DEFRA^® is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (see section 5.1 for important information on the populations for which efficacy has been established).

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

Posology

The starting dose is 120 mg twice a day. After 7 days, the dose should be increased to the recommended maintenance dose of 240 mg twice a day (see section 4.4).

If a patient misses a dose, a double dose should not be taken. The patient may take the missed dose only if they leave 4 hours between doses. Otherwise the patient should wait until the next scheduled dose.

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

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

Special populations

Elderly

Clinical studies of DEFRA ^® 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

DEFRA ^® 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 DEFRA ^® in children and adolescents aged 10 to 18 years have not yet been established.

Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made. There is no relevant use of DEFRA ^® in children aged less than 10 years for the indication of relapsing remitting multiple sclerosis.

Method of administration

For oral use.

The capsule should be swallowed whole. 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.

Blood/laboratory tests

Changes in renal laboratory tests have been seen in clinical trials in subjects treated with dimethyl fumarate (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 upper limit of normal (ULN)) and elevation of total bilirubin levels (≥ 2 ULN) can result from treatment with dimethyl fumarate. The time to onset can be directly, several weeks or longer. Resolution of the adverse reactions has been observed after treatment was discontinued. Assessment of serum aminotransferases (e.g. alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels are recommended prior to treatment initiation and during treatment as clinically indicated.

Patients treated with DEFRA ^® may develop severe prolonged lymphopenia (see section 4.8). Dimethyl fumarate 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 DEFRA ^®, 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 DEFRA ^®.

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

Interruption of DEFRA ^® should be considered 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 DEFRA

® after treatment discontinuation should be based on clinical judgement.

The benefit/risk in patients with lymphocyte counts ≥0.5 x 109/L and <0.8 x 109/L for more than six months should be assessed.

Magnetic Resonance imaging (MRI)

Before initiating treatment with DEFRA ®, 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 dimethyl fumarate and other medicinal 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 dimethyl fumarate 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, DEFRA ® should be withheld and appropriate diagnostic evaluations need to be performed. 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 DEFRA ® when switching patients from other disease modifying therapies to DEFRA ®. The contribution of prior immunosuppressive therapy to the development of PML in dimethyl fumarate treated patients is unknown. When switching patients from another disease modifying therapy to DEFRA ®, 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 DEFRA ^® and regularly during treatment (see Blood/laboratory tests above).

DEFRA ^® can generally be started immediately after discontinuation of interferon or glatiramer acetate.

Severe renal and hepatic impairment

DEFRA ^® 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

DEFRA ^® 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 DEFRA ^® treated patients experienced flushing. In the majority of patients who experienced flushing, it was mild or moderate in severity. Data from healthy volunteer studies suggest that dimethyl fumarate-associated flushing is likely to be prostaglandin mediated. A short course of treatment with 75 mg non-enteric coated acetylsalicylic acid may be beneficial in patients affected by intolerable flushing (see section 4.5). In two healthy volunteer studies, the occurrence and severity of flushing over the dosing period was reduced.

In clinical trials, 3 patients out of a total of 2,560 patients treated with dimethyl fumarate 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).

Anaphylactic reactions

Cases of anaphylaxis/anaphylactoid reaction have been reported following DEFRA ^® administration in the post-marketing setting. Symptoms may include dyspnoea, hypoxia, hypotension, angioedema, rash or urticaria. The mechanism of dimethyl fumarate induced anaphylaxis is unknown. Reactions generally occur after the first dose, but may also occur at any time during treatment, and may be serious and life threatening. Patients should be instructed to discontinue DEFRA ^® and seek immediate medical care if they experience signs or symptoms of anaphylaxis. Treatment should not be restarted (see section 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 DEFRA ^® or placebo, respectively. However, due to DEFRA ^® immunomodulatory properties (see section 5.1), if a patient develops a serious infection, suspending treatment with DEFRA ^® should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving DEFRA ^® should be instructed to report symptoms of infections to a physician. Patients with serious infections should not start treatment with DEFRA ^® until the infection(s) is resolved.

There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x10⁹/L or <0.5x10⁹/L (see Section 4.8). If therapy is continued in the presence of moderate to severe prolonged lymphopenia, the risk of an opportunistic infection, including PML, cannot be ruled out (see section 4.4 subsection PML).

Treatment initiation

DEFRA ^® treatment should be started gradually to reduce the occurrence of flushing and gastrointestinal adverse reactions (see section 4.2).

DEFRA ^® 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.

Concomitant administration of non-live vaccines according to national vaccination schedules may be considered during DEFRA ^® therapy. In a clinical study involving a total of 71 patients with relapsing remitting multiple sclerosis, patients on DEFRA ^® 240 mg twice daily for at least 6 months (n=38) or non-pegylated interferon for at least 3 months (n=33), mounted a comparable immune response (defined as ≥2-fold increase from pre- to post-vaccination titer) to tetanus toxoid (recall antigen) and a conjugated meningococcal C polysaccharide vaccine (neoantigen), while the immune response to different serotypes of an unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell independent antigen) varied in both treatment groups. A positive immune response defined as a ≥4-fold increase in antibody titer to the three vaccines, was achieved by fewer subjects in both treatment groups. Small numerical differences in the response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were noted in favour of non-pegylated interferon.

No clinical data are available on the efficacy and safety of live attenuated vaccines in patients taking DEFRA ^®. Live vaccines might carry an increased risk of clinical infection and should not be given to patients treated with DEFRA

® unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating.

During treatment with DEFRA ®, 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.

Evidence from healthy volunteer studies suggests that DEFRA ® -associated flushing is likely to be prostaglandin mediated. In two healthy volunteer studies, the administration of 325 mg (or equivalent) non-enteric coated acetylsalicylic acid, 30 minutes prior to DEFRA ®, dosing over 4 days and over 4 weeks, respectively, did not alter the pharmacokinetic profile of. Potential risks associated with acetylsalicylic acid therapy should be considered prior to co-administration with DEFRA ® in patients with Relapsing Remitting MS. Long term (> 4 weeks) continuous use of acetylsalicylic acid has not been studied (see sections DEFRA ® 4.4 and 4.8).

Concurrent therapy with nephrotoxic medicinal products (such as aminoglycosides, diuretics, non-steroidal anti-inflammatory drugs or lithium) may increase the potential of renal adverse reactions (e.g. proteinuria see section 4.8) in patients taking DEFRA ® (see section 4.4 Blood/laboratory tests).

Consumption of moderate amounts of alcohol did not alter exposure to dimethyl fumarate and was not associated with an increase in adverse reactions. Consumption of large quantities of strong alcoholic drinks (more than 30% alcohol by volume) should be avoided within an hour of taking DEFRA ®, as alcohol may lead to increased frequency of gastrointestinal adverse reactions.

In vitro CYP induction studies did not demonstrate an interaction between DEFRA ® and oral contraceptives. In an in vivo study, co-administration of DEFRA ® 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 DEFRA ® on their exposure is not expected.

Paediatric population

Interaction studies have only been performed in adults.

DEFRA ^® 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.

Concomitant administration of non-live vaccines according to national vaccination schedules may be considered during DEFRA ^® therapy. In a clinical study involving a total of 71 patients with relapsing remitting multiple sclerosis, patients on DEFRA ^® 240 mg twice daily for at least 6 months (n=38) or non-pegylated interferon for at least 3 months (n=33), mounted a comparable immune response (defined as ≥2-fold increase from pre- to post-vaccination titer) to tetanus toxoid (recall antigen) and a conjugated meningococcal C polysaccharide vaccine (neoantigen), while the immune response to different serotypes of an unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell independent antigen) varied in both treatment groups. A positive immune response defined as a ≥4-fold increase in antibody titer to the three vaccines, was achieved by fewer subjects in both treatment groups. Small numerical differences in the response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were noted in favour of non-pegylated interferon.

No clinical data are available on the efficacy and safety of live attenuated vaccines in patients taking DEFRA ^®. Live vaccines might carry an increased risk of clinical infection and should not be given to patients treated with DEFRA

® unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating.

During treatment with DEFRA ®, 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.

Evidence from healthy volunteer studies suggests that DEFRA ® -associated flushing is likely to be prostaglandin mediated. In two healthy volunteer studies, the administration of 325 mg (or equivalent) non-enteric coated acetylsalicylic acid, 30 minutes prior to DEFRA ®, dosing over 4 days and over 4 weeks, respectively, did not alter the pharmacokinetic profile of. Potential risks associated with acetylsalicylic acid therapy should be considered prior to co-administration with DEFRA ® in patients with Relapsing Remitting MS. Long term (> 4 weeks) continuous use of acetylsalicylic acid has not been studied (see sections DEFRA ® 4.4 and 4.8).

Concurrent therapy with nephrotoxic medicinal products (such as aminoglycosides, diuretics, non-steroidal anti-inflammatory drugs or lithium) may increase the potential of renal adverse reactions (e.g. proteinuria see section 4.8) in patients taking DEFRA ® (see section 4.4 Blood/laboratory tests).

Consumption of moderate amounts of alcohol did not alter exposure to dimethyl fumarate and was not associated with an increase in adverse reactions. Consumption of large quantities of strong alcoholic drinks (more than 30% alcohol by volume) should be avoided within an hour of taking DEFRA ®, as alcohol may lead to increased frequency of gastrointestinal adverse reactions.

In vitro CYP induction studies did not demonstrate an interaction between DEFRA ® and oral contraceptives. In an in vivo study, co-administration of DEFRA ® 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 DEFRA ® on their exposure is not expected.

Paediatric population

Interaction studies have only been performed in adults.

DEFRA ^® has no or negligible influence on the ability to drive and use machines. No studies on the ability to drive and use machines have been conducted but no effects potentially influencing this ability were found to be related to dimethyl fumarate in clinical studies

Summary of the safety profile

The most common adverse reactions (incidence ≥10%) for patients treated with dimethyl fumarate 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 DEFRA

®. The most commonly reported adverse reactions leading to discontinuation (incidence >1%) in patients treated with DEFRA ® were flushing (3%) and gastrointestinal events (4%).

In placebo-controlled and uncontrolled clinical studies, a total of 2,468 patients have received DEFRA ® 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 DEFRA ®. 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 DEFRA ® 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 DEFRA ® 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 DEFRA ® 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 (frequency cannot be estimated from the available data)

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 DEFRA ^® 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 DEFRA ^®. In patients with flushing, the majority had flushing events that were mild or moderate in severity. Overall, 3% of patients treated with DEFRA ^® 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 DEFRA ^® (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 DEFRA ^® 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 DEFRA ^®. In the majority of patients who experienced gastrointestinal events, it was mild or moderate in severity. Four per cent (4%) of patients treated with DEFRA ^® discontinued due to gastrointestinal events. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% of patients treated with DEFRA ^® (see section 4.2).

Hepatic function

Based on data from placebo-controlled studies, 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 DEFRA ^® 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 DEFRA ^®. Discontinuations due to elevated hepatic transaminases were <1% and similar in patients treated with DEFRA ^® 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 DEFRA ^® administration, which resolved upon treatment discontinuation.

Lymphopenia

In the placebo-controlled studies most patients (>98%) had normal lymphocyte values prior to initiating treatment. Upon treatment with DEFRA ^®, 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 DEFRA ^®. A lymphocyte count <0.2x10⁹/l was observed in 1 patient treated with DEFRA ^® and in no patients treated with placebo.

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, and in this group the majority of lymphocyte counts remained <0.5 x 10⁹/L with continued therapy.

PML has occurred in the setting of moderate to severe prolonged lymphopenia (see section 4.4).

Laboratory abnormalities

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

Levels of 1,25-dihydroxyvitamin D decreased in DEFRA ^® 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 DEFRA ^® 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.

A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.

Paediatric population

The safety of DEFRA ^® in paediatric patients with multiple sclerosis below the age of 18 has not yet been established. In a small 24-week open-label uncontrolled study in paediatric patients with RRMS aged 13 to 17 years (120 mg twice a day for 7 days followed by 240 mg twice a day for the remainder of treatment; safety population, n=22), the safety profile appeared similar to that observed in adult patients.

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.

To report any side effect(s):

• Saudi Arabia:

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

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, ATC code: L04AX07

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, dimethyl fumarate 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 (T

H1, 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 in MS patients, upon treatment with DEFRA ® mean lymphocyte counts decreased on average by approximately 30% of their baseline value over the first year with a subsequent plateau.

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, in the 6 weeks before 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 DEFRA ® 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.

^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

DEFRA ^® was evaluated in a prospective open-label, uncontrolled study in 22 paediatric patients with RRMS aged 13 to 17 years (4 patients aged ≤14 years). Subjects received DEFRA ^® 120 mg twice a day for 7 days followed by 240 mg twice a day for 24 weeks. The median number of new or newly enlarging T2 hyperintense lesions changed from 2 in the 8 week pre-treatment evaluation period to 0 in the final 8 weeks of the treatment period (median change -2, n=16). These data should be considered cautiously regarding limitations of the study design (no control arm, pre- versus post-dose comparison) (see section 4.2).

Orally administered 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 DEFRA ^®. 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 T_max of monomethyl fumarate is 2 to 2.5 hours. As DEFRA ^® 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 (C_max) was 1.72 mg/l and overall area under the curve (AUC) exposure was 8.02 h.mg/l in subjects with multiple sclerosis. Overall, C_max 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, DEFRA ^® 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 dimethyl fumarate 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 C_max and AUC) in 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 pharmacokinetic profile of 240 mg dimethyl fumarate twice a day was evaluated in a small, open-label, uncontrolled study in patients with RRMS aged 13 to 17 years (n=21). The pharmacokinetics of DEFRA ^® in these adolescent patients was consistent with that previously observed in adult patients (C_max: 2.00±1.29 mg/l; AUC_0-12hr: 3.62±1.16 h.mg/l, which corresponds to an overall daily AUC of 7.24 h.mg/l).

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.

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

Not applicable

Store below 30^oC in a dry place. Protect from light.

Keep out of reach of children.

As with all medicines, keep this product out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

DEFRA ^® 120mg delayed release capsules: 25 micron Aluminium foil / 6-8 gsm HSL,/ Clear PVC/PE/PVdC film 250/25/90 gsm

DEFRA ^® 240mg delayed release capsules: 25 micron Aluminium foil / 6-8 gsm HSL,/ Clear PVC/PE/PVdC film 250/25/90 gsm

No special requirements.

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