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

Tecfidera (dimethyl fumarate) – Summary of product characteristics - N07XX09

Updated on site: 10-Oct-2017

Medication nameTecfidera
ATC CodeN07XX09
Substancedimethyl fumarate
ManufacturerBiogen Idec Ltd

1.NAME OF THE MEDICINAL PRODUCT

Tecfidera 120 mg gastro-resistant hard capsules

Tecfidera 240 mg gastro-resistant hard capsules

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Tecfidera 120mg capsule

Each capsule contains 120 mg dimethyl fumarate.

Tecfidera 240mg capsule

Each capsule contains 240 mg dimethyl fumarate

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Gastro-resistant hard capsule

Tecfidera 120mg capsule

Green and white gastro-resistant hard capsule printed with ‘BG-12 120 mg’.

Tecfidera 240mg capsule

Green gastro-resistant hard capsule printed with ‘BG-12 240 mg’

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Tecfidera is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (please refer to section 5.1 for important information on the populations for which efficacy has been established).

4.2Posology and method of administration

Treatment should be initiated under supervision of a physician experienced in the treatment of the disease.

Posology

The starting dose is 120 mg twice a day. After 7 days, the dose is increased to the recommended dose of 240 mg twice a day.

Temporary dose reduction to 120 mg twice a day may reduce the occurrence of flushing and gastrointestinal adverse reactions. Within 1 month, the recommended dose of 240 mg twice a day should be resumed.

Tecfidera should be taken with food (see section 5.2). For those patients who may experience flushing or gastrointestinal adverse reactions, taking Tecfidera with food may improve tolerability (see sections 4.4, 4.5 and 4.8).

Elderly

Clinical studies of Tecfidera had limited exposure to patients aged 55 years and above, and did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients (see section 5.2). Based on the mode of action of the active substance there are no theoretical reasons for any requirement for dose adjustments in the elderly.

Renal and hepatic impairment

Tecfidera has not been studied in patients with renal or hepatic impairment. Based on clinical pharmacology studies, no dose adjustments are needed (see section 5.2). Caution should be used when treating patients with severe renal or severe hepatic impairment (see section 4.4).

Paediatric population

The safety and efficacy of Tecfidera in children and adolescents aged 10 to 18 years have not been established. No data are available. There is no relevant use of Tecfidera in children aged less than 10 years for the indication of relapsing remitting multiple sclerosis.

Method of administration

For oral use.

The capsule or its contents should not be crushed, divided, dissolved, sucked or chewed as the enteric- coating of the microtablets prevents irritant effects on the gut.

4.3Contraindications

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

4.4Special warnings and precautions for use

Blood/laboratory tests

Changes in renal laboratory tests have been seen in clinical trials in subjects treated with Tecfidera (see section 4.8). The clinical implications of these changes are unknown. Assessment of renal function (e.g. creatinine, blood urea nitrogen and urinalysis) is recommended prior to treatment initiation, after 3 and 6 months of treatment, every 6 to 12 months thereafter and as clinically indicated.

Drug-induced liver injury, including liver enzyme increase (≥ 3 ULN) and elevation of total bilirubin levels (≥ 2 ULN) can result from treatment with Tecfidera. The time to onset can be directly, several weeks or longer. Resolution of the adverse events has been observed after treatment was discontinued. Assessment of serum aminotransferases (e.g. ALT, AST) and total bilirubin levels are recommended prior to treatment initiation and during treatment as clinically indicated.

Patients treated with Tecfidera may develop severe prolonged lymphopenia (see section 4.8). Tecfidera has not been studied in patients with pre-existing low lymphocyte counts and caution should be exercised when treating these patients. Prior to initiating treatment with Tecfidera, a current complete blood count, including lymphocytes, must be performed. If lymphocyte count is found to be below the normal range, thorough assessment of possible causes should be completed prior to initiation of treatment with Tecfidera.

After starting therapy, complete blood counts, including lymphocytes, must be performed every 3 months.

Consider interruption of Tecfidera in patients with lymphocyte counts <0.5x109/L persisting for more than 6 months. The benefit/risk balance of the therapy should be reconsidered in discussion with the patient in the context of other therapeutic options available. Clinical factors, evaluation of any laboratory and imaging investigations could be included as part of this re-consideration. If treatment is continued despite a persistent lymphocyte count < 0.5x109/L, enhanced vigilance is recommended (see also subsection on PML). Lymphocyte counts should be followed until recovery. Upon recovery and in the absence of alternative treatment options, decisions about whether or not to restart Tecfidera after treatment discontinuation should be based on clinical judgement.

Assess the benefit/risk in patients with lymphocyte counts ≥0.5 x 109/L and <0.8 x 109/L for more than six months.

MR imaging

Before initiating treatment with Tecfidera, a baseline MRI should be available (usually within 3 months) as a reference. The need for further MRI scanning should be considered in accordance with national and local recommendations. MRI imaging may be considered as part of increased vigilance in patients considered at increased risk of PML. In case of clinical suspicion of PML, MRI should be performed immediately for diagnostic purposes.

Progressive Multifocal Leukoencephalopathy (PML)

PML cases have occurred with Tecfidera and other products containing fumarates in the setting of moderate to severe prolonged lymphopenia. PML is an opportunistic infection caused by John- Cunningham virus (JCV), which may be fatal or result in severe disability. PML can only occur in the presence of a JCV infection. If JCV testing is undertaken, it should be considered that the influence of lymphopenia on the accuracy of anti-JCV antibody test has not been studied in Tecfidera treated patients. It should also be noted that a negative anti JCV antibody test (in the presence of normal lymphocyte counts) does not preclude the possibility of subsequent JCV infection.

At the first sign or symptom suggestive of PML, withhold Tecfidera and perform appropriate diagnostic evaluations. The symptoms of PML may be similar to an MS relapse. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

Prior treatment with immunosuppressive or immunomodulating therapies

No studies have been performed evaluating the efficacy and safety of Tecfidera when switching patients from other disease modifying therapies to Tecfidera. The contribution of prior immunosuppressive therapy to the development of PML in Tecfidera treated patients is unknown. When switching patients from another disease modifying therapy to Tecfidera, the half-life and mode of action of the other therapy should be considered in order to avoid an additive immune effect while at the same time, reducing the risk of reactivation of MS.

A complete blood count is recommended prior to initiating Tecfidera and regularly during treatment (see Blood/laboratory tests above).

Tecfidera can generally be started immediately after discontinuation of interferon or glatiramer acetate.

Severe renal and hepatic impairment

Tecfidera has not been studied in patients with severe renal or severe hepatic impairment and caution should, therefore, be used in these patients (see section 4.2).

Severe active gastrointestinal disease

Tecfidera has not been studied in patients with severe active gastrointestinal disease and caution should, therefore, be used in these patients.

Flushing

In clinical trials, 34% of Tecfidera treated patients experienced flushing. In the majority of patients who experienced flushing, it was mild or moderate in severity.

In clinical trials, 3 patients out of a total of 2,560 patients treated with Tecfidera experienced serious flushing symptoms that were probable hypersensitivity or anaphylactoid reactions. These events were not life-threatening, but led to hospitalisation. Prescribers and patients should be alert to this possibility in the event of severe flushing reactions (see sections 4.2, 4.5 and 4.8).

Infections

In phase III placebo-controlled studies, the incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with Tecfidera or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or <0.5x109/L. During treatment with Tecfidera in the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% from baseline at one year and then plateaued (see section 4.8). Mean lymphocyte counts remained within normal limits. Patients with lymphocyte counts <0.5x109/L were observed in <1% of patients treated with placebo and 6% of patients treated with Tecfidera. In clinical studies (both controlled and uncontrolled), 9% of patients had lymphocyte counts ≥0.5 x 109/L and <0.8 x 109/L for at least six months. 2% of patients experienced lymphocyte counts <0.5 x 109/L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5 x 109/L with continued therapy.

If therapy is continued in the presence of moderate to severe prolonged lymphopenia, the risk of an opportunistic infection, including Progressive Multifocal Leukoencephalopathy (PML) cannot be ruled out (please refer to subsection PML above for further details).

If a patient develops a serious infection, suspending treatment with Tecfidera should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving Tecfidera should be instructed to report symptoms of infections to a physician. Patients with serious infections should not start treatment with Tecfidera until the infection(s) is resolved.

4.5Interaction with other medicinal products and other forms of interaction

Tecfidera has not been studied in combination with anti-neoplastic or immunosuppressive therapies and caution should, therefore, be used during concomitant administration. In multiple sclerosis clinical studies, the concomitant treatment of relapses with a short course of intravenous corticosteroids was not associated with a clinically relevant increase of infection.

Vaccination during treatment with Tecfidera has not been studied. It is not known whether treatment with Tecfidera might reduce the effectiveness of some vaccines. Live vaccines might carry an increased risk of clinical infection and should not be given to patients treated with Tecfidera unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating.

During treatment with Tecfidera, simultaneous use of other fumaric acid derivatives (topical or systemic) should be avoided.

In humans, dimethyl fumarate is extensively metabolised by esterases before it reaches the systemic circulation and further metabolism occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450 (CYP) system. Potential drug interaction risks were not identified from in vitro

CYP-inhibition and induction studies, a p-glycoprotein study, or studies of the protein binding of dimethyl fumarate and monomethyl fumarate (a primary metabolite of dimethyl fumarate).

Commonly used medicinal products in patients with multiple sclerosis, intramuscular interferon beta-1a and glatiramer acetate, were clinically tested for potential interactions with dimethyl fumarate and did not alter the pharmacokinetic profile of dimethyl fumarate.

Administration of 325 mg (or equivalent) non-enteric coated acetylsalicylic acid, 30 minutes prior to Tecfidera, over 4 days of dosing, did not alter the pharmacokinetic profile of Tecfidera and reduced the occurrence and severity of flushing in a healthy volunteer study. However, long term use of acetylsalicylic acid is not recommended for the management of flushing. Potential risks associated with acetylsalicylic acid therapy should be considered prior to co-administration with Tecfidera. (see sections 4.2, 4.4 and 4.8).

Concurrent therapy with nephrotoxic medicinal products (such as aminoglycosides, diuretics, NSAIDs or lithium) may increase the potential of renal adverse reactions (e.g. proteinuria) in patients taking Tecfidera (see section 4.8).

Consumption of moderate amounts of alcohol did not alter exposure to Tecfidera and was not associated with an increase in adverse reactions. Consumption of large quantities of undiluted strong alcoholic drinks (more than 30% alcohol by volume) may lead to increased dissolution rates of Tecfidera and, therefore, may increase the frequency of gastrointestinal adverse reactions.

In vitro CYP induction studies did not demonstrate an interaction between Tecfidera and oral contraceptives. In an in vivo study, co-administration of Tecfidera with a combined oral contraceptive (norgestimate and ethinyl estradiol) did not elicit any relevant change in oral contraceptive exposure. No interaction studies have been performed with oral contraceptives containing other progestogens, however an effect of Tecfidera on their exposure is not expected.

Paediatric population

Interaction studies have only been performed in adults.

4.6Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of dimethyl fumarate in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Tecfidera is not recommended during pregnancy and in women of childbearing potential not using appropriate contraception (see

section 4.5). Tecfidera should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Tecfidera therapy. The benefit of breast-feeding for the child and the benefit of therapy for the woman should be taken into account.

Fertility

There are no data on the effects of Tecfidera on human fertility. Data from preclinical studies do not suggest that dimethyl fumarate would be associated with an increased risk of reduced fertility (see section 5.3).

4.7Effects on ability to drive and use machines

No studies on the ability to drive and use machines have been conducted.

4.8Undesirable effects

Summary of the safety profile

The most common adverse reactions (incidence ≥10%) for patients treated with Tecfidera were flushing and gastrointestinal events (i.e. diarrhoea, nausea, abdominal pain, abdominal pain upper). Flushing and gastrointestinal events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience flushing and gastrointestinal events, these events may continue to occur intermittently throughout treatment with Tecfidera. The most commonly reported adverse reactions leading to discontinuation (incidence >1%) in patients treated with Tecfidera were flushing (3%) and gastrointestinal events (4%).

In placebo-controlled and uncontrolled clinical studies, a total of 2,468 patients have received Tecfidera and been followed for periods up to 4 years with an overall exposure equivalent to

3,588 person-years. Approximately 1,056 patients have received more than 2 years of treatment with Tecfidera. The experience in uncontrolled clinical trials is consistent with the experience in the placebo-controlled clinical trials.

Tabulated summary of adverse reactions

Adverse reactions, which were more frequently reported in Tecfidera versus placebo-treated patients, are presented in the table below. These data were derived from 2 pivotal Phase 3 placebo-controlled, double-blind clinical trials with a total of 1,529 patients treated with Tecfidera and for up to 24 months with an overall exposure of 2,371 person-years (see section 5.1). The frequencies described in the table below are based on 769 patients treated with Tecfidera 240 mg twice a day and 771 patients treated with placebo.

The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ Class. The incidence of the adverse reactions below are expressed according to the following categories:

-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)

-Not known (cannot be estimated from the available data)

MedDRA System Organ Class

Adverse reaction

Frequency category

Infections and infestations

Gastroenteritis

Common

 

Progressive multifocal

Not known

 

leukoencephalopathy (PML) 1

 

 

Blood and lymphatic system

Lymphopenia

Common

disorders

Leucopenia

Common

Immune system disorders

Hypersensitivity

Uncommon

Nervous system disorders

Burning sensation

Common

Vascular disorders

Flushing

Very common

 

Hot flush

Common

Gastrointestinal disorders

Diarrhoea

Very common

 

Nausea

Very common

 

Abdominal pain upper

Very common

 

Abdominal pain

Very common

 

Vomiting

Common

 

 

MedDRA System Organ Class

Adverse reaction

Frequency category

 

Dyspepsia

Common

 

Gastritis

Common

 

Gastrointestinal disorder

Common

Hepatobiliary disorders

Aspartate aminotransferase increased

Common

 

Alanine aminotransferase increased

Common

 

Drug-induced liver injury1

Not known

Skin and subcutaneous tissue

Pruritus

Common

disorders

Rash

Common

 

Erythema

Common

Renal and urinary disorders

Proteinuria

Common

General disorders and

Feeling hot

Common

administration site conditions

 

 

Investigations

Ketones measured in urine

Very common

 

Albumin urine present

Common

 

White blood cell count decreased

Common

1 Adverse reactions derived only during post marketing experience

Description of selected adverse reactions

Flushing

In the placebo-controlled studies, the incidence of flushing (34% versus 4%) and hot flush

(7% versus 2%) was increased in patients treated with Tecfidera compared to placebo, respectively. Flushing is usually described as flushing or hot flush, but can include other events (e.g. warmth, redness, itching, and burning sensation). Flushing events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience flushing, these events may continue to occur intermittently throughout treatment with Tecfidera. In patients with flushing, the majority had flushing events that were mild or moderate in severity. Overall, 3% of patients treated with Tecfidera discontinued due to flushing. The incidence of serious flushing, which may be characterised by generalised erythema, rash and/or pruritus, was seen in less than 1% of patients treated with Tecfidera (see sections 4.2, 4.4 and 4.5).

Gastrointestinal

The incidence of gastrointestinal events (e.g. diarrhoea [14% versus 10%], nausea [12% versus 9%], upper abdominal pain [10% versus 6%], abdominal pain [9% versus 4%], vomiting [8% versus 5%] and dyspepsia [5% versus 3%]) was increased in patients treated with Tecfidera compared to placebo, respectively. Gastrointestinal events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience gastrointestinal events, these events may continue to occur intermittently throughout treatment with Tecfidera. In the majority of patients who experienced gastrointestinal events, it was mild or moderate in severity. Four per cent (4%) of patients treated with Tecfidera discontinued due to gastrointestinal events. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% of patients treated with Tecfidera (see

section 4.2).

Hepatic function

In placebo-controlled studies, elevations of hepatic transaminases were observed. The majority of patients with elevations had hepatic transaminases that were <3 times the upper limit of normal (ULN). The increased incidence of elevations of hepatic transaminases in patients treated with Tecfidera relative to placebo was primarily seen during the first 6 months of treatment. Elevations of alanine aminotransferase and aspartate aminotransferase ≥3 times ULN, respectively, were seen in 5% and 2% of patients treated with placebo and 6% and 2% of patients treated with Tecfidera.. Discontinuations due to elevated hepatic transaminases were <1% and similar in patients treated with

Tecfidera or placebo. Elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN, were not observed in placebo-controlled studies.

Increase of liver enzymes and cases of drug-induced liver injury (elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN), have been reported in post marketing experience following Tecfidera administration, which resolved upon treatment discontinuation.

Renal

In placebo-controlled studies, the incidence of proteinuria was higher in patients treated with Tecfidera (9%) compared to placebo (7%). The overall incidence of renal and urinary adverse events was similar for Tecfidera and placebo-treated patients. There were no reports of serious renal failure. On urinalysis, the percentage of patients with protein values of 1+ or greater was similar for Tecfidera (43%) and placebo-treated patients (40%). Typically, laboratory observations of proteinuria were not progressive. Compared to patients treated with placebo, estimated glomerular filtration rate (eGFR) was observed to increase in patients treated with Tecfidera, including those patients with 2 consecutive occurrences of proteinuria (≥1+).

Haematological

In the placebo-controlled studies, most patients (>98%) had normal lymphocyte values prior to initiating treatment. Upon treatment with Tecfidera, mean lymphocyte counts decreased over the first year with a subsequent plateau. On average, lymphocyte counts decreased by approximately 30% of baseline value. Mean and median lymphocyte counts remained within normal limits. Lymphocyte counts <0.5x109/l were observed in <1% of patients treated with placebo and 6% of patients treated with Tecfidera. A lymphocyte count <0.2x109/l was observed in 1 patient treated with Tecfidera and in no patients treated with placebo. The incidence of infections (58% versus 60%) and serious infections (2% versus 2%) was similar in patients treated with placebo or Tecfidera. An increased incidence of infections and serious infections was not observed in patients with lymphocyte counts <0.8x109/l or <0.5x109/l. PML has occurred in the setting of moderate to severe prolonged lymphopenia (see section 4.4). A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.

Laboratory abnormalities

In the placebo-controlled studies, measurement of urinary ketones (1+ or greater) was higher in patients treated with Tecfidera (45%) compared to placebo (10%). No untoward clinical consequences were observed in clinical trials.

Levels of 1,25-dihydroxyvitamin D decreased in Tecfidera treated patients relative to placebo (median percentage decrease from baseline at 2 years of 25% versus 15%, respectively) and levels of parathyroid hormone (PTH) increased in Tecfidera treated patients relative to placebo (median percentage increase from baseline at 2 years of 29% versus 15%, respectively). Mean values for both parameters remained within normal range.

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.

4.9Overdose

Cases of overdose with Tecfidera have been reported. The symptoms described in these cases were consistent with the known adverse event profile of Tecfidera. There are no known therapeutic interventions to enhance elimination of Tecfidera nor is there a known antidote. In the event of overdose, it is recommended that symptomatic supportive treatment be initiated as clinically indicated.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX09

Mechanism of action

The mechanism by which dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fully understood. Preclinical studies indicate that dimethyl fumarate pharmacodynamic responses appear to be primarily mediated through activation of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway. Dimethyl fumarate has been shown to up regulate Nrf2-dependent antioxidant genes in patients (e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1]).

Pharmacodynamic effects

Effects on the immune system

In preclinical and clinical studies, Tecfidera demonstrated anti-inflammatory and immunomodulatory properties. Dimethyl fumarate and monomethyl fumarate, the primary metabolite of dimethyl fumarate, significantly reduced immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli in preclinical models. In clinical studies with psoriasis patients, dimethyl fumarate affected lymphocyte phenotypes through a down-regulation of pro- inflammatory cytokine profiles (TH1, TH17), and biased towards anti-inflammatory production (TH2). Dimethyl fumarate demonstrated therapeutic activity in multiple models of inflammatory and neuroinflammatory injury. In Phase 3 studies, upon treatment with Tecfidera mean lymphocyte counts decreased on average by approximately 30% of their baseline value over the first year with a subsequent plateau.

Effect on cardiovascular system

Single doses of 240 mg or 360 mg Tecfidera did not have any effect on the QTc interval when compared to placebo in a QTc study.

Clinical efficacy and safety

Two, 2-year, randomised, double-blind, placebo controlled studies [Study 1 (DEFINE) with 1234 subjects and Study 2 (CONFIRM) with 1417 subjects] of subjects with relapsing-remitting

multiple sclerosis (RRMS) were performed. Subjects with progressive forms of MS were not included in these studies. Efficacy (see table below) and safety were demonstrated in subjects with Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5 inclusive, who had experienced at least

1 relapse during the year prior to randomisation, or, within 6 weeks of randomisation had a brain Magnetic Resonance Imaging (MRI) demonstrating at least one gadolinium-enhancing (Gd+) lesion. Study 2 contained a rater-blinded (i.e. study physician/ investigator assessing the response to study treatment was blinded) reference comparator of glatiramer acetate.

In Study 1, patients had the following median baseline characteristics: age 39 years, disease duration 7.0 years, EDSS score 2.0. In addition, 16% of patients had an EDSS score >3.5, 28% had ≥2 relapses

in the prior year and 42% had previously received other approved MS treatments. In the MRI cohort 36% of patients entering the study had Gd+ lesions at baseline (mean number of Gd+ lesions 1.4).

In Study 2, patients had the following median baseline characteristics: age 37 years, disease duration 6.0 years, EDSS score 2.5. In addition, 17% of patients had an EDSS score >3.5, 32% had ≥2 relapses in the prior year and 30% had previously received other approved MS treatments. In the MRI cohort 45% of patients entering the study had Gd+ lesions at baseline (mean number of Gd+ lesions 2.4).

Compared to placebo, subjects treated with Tecfidera had a clinically meaningful and statistically significant reduction on: the primary endpoint in Study 1, proportion of subjects relapsed at 2 years; and the primary endpoint in Study 2, annualised relapse rate at 2 years.

The annualised relapse rate for glatiramer acetate and placebo was 0.286 and 0.401 respectively in Study 2, corresponding to a reduction of 29% (p=0.013), which is consistent with approved prescribing information.

 

 

DEFINE

 

CONFIRM

 

 

Placebo

 

Tecfidera

Placebo

Tecfidera

Glatiramer

 

 

 

240 mg

 

240 mg

acetate

 

 

 

twice a day

 

twice a day

 

Clinical Endpointsa

 

 

 

 

 

 

No. subjects

 

Annualised relapse rate

0.364

 

0.172***

0.401

0.224***

0.286*

Rate ratio

 

 

0.47

 

0.56

0.71

(95% CI)

 

 

(0.37, 0.61)

 

(0.42, 0.74)

(0.55, 0.93)

Proportion relapsed

0.461

 

0.270***

0.410

0.291**

0.321**

Hazard ratio

 

 

0.51

 

0.66

0.71

(95% CI)

 

 

(0.40, 0.66)

 

(0.51, 0.86)

(0.55, 0.92)

Proportion with 12-week

0.271

 

0.164**

0.169

0.128#

0.156#

confirmed disability

 

 

 

 

 

 

progression

 

 

 

 

 

 

Hazard ratio

 

 

0.62

 

0.79

0.93

(95% CI)

 

 

(0.44, 0.87)

 

(0.52, 1.19)

(0.63, 1.37)

Proportion with 24 week

0.169

 

0.128#

0.125

0.078#

0.108#

confirmed disability

 

 

 

 

 

 

progression

 

 

 

 

 

 

Hazard ratio

 

 

0.77

 

0.62

0.87

(95% CI)

 

 

(0.52, 1.14)

 

(0.37, 1.03)

(0.55, 1.38)

MRI Endpointsb

 

 

 

 

 

 

No. subjects

Mean (median) number of

16.5

3.2

19.9

5.7

9.6

new or newly enlarging

(7.0)

(1.0)***

(11.0)

(2.0)***

(3.0)***

T2 lesions over 2 years

 

 

 

 

 

 

Lesion mean ratio

 

0.15

 

0.29

0.46

(95% CI)

 

(0.10, 0.23)

 

(0.21, 0.41)

(0.33, 0.63)

Mean (median) number of

1.8

0.1

2.0

0.5

0.7

Gd lesions at 2 years

(0)

(0)***

(0.0)

(0.0)***

(0.0)**

Odds ratio

 

0.10

 

0.26

0.39

(95% CI)

 

(0.05, 0.22)

 

(0.15, 0.46)

(0.24, 0.65)

Mean (median) number of

5.7

2.0

8.1

3.8

4.5

new T1 hypointense

(2.0)

(1.0)***

(4.0)

(1.0)***

(2.0)**

lesions over 2 years

 

 

 

 

 

 

Lesion mean ratio

 

0.28

 

0.43

0.59

(95% CI)

 

(0.20, 0.39)

 

(0.30, 0.61)

(0.42, 0.82)

aAll analyses of clinical endpoints were intent-to-treat; bMRI analysis used MRI cohort

*P-value < 0.05; **P-value < 0.01; ***P-value < 0.0001; #not statistically significant

Efficacy in patients with high disease activity:

Consistent treatment effect on relapses in a subgroup of patients with high disease activity was observed, whilst the effect on time to 3-month sustained disability progression was not clearly established. Due to the design of the studies, high disease activity was defined as follows:

-Patients with 2 or more relapses in one year, and with one or more Gd-enhancing lesions on brain MRI (n=42 in DEFINE; n=51 in CONFIRM) or,

-Patients who have failed to respond to a full and adequate course (at least one year of treatment) of beta-interferon, having had at least 1 relapse in the previous year while on therapy, and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or patients having an unchanged or increased relapse rate in the prior year as compared to the previous 2 years (n=177 in DEFINE; n=141 in CONFIRM).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Tecfidera in one or more subsets of the paediatric population in multiple sclerosis (see section 4.2 for information on paediatric use).

5.2Pharmacokinetic properties

Orally administered Tecfidera (dimethyl fumarate) undergoes rapid presystemic hydrolysis by esterases and is converted to its primary metabolite, monomethyl fumarate, which is also active. Dimethyl fumarate is not quantifiable in plasma following oral administration of Tecfidera. Therefore, all pharmacokinetic analyses related to dimethyl fumarate were performed with plasma monomethyl fumarate concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers.

Absorption

The Tmax of monomethyl fumarate is 2 to 2.5 hours. As Tecfidera gastro-resistant hard capsules contain microtablets, which are protected by an enteric coating, absorption does not commence until they leave the stomach (generally less than 1 hour). Following 240 mg twice a day administered with food, the median peak (Cmax) was 1.72 mg/l and overall (AUC) exposure was 8.02 h.mg/l in subjects with multiple sclerosis. Overall, Cmax and AUC increased approximately dose- proportionally in the dose range studied (120 mg to 360 mg). In subjects with multiple sclerosis, two 240 mg doses were administered 4 hours apart as part of a three times a day dosing regimen. This resulted in a minimal accumulation of exposure yielding an increase in the median Cmax of 12% compared to the twice daily dosing (1.72 mg/l for twice daily compared to 1.93 mg/l for three times daily) with no safety implications.

Food does not have a clinically significant effect on exposure of dimethyl fumarate. However, Tecfidera should be taken with food due to improved tolerability with respect to flushing or gastrointestinal adverse events (see section 4.2).

Distribution

The apparent volume of distribution following oral administration of 240 mg Tecfidera varies between 60 L and 90 L. Human plasma protein binding of monomethyl fumarate generally ranges between 27% and 40%.

Biotransformation

In humans, dimethyl fumarate is extensively metabolised with less than 0.1% of the dose excreted as unchanged dimethyl fumarate in urine. It is initially metabolised by esterases, which are ubiquitous in the gastrointestinal tract, blood and tissues, before it reaches the systemic circulation. Further

metabolism occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450 (CYP) system. A single 240 mg 14C-dimethyl fumarate dose study identified glucose as the predominant metabolite in human plasma. Other circulating metabolites included fumaric acid, citric acid and monomethyl fumarate. The downstream metabolism of fumaric acid occurs through the tricarboxylic acid cycle, with exhalation of CO2 serving as a primary route of elimination.

Elimination

Exhalation of CO2 is the primary route of dimethyl fumarate elimination accounting for 60% of the dose. Renal and faecal elimination are secondary routes of elimination, accounting for 15.5% and 0.9% of the dose respectively.

The terminal half-life of monomethyl fumarate is short (approximately 1 hour) and no circulating monomethyl fumarate is present at 24 hours in the majority of individuals. Accumulation of parent drug or monomethyl fumarate does not occur with multiple doses of dimethyl fumarate at the therapeutic regimen.

Linearity

Dimethyl fumarate exposure increases in an approximately dose proportional manner with single and multiple doses in the 120 mg to 360 mg dose range studied.

Pharmacokinetics in special patient groups

Based on the results of Analysis of Variance (ANOVA), body weight is the main covariate of exposure (by Cmax and AUC) in relapsing remitting multiple sclerosis (RRMS) subjects, but did not affect safety and efficacy measures evaluated in the clinical studies.

Gender and age did not have a clinically significant impact on the pharmacokinetics of dimethyl fumarate. The pharmacokinetics in patients aged 65 and over has not been studied.

Paediatric population

The pharmacokinetics in patients below the age of 18 has not been studied.

Renal impairment

Since the renal pathway is a secondary route of elimination for dimethyl fumarate accounting for less than 16% of the dose administered, evaluation of pharmacokinetics in individuals with renal impairment was not conducted.

Hepatic impairment

As dimethyl fumarate and monomethyl fumarate are metabolised by esterases, without the involvement of the CYP450 system, evaluation of phamacokinetics in individuals with hepatic impairment was not conducted.

5.3Preclinical safety data

The adverse reactions described in the Toxicology and Reproduction toxicity sections below were not observed in clinical studies, but were seen in animals at exposure levels similar to clinical exposure levels.

Mutagenesis

Dimethyl fumarate and mono-methylfumarate were negative in a battery of in vitro assays (Ames, chromosomal aberration in mammalian cells). Dimethyl fumarate was negative in the in vivo

micronucleus assay in the rat.

Carcinogenesis

Carcinogenicity studies of dimethyl fumarate were conducted for up to 2 years in mice and rats. Dimethyl fumarate was administered orally at doses of 25, 75, 200 and 400 mg/kg/day in mice, and at doses of 25, 50, 100, and 150 mg/kg/day in rats. In mice, the incidence of renal tubular carcinoma was increased at 75 mg/kg/day, at equivalent exposure (AUC) to the recommended human dose. In rats, the incidence of renal tubular carcinoma was increased at 100 mg/kg/day, approximately 2 times higher exposure than the recommended human dose. The relevance of these findings to human risk is unknown.

The incidence of squamous cell papilloma and carcinoma in the nonglandular stomach (forestomach) was increased at equivalent exposure to the recommended human dose in mice and below exposure to the recommended human dose in rats (based on AUC). The forestomach in rodents does not have a human counterpart.

Toxicology

Nonclinical studies in rodent, rabbits, and monkeys were conducted with a dimethyl fumarate suspension (dimethyl fumarate in 0.8% hydroxypropyl methylcellulose) administered by oral gavage. The chronic dog study was conducted with oral administration of the dimethyl fumarate capsule.

Kidney changes were observed after repeated oral administration of dimethyl fumarate in mice, rats, dogs, and monkeys. Renal tubule epithelial regeneration, suggestive of injury, was observed in all species. Renal tubular hyperplasia was observed in rats with life time dosing (2-year study). In dogs that received daily oral doses of dimethyl fumarate for 11 months, the margin calculated for cortical atrophy was observed at 3 times the recommended dose based on AUC. In monkeys that received daily oral doses of dimethyl fumarate for 12 months, single cell necrosis was observed at 2 times the recommended dose based on AUC. Interstitial fibrosis and cortical atrophy were observed at 6 times the recommended dose based on AUC. The relevance of these findings to humans is not known.

In the testes, degeneration of the seminiferous epithelium was seen in rats and dogs. The findings were observed at approximately the recommended dose in rats and 3 times the recommended dose in dogs (AUC basis). The relevance of these findings to humans is not known.

Findings in the forestomach of mice and rats consisted of squamous epithelial hyperplasia and hyperkeratosis; inflammation; and squamous cell papilloma and carcinoma in studies of 3 months or longer in duration. The forestomach of mice and rats does not have a human counterpart.

Reproduction toxicity

Oral administration of dimethyl fumarate to male rats at 75, 250, and 375 mg/kg/day prior to and during mating had no effects on male fertility up to the highest dose tested (at least 2 times the recommended dose on an AUC basis). Oral administration of dimethyl fumarate to female rats at

25, 100, and 250 mg/kg/day prior to and during mating, and continuing to Day 7 of gestation, induced reduction in the number of estrous stages per 14 days and increased the number of animals with prolonged diestrus at the highest dose tested (11 times the recommended dose on an AUC basis). However, these changes did not affect fertility or the number of viable fetuses produced.

Dimethyl fumarate has been shown to cross the placental membrane into fetal blood in rats and rabbits, with ratios of fetal to maternal plasma concentrations of 0.48 to 0.64 and 0.1 respectively. No malformations were observed at any dose of dimethyl fumarate in rats or rabbits. Administration of dimethyl fumarate at oral doses of 25, 100, and 250 mg/kg/day to pregnant rats during the period of organogenesis resulted in maternal adverse effects at 4 times the recommended dose on an AUC basis, and low fetal weight and delayed ossification (metatarsals and hindlimb phalanges) at 11 times the recommended dose on an AUC basis. The lower fetal weight and delayed ossification were considered

secondary to maternal toxicity (reduced body weight and food consumption).

Oral administration of dimethyl fumarate at 25, 75, and 150 mg/kg/day to pregnant rabbits during organogenesis had no effect on embryo-fetal development and resulted in reduced maternal body weight at 7 times the recommended dose and increased abortion at 16 times the recommended dose, on an AUC basis.

Oral administration of dimethyl fumarate at 25, 100, and 250 mg/kg/day to rats during pregnancy and lactation resulted in lower body weights in the F1 offspring, and delays in sexual maturation in F1 males at 11 times the recommended dose on an AUC basis. There were no effects on fertility in the F1 offspring. The lower offspring body weight was considered secondary to maternal toxicity.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Enteric-coated microtablets

Microcrystalline cellulose

Croscarmellose sodium

Talc

Silica, colloidal anhydrous

Magnesium stearate

Triethyl citrate

Methacrylic acid – methyl methacrylate copolymer (1:1)

Methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30%

Simeticone

Sodium laurilsulfate

Polysorbate 80

Capsule shell

Gelatin

Titanium dioxide (E171)

Brilliant Blue FCF (E133)

Yellow iron oxide (E172)

Capsule print (black ink)

Shellac

Potassium hydroxide

Black iron oxide (E172)

6.2Incompatibilities

Not applicable.

6.3Shelf life

120 mg gastro-resistant hard capsules: 4 years

240 mg gastro-resistant hard capsules: 4 years

6.4Special precautions for storage

Do not store above 30ºC.

Keep the blisters in the outer carton in order to protect from light.

6.5Nature and contents of container

120 mg capsules: 14 capsules in PVC/PE/PVDC-PVC aluminium blister packs.

240 mg capsules: 56 or 168 capsules in PVC/PE/PVDC-PVC aluminium blister packs.

Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Biogen Idec Ltd

Innovation House

70 Norden Road

Maidenhead

Berkshire

SL6 4AY

United Kingdom

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/13/837/001

EU/1/13/837/002

EU/1/13/837/003

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 30 January 2014

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.

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