Dimethyl Fumarate 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.
Dimethyl Fumarate Delayed Release Capsules should be taken with food (see section 5.2). For those patients who may experience flushing or gastrointestinal adverse reactions, taking Dimethyl Fumarate Delayed Release Capsules with food may improve tolerability (see sections 4.4, 4.5 and 4.8).
Special populations Elderly
Clinical studies of Dimethyl Fumarate Delayed Release Capsules 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
Dimethyl Fumarate Delayed Release Capsules 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).
Pediatric population
The safety and efficacy of Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules, 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 Dimethyl Fumarate Delayed Release Capsules.
After starting therapy, complete blood counts, including lymphocytes, must be performed every 3 months.
Interruption of Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules, 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, Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules when switching patients from other disease modifying therapies to Dimethyl Fumarate Delayed Release Capsules. 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 Dimethyl Fumarate Delayed Release Capsules, 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 Dimethyl Fumarate Delayed Release Capsules and regularly during treatment (see Blood/laboratory tests above).
Dimethyl Fumarate Delayed Release Capsules can generally be started immediately after discontinuation of interferon or glatiramer acetate.
Severe renal and hepatic impairment
Dimethyl Fumarate Delayed Release Capsules 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
Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules or placebo, respectively. However, due to Dimethyl Fumarate Delayed Release Capsules immunomodulatory properties (see section 5.1), if a patient develops a serious infection, suspending treatment with Dimethyl Fumarate
Delayed Release Capsules should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving Dimethyl Fumarate Delayed Release Capsules should be instructed to report symptoms of infections to a physician. Patients with serious infections should not start treatment with Dimethyl Fumarate Delayed Release Capsules 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
Dimethyl Fumarate Delayed Release Capsules treatment should be started gradually to reduce the occurrence of flushing and gastrointestinal adverse reactions (see section 4.2).

Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules therapy. In a clinical study involving a total of 71 patients with relapsing remitting multiple sclerosis, patients on Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules. Live vaccines might carry an increased risk of clinical infection and should not be given to patients treated with Dimethyl Fumarate
Delayed Release Capsules unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating.
During treatment with Dimethyl Fumarate Delayed Release Capsules, 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 Dimethyl Fumarate Delayed Release Capsules-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 Dimethyl Fumarate Delayed Release Capsules, dosing over 4 days and over 4 weeks, respectively, did not alter the pharmacokinetic profile of Dimethyl Fumarate Delayed Release Capsules. Potential risks associated with acetylsalicylic acid therapy should be considered prior to co-administration with Dimethyl Fumarate Delayed Release Capsules in patients with Relapsing Remitting MS. Long term (> 4 weeks) continuous use of acetylsalicylic acid has not been studied (see sections 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 Dimethyl Fumarate Delayed Release Capsules (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 Dimethyl Fumarate Delayed Release Capsules, as alcohol may lead to increased frequency of gastrointestinal adverse reactions.
In vitro CYP induction studies did not demonstrate an interaction between Dimethyl Fumarate Delayed Release Capsules and oral contraceptives. In an in vivo study, co-administration of Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules on their exposure is not expected.
Paediatric population
Interaction studies have only been performed in adults.

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). Dimethyl Fumarate Delayed Release Capsules is not recommended during pregnancy and in women of childbearing potential not using appropriate contraception (see section 4.5). Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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 dimethyl fumarate 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).

Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules. The most commonly reported adverse reactions leading to discontinuation (incidence >1%) in patients treated with Dimethyl Fumarate Delayed Release Capsules were flushing (3%) and gastrointestinal events (4%).
In placebo-controlled and uncontrolled clinical studies, a total of 2,468 patients have received Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules. 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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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)

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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules. In patients with
flushing, the majority had flushing events that were mild or moderate in severity. Overall, 3% of patients treated with Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules (see sections 4.2, 4.4 and 4.5).
Gastrointestinal
The incidence of gastrointestinal events (e.g. diarrhea [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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules. In the majority of patients who experienced gastrointestinal events, it was mild or moderate in severity. Four per cent (4%) of patients treated with Dimethyl Fumarate Delayed Release Capsules discontinued due to gastrointestinal events. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% of patients treated with Dimethyl Fumarate Delayed Release Capsules (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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules. Discontinuations due to elevated hepatic transaminases were <1% and similar in patients treated with Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules, 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 Dimethyl Fumarate Delayed Release Capsules. A lymphocyte count <0.2x109/l was observed in 1 patient treated with Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules (45%) compared to placebo (10%). No untoward clinical consequences were observed in clinical trials.
Levels of 1,25-dihydroxyvitamin D decreased in Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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.
Pediatric population
The safety of Dimethyl Fumarate Delayed Release Capsules 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 pediatric 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.

Cases of overdose with Dimethyl Fumarate Delayed Release Capsules have been reported. The symptoms described in these cases were consistent with the known adverse reaction profile of Dimethyl Fumarate Delayed Release Capsules. There are no known therapeutic interventions to enhance elimination of Dimethyl
Fumarate 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: 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, 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 (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 in MS patients, upon treatment with Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules 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.

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).
Pediatric population
Dimethyl Fumarate Delayed Release Capsules was evaluated in a prospective open-label, uncontrolled study in 22 pediatric patients with RRMS aged 13 to 17 years (4 patients aged ≤14 years). Subjects received Dimethyl Fumarate Delayed Release Capsules 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 Dimethyl Fumarate Delayed Release Capsules. 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 Dimethyl Fumarate Delayed Release 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 area under the curve (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 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, Dimethyl Fumarate Delayed Release Capsules 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 Cmax 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 Dimethyl
Fumarate in these adolescent patients was consistent with that previously observed in adult patients (Cmax: 2.00±1.29 mg/l; AUC0-12hr: 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.

Microcrystalline cellulose (PH 102), Croscarmellose sodium, Talc, Colloidal Silica dioxide, Magnesium stearate, Methacrylic acid methyl methacrylate copolymer (1:1), Triethyl citrate, Talc, Isopropyl alcohol, purified water, Methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30%, Size ''0'' empty hard gelatin capsule shell with white opaque cap and white opaque body imprinted with ''120 mg'' with black in, Size ''0'' empty hard gelatin capsule shell with white opaque cap and white opaque body imprinted with ''240 mg'' with black ink.

Not applicable.

Do not store above 30°C. Protect from light. Keep out of the sight and reach of children.

10's PVC/PE/PVdC-Alu Blister Pack

No special requirements.