VUMERITY 231mg gastro-resistant capsules medication leaflet

Vumerity 231 mg gastro-resistant hard capsules

Each gastro-resistant hard capsule contains 231 mg diroximel fumarate.

For the full list of excipients, see section 6.1.

Gastro-resistant hard capsule

White capsule, size 0 (approximately 22 mm in length), printed with ‘DRF 231 mg’ in black ink.

Vumerity 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 ofmultiple sclerosis.

The starting dose is 231 mg twice a day. After 7 days, the dose should be increased to therecommended maintenance dose of 462 mg twice a day (see section 4.4).

Temporary dose reductions to 231 mg twice a day may reduce the occurrence of flushing andgastrointestinal adverse reactions. Within 1 month, the recommended dose of 462 mg twice a dayshould be resumed.

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.

Based on uncontrolled study data, the safety profile of diroximel fumarate in patients ≥55 years of ageseems to be comparable to patients <55 years of age. Clinical studies with diroximel fumarate hadlimited exposure to patients aged 65 years and above and did not include sufficient numbers ofpatients aged 65 years and above to determine whether they respond differently than younger patients(see section 5.2). Based on the mechanism of action of the active substance there are no theoreticalreasons for any requirement for dose adjustments in the elderly.

No dose adjustment is necessary in patients with renal impairment (see section 5.2). Long-term safetyof diroximel fumarate has not been studied in patients with moderate or severe renal impairment (seesections 4.4 and 5.2).

No dose adjustment is necessary for patients with hepatic impairment (see sections 4.4 and 5.2).

Diroximel fumarate has not been studied in patients with hepatic impairment.

The safety and efficacy of Vumerity in children and adolescents aged 10 to less than 18 years have notyet been established.

There is no relevant use of Vumerity in children aged less than 10 years for the indication of relapsingremitting multiple sclerosis.

For oral use.

Vumerity should be swallowed whole and intact. The capsules should not be crushed or chewed andthe contents should not be sprinkled on food because the enteric-coating of the capsule contentsprevents irritant effects on the gut.

Vumerity can be taken with or without food (see section 5.2). For those patients who may experienceflushing or gastrointestinal adverse reactions, taking with food may improve tolerability (see sections4.4 and 4.8).

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or other fumaricacid esters (see section 4.5).

Suspected or confirmed Progressive Multifocal Leukoencephalopathy (PML).

Diroximel fumarate and dimethyl fumarate are metabolised to monomethyl fumarate upon oraladministration (see section 5.2). The risks associated with diroximel fumarate are expected to besimilar to those reported for dimethyl fumarate even though not all the risks listed below have beenobserved specifically for diroximel fumarate.

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 with Vumerity, after 3 and 6 months of treatment, every 6 to 12 months thereafter and asclinically indicated.

Drug-induced liver injury, including liver enzyme increase (≥ 3 x upper limit of normal (ULN)) andelevation of total bilirubin levels (≥ 2 x ULN) can result from treatment with dimethyl fumarate. Thetime to onset can be directly, 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 diroximel fumarate may develop lymphopenia (see section 4.8). Prior to initiatingtreatment, a current complete blood count, including lymphocytes, must be performed. If thelymphocyte count is found to be below the normal range, a thorough assessment of possible causesshould be completed prior to initiation of treatment. Vumerity has not been studied in patients withpre-existing low lymphocyte counts and caution should be exercised when treating these patients.

Treatment should not be initiated in patients with severe lymphopenia (lymphocyte counts<0.5 x 109/L).

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

Enhanced vigilance due to an increased risk for Progressive Multifocal Leukoencephalopathy (PML)is recommended in patients with lymphopenia as follows:

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

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

- In patients with lymphocyte counts below LLN, as defined by local laboratory reference range,regular monitoring of absolute lymphocyte counts is recommended. Additional factors thatmight further augment the individual PML risk should be considered (see subsection on PML).

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 Vumerity aftertreatment discontinuation should be based on clinical judgement.

Magnetic resonance imaging (MRI)

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

PML has been reported in patients treated with dimethyl fumarate (see section 4.8). PML is anopportunistic infection caused by John Cunningham virus (JCV), which may be fatal or result insevere disability.

PML cases have occurred with dimethyl fumarate and other medicinal products containing fumaratesin the setting of lymphopenia (lymphocyte counts below lower limit of normal [LLN]). Prolongedmoderate to severe lymphopenia appears to increase the risk of PML with dimethyl fumarate,however, risk cannot be excluded in patients with mild lymphopenia.

Additional factors that might contribute to an increased risk for PML in the setting of lymphopeniaare:

- duration of Vumerity therapy. Cases of PML have occurred after approximately 1 to 5 years ofdimethyl fumarate treatment, although the exact relationship with duration of treatment isunknown.

- profound decreases in CD4+ and especially in CD8+ T cell counts, which are important forimmunological defense (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, Vumerity 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 or Vumerity 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 JCVinfection.

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

Prior treatment with immunosuppressive or immunomodulating therapies

No studies have been performed evaluating the efficacy and safety of diroximel fumarate whenswitching patients from other disease modifying therapies. The contribution of priorimmunosuppressive therapy to the development of PML is possible.

PML cases have occurred in patients who had previously been treated with natalizumab, for which

PML is an established risk. Physicians should be aware that cases of PML occurring following recentdiscontinuation of natalizumab may not have lymphopenia.

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

When switching patients from another disease modifying therapy to Vumerity, the half-life andmechanism of action of the other therapy should be considered in order to avoid an additive immuneeffect while at the same time, reducing the risk of reactivation of MS. A complete blood count isrecommended prior to treatment initiation and regularly during treatment (see Blood/laboratory testsabove).

The long-term safety of diroximel fumarate has not been studied in patients with moderate or severerenal impairment. Therefore, caution should be used when considering treatment in these patients (seesections 4.2 and 5.2).

Diroximel fumarate has not been studied in patients with severe hepatic impairment. Therefore,caution should be used when considering treatment in these patients (see sections 4.2 and 5.2).

Severe active gastrointestinal disease

Diroximel fumarate has not been studied in patients with severe active gastrointestinal disease.

Therefore, caution should be used when considering treatment in these patients.

Flushing

In dimethyl fumarate pivotal clinical trials, 3 patients out of a total of 2,560 patients treated withdimethyl fumarate experienced serious flushing symptoms that were probable hypersensitivity oranaphylactoid reactions. These adverse reactions were not life-threatening but led to hospitalisation.

Prescribers and patients should be alert to this possibility in the event of severe flushing reactions with

Vumerity (see sections 4.2, 4.5 and 4.8).

Data from healthy volunteer studies suggest that dimethyl fumarate-associated flushing is likely to beprostaglandin mediated. A short course of treatment with 75 mg non-enteric coated acetylsalicylic acidmay be beneficial in patients affected by intolerable flushing (see section 4.5). In two healthyvolunteer studies, the occurrence and severity of flushing over the dosing period was reduced.

Anaphylactic reactions

Cases of anaphylaxis/anaphylactoid reaction have been reported following dimethyl fumarateadministration 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, andmay be serious and life threatening. Patients should be instructed to discontinue Vumerity and seekimmediate medical care if they experience signs or symptoms of anaphylaxis. Treatment should not berestarted (see section 4.8).

In the phase 3 placebo-controlled studies with dimethyl fumarate, the incidence of infections (60%versus 58%) and serious infections (2% versus 2%) was similar in patients treated with dimethylfumarate or placebo, respectively.

Diroximel fumarate exerts immunomodulatory properties (see section 5.1).

Patients receiving Vumerity should be instructed to report symptoms of infections to a physician. If apatient develops a serious infection, suspending treatment should be considered and the benefits andrisks should be reassessed prior to re-initiation of therapy. Patients with serious infections should notstart treatment until the infection(s) is resolved.

There was no increased incidence of serious infections observed in patients treated with dimethylfumarate with lymphocyte counts < 0.8 x 109/L or < 0.5 x 109/L. If Vumerity therapy is continued inthe presence of moderate to severe prolonged lymphopenia, the risk of an opportunistic infection,including PML, cannot be ruled out (see subsection on PML).

Herpes zoster infections

Cases of herpes zoster have occurred with diroximel fumarate and dimethyl fumarate. The majority ofcases with dimethyl fumarate were non-serious, however, serious cases, including disseminated herpeszoster, herpes zoster ophthalmicus, herpes zoster oticus, herpes zoster infection neurological, herpeszoster meningoencephalitis and herpes zoster meningomyelitis have been reported. These events mayoccur at any time during treatment. Patients should be monitored for signs and symptoms of herpeszoster especially when concurrent lymphocytopenia is reported. If herpes zoster occurs, appropriatetreatment for herpes zoster should be administered. Withholding treatment should be considered inpatients with serious 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 for a medicinal product containing dimethyl fumaratein combination with other fumaric acid esters. Early diagnosis of Fanconi syndrome anddiscontinuation of Vumerity treatment are important to prevent the onset of renal impairment andosteomalacia, 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 withnon-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.

During treatment, simultaneous use of other fumaric acid esters (topical or systemic) should beavoided.

Vumerity should not be administered concomitantly with dimethyl fumarate.

Potential interaction risks were not identified from in vitro and/or in vivo inhibition studies oftransporters, from in vitro CYP-inhibition and induction studies, or studies of the protein binding ofdiroximel fumarate and its major metabolites, active metabolite monomethyl fumarate (MMF) andinactive metabolite 2-hydroxyethyl succinimide (HES).

Although not studied with diroximel fumarate, in vitro CYP induction studies did not demonstrate aninteraction between dimethyl fumarate and oral contraceptives. In an in vivo study, co-administrationof dimethyl fumarate with a combined oral contraceptive (norgestimate and ethinyl estradiol) did notelicit any relevant change in oral contraceptive exposure. No interaction studies have been performedwith oral contraceptives containing other progestogens, however an effect of diroximel fumarate ontheir exposure is not expected.

Diroximel fumarate has not been studied in combination with anti-neoplastic or immunosuppressivetherapies and caution should, therefore, be used during concomitant administration. In MS clinicalstudies, the concomitant treatment of relapses with a short course of intravenous corticosteroids wasnot associated with a clinically relevant increase of infection.

Concomitant administration of non-live vaccines according to national vaccination schedules may beconsidered during Vumerity therapy. In a clinical study involving a total of 71 patients with relapsingremitting multiple sclerosis (RRMS), patients on dimethyl fumarate 240 mg twice daily for at least6 months (n=38) or non-pegylated interferon for at least 3 months (n=33), mounted a comparableimmune response (defined as ≥ 2-fold increase from pre- to post-vaccination titre) to tetanus toxoid(recall antigen) and a conjugated meningococcal C polysaccharide vaccine (neoantigen), while theimmune response to different serotypes of an unconjugated 23-valent pneumococcal polysaccharidevaccine (T-cell independent antigen) varied in both treatment groups. A positive immune responsedefined as a ≥ 4-fold increase in antibody titre to the three vaccines, was achieved by fewer patients inboth treatment groups. Small numerical differences in the response to tetanus toxoid andpneumococcal 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

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

Evidence from healthy volunteer studies suggests that dimethyl fumarate-associated flushing is likelyto be prostaglandin mediated. In two healthy volunteer studies with dimethyl fumarate, theadministration of 325 mg (or equivalent) non enteric coated acetylsalicylic acid, 30 minutes prior todimethyl fumarate, dosing over 4 days and over 4 weeks, respectively, did not alter thepharmacokinetic profile of dimethyl fumarate. Potential risks associated with acetylsalicylic acidtherapy should be considered prior to co-administration with Vumerity in patients with relapsingremitting MS. Long term (> 4 weeks) continuous use of acetylsalicylic acid has not been studied (seesections 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 Vumerity (see section 4.4).

Interaction studies have only been performed in adults.

There are no or limited amount of data from the use of diroximel fumarate in pregnant women. Animalstudies have shown reproductive toxicity (see section 5.3). Vumerity is not recommended duringpregnancy and in women of childbearing potential not using appropriate contraception (seesection 4.5). Vumerity should be used during pregnancy only if clearly needed and if the potentialbenefit justifies the potential risk to the foetus.

It is unknown whether diroximel 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 Vumerity 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 Vumerity on human fertility. Data from animal studies withdiroximel fumarate showed no impairment of male or female fertility (see section 5.3).

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

Upon oral administration, diroximel fumarate and dimethyl fumarate are rapidly metabolised tomonomethyl fumarate before they reach the systemic circulation, adverse reactions are similar oncemetabolised.

The most common adverse reactions for dimethyl fumarate were flushing (35%) and gastrointestinalevents (i.e. diarrhoea 14%, nausea 12%, abdominal pain 10% and abdominal pain upper 10%). Themost commonly reported adverse reactions leading to discontinuation in patients treated with dimethylfumarate were flushing (3%) and gastrointestinal events (4%).

The adverse reactions which were more frequently reported in dimethyl fumarate-treated patients ascompared to placebo-treated patients from two pivotal phase 3 placebo controlled clinical trials andpost marketing experience are presented in Table 1.

The adverse reactions are presented as MedDRA preferred terms under the MedDRA system organclass (SOC). 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), and not known (frequency cannot be estimatedfrom the available data).

Table 1: Adverse reactions

MedDRA System Organ Class Adverse reaction Frequency category

Infections and infestations Gastroenteritis Common

Progressive multifocalleukoencephalopathy (PML)1 Not known

Herpes zoster1 Not known

Blood and lymphatic system Lymphopenia1, 2 Commondisorders Leukopenia 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 Flushing1 Very common

Hot flush Common

Respiratory, thoracic andmediastinal disorders Rhinorrhoea Not known

Gastrointestinal disorders Diarrhoea Very common

Nausea Very common

Abdominal pain upper Very common

Abdominal pain Very common

Vomiting Common

Dyspepsia Common

Gastritis Common

Gastrointestinal disorder Common

Hepatobiliary disorders Aspartate aminotransferaseincreased1 Common

Alanine aminotransferase increased1 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

MedDRA System Organ Class Adverse reaction Frequency category

Investigations Ketones measured in urine Very common

Albumin urine present Common

White blood cell count decreased Common1 See ‘Description of selected adverse reactions’ for further information2 Lymphopenia was reported with the frequency “very common” in a phase 3, open-label, uncontrolled studywith diroximel fumarate

Flushing

In the placebo-controlled dimethyl fumarate studies, the incidence of flushing (34% versus 5%) andhot flush (7% versus 2%) was increased in patients treated with dimethyl fumarate 240 mg twice dailycompared to placebo, respectively. Flushing is usually described as flushing or hot flush, but caninclude other events (e.g. warmth, redness, itching, and burning sensation). Flushing events tend tobegin early in the course of treatment (primarily during the first month) and in patients who experienceflushing, these events may continue to occur intermittently throughout treatment with dimethylfumarate. In patients with flushing, the majority had flushing events that were mild or moderate inseverity. Overall, 3% of patients treated with dimethyl fumarate discontinued due to flushing. Theincidence of serious flushing, which may be characterised by generalised erythema, rash and/orpruritus, was seen in less than 1% of patients treated with dimethyl fumarate (see sections 4.2, pct. 4.4and 4.5).

In the diroximel fumarate phase 3 double-blind trial (see section 5.1), flushing and hot flush werereported in 32.8% and 1.6% of diroximel fumarate-treated patients and in 40.6% and 0.8% of dimethylfumarate-treated patients. There were no serious events of flushing or discontinuations due to flushing.

Gastrointestinal

The incidence of gastrointestinal events (e.g. diarrhoea [14% versus 10%], nausea [12% versus 9%],upper abdominal pain [10% versus 6%], abdominal pain [9% versus 4%], vomiting [8% versus 5%]and dyspepsia [5% versus 3%]) was increased in patients treated with dimethyl fumarate compared toplacebo, respectively. Gastrointestinal events tend to begin early in the course of treatment (primarilyduring the first month) and in patients who experience gastrointestinal events, these events maycontinue to occur intermittently throughout treatment with dimethyl fumarate. In the majority ofpatients who experienced gastrointestinal events, it was mild or moderate in severity. Four per cent(4%) of patients treated with dimethyl fumarate discontinued due to gastrointestinal events. Theincidence of serious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% ofpatients treated with dimethyl fumarate (see section 4.4).

Gastrointestinal adverse reactions reported in the clinical study with diroximel fumarate and dimethylfumarate are presented in section 5.1.

Hepatic function

Based on data from placebo-controlled studies with dimethyl fumarate, the majority of patients withelevations had hepatic transaminases that were < 3 times the upper limit of normal (ULN). Theincreased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumaraterelative to placebo was primarily seen during the first 6 months of treatment. Elevations of alanineaminotransferase and aspartate aminotransferase ≥ 3 x ULN, respectively, were seen in 5% and 2% ofpatients treated with placebo and 6% and 2% of patients treated with dimethyl fumarate.

Discontinuations due to elevated hepatic transaminases were < 1% and similar in patients treated withdimethyl fumarate or placebo. Elevations in transaminases ≥ 3 x ULN with concomitant elevations intotal bilirubin > 2 x ULN indicative of drug-induced liver injury were not observed during placebo-controlled studies, but have been reported in post marketing experience following dimethyl fumarateadministration, which resolved upon treatment discontinuation.

Lymphopenia

In the diroximel fumarate phase 3, open-label, uncontrolled trial, treatment was discontinued inpatients with confirmed lymphocyte counts < 0.5 x 109/L which persisted for ≥ 4 weeks.

In the placebo-controlled studies for dimethyl fumarate, most patients (> 98%) had normal lymphocytevalues prior to initiating treatment. Upon treatment with dimethyl fumarate, mean lymphocyte countsdecreased over the first year with a subsequent plateau. On average, lymphocyte counts decreased byapproximately 30% of baseline value. Mean and median lymphocyte counts remained within normallimits. Lymphocyte counts < 0.5 x 109/L were observed in < 1% of patients treated with placebo and6% of patients treated with dimethyl fumarate. A lymphocyte count < 0.2 x 109/L was observed in1 patient treated with dimethyl fumarate and in no patients treated with placebo.

In clinical studies (both controlled and uncontrolled), 41% of patients treated with dimethyl fumaratehad lymphopenia (defined in these studies as < 0.91 x 109/L). Mild lymphopenia (counts ≥ 0.8 x 109/Lto < 0.91 x 109/L) was observed in 28% of patients; moderate lymphopenia (counts ≥ 0.5 x 109/L to< 0.8 x 109/L) persisting for at least six months was observed in 11% of patients; severe lymphopenia(counts < 0.5 x 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 x 109/L with continuedtherapy.

In addition, in an uncontrolled, prospective, post-marketing study, at week 48 of treatment withdimethyl fumarate (n=185) CD4+ T cells were moderately (counts ≥ 0.2 x 109/L to < 0.4 x 109/L) orseverely (< 0.2 x 109/L) decreased in up to 37% or 6% of patients, respectively, while CD8+ T cellswere more frequently reduced with up to 59% of patients at counts < 0.2 x 109/L and 25% of patientsat counts < 0.1 x 109/L.

In controlled and uncontrolled clinical studies, patients who discontinued dimethyl fumarate therapywith lymphocyte counts below the lower limit of normal (LLN) were monitored for recovery oflymphocyte count to the LLN (see section 5.1).

Cases of infections with JCV causing PML have been reported with dimethyl fumarate (seesection 4.4). PML may be fatal or result in severe disability. In one of the clinical trials, one patienttaking dimethyl fumarate developed PML in the setting of prolonged severe lymphopenia (lymphocytecounts predominantly < 0.5 x 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 x 109/L to <LLN, asdefined 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 x 109/L, whereas reductions in CD4+ T cells countswere variable (ranging from < 0.05 to 0.5 x 109/L) and correlated more with the overall severity oflymphopenia (< 0.5 x 109/L to <LLN). Consequently, the CD4+/CD8+ ratio was increased in thesepatients.

Prolonged moderate to severe lymphopenia appears to increase the risk of PML with dimethylfumarate and likewise diroximel fumarate, however, PML also occurred in patients treated withdimethyl fumarate with mild lymphopenia. Additionally, the majority of PML cases in the post-marketing setting have occurred in patients > 50 years.

Herpes zoster infections have been reported with dimethyl fumarate use. In the long-term extensionstudy, in which 1,736 MS patients were treated with dimethyl fumarate, 5% experienced one or moreevents of herpes zoster, the majority of which were mild to moderate in severity. Most patients,including those who experienced a serious herpes zoster infection, had lymphocyte counts above thelower limit of normal. In a majority of patients with concurrent lymphocyte counts below the LLN,lymphopenia was rated moderate or severe. In the post-marketing setting most cases of herpes zosterinfection were non-serious and resolved with treatment. Limited data is available on absolutelymphocyte count (ALC) in patients with herpes zoster infection in the post-marketing setting.

However, when reported, most patients experienced moderate (≥ 0.5 x 109/L to < 0.8 x 109/L) orsevere (< 0.5 x 109/L to 0.2 x 109/L) lymphopenia (see section 4.4).

In the placebo-controlled studies for dimethyl fumarate, measurement of urinary ketones (1+ orgreater) was higher in patients treated with dimethyl fumarate (45%) compared to placebo (10%). Nountoward clinical consequences were observed in clinical trials.

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

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

The safety of Vumerity in paediatric patients has not yet been established.

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.

In reported cases of overdose, the symptoms described were consistent with the known adversereaction profile of the product. There are no known therapeutic interventions to enhance elimination ofdiroximel fumarate nor is there a known antidote. In the event of overdose, it is recommended thatsymptomatic supportive treatment be initiated as clinically indicated.

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants. ATC code: L04AX09

The mechanism by which diroximel fumarate exerts therapeutic effects in MS is not fully understood.

Diroximel fumarate acts via the major active metabolite, monomethyl fumarate. Preclinical studiesindicate that the pharmacodynamic responses of monomethyl fumarate appears to be mediated, at leastin part, through activation of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptionalpathway. Dimethyl fumarate has been shown to up regulate Nrf2-dependent antioxidant genes inpatients.

Effects on Immune System

In clinical studies, dimethyl fumarate demonstrated anti-inflammatory and immunomodulatoryproperties. Dimethyl fumarate and monomethyl fumarate (the active metabolite of diroximel fumarateand dimethyl fumarate) significantly reduce immune cell activation and subsequent release ofpro-inflammatory cytokines in response to inflammatory stimuli and moreover affect lymphocytephenotypes through a down-regulation of pro-inflammatory cytokine profiles (TH1, TH17), and biasedtowards anti-inflammatory production (TH2). In phase 3 studies in MS patients (DEFINE, CONFIRMand ENDORSE), upon treatment with dimethyl fumarate mean lymphocyte counts decreased onaverage by approximately 30% of their baseline value over the first year with a subsequent plateau. Inthese studies, patients who discontinued dimethyl fumarate therapy with lymphocyte counts below thelower limit of normal (LLN, 910 cells/mm3) 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 dimethyl fumarate discontinuation. The estimated proportion of patientsrecovering to LLN (ALC ≥ 0.9 x 109/L) at Week 12 and Week 24, who had mild, moderate, or severelymphopenia at RBL are presented in Table 2, Table 3, and Table 4 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 LLNfrom the Recovery Baseline (RBL)

Table 2: 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 < 910 and ≥ 800 cells/mm3 at RBL, excluding patients with prolonged severelymphopenia.

Table 3: 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 < 800 and ≥ 500 cells/mm3 at RBL, excluding patients with prolonged severelymphopenia.

Table 4: 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 < 500 cells/mm3 at RBL, excluding patients with prolonged severe lymphopenia.

Diroximel fumarate and dimethyl fumarate are rapidly metabolised by esterases before they reach thesystemic circulation to the same active metabolite, monomethyl fumarate, upon oral administration.

The PK comparability of diroximel fumarate to dimethyl fumarate through the analysis ofmonomethyl fumarate exposure has been demonstrated (see section 5.2), thus efficacy profiles areexpected to be similar.

Clinical studies with dimethyl fumarate

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 below) 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 theyear 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 CONFIRMcontained a rater-blinded (i.e. study physician/ investigator assessing the response to study treatmentwas blinded) reference comparator of glatiramer 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 dimethyl fumarate had a clinically meaningful andstatistically significant reduction on the primary endpoint in study DEFINE, proportion of patientsrelapsed at 2 years; and the primary endpoint in study CONFIRM, annualised relapse rate (ARR) at2 years.

The ARR for glatiramer acetate and placebo was 0.286 and 0.401 respectively in study CONFIRM,corresponding to a reduction of 29% (p=0.013).

DEFINE CONFIRM

Placebo dimethyl Placebo dimethyl Glatiramerfumarate fumarate acetate240 mg 240 mgtwice 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

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 dimethyl fumarate in patients with RRMS. Of the 1,736 patients,approximately half (909, 52%) were treated for 6 years or longer. 501 patients were continuouslytreated with dimethyl fumarate 240 mg twice daily across all 3 studies and 249 patients who werepreviously treated with placebo in studies DEFINE and CONFIRM received treatment 240 mg twicedaily in study ENDORSE. Patients who received treatment twice daily continuously were treated forup to 12 years.

During study ENDORSE, more than half of all patients treated with dimethyl fumarate 240 mg twicedaily did not have a relapse. For patients continuously treated twice daily across all 3 studies, theadjusted ARR was 0.187 (95% CI: 0.156, 0.224) in studies DEFINE and CONFIRM and 0.141 (95%

CI: 0.119, 0.167) in study ENDORSE. For patients previously treated with placebo, the adjusted ARRdecreased from 0.330 (95% CI: 0.266, 0.408) in studies DEFINE and CONFIRM to 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 dimethyl fumarate 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

T1 lesions 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).

Clinical studies with Vumerity

The gastrointestinal tolerability of diroximel fumarate was evaluated in a randomised, multi-centre,phase 3 study (EVOLVE-MS-2) in 504 adult patients with RRMS. The study included a 5-week,double-blind treatment period with two treatment arms. Patients had a 1-week titration period andwere randomised (1:1) to receive diroximel fumarate 462 mg twice daily (n=253) or dimethylfumarate 240 mg twice daily (n=251). Patients had the following median baseline characteristics: age44 years, disease duration 6.0 years and EDSS score 2.5. In this study, GI tolerability was investigatedusing the Individual GI Symptom and Impact Scale (IGISIS), which evaluated the incidence, intensity,onset, duration, and functional impact of five individual GI symptoms: nausea, vomiting, upperabdominal pain, lower abdominal pain, and diarrhoea.

Overall gastrointestinal adverse reactions were observed in 34.8% of diroximel fumarate-treatedpatients and in 49.0% of dimethyl fumarate-treated patients. Treatment discontinuations were in total1.6% and 6.0%, for diroximel fumarate and dimethyl fumarate, respectively. The discontinuations forgastrointestinal tolerability reasons were 0.8% and 4.8%, for diroximel fumarate and dimethylfumarate, respectively. Treatment-emergent gastrointestinal adverse reactions of ≥ 5% for diroximelfumarate and dimethyl fumarate, respectively, were diarrhoea (15.4% and 22.3%), nausea (14.6% and20.7%), upper abdominal pain (6.7% and 15.5%), abdominal pain (6.3% and 9.6%), lower abdominalpain (5.9% and 6.8%), and vomiting (3.6% and 8.8%).

The efficacy of Vumerity in paediatric patients has not been established.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Vumerity in one or more subsets of the paediatric population in the treatment of MS (see section 4.2for information on paediatric use).

Orally administered diroximel fumarate undergoes rapid presystemic hydrolysis by esterases and isprimarily converted to the active metabolite, monomethyl fumarate, and the major inactive metabolite

HES. Diroximel fumarate is not quantifiable in plasma following oral administration. Therefore, allpharmacokinetic analyses related to diroximel fumarate were performed with plasma monomethylfumarate concentrations. Pharmacokinetic data were obtained from 10 clinical studies with healthyvolunteers, 2 studies with MS patients and population PK analyses. Pharmacokinetic assessment hasdemonstrated that the exposure of monomethyl fumarate after oral administration of 462 mg diroximelfumarate and 240 mg dimethyl fumarate in adults is bioequivalent; therefore, diroximel fumarate isexpected to provide a similar overall efficacy and safety profile to dimethyl fumarate.

The median Tmax of monomethyl fumarate is 2.5 to 3 hours. The peak plasma concentration (Cmax) andoverall exposure (AUC) increased dose proportionally in the dose range studied (49 mg to 980 mg).

Following administration of diroximel fumarate 462 mg twice a day in MS patients in EVOLVE-MS-1, the mean Cmax of monomethyl fumarate was 2.11 mg/L. The mean AUClast after a morning dose was4.15 mg.h/L. The mean steady state daily AUC (AUCss) of monomethyl fumarate was estimated to be8.32 mg.h/L in MS patients.

Co-administration of diroximel fumarate with a high-fat, high-calorie meal did not affect the AUC ofmonomethyl fumarate but resulted in an approximately 44% reduction in Cmax compared to fastedstate. The monomethyl fumarate Cmax with low-fat and medium-fat meals was reduced byapproximately 12% and 25%, respectively.

Food does not have a clinically significant effect on exposure of monomethyl fumarate. Therefore,

Vumerity may be taken with or without food (see section 4.2).

The apparent volume of distribution (Vd) for monomethyl fumarate is between 72 L and 83 L inhealthy subjects after administration of diroximel fumarate. Human plasma protein binding ofmonomethyl fumarate was less than 25% and was not concentration dependent.

In humans, diroximel fumarate is extensively metabolised by esterases, which are ubiquitous in thegastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Esterasemetabolism of diroximel fumarate produces predominantly both monomethyl fumarate, the activemetabolite, and HES, an inactive metabolite.

Further metabolism of monomethyl fumarate occurs through esterases followed by the tricarboxylicacid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. Fumaric and citricacid, and glucose are the resulting metabolites of monomethyl fumarate in plasma.

Monomethyl fumarate is mainly eliminated as carbon dioxide in the expired air with only traceamounts recovered in urine. The terminal half-life (t1/2) of monomethyl fumarate is approximately1 hour, and no accumulation in monomethyl fumarate plasma exposures occurred with multiple dosesof diroximel fumarate. In a study with dimethyl fumarate, exhalation of CO2 was determined to be theprimary route of elimination accounting for approximately 60% of the dose. Renal and faecalelimination are secondary routes of elimination, accounting for 15.5% and 0.9% of the dose,respectively.

HES is eliminated from plasma with a t1/2 of 10.7 hours to 14.8 hours. HES is mainly eliminated inurine.

Monomethyl fumarate exposure increases in an approximately dose proportional manner with singleand multiple doses in the 49 to 980 mg dose range studied.

Body weight is the main covariate with monomethyl fumarate exposure increasing in Cmax and AUC inparticipants with lower body weight after administration of diroximel fumarate. No effect was seen onsafety and efficacy measures evaluated in the clinical studies. Therefore, no dose adjustments based onbody weight are required.

Gender and age did not have a statistically significant impact on Cmax and AUC of diroximel fumarate.

The pharmacokinetics in patients aged 65 and over has not been studied.

The pharmacokinetic profile of monomethyl fumarate after administration of diroximel fumarate hasnot been studied. The pharmacokinetic parameters of monomethyl fumarate after administration ofdiroximel fumarate are correlated to body weight. Therefore, it is anticipated that the same dose leadsto a higher exposure in paediatric patients with lower body weight compared to adults. Thepharmacokinetic 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). Thepharmacokinetics of dimethyl fumarate in these adolescent patients was similar with that previouslyobserved in adult patients.

Race and ethnicity have no effect on the pharmacokinetic profile of monomethyl fumarate or HESafter administration of diroximel fumarate.

In a study investigating the effect of renal impairment on the pharmacokinetic profile of diroximelfumarate, participants with mild (eGFR 60-89 mL/min/1.73 m2), moderate renal impairment (eGFR30-59 mL/min/1.73 m2) or severe renal impairment (eGFR < 30 mL/min/1.73 m2) had no clinicallyrelevant changes in MMF exposure. However, HES exposure increased by 1.3-, 1.8-, and 2.7-fold withmild, moderate, and severe renal impairment, respectively (see section 4.8). There are no dataavailable on long-term use of diroximel fumarate in patients with moderate or severe renal impairment(see sections 4.2 and 4.4).

As diroximel fumarate and monomethyl fumarate are metabolised by esterases, without theinvolvement of the CYP450 system, evaluation of pharmacokinetics in individuals with hepaticimpairment was not conducted (see section 4.2 and 4.4).

Kidney toxicity in rats and monkeys included tubular degeneration/necrosis with regeneration, tubularhypertrophy and/or interstitial fibrosis, increased kidney weights, and changes in clinical pathologyparameters (urine volume, specific gravity, and biomarkers of kidney injury). In chronic toxicologystudies, adverse renal findings occurred at monomethyl fumarate exposure that equalled the AUC atthe maximum recommended human dose (MRHD) of diroximel fumarate.

Gastrointestinal toxicity in mice and rats consisted of mucosal hyperplasia and hyperkeratosis in thenon-glandular stomach (forestomach) and duodenum. In monkeys, the poor gastrointestinal tolerabilitywas characterised by dose-dependent emesis/vomitus, stomach irritation, haemorrhage andinflammation as well as diarrhoea. These findings developed at monomethyl fumarate exposure atleast 2 the AUC at the MRHD of diroximel fumarate.

Cardiac inflammation and necrosis was seen in three male rats in the 91-day toxicity study atmonomethyl fumarate exposure that was 4 the AUC at the MRHD of diroximel fumarate. Thesecardiac findings were also detected in other toxicity studies in rats including untreated controls, but notin monkeys. These cardiac inflammations therefore likely represent the exacerbation of commonbackground lesions in rats without human relevance.

Partially-reversible physeal dysplasia of proximal and distal femur and proximal tibia was seen inmonkeys in the 91-day toxicity study at monomethyl fumarate exposure that was 15 the AUC at the

MRHD of diroximel fumarate. Bone toxicity might be related to the pre-pupertal age of the monkeys,because bone development was also impaired in juvenile rats (see below), but not affected at lowerdoses in the chronic monkey study or in mature adult rats. The bone findings are of limited relevancefor adult patients at the therapeutic dose.

Testicular toxicity consisting of minimal germinal epithelial degeneration, increased incidence of giantspermatids, slight decrease in spermatids in the tubular epithelium, and decrease in testes weight wasobserved in wild type littermates of rasH2 mice. These findings occurred at monomethyl fumarateexposure that was 15 the AUC at the MRHD of diroximel fumarate, indicating limited humanrelevance at the therapeutic dose.

In vitro and in vivo studies with diroximel fumarate did not provide evidence for a clinically relevantgenotoxic potential.

Diroximel fumarate was tested in a transgenic bioassay in transgenic rasH2 mice and a 2 year bioassayin rats. Diroximel fumarate was not carcinogenic in transgenic mice and in female rats, but increasedthe incidence of testicular Leydig cell adenomas at 150 mg/kg/day in male rats (monomethyl fumarateexposure was approximately 2 higher than the AUC at the MRHD). The relevance of these findingsto human risk is unknown.

Reproduction and developmental toxicity

Diroximel fumarate did not impair male or female fertility in rats at monomethyl fumarate exposurethat was approximately 7 the AUC at the MRHD of diroximel fumarate.

In rats administered diroximel fumarate orally during the period of organogenesis at doses of 40, 100and 400 mg/kg/day lower fetal body weights and fetal skeletal ossification variations were observed ata maternally toxic diroximel fumarate dose of 400 mg/kg/day. The exposure at the NOAEL wasapproximately 2 the AUC of monomethyl fumarate at the MRHD of diroximel fumarate.

In rabbits administered diroximel fumarate orally throughout organogenesis at doses of 50, 150 and350 mg/kg/day, increases in skeletal malformations (vertebral centra anomaly, severely malalignedsternebra[e] and vertebral anomaly with associated rib anomaly) were observed at ≥ 150 mg/kg/day.

At 350 mg/kg/day, increases in skeletal variations, abortions, higher post-implantation loss andcorresponding decreases in fetal viability also occurred, possibly associated with maternal toxicity .

The exposure at the NOAEL was approximately 2 the AUC of monomethyl fumarate at the MRHDof diroximel fumarate. The relevance of the skeletal malformations for humans is currently unknown.

In a pre- and post-natal development study in pregnant rats administered diroximel fumarate at oraldoses of 40, 100, or 400 mg/kg/day during gestation through delivery and lactation reduced maternalbody weight/weight gains and food consumption associated with reduced pup birth weights and bodyweight/weight gains were observed. The exposure at the NOAEL was approximately 3 the AUC ofmonomethyl fumarate at the MRHD of diroximel fumarate.

Toxicity in juvenile animals

In a juvenile rat toxicity study, diroximel fumarate was administered orally from postnatal day(PND) 25 through PND 63, equivalent to approximately 2-3 years old through to puberty in humans.

In addition to the target organ toxicities in the kidney and non-glandular stomach, adverse effects inthe bone were observed including decreased femur size, mass and density and changes in bonegeometry. A relation of the bone effects to lower body weight is possible, but the involvement of adirect effect cannot be excluded. The exposure at the NOAEL was approximately 1.4 the AUC ofmonomethyl fumarate at the MRHD for adult patients of diroximel fumarate. The bone findings are oflimited relevance for adult patients. The relevance for paediatric patients is not known.

Methacrylic acid-ethyl acrylate copolymer (1: 1) type A

Crospovidone type A

Cellulose, microcrystalline

Silica, colloidal anhydrous

Triethyl citrate

Talc

Magnesium stearate

Hypromellose

Titanium dioxide (E171)

Potassium chloride

Carrageenan

Capsule print (black ink)

Shellac

Potassium hydroxide

Black iron oxide (E172)

Not applicable.

32 months

Store below 25°C.

Store in the original bottle in order to protect from moisture.

HDPE bottle with a polypropylene child-resistant closure and a silica gel desiccant.

Packs of 120 (1 bottle) or 360 (3 bottles) gastro-resistant hard capsules.

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/1/21/1585/001

EU/1/21/1585/002

Date of first authorisation: 15 November 2021

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

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