to be

 

no

effective in reducing the risk of PCP and herpes infecti ns (see section 4.4).

EBV-associated lymphoproliferative disorders, in some cases fatal, have been reported.

product

 

Blood and lymphatic system disorders: Severe bleeding reactions have been reported.

Immune system disorders: Serio s and sometimes fatal autoimmune phenomena including autoimmune haemolytic anaemia, a toimmune thrombocytopenia, aplastic anaemia, Guillain Barré syndrome and its chronic form, chronic inflammatory demyelinating polyradiculoneuropathy have been reported. A positive C mbs test has also been observed. Fatal Transfusion Associated Graft Versus Host Disease (TAGVHD) has also been reported.

Metabolism and nutritional disorders: Tumour lysis syndrome with fatal outcome has been reported.

MedicinalNervous system disorders: Intracranial haemorrhage has occurred with fatal outcome, in patients with thrombocytopenia.

Card ac disorders: Congestive heart failure, cardiomyopathy, and decreased ejection fraction have been reported patients previously treated with potentially cardiotoxic agents.

4.9 Overdose

Patients have received repeated unit doses of up to 240 mg of MabCampath. The frequency of grade 3 or 4 adverse events, such as fever, hypotension and anaemia, may be higher in these patients. There is no known specific antidote for MabCampath. Treatment consists of discontinuation of MabCampath and supportive therapy.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC04.

Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibody specific for 21-28 kD lymphocyte cell surface glycoprotein (CD52) expressed primarily on the surface of normal and malignant peripheral blood B and T cell lymphocytes. Alemtuzumab was generated by the insertion of six complementarity-determining regions from an IgG2a rat monoclonal antibody into a human IgG1 immunoglobulin molecule.

 

First line B-CLL patients

 

authorised

 

 

The safety and efficacy of MabCampath were evaluated in a Phase 3, op

-label, randomized

 

comparative trial of first line (previously untreated) Rai stage I-IV B-CLL patients requiring therapy

 

(Study 4). MabCampath was shown to be superior to chlorambucil as measured by the primary

 

endpoint progression free survival (PFS) (see Figure 1).

 

Alemtuzumab causes the lysis of lymphocytes by binding to CD52, a highly expressed, non- modulating antigen which is present on the surface of essentially all B and T cell lymphocytes as well as monocytes, thymocytes and macrophages. The antibody mediates the lysis of lymphocy es via complement fixation and antibody-dependent cell mediated cytotoxicity. The antigen has been found on a small percentage (< 5%) of granulocytes, but not on erythrocytes or platelets. Alemt z mab does not appear to damage haematopoietic stem cells or progenitor cells.

Figure 1: Progression free survival in first ine study (by treatment group)

 

 

no

longer

 

product

 

Medicinal

 

 

 

 

 

The secondary objectives included complete response (CR) and overall response (CR or partial response) rates using the 1996 NCIWG criteria, the duration of response, time to alternative treatment and safety of the two treatment arms.

Summary of first-line patient population and outcomes

 

Independent review of response rate and duration

 

 

MabCampath

 

Chlorambucil

P value

 

 

n=149

 

n=148

 

 

Median Age (Years)

 

Not Applicable

 

Rai Stage III/IV Disease

33.6%

 

33.1%

Not Applicable

 

 

 

 

 

 

 

Overall Response Rate

83.2%

 

55.4%

<0.0001*

 

Complete Response

24.2%

 

2.0%

<0.0001*

 

MRD negative****

7.4%

 

0.0%

0.0008*

 

Partial Response

59.1%

 

53.4%

Not Applicable

 

Duration of Response**, CR or

N=124

 

N=82

Not Applicable

 

PR (Months)

16.2

 

12.7

 

 

K-M median (95% Confidence

(11.5, 23.0)

 

(10.2, 14.3)

 

 

Interval)

 

 

 

 

 

Time to Alternative Treatment

23.3

 

14.7

0.0001***

 

(Months)

(20.7, 31.0)

 

(12.6, 16.8)

authorised

 

 

 

K-M median (95% Confidence

 

 

 

 

 

Interval)

 

 

 

 

 

*Pearson chi-square test or Exact test

 

longer

 

 

** Duration of best response

 

 

 

*** log-rank test stratified by Rai group (Stage I-II vs III-IV)

 

 

**** by 4-colour flow

 

 

 

Cytogenetic Analyses in first line B-CLL patie ts:

 

 

 

 

 

 

The cytogenetic profile of B-CLL has been i creasi gly recognized as providing important prognostic

information and may predict response

er ainnotherapies. Of the first-line patients (n=282) in whom

baseline cytogenetic (FISH) data were available in Study 4, chromosomal aberrations were detected in

82%, while normal karyotype was dete ted in 18%. Chromosomal aberrations were categorized

according to Döhner’s hierarchical model. In first line patients, treated with either MabCampath or

chlorambucil, thereproductwere 21 patients with the 17p deletion, 54 patients with 11q deletion, 34 patients with trisomy 12, 51 patients with normal karyotype and 67 patients with sole 13q deletion.

ORR was superior in atients with any 11q deletion (87% v 29%; p<0.0001) or sole deletion 13q (91% v 62%; p=0.0087) treated with MabCampath compared to chlorambucil. A trend toward improved

ORR was observed in patients with 17p deletion treated with MabCampath (64% v 20%; p=0.0805). MedicinalComplete remissions were also superior in patients with sole 13q deletion treated with MabCampath

(27% v 0%; p=0.0009). Median PFS was superior in patients with sole 13q deletion treated with MabCampath (24.4 v 13.0 months; p=0.0170 stratified by Rai Stage). A trend towards improved PFS was observed patients with 17p deletion, trisomy 12 and normal karyotype, which did not reach

s gnifi ance due to small sample size.

Assessment of CMV by PCR:

In the randomized controlled trial in first line patients (Study 4), patients in the MabCampath arm were tested weekly for CMV using a PCR (polymerase chain reaction) assay from initiation through completion of therapy, and every 2 weeks for the first 2 months following therapy. In this study, asymptomatic positive PCR only for CMV was reported in 77/147 (52.4%) of MabCampath-treated patients; symptomatic CMV infection was reported less commonly in 23/147 MabCampath treated patients (16%). In the MabCampath arm 36/77 (46.8%) of patients with asymptomatic PCR positive CMV received antiviral therapy and 47/77 (61%) of these patients had MabCampath therapy interrupted. The presence of asymptomatic positive PCR for CMV or symptomatic PCR positive

CMV infection during treatment with MabCampath had no measurable impact on progression free survival (PFS).

Previously treated B-CLL patients:

Determination of the efficacy of MabCampath is based on overall response and survival rates. Data available from three uncontrolled B-CLL studies are summarised in the following table:

Efficacy parameters

 

Study 1

 

Study 2

 

 

Study 3

 

Number of Patients

 

 

 

 

 

 

Diagnostic Group

 

B-CLL pts who had

B-CLL pts who had

B-CLL (plus a PLL)

 

 

 

received an alkylating

failed to respond

pts who had failed to

 

 

 

agent and had failed

relapsed following

resp

nd relapsed

 

 

 

fludarabine

 

treatment with

following treatment

 

 

 

 

 

 

conventional

wi

fludarabine

 

 

 

 

 

 

chemotherapy

 

 

 

Median Age (years)

 

 

 

 

 

 

Disease Characteristics (%)

 

 

 

 

 

 

 

 

Rai Stage III/IV

 

 

 

 

 

 

B Symptoms

 

 

 

 

 

 

 

 

 

 

 

 

 

authorised

 

Prior Therapies (%):

 

 

 

 

 

 

 

 

 

Alkylating Agents

 

 

 

 

 

 

Fludarabine

 

 

 

 

 

 

Number of Prior Regimens (range)

 

3 (2-7)

 

3 (1-10)

 

 

3 (1-8)

 

Initial Dosing Regimen

 

Gradual escalati

 

Gradual escalation

Gradual escalation

 

 

 

from 3 to 10 to 30 mg

from 10 to 30 mg

from 10 to 30 mg

 

Final Dosing Regimen

 

30 mg iv 3 x week y

30 mg iv 3 x weekly

30 mg iv 3 x weekly

 

Overall Response Rate (%)

 

 

 

 

 

(95% Confidence Interval)

 

(23-43)

 

longer

 

 

(11-47)

 

 

 

(8-33)

 

 

 

Complete Response

 

 

 

 

 

 

Partial Response

 

 

 

 

 

 

 

 

no

 

 

 

 

 

 

Median Duration of Response (months)

 

 

 

 

 

(95% Confidence Interval)

 

(5-8)

 

(5-23)

 

 

(6-19)

 

Median time to Response (months)

 

 

 

 

 

(95% Confidence Interval)

 

(1-2)

 

(1-5)

 

 

(2-4)

 

Progression-Free Survival (m nths)

 

 

 

 

 

(95% Confidence Interval)

 

(3-5)

 

(3-7)

 

 

(3-9)

 

Survival (months):

 

 

 

 

 

 

 

 

 

(95% Confidence Interval)

16 (12-22)

 

26 (12-44)

 

 

28 (7-33)

 

All patients

 

 

 

 

 

Responders

 

33 (26-NR)

 

44 (28-NR)

 

36 (19-NR)

 

 

product

 

 

 

 

 

 

 

MedicinalNR = not re ched

5.2 Pharmacokinetic properties

Pharmacokinetics were characterised in MabCampath-naive patients with B-cell chronic lymphocytic leukaemia (B-CLL) who had failed previous therapy with purine analogues. MabCampath was

ministered as 2 hour intravenous infusion, at the recommended dosing schedule, starting at 3 mg and increasing to 30 mg, 3 times weekly, for up to 12 weeks. MabCampath pharmacokinetics followed 2-compartment model and displayed non-linear elimination kinetics. After the last 30 mg dose, the

median volume of distribution at steady-state was 0.15 l/kg (range: 0.1-0.4 l/kg), indicating that distribution was primarily to the extracellular fluid and plasma compartments. Systemic clearance

decreased with repeated administration due to decreased receptor-mediated clearance (i.e. loss of

CD52 receptors in the periphery). With repeated administration and consequent plasma concentration accumulation, the rate of elimination approached zero-order kinetics. As such, half-life was 8 hours (range: 2-32 hours) after the first 30 mg dose and was 6 days (range: 1-14 days) after the last 30 mg

dose. Steady-state concentrations were reached after about 6 weeks of dosing. No apparent difference in pharmacokinetics between males and females was observed nor was any apparent age effect observed.

5.3 Preclinical safety data

Preclinical evaluation of alemtuzumab in animals has been limited to the cynomolgus monkey because of the lack of expression of the CD52 antigen on non-primate species.

Lymphocytopenia was the most common treatment-related effect in this species. A slight cumulative effect on the degree of lymphocyte depletion was seen in repeated dose studies compared to single dose studies. Lymphocyte depletion was rapidly reversible after cessation of dosing. Reversible neutropenia was seen following daily intravenous or subcutaneous dosing for 30 days, but n t following single doses or daily dosing for 14 days. Histopathology results from bone marrow samples revealed no remarkable changes attributable to treatment. Single intravenous doses of 10 and 30 mg/kg produced moderate to severe dose related hypotension accompanied by a slight tachycardia.

No short or long term animal studies have been conducted with MabCampath to assess carcinogenic and mutagenic potential.

MabCampath Fab binding was observed in lymphoid tissues and the mononucle ph gocyte system.

Significant Fab binding was also observed in the male reproductive tract (epididymis, sperm, seminal

vesicle) and the skin.

 

 

authorised

No other findings, in the above toxicity studies, provide information of si

nificant relevance to clinical

use.

longer

 

 

 

6. PHARMACEUTICAL PARTICULARSno6.1 List of excipientsDisodium edetate

Polysorbate 80

product

 

Potassium chloride

Potassium dihydrogen phosphate

Sodium chloride

 

Dibasic sodium phosphate

Water for injections

Medicinal6.2 Incompatibi ities

This medicin product must not be mixed with other medicinal products except those mentioned in sect on 6.6.

There are no known incompatibilities with other medicinal products. However, other medicinal

produ ts should not be added to the MabCampath infusion or simultaneously infused through the same ntravenous line.

6.3 Shelf life

Unopen vial: 3 years.

Reconstituted solution: MabCampath contains no antimicrobial preservative. MabCampath should be used within 8 hours after dilution. Solutions may be stored at 15 C-30 C or refrigerated. This can only be accepted if preparation of the solution takes place under strictly aseptic conditions and the solution is protected from light.

Pack size: carton of 3 vials.
6.4 Special precautions for storage
Store in a refrigerator (2 C-8 C). Do not freeze.
Store in the original package in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

Clear type I glass vial, closed with a rubber stopper, containing 1 ml of concentrate.

6.6 Special precautions for disposal and other handling

 

 

 

 

 

authorised

The vial contents should be inspected for particulate matter and discolouration prior to dministration.

If particulate matter is present or the concentrate is coloured, then the vial should not be used.

 

 

 

 

longer

 

MabCampath contains no antimicrobial preservatives, therefore, it is r comm nded that MabCampath

should be prepared for intravenous infusion using aseptic techniques and that the diluted solution for

infusion should be administered within 8 hours after preparation and protected from light. The

required amount of the vial contents should be added to 100 ml of sodium chloride 9 mg/ml (0.9%)

solution for infusion or glucose (5%) solution for infusi

. The bag should be inverted gently to mix

the solution. Care should be taken to ensure the sterility

f the prepared solution particularly as it

contains no antimicrobial preservatives.

no

 

 

 

 

 

 

 

Other medicinal products should not be added to the MabCampath infusion solution or simultaneously

infused through the same intravenous line (see section 4.5).

 

 

 

product

 

 

 

Caution should be exercised in the handling and preparation of the MabCampath solution. The use of

latex gloves and safety glasses is re ommended to avoid exposure in case of breakage of the vial or

other accidental spillage. Women who are pregnant or trying to become pregnant should not handle

MabCampath.

 

 

 

 

Procedures for proper han ling and isposal should be observed. Any spillage or waste material

should be disposed of by incineration.

 

 

 

7.

MARKETING AUTHORISATION HOLDER

 

 

Medicinal

 

 

 

 

Genzyme Europe BV

 

 

 

Goo meer 10

 

 

 

 

1411 DD Naarden

 

 

 

 

Netherlands

 

 

 

 

8.

MARKETING AUTHORISATION NUMBER(S)

 

EU/1/01/193/002

 

 

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 06/07/2001 Date of latest renewal: 10/07/2011

10. DATE OF REVISION OF THE TEXT

 

 

 

 

authorised

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: http://www.ema.europa.eu.

 

 

 

 

 

no

longer

 

 

product

 

 

Medicinal

 

 

 

 

 

 

 

Comments

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
  • Help
  • Get it on Google Play
  • About
  • Info on site by:

  • Presented by RXed.eu

  • 27558

    prescription drugs listed