TECFIDERA 240mg gastro-resistant capsules medication leaflet

Tecfidera 120 mg gastro-resistant hard capsules

Tecfidera 240 mg gastro-resistant hard capsules

Tecfidera 120 mg gastro-resistant hard capsules

Each gastro-resistant hard capsule contains 120 mg dimethyl fumarate.

Tecfidera 240 mg gastro-resistant hard capsules

Each gastro-resistant hard capsule contains 240 mg dimethyl fumarate.

For the full list of excipients, see section 6.1.

Gastro-resistant hard capsule

Tecfidera 120 mg gastro-resistant hard capsules

Green and white gastro-resistant hard capsules, size 0, printed with ‘BG-12 120 mg’ containingmicrotablets.

Tecfidera 240 mg gastro-resistant hard capsules

Green gastro-resistant hard capsules, size 0, printed with ‘BG-12 240 mg’ containing microtablets.

Tecfidera is indicated for the treatment of adult and paediatric patients aged 13 years and older withrelapsing remitting multiple sclerosis (RRMS).

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

The starting dose is 120 mg twice a day. After 7 days, the dose should be increased to therecommended 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 doseonly if they leave 4 hours between doses. Otherwise the patient should wait until the next scheduleddose.

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

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

Clinical studies of Tecfidera had limited exposure to patients aged 55 years and above, and did notinclude sufficient numbers of patients aged 65 and over to determine whether they respond differentlythan younger patients (see section 5.2). Based on the mode of action of the active substance there areno theoretical reasons for any requirement for dose adjustments in the elderly.

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

The posology is the same in adults and in paediatric patients aged 13 years and older.

There are limited data available in children between 10 and 12 years old. Currently available data aredescribed in sections 4.8 and 5.1 but no recommendation on a posology can be made.

The safety and efficacy of Tecfidera in children aged less than 10 years have not been established. Nodata are available.

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 thegastrointestinal tract.

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

Suspected or confirmed progressive multifocal leukoencephalopathy (PML).

Blood/laboratory tests

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

Hepatic function

Drug-induced liver injury, including liver enzyme increase (≥ 3 times 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 days, several weeks or longer. Resolution of the adverse reactions has beenobserved after treatment was discontinued. Assessment of serum aminotransferases (e.g. alanineaminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels arerecommended prior to treatment initiation and during treatment as clinically indicated.

Patients treated with Tecfidera may develop lymphopenia (see section 4.8). Prior to initiatingtreatment 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 causesshould be completed prior to initiation of treatment. Dimethyl fumarate has not been studied inpatients with pre-existing low lymphocyte counts and caution should be exercised when treating thesepatients. Treatment should not be initiated in patients with severe lymphopenia (lymphocyte counts< 0.5 × 109/L).

After starting therapy, complete blood counts, including lymphocytes, must be performed every3 months.

Enhanced vigilance due to an increased risk of PML is recommended in patients with lymphopenia asfollows:

- Treatment should be discontinued in patients with prolonged severe lymphopenia (lymphocytecounts < 0.5 × 109/L) persisting for more than 6 months.

- In patients with sustained moderate reductions of absolute lymphocyte counts ≥ 0.5 × 109/L to< 0.8 × 109/L for more than 6 months, the benefit/risk balance of treatment with Tecfiderashould be re-assessed.

- In patients with lymphocyte counts below lower limit of normal (LLN) as defined by locallaboratory reference range, regular monitoring of absolute lymphocyte counts is recommended.

Additional factors that might further augment the individual PML risk should be considered (seesubsection on PML below).

Lymphocyte counts should be followed until recovery (see section 5.1). Upon recovery and in theabsence of alternative treatment options, decisions about whether or not to restart Tecfidera aftertreatment discontinuation should be based on clinical judgement.

Magnetic resonance imaging (MRI)

Before initiating treatment with Tecfidera, a baseline MRI should be available (usually within3 months) as a reference. The need for further MRI scanning should be considered in accordance withnational and local recommendations. MRI imaging may be considered as part of increased vigilance inpatients considered at increased risk of PML. In case of clinical suspicion of PML, MRI should beperformed immediately for diagnostic purposes.

PML has been reported in patients treated with Tecfidera (see section 4.8). PML is an opportunisticinfection caused by John-Cunningham virus (JCV), which may be fatal or result in severe disability.

PML cases have occurred with dimethyl fumarate and other medicinal products containing fumaratesin the setting of lymphopenia (lymphocyte counts below LLN). Prolonged moderate to severelymphopenia appears to increase the risk of PML with Tecfidera, however, risk cannot be excluded inpatients with mild lymphopenia.

Additional factors that might contribute to an increased risk of PML in the setting of lymphopenia are:

- duration of Tecfidera therapy. Cases of PML have occurred after approximately 1 to 5 years oftreatment, although the exact relationship with duration of treatment is unknown.

- profound decreases in CD4+ and especially in CD8+ T cell counts, which are important forimmunological defence (see section 4.8), and

- prior immunosuppressive or immunomodulatory therapy (see below).

Physicians should evaluate their patients to determine if the symptoms are indicative of neurologicaldysfunction and, if so, whether these symptoms are typical of MS or possibly suggestive of PML.

At the first sign or symptom suggestive of PML, Tecfidera should be withheld and appropriatediagnostic evaluations, including determination of JCV DNA in cerebrospinal fluid (CSF) byquantitative polymerase chain reaction (PCR) methodology, need to be performed. The symptoms of

PML may be similar to an MS relapse. Typical symptoms associated with PML are diverse, progressover 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 andpersonality changes. Physicians should be particularly alert to symptoms suggestive of PML that thepatient may not notice. Patients should also be advised to inform their partner or caregivers about theirtreatment, since they may notice symptoms that the patient is not aware of.

PML can only occur in the presence of a JCV infection. It should be considered that the influence oflymphopenia on the accuracy of serum anti-JCV antibody testing has not been studied in dimethylfumarate treated patients. It should also be noted that a negative anti-JCV antibody test (in thepresence of normal lymphocyte counts) does not preclude the possibility of subsequent JCV infection.

If a patient develops PML, Tecfidera must be permanently discontinued.

Prior treatment with immunosuppressive or immunomodulating therapies

No studies have been performed evaluating the efficacy and safety of Tecfidera when switchingpatients from other disease modifying therapies to Tecfidera. The contribution of priorimmunosuppressive therapy to the development of PML in dimethyl fumarate treated patients ispossible.

PML cases have been reported in patients who had previously been treated with natalizumab, forwhich PML is an established risk. Physicians should be aware that cases of PML occurring followingrecent discontinuation of natalizumab may not have lymphopenia.

In addition, a majority of confirmed PML cases with Tecfidera occurred in patients with priorimmunomodulatory treatment.

When switching patients from another disease modifying therapy to Tecfidera, the half-life and modeof action of the other therapy should be considered in order to avoid an additive immune effect whileat the same time, reducing the risk of reactivation of MS. A complete blood count is recommendedprior to initiating Tecfidera and regularly during treatment (see Blood/laboratory tests above).

Severe renal or hepatic impairment

Tecfidera has not been studied in patients with severe renal or severe hepatic impairment and cautionshould, 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 cautionshould, therefore, be used in these patients.

Flushing

In clinical trials, 34% of Tecfidera treated patients experienced flushing. In the majority of patientswho experienced flushing, it was mild or moderate in severity. Data from healthy volunteer studiessuggest that dimethyl fumarate-associated flushing is likely to be prostaglandin mediated. A shortcourse of treatment with 75 mg non-enteric coated acetylsalicylic acid may be beneficial in patientsaffected by intolerable flushing (see section 4.5). In two healthy volunteer studies, the occurrence andseverity 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 experiencedserious flushing symptoms that were probable hypersensitivity or anaphylactoid reactions. Theseadverse reactions were not life-threatening, but led to hospitalisation. Prescribers and patients shouldbe 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 Tecfidera administration inthe post-marketing setting (see section 4.8). 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, andmay be serious and life-threatening. Patients should be instructed to discontinue Tecfidera and seekimmediate medical care if they experience signs or symptoms of anaphylaxis. Treatment should not berestarted (see section 4.8).

In phase 3 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. However, due to

Tecfidera immunomodulatory properties (see section 5.1), if a patient develops a serious infection,suspending treatment with Tecfidera should be considered and the benefits and risks should bereassessed prior to re-initiation of therapy. Patients receiving Tecfidera should be instructed to reportsymptoms of infections to a physician. Patients with serious infections should not start treatment with

Tecfidera until the infection(s) is(are) resolved.

There was no increased incidence of serious infections observed in patients with lymphocyte counts< 0.8 × 109/L or < 0.5 × 109/L (see section 4.8). If therapy is continued in the presence of moderate tosevere prolonged lymphopenia, the risk of an opportunistic infection, including PML, cannot be ruledout (see section 4.4 subsection PML).

Herpes zoster infections

Cases of herpes zoster have been reported with Tecfidera (see section 4.8). The majority of cases werenon-serious; however, serious cases, including disseminated herpes zoster, herpes zoster ophthalmicus,herpes zoster oticus, herpes zoster infection neurological, herpes zoster meningoencephalitis andherpes zoster meningomyelitis have been reported. These adverse reactions may occur at any timeduring the treatment. Patients should be monitored for signs and symptoms of herpes zoster, especiallywhen concurrent lymphocytopenia is reported. If herpes zoster occurs, appropriate treatment forherpes zoster should be administered. Withholding treatment should be considered in patients withserious infections until the infection has resolved (see section 4.8).

Treatment initiation

Treatment should be started gradually to reduce the occurrence of flushing and gastrointestinal adversereactions (see section 4.2).

Fanconi syndrome

Cases of Fanconi syndrome have been reported with a medicinal product containing dimethylfumarate in combination with other fumaric acid esters. Early diagnosis of Fanconi syndrome anddiscontinuation of dimethyl fumarate treatment are important to prevent the onset of renal impairmentand osteomalacia, as the syndrome is usually reversible. The most important signs are proteinuria,glucosuria (with normal blood sugar levels), hyperaminoaciduria and phosphaturia (possiblyconcurrent with hypophosphatemia). Progression might involve symptoms such as polyuria,polydipsia and proximal muscle weakness. In rare cases, hypophosphataemic osteomalacia with non-localised bone pain, elevated alkaline phosphatase in serum and stress fractures may occur.

Importantly, Fanconi syndrome can occur without elevated creatinine levels or low glomerularfiltration rate. In case of unclear symptoms, Fanconi syndrome should be considered and appropriateexaminations should be performed.

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially‘sodium free’.

Anti-neoplastic, immunosuppressive or corticosteroid therapies

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

Vaccines

Concomitant administration of non-live vaccines according to national vaccination schedules may beconsidered during Tecfidera therapy. In a clinical study involving a total of 71 patients with RRMS,patients on Tecfidera 240 mg twice daily for at least 6 months (n=38) or non-pegylated interferon forat least 3 months (n=33), mounted a comparable immune response (defined as ≥ 2-fold increase frompre- to post-vaccination titre) to tetanus toxoid (recall antigen) and a conjugated meningococcal Cpolysaccharide vaccine (neoantigen), while the immune response to different serotypes of anunconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell independent antigen) varied inboth treatment groups. A positive immune response defined as a ≥ 4-fold increase in antibody titre tothe three vaccines, was achieved by fewer subjects in both treatment groups. Small numericaldifferences in the response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were notedin favour of non-pegylated interferon.

No clinical data are available on the efficacy and safety of live attenuated vaccines in patients taking

Tecfidera. Live vaccines might carry an increased risk of clinical infection and should not be given topatients treated with Tecfidera unless, in exceptional cases, this potential risk is considered to beoutweighed by the risk to the individual of not vaccinating.

Other fumaric acid derivatives

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

In humans, dimethyl fumarate is extensively metabolised by esterases before it reaches the systemiccirculation and further metabolism occurs through the tricarboxylic acid cycle, with no involvement ofthe cytochrome P450 (CYP) system. Potential interaction risks were not identified from in vitro CYP-inhibition and induction studies, a p-glycoprotein study, or studies of the protein binding of dimethylfumarate and monomethyl fumarate (the primary metabolite of dimethyl fumarate).

Effects of other substances on dimethyl fumarate

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

Evidence from healthy volunteer studies suggests that Tecfidera-associated flushing is likely to beprostaglandin mediated. In two healthy volunteer studies, the administration of 325 mg (or equivalent)non-enteric coated acetylsalicylic acid, 30 minutes prior to Tecfidera, dosing over 4 days and over4 weeks, respectively, did not alter the pharmacokinetic profile of Tecfidera. Potential risks associatedwith acetylsalicylic acid therapy should be considered prior to co-administration with Tecfidera inpatients with RRMS. Long term (> 4 weeks) continuous use of acetylsalicylic acid has not beenstudied (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 Tecfidera (see section 4.4 Blood/laboratory tests).

Consumption of moderate amounts of alcohol did not alter exposure to dimethyl fumarate and was notassociated with an increase in adverse reactions. Consumption of large amounts of strong alcoholicdrinks (more than 30% alcohol by volume) should be avoided within an hour of taking Tecfidera, asalcohol may lead to increased frequency of gastrointestinal adverse reactions.

Effects of dimethyl fumarate on other substances

In vitro CYP induction studies did not demonstrate an interaction between Tecfidera and oralcontraceptives. In an in vivo study, co-administration of Tecfidera with a combined oral contraceptive(norgestimate and ethinyl oestradiol) 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.

Interaction studies have only been performed in adults.

A moderate amount of data on pregnant women are available (between 300-1,000 pregnancyoutcomes), based on a pregnancy registry and post-marketing spontaneous reports. In the Tecfiderapregnancy registry, 289 prospectively collected pregnancy outcomes were documented in patients with

MS who were exposed to dimethyl fumarate. The median duration of exposure to dimethyl fumaratewas 4.6 gestational weeks with limited exposure after the sixth gestational week (44 pregnancyoutcomes). Exposure to dimethyl fumarate during such early pregnancy indicates no malformative orfoeto/neonatal toxicity compared to the general population. The risk of longer dimethyl fumarateexposure or exposure in later stages of pregnancy is not known.

Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it ispreferable to avoid the use of Tecfidera during pregnancy. Tecfidera should be used during pregnancyonly if clearly needed and if the potential benefit justifies the potential risk to the foetus.

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

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

Tecfidera has no or negligible influence on the ability to drive and use machines.

The most common adverse reactions are flushing (35%) and gastrointestinal events (i.e. diarrhoea(14%), nausea (12%), abdominal pain (10%), abdominal pain upper (10%)). Flushing andgastrointestinal 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 tooccur intermittently throughout treatment with Tecfidera. The most commonly reported adversereactions leading to treatment discontinuation are flushing (3%) and gastrointestinal events (4%).

In phase 2 and 3 placebo-controlled and uncontrolled clinical studies, a total of 2,513 patients havereceived Tecfidera for periods of up to 12 years with an overall exposure equivalent to 11,318 person-years. A total of 1,169 patients have received at least 5 years of treatment with Tecfidera, and426 patients have received at least 10 years of treatment with Tecfidera. The experience inuncontrolled clinical trials is consistent with the experience in the placebo-controlled clinical trials.

Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneousreports, are presented in the table below.

The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ

Class. The incidence of the adverse reactions below is expressed according to the followingcategories:

- 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)

MedDRA system organ class Adverse reaction Frequency category

Infections and infestations Gastroenteritis Common

Progressive multifocalleukoencephalopathy (PML) Not known

Herpes zoster Not known

Blood and lymphatic system Lymphopenia Commondisorders Leucopenia Common

Thrombocytopenia Uncommon

Immune system disorders Hypersensitivity Uncommon

Anaphylaxis Not known

Dyspnoea Not known

Hypoxia Not known

Hypotension Not known

Angioedema Not known

Nervous system disorders Burning sensation Common

Vascular disorders Flushing Very common

Hot flush Common

Respiratory, thoracic andmediastinal disorders Rhinorrhoea Not known

Gastrointestinal disorders Diarrhoea Very common

MedDRA system organ class Adverse reaction Frequency category

Nausea Very common

Abdominal pain upper Very common

Abdominal pain Very common

Vomiting Common

Dyspepsia Common

Gastritis Common

Gastrointestinal disorder Common

Hepatobiliary disorders Aspartate aminotransferase increased Common

Alanine aminotransferase increased Common

Drug-induced liver injury Rare

Skin and subcutaneous tissue Pruritus Commondisorders Rash Common

Erythema Common

Alopecia Common

Renal and urinary disorders Proteinuria Common

General disorders andadministration site conditions Feeling hot Common

Investigations Ketones measured in urine Very common

Albumin urine present Common

White blood cell count decreased Common

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 continueto occur intermittently throughout treatment with Tecfidera. In patients with flushing, the majority hadflushing events that were mild or moderate in severity. Overall, 3% of patients treated with Tecfideradiscontinued due to flushing. The incidence of serious flushing, which may be characterised bygeneralised erythema, rash and/or pruritus, was seen in less than 1% of patients treated with Tecfidera(see sections 4.2, pct. 4.4 and 4.5).

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 adverse reactions tend to begin early in the course of treatment(primarily during the first month) and in patients who experience gastrointestinal events, these eventsmay continue to occur intermittently throughout treatment with Tecfidera. In the majority of patientswho experienced gastrointestinal events, it was mild or moderate in severity. Four per cent (4%) ofpatients treated with Tecfidera discontinued due to gastrointestinal adverse reactions. The incidence ofserious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% of patientstreated with Tecfidera (see section 4.2).

Hepatic function

Based on data from placebo-controlled studies, the majority of patients with elevations had hepatictransaminases that were < 3 times the ULN. The increased incidence of elevations of hepatictransaminases in patients treated with Tecfidera relative to placebo was primarily seen during the first6 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% and2% 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 postmarketing experience following Tecfidera administration, which resolved upon treatmentdiscontinuation.

Lymphopenia

In the placebo-controlled studies, most patients (> 98%) had normal lymphocyte counts prior toinitiating treatment. Upon treatment with Tecfidera, mean lymphocyte counts decreased over the firstyear with a subsequent plateau. On average, lymphocyte counts decreased by approximately 30% ofbaseline value. Mean and median lymphocyte counts remained within normal limits. Lymphocytecounts < 0.5 × 109/L were observed in < 1% of patients treated with placebo and 6% of patients treatedwith Tecfidera. A lymphocyte count < 0.2 × 109/L was observed in 1 patient treated with Tecfideraand in no patients treated with placebo.

In clinical studies (both controlled and uncontrolled), 41% of patients treated with Tecfidera hadlymphopenia (defined in these studies as < 0.91 × 109/L). Mild lymphopenia (counts ≥ 0.8 × 109/L to< 0.91 × 109/L) was observed in 28% of patients; moderate lymphopenia (counts ≥ 0.5 × 109/L to< 0.8 × 109/L) persisting for at least six months was observed in 11% of patients; severe lymphopenia(counts < 0.5 × 109/L) persisting for at least six months was observed in 2% of patients. In the groupwith severe lymphopenia, the majority of lymphocyte counts remained < 0.5 × 109/L with continuedtherapy.

In addition, in an uncontrolled, prospective, post-marketing study, at week 48 of treatment with

Tecfidera (n=185), CD4+ T cells were moderately (counts ≥ 0.2 × 109/L to < 0.4 × 109/L) or severely(<0.2 × 109/L) decreased in up to 37% or 6% of patients, respectively, while CD8+ T cells were morefrequently reduced with up to 59% of patients at counts < 0.2 × 109/L and 25% of patients at counts< 0.1 × 109/L. In controlled and uncontrolled clinical studies, patients who discontinued Tecfideratherapy with lymphocyte counts below the LLN were monitored for recovery of lymphocyte count tothe LLN (see section 5.1).

Cases of infections with John Cunningham virus (JCV) causing PML have been reported with

Tecfidera (see section 4.4). PML may be fatal or result in severe disability. In one of the clinical trials,1 patient taking Tecfidera developed PML in the setting of prolonged severe lymphopenia(lymphocyte counts predominantly < 0.5 × 109/L for 3.5 years), with a fatal outcome. In the post-marketing setting, PML has also occurred in the presence of moderate and mild lymphopenia(> 0.5 × 109/L to < LLN, as defined by local laboratory reference range).

In several PML cases with determination of T cell subsets at the time of diagnosis of PML,

CD8+ T cell counts were found to be decreased to < 0.1 × 109/L, whereas reductions in CD4+ T cellscounts were variable (ranging from < 0.05 to 0.5 × 109/L) and correlated more with the overallseverity of lymphopenia (< 0.5 × 109/L to < LLN). Consequently, the CD4+/CD8+ ratio was increasedin these patients.

Prolonged moderate to severe lymphopenia appears to increase the risk of PML with Tecfidera.

However, PML also occurred in patients with mild lymphopenia. Additionally, the majority of PMLcases in the post-marketing setting have occurred in patients > 50 years.

Herpes zoster infections

Herpes zoster infections have been reported with Tecfidera. In the long-term extension study, in which1,736 MS patients were treated, approximately 5% experienced one or more events of herpes zoster, ofwhich 42% were mild, 55% were moderate, and 3% were severe. The time to onset from first

Tecfidera dose ranged from approximately 3 months to 10 years. Four patients experienced seriousevents, all of which resolved. Most subjects, including those who experienced a serious herpes zosterinfection, had lymphocyte counts above the lower limit of normal. In a majority of subjects withconcurrent lymphocyte counts below the LLN, lymphopenia was rated moderate or severe. In the post-marketing setting, most cases of herpes zoster infection were non-serious and resolved with treatment.

Limited data are available on absolute lymphocyte count (ALC) in patients with herpes zosterinfection in the post-marketing setting. However, when reported, most patients experienced moderate(≥ 0.5 × 109/L to < 0.8 × 109/L) or severe (< 0.5 × 109/L to 0.2 × 109/L) lymphopenia (see section 4.4).

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

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

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

In a 96-week open-label, randomised active controlled trial paediatric patients with RRMS (n=7 aged10 to less than 13 years and n=71 aged 13 to less than 18 years) were treated with 120 mg twice a dayfor 7 days followed by 240 mg twice a day for the remainder of treatment. The safety profile inpaediatric patients appeared similar to that previously observed in adult patients.

The paediatric clinical trial design differed from the adult placebo-controlled clinical trials. Therefore,a contribution of clinical trial design to numerical differences in adverse events between the paediatricand adult populations, cannot be excluded. Gastrointestinal disorders as well as respiratory, thoracicand mediastinal disorders and the adverse events of headache and dysmenorrhea were more frequentlyreported (≥10%) in the paediatric population than in the adult population. These adverse events werereported in the following percentages in paediatric patients:

- Headache was reported in 28% of patients treated with Tecfidera versus 36% in patients treatedwith interferon beta-1a.

- Gastrointestinal disorders were reported in 74% of patients treated with Tecfidera versus 31% inpatients treated with interferon beta-1a. Among them, abdominal pain and vomiting were themost frequently reported with Tecfidera.

- Respiratory, thoracic and mediastinal disorders were reported in 32% of patients treated with

Tecfidera versus 11% in patients treated with interferon beta-1a. Among them, oropharyngealpain and cough were the most frequently reported with Tecfidera.

- Dysmenorrhea was reported in 17% of patients treated with Tecfidera versus 7% of patientstreated with interferon beta-1a.

In a small 24-week open-label uncontrolled study in paediatric patients with RRMS aged 13 to17 years (120 mg twice a day for 7 days followed by 240 mg twice a day for the remainder oftreatment; n=22), followed by a 96-week extension study (240 mg twice per day; n=20), the safetyprofile appeared similar to that observed in adult patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, ATC code: L04AX07

The mechanism by which dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fullyunderstood. Preclinical studies indicate that dimethyl fumarate pharmacodynamic responses appear tobe 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 antioxidantgenes in patients (e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1]).

Effects on the immune system

In preclinical and clinical studies, dimethyl fumarate demonstrated anti-inflammatory andimmunomodulatory properties. Dimethyl fumarate and monomethyl fumarate, the primary metaboliteof dimethyl fumarate, significantly reduced immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli in preclinical models. In clinical studieswith psoriasis patients, dimethyl fumarate affected lymphocyte phenotypes through a down-regulationof pro-inflammatory cytokine profiles (TH1, TH17), and biased towards anti-inflammatory production(TH2). Dimethyl fumarate demonstrated therapeutic activity in multiple models of inflammatory andneuroinflammatory injury. In phase 3 studies in MS patients (DEFINE, CONFIRM and ENDORSE),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. In these studies, patients whodiscontinued treatment with lymphocyte counts below the lower limit of normal (LLN, 0.9 × 109/L)were monitored for recovery of lymphocyte counts to the LLN.

Figure 1 shows the proportion of patients estimated to reach the LLN based on the Kaplan-Meiermethod without prolonged severe lymphopenia. The recovery baseline (RBL) was defined as the laston-treatment ALC prior to treatment discontinuation. The estimated proportion of patients recoveringto LLN (ALC ≥ 0.9 × 109/L) at Week 12 and Week 24, who had mild, moderate, or severelymphopenia at RBL are presented in Table 1, Table 2, and Table 3 with 95% pointwise confidenceintervals. The standard error of the Kaplan-Meier estimator of the survival function is computed using

Greenwood’s formula.

Figure 1: Kaplan-Meier method; proportion of patients with recovery to ≥ 910 cells/mm3(0.9 × 109/L) LLN from the recovery baseline (RBL)

Note: 500 cells/mm3, 800 cells/mm3, 910 cells/mm3 correspond to 0.5 × 109/L, 0.8 × 109/L and0.9 × 109/L respectively.

Table 1: Kaplan-Meier method; proportion of patients estimated to reach LLN, mildlymphopenia at the recovery baseline (RBL), excluding patients with prolonged severelymphopenia

Number of patients with mild Baseline Week 12 Week 24lymphopeniaa at risk N=86 N=12 N=4

Proportion reaching 0.81 0.90

LLN (95% CI) (0.71, 0.89) (0.81, 0.96)a Patients with ALC < 0.9 × 109/L and ≥ 0.8 × 109/L at RBL, excluding patients with prolonged severelymphopenia.

Table 2: Kaplan-Meier method; proportion of patients estimated to reach LLN, moderatelymphopenia at the recovery baseline (RBL), excluding patients with prolonged severelymphopenia

Number of patients with moderate Baseline Week 12 Week 24lymphopeniaa at risk N=124 N=33 N=17

Proportion reaching 0.57 0.70

LLN (95% CI) (0.46, 0.67) (0.60, 0.80)a Patients with ALC < 0.8 × 109/L and ≥ 0.5 × 109/L at RBL, excluding patients with prolonged severelymphopenia.

Table 3: Kaplan-Meier method; proportion of patients estimated to reach LLN, severelymphopenia at the recovery baseline (RBL), excluding patients with prolonged severelymphopenia

Number of patients with severe Baseline Week 12 Week 24lymphopeniaa at risk N=18 N=6 N=4

Proportion reaching 0.43 0.62

LLN (95% CI) (0.20, 0.75) (0.35, 0.88)a Patients with ALC < 0.5 × 109/L at RBL, excluding patients with prolonged severe lymphopenia.

Two, 2-year, randomised, double-blind, placebo-controlled studies (DEFINE with 1,234 patients and

CONFIRM with 1,417 patients) of patients with RRMS were performed. Patients with progressiveforms of MS were not included in these studies.

Efficacy (see Table 4) and safety were demonstrated in patients with expanded disability status scale(EDSS) scores ranging from 0 to 5 inclusive, who had experienced at least 1 relapse during the yearprior to randomisation, or, in the 6 weeks before randomisation had a brain MRI demonstrating at leastone gadolinium-enhancing (Gd+) lesion. Study CONFIRM contained a rater-blinded (i.e. studyphysician/investigator assessing the response to study treatment was blinded) reference comparator ofglatiramer acetate.

In DEFINE, patients had the following median baseline characteristics: age 39 years, disease duration7.0 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 CONFIRM, patients had the following median baseline characteristics: age 37 years, diseaseduration 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, patients treated with Tecfidera had a clinically meaningful and statisticallysignificant reduction on the primary endpoint in study DEFINE, proportion of patients relapsed at2 years; and the primary endpoint in study CONFIRM, annualised relapse rate (ARR) at 2 years.

Table 4: Clinical and MRI endpoints for studies DEFINE and CONFIRM

DEFINE CONFIRM

Placebo Tecfidera Placebo Tecfidera Glatiramer240 mg 240 mg acetatetwice a day twice a day

Clinical endpointsa

No. patients 408 410 363 359 350

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 disabilityprogression

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 disabilityprogression

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. patients 165 152 144 147 161

DEFINE CONFIRM

Placebo Tecfidera Placebo Tecfidera Glatiramer240 mg 240 mg acetatetwice a day twice a day

Mean (median) number of 16.5 3.2 19.9 5.7 9.6new 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 4.5new 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

An open non-controlled 8-year extension study (ENDORSE) enrolled 1,736 eligible RRMS patientsfrom the pivotal studies (DEFINE and CONFIRM). The primary objective of the study was to assessthe long-term safety of Tecfidera in patients with RRMS. Of the 1,736 patients, approximately half(909, 52%) were treated for 6 years or longer. 501 patients were continuously treated with Tecfidera240 mg twice daily across all 3 studies and 249 patients who were previously treated with placebo instudies DEFINE and CONFIRM received treatment 240 mg twice daily in study ENDORSE. Patientswho received treatment twice daily continuously were treated for up to 12 years.

During study ENDORSE, more than half of all patients treated with Tecfidera 240 mg twice daily didnot have a relapse. For patients continuously treated twice daily across all 3 studies, the adjusted ARRwas 0.187 (95% CI: 0.156, 0.224) in studies DEFINE and CONFIRM and0.141 (95% CI: 0.119, 0.167) in study ENDORSE. For patients previously treated with placebo, theadjusted ARR decreased from 0.330 (95% CI: 0.266, 0.408) in studies DEFINE and CONFIRMto 0.149 (95% CI: 0.116, 0.190) in study ENDORSE.

In study ENDORSE, the majority of patients (> 75%) did not have confirmed disability progression(measured as 6-month sustained disability progression). Pooled results from the three studiesdemonstrated Tecfidera treated patients had consistent and low rates of confirmed disabilityprogression with slight increase in mean EDSS scores across ENDORSE. MRI assessments (up toyear 6, including 752 patients who had previously been included in the MRI cohort of studies DEFINEand CONFIRM) showed that the majority of patients (approximately 90%) had no Gd-enhancinglesions. Over the 6 years, the annual adjusted mean number of new or newly enlarging T2 and new T1lesions remained low.

Efficacy in patients with high disease activity

In studies DEFINE and CONFIRM, consistent treatment effect on relapses in a subgroup of patientswith high disease activity was observed, whilst the effect on time to 3-month sustained disabilityprogression was not clearly established. Due to the design of the studies, high disease activity wasdefined as follows:

- Patients with 2 or more relapses in one year, and with one or more Gd-enhancing lesions onbrain 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 atleast 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or patientshaving an unchanged or increased relapse rate in the prior year as compared to the previous2 years (n=177 in DEFINE; n=141 in CONFIRM).

The safety and efficacy of Tecfidera in paediatric RRMS was evaluated in a randomised, open-label,active-controlled (interferon beta-1a) parallel group study in patients with RRMS aged 10 to less than18 years of age. One hundred and fifty patients were randomised to dimethyl fumarate (240 mg twicedaily oral) or interferon beta-1a (30 μg IM once a week) for 96 weeks. The primary endpoint was theproportion of patients free of new or newly enlarging T2 hyperintense lesions on brain MRI scans atweek 96. The main secondary endpoint was the number of new or newly enlarging T2 hyperintenselesions on brain MRI scans at week 96. Descriptive statistics are presented as no confirmatoryhypothesis was pre-planned for the primary endpoint.

The proportion of patients in the ITT population with no new or newly enlarging T2 MRI lesions atweek 96 relative to baseline was 12.8% for dimethyl fumarate versus 2.8% in the interferon beta-1agroup. The mean number of new or newly enlarging T2 lesions at week 96 relative to baseline,adjusted for baseline number of T2 lesions and age (ITT population excluding patients without MRImeasurements) was 12.4 for dimethyl fumarate and 32.6 for interferon beta-1a.

The probability for clinical relapse was 34% in the dimethyl fumarate group and 48% in the interferonbeta-1a group by the end of the 96 week open-label study period.

The safety profile in paediatric patients (aged 13 to less than 18 years of age) receiving Tecfidera wasqualitatively consistent with that previously observed in adult patients (see section 4.8).

Orally administered dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and isconverted to its primary metabolite, monomethyl fumarate, which is also active. Dimethyl fumarate isnot quantifiable in plasma following oral administration of Tecfidera. Therefore, all pharmacokineticanalyses related to dimethyl fumarate were performed with plasma monomethyl fumarateconcentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthyvolunteers.

The Tmax of monomethyl fumarate is 2 to 2.5 hours. As Tecfidera gastro-resistant hard capsulescontain microtablets, which are protected by an enteric coating, absorption does not commence untilthey leave the stomach (generally less than 1 hour). Following 240 mg twice a day administered withfood, the median peak (Cmax) was 1.72 mg/l and overall area under the curve (AUC) exposure was8.02 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, two240 mg doses were administered 4 hours apart as part of a three times a day dosing regimen. Thisresulted 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 timesdaily) 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 orgastrointestinal adverse events (see section 4.2).

The apparent volume of distribution following oral administration of 240 mg dimethyl fumarate variesbetween 60 L and 90 L. Human plasma protein binding of monomethyl fumarate generally rangesbetween 27% and 40%.

In humans, dimethyl fumarate is extensively metabolised with less than 0.1% of the dose excreted asunchanged dimethyl fumarate in urine. It is initially metabolised by esterases, which are ubiquitous inthe gastrointestinal tract, blood and tissues, before it reaches the systemic circulation. Furthermetabolism 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 thepredominant metabolite in human plasma. Other circulating metabolites included fumaric acid, citricacid and monomethyl fumarate. The downstream metabolism of fumaric acid occurs through thetricarboxylic acid cycle, with exhalation of CO2 serving as the primary route of elimination.

Exhalation of CO2 is the primary route of dimethyl fumarate elimination accounting for 60% of thedose. Renal and faecal elimination are secondary routes of elimination, accounting for 15.5% and0.9% of the dose respectively.

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

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

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 theclinical studies.

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

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

As dimethyl fumarate and monomethyl fumarate are metabolised by esterases, without theinvolvement of the CYP450 system, evaluation of pharmacokinetics in individuals with hepaticimpairment was not conducted.

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

Tecfidera 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 of7.24 h.mg/l).

The adverse reactions described in the Toxicology and Reproduction toxicity sections below were notobserved in clinical studies, but were seen in animals at exposure levels similar to clinical exposurelevels.

Dimethyl fumarate and monomethyl fumarate were negative in a battery of in vitro assays (Ames,chromosomal aberration in mammalian cells). Dimethyl fumarate was negative in the in vivomicronucleus assay in rats.

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 atdoses 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 equivalentexposure (AUC) to the recommended human dose. In rats, the incidence of renal tubular carcinomaand testicular Leydig cell adenoma was increased at 100 mg/kg/day, approximately 2 times higherexposure than the recommended human dose. The relevance of these findings to human risk isunknown.

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 tothe recommended human dose in rats (based on AUC). The forestomach in rodents does not have ahuman counterpart.

Nonclinical studies in rodent, rabbits, and monkeys were conducted with a dimethyl fumaratesuspension (dimethyl fumarate in 0.8% hydroxypropyl methylcellulose) administered by oral gavage.

The chronic toxicity study in dogs was conducted with oral administration of the dimethyl fumaratecapsule.

Kidney changes were observed after repeated oral administration of dimethyl fumarate in mice, rats,dogs, and monkeys. Renal tubular epithelial regeneration, suggestive of injury, was observed in allspecies. Renal tubular hyperplasia was observed in rats with lifetime dosing (2-year study). In dogsthat received daily oral doses of dimethyl fumarate for 11 months, the margin calculated for corticalatrophy was observed at 3 times the recommended dose based on AUC. In monkeys that receiveddaily oral doses of dimethyl fumarate for 12 months, single cell necrosis was observed at 2 times therecommended dose based on AUC. Interstitial fibrosis and cortical atrophy were observed at 6 timesthe 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 wereobserved 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 andhyperkeratosis; inflammation; and squamous cell papilloma and carcinoma in studies of 3 months orlonger in duration. The forestomach of mice and rats does not have a human counterpart.

Toxicity to reproduction and development

Oral administration of dimethyl fumarate to male rats at 75, 250, and 375 mg/kg/day prior to andduring mating had no effects on male fertility up to the highest dose tested (at least 2 times therecommended dose on an AUC basis). Oral administration of dimethyl fumarate to female rats at25, 100, and 250 mg/kg/day prior to and during mating, and continuing to Day 7 of gestation, inducedreduction in the number of oestrous stages per 14 days and increased the number of animals withprolonged dioestrus 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 foetuses produced.

Dimethyl fumarate has been shown to cross the placental membrane into foetal blood in rats andrabbits, with ratios of foetal to maternal plasma concentrations of 0.48 to 0.64 and 0.1 respectively. Nomalformations were observed at any dose of dimethyl fumarate in rats or rabbits. Administration ofdimethyl fumarate at oral doses of 25, 100, and 250 mg/kg/day to pregnant rats during the period oforganogenesis resulted in maternal adverse effects at 4 times the recommended dose on an AUC basis,and low foetal weight and delayed ossification (metatarsals and hindlimb phalanges) at 11 times therecommended dose on an AUC basis. The lower foetal weight and delayed ossification wereconsidered 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 duringorganogenesis had no effect on embryo-foetal development and resulted in reduced maternal bodyweight 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 andlactation resulted in lower body weights in the F1 offspring, and delays in sexual maturation in F1males at 11 times the recommended dose on an AUC basis. There were no effects on fertility in the F1offspring. The lower offspring body weight was considered secondary to maternal toxicity.

Toxicity in juvenile animals

Two toxicity studies in juvenile rats with daily oral administration of dimethyl fumarate from postnatalday (PND) 28 through PND 90 to 93 (equivalent to approximately 3 years and older in humans)revealed similar target organ toxicities in the kidney and forestomach as observed in adult animals. Inthe first study, dimethyl fumarate did not affect development, neurobehavior or male and femalefertility up to the highest dose of 140 mg/kg/day (approximately 4.6 times the recommended humandose based on limited AUC data in paediatric patients). Likewise, no effects on male reproductive andaccessory organs were observed up to the highest dimethyl fumarate dose of 375 mg/kg/day in thesecond study in male juvenile rats (about 15-times the putative AUC at the recommended paediatricdose). However, decreased bone mineral content and density in the femur and lumbar vertebrae wereevident in male juvenile rats. Bone densitometry changes were also observed in juvenile rats followingoral diroximel fumarate administration, another fumaric ester that is metabolised to the same activemetabolite monomethyl fumarate in vivo. The NOAEL for the densitometry changes in juvenile rats isapproximately 1.5 times the presumptive AUC at the recommended paediatric dose. A relation of thebone effects to lower body weight is possible, but the involvement of a direct effect cannot beexcluded. The bone findings are of limited relevance for adult patients. The relevance for paediatricpatients is not known.

Capsule contents (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

Gelatin

Titanium dioxide (E171)

Brilliant Blue FCF (E133)

Yellow iron oxide (E172)

Capsule print (black ink)

Shellac

Potassium hydroxide

Black iron oxide (E172)

Not applicable.

4 years

Do not store above 30ºC.

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

120 mg gastro-resistant hard capsules14 gastro-resistant hard capsules in PVC/PE/PVDC-PVC aluminium blister packs.

240 mg gastro-resistant hard capsules56 or 168 gastro-resistant hard capsules in PVC/PE/PVDC-PVC aluminium blister packs.

Not all pack sizes may be marketed.

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

Biogen Netherlands B.V.

Prins Mauritslaan 131171 LP Badhoevedorp

The Netherlands

EU/1/13/837/001

EU/1/13/837/002

EU/1/13/837/003

Date of first authorisation: 30 January 2014

Date of latest renewal: 15 September 2023

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

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