4.1. Therapeutic indications

Dimethyl fumarate Gastro-resistant Capsules are indicated for the treatment of adult and paediatric patients aged 13 years and older with relapsing remitting multiple sclerosis (RRMS).

4.2. Posology and method of administration

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

Posology

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

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

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

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

Special populations

Elderly

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

Renal and hepatic impairment

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

Paediatric population

The 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 are described in sections 4.8 and 5.1, but no recommendation on a posology can be made.

The safety and efficacy of dimethyl fumarate in children aged less than 10 years have not been established. No data are available.

Method of administration

For oral use.

The capsule should be swallowed whole. The capsule or its contents should not be crushed, divided, dissolved, sucked or chewed as the enteric-coating of the minitablets prevents irritant effects on the gastrointestinal tract.

4.3. Contraindications

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

Suspected or confirmed progressive multifocal leukoencephalopathy (PML).

4.4. Special warnings and precautions for use

Blood/laboratory tests

Renal function

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

Hepatic function

Drug-induced liver injury, including liver enzyme increase (≥ 3 times upper limit of normal (ULN)) and elevation of total bilirubin levels (≥ 2 x 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 been observed after treatment was discontinued. Assessment of serum aminotransferases (e.g. alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels are recommended prior to treatment initiation and during treatment as clinically indicated.

Lymphocytes

Patients treated with dimethyl fumarate may develop lymphopenia (see section 4.8). Prior to initiating treatment with dimethyl fumarate, a current complete blood count, including lymphocytes, must be performed.

If lymphocyte count is found to be below the normal range, thorough assessment of possible causes should be completed prior to initiation of treatment. Dimethyl fumarate has not been studied in patients with pre-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 < 0.5×109/L).

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

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

• Treatment should be discontinued in patients with prolonged severe lymphopenia (lymphocyte counts < 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 Dimethyl fumarate Gastro resistant Capsules should be re-assessed.

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

Lymphocyte counts should be followed until recovery (see section 5.1). Upon recovery and in the absence of alternative treatment options, decisions about whether or not to restart Dimethyl fumarate Gastro-resistant Capsules after treatment discontinuation should be based on clinical judgement.

Magnetic resonance imaging (MRI)

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

Progressive multifocal leukoencephalopathy (PML)

PML has been reported in patients treated with dimethyl fumarate (see section 4.8). PML is an opportunistic infection 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 fumarates in the setting of lymphopenia (lymphocyte counts below LLN). Prolonged moderate 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 of PML in the setting of lymphopenia are:

– Duration of dimethyl fumarate therapy. Cases of PML have occurred after approximately 1 to 5 years of treatment, although the exact relationship with duration of treatment is unknown.

– Profound decreases in CD4+ and especially in CD8+ T cell counts, which are important for immunological 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 neurological dysfunction and, if so, whether these symptoms are typical of MS or possibly suggestive of PML.

At the first sign or symptom suggestive of PML, Dimethyl fumarate Gastro-resistant Capsules should be withheld and appropriate diagnostic evaluations, including determination of JCV DNA in cerebrospinal fluid (CSF) by quantitative 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, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. Physicians should be particularly alert to symptoms suggestive of PML that the patient may not notice. Patients should also be advised to inform their partner or caregivers about their treatment, 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 of lymphopenia on the accuracy of serum anti-JCV antibody testing has not been studied in dimethyl fumarate treated patients. It should also be noted that a negative anti-JCV antibody test (in the presence of normal lymphocyte counts) does not preclude the possibility of subsequent JCV infection.

If a patient develops PML, Dimethyl fumarate Gastro-resistant Capsules must be permanently discontinued.

Prior treatment with immunosuppressive or immunomodulating therapies

No studies have been performed evaluating the efficacy and safety of dimethyl fumarate when switching patients from other disease modifying therapies to dimethyl fumarate. The contribution of prior immunosuppressive therapy to the development of PML in dimethyl fumarate treated patients is possible.

PML cases have been reported 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 recent discontinuation of natalizumab may not have lymphopenia.

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

When switching patients from another disease modifying therapy to dimethyl fumarate, the half-life and mode of action of the other therapy should be considered in order to avoid an additive immune effect while at the same time, reducing the risk of reactivation of MS. A complete blood count is recommended prior to initiating Dimethyl fumarate Gastro-resistant Capsules and regularly during treatment (see Blood/laboratory tests above).

Severe renal or hepatic impairment

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

Severe active gastrointestinal disease

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

Flushing

In clinical trials, 34% of dimethyl fumarate treated patients experienced flushing. In the majority of patients who experienced flushing, it was mild or moderate in severity. Data from healthy volunteer studies suggest that dimethyl fumarate-associated flushing is likely to be prostaglandin mediated. A short course of treatment with 75 mg non-enteric coated acetylsalicylic acid may be beneficial in patients affected by intolerable flushing (see section 4.5). In two healthy volunteer studies, the occurrence and severity of flushing over the dosing period was reduced.

In clinical trials, 3 patients out of a total of 2,560 patients treated with dimethyl fumarate experienced serious flushing symptoms that were probable hypersensitivity or anaphylactoid reactions. These 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 (see sections 4.2, 4.5 and 4.8).

Anaphylactic reactions

Cases of anaphylaxis/anaphylactoid reaction have been reported following dimethyl fumarate administration in the 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, and may be serious and life threatening.

Patients should be instructed to discontinue Dimethyl fumarate Gastro-resistant Capsules and seek immediate medical care if they experience signs or symptoms of anaphylaxis. Treatment should not be restarted (see section 4.8).

Infections

In phase 3 placebo-controlled studies, the incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with dimethyl fumarate or placebo, respectively. However, due to dimethyl fumarate immunomodulatory properties (see section 5.1), if a patient develops a serious infection, suspending treatment with Dimethyl fumarate Gastro-resistant Capsules should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving Dimethyl fumarate Gastro-resistant Capsules should be instructed to report symptoms of infections to a physician. Patients with serious infections should not start treatment with this medicinal product 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 to severe prolonged lymphopenia, the risk of an opportunistic infection, including PML, cannot be ruled out (see section 4.4 subsection PML).

Herpes zoster infections

Cases of herpes zoster have been reported with dimethyl fumarate (see section 4.8). The majority of cases were non-serious, however, serious cases, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster oticus, herpes zoster infection neurological, herpes zoster meningoencephalitis and herpes zoster meningomyelitis have been reported. These adverse reactions may occur at any time during the treatment.

Patients should be monitored for signs and symptoms of herpes zoster especially when concurrent lymphocytopenia is reported. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered. Withholding treatment should be considered in patients 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 adverse reactions (see section 4.2).

Fanconi syndrome

Cases of Fanconi syndrome have been reported with a medicinal product containing dimethyl fumarate in combination with other fumaric acid esters. Early diagnosis of Fanconi syndrome and discontinuation of dimethyl fumarate treatment are important to prevent the onset of renal impairment and osteomalacia, as the syndrome is usually reversible. The most important signs are: proteinuria, glucosuria (with normal blood sugar levels), hyperaminoaciduria and phosphaturia (possibly concurrent 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 glomerular filtration rate. In case of unclear symptoms Fanconi syndrome should be considered and appropriate examinations should be performed.

4.5. Interaction with other medicinal products and other forms of interaction

Anti-neoplastic, immunosuppressive or corticosteroid therapies

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

Vaccines

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

No clinical data are available on the efficacy and safety of live attenuated vaccines in patients taking dimethyl fumarate. Live vaccines might carry an increased risk of clinical infection and should not be given to patients treated with Dimethyl fumarate Gastro-resistant Capsules unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating.

Other fumaric acid derivatives

During treatment with Dimethyl fumarate Gastro-resistant Capsules, simultaneous use of other fumaric acid derivatives (topical or systemic) should be avoided.

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

Effects of other substances on dimethyl fumarate

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

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

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

Consumption of moderate amounts of alcohol did not alter exposure to dimethyl fumarate and was not associated with an increase in adverse reactions. Consumption of large amounts of strong alcoholic drinks (more than 30% alcohol by volume) should be avoided within an hour of taking Dimethyl fumarate Gastro-resistant Capsules, as alcohol 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 dimethyl fumarate and oral contraceptives. In an in vivo study, co-administration of dimethyl fumarate 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 dimethyl fumarate on their exposure is not expected.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women are available (between 300-1,000 pregnancy outcomes), based on a pregnancy registry and post-marketing spontaneous reports. In the dimethyl fumarate pregnancy 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 fumarate was 4.6 gestational weeks with limited exposure after the sixth gestational week (44 pregnancy outcomes). Exposure to dimethyl fumarate during such early pregnancy indicates no malformative or foeto/neonatal toxicity compared to the general population. The risk of longer dimethyl fumarate exposure 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 is preferable to avoid the use of dimethyl fumarate during pregnancy. Dimethyl fumarate should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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 and gastrointestinal events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience flushing and gastrointestinal events, these events may continue to occur intermittently throughout treatment with dimethyl fumarate. The most commonly reported adverse reactions 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 have received dimethyl fumarate for periods 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 dimethyl fumarate and 426 patients have received at least 10 years of treatment with dimethyl fumarate. The experience in uncontrolled clinical trials is consistent with the experience in the placebo-controlled clinical trials.

Tabulated list of adverse reactions

Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneous reports, 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 following categories: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (frequency cannot be estimated from the available data).

MedDRA system organ class

Adverse reaction

Frequency category

Infections and infestations

Gastroenteritis

Common

Progressive multifocal leukoencephalopathy (PML)

Not known

Herpes zoster

Not known

Blood and lymphatic system disorders

Lymphopenia

Common

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 and mediastinal 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 aminotransferase increased

Common

Alanine aminotransferase increased

Common

Drug-induced liver injury

Rare

Skin and subcutaneous tissue disorders

Pruritus

Common

Rash

Common

Erythema

Common

Alopecia

Common

Renal and urinary disorders

Proteinuria

Common

General disorders and administration site conditions

Feeling hot

Common

Investigations

Ketones measured in urine

Very common

Albumin urine present

Common

White blood cell count decreased

Common

Description of selected adverse reactions

Flushing

In the placebo-controlled studies, the incidence of flushing (34% versus 4%) and hot flush (7% versus 2%) was increased in patients treated with dimethyl fumarate compared to placebo, respectively. Flushing is usually described as flushing or hot flush, but can include other events (e.g. warmth, redness, itching, and burning sensation). Flushing events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience flushing, these events may continue to occur intermittently throughout treatment with dimethyl fumarate. In patients with flushing, the majority had flushing events that were mild or moderate in severity. Overall, 3% of patients treated with dimethyl fumarate discontinued due to flushing. The incidence of serious flushing, which may be characterised by generalised erythema, rash and/or pruritus, was seen in less than 1% of patients treated with dimethyl fumarate (see sections 4.2, 4.4 and 4.5).

Gastrointestinal adverse reactions

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 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 events may continue to occur intermittently throughout treatment with dimethyl fumarate. In the majority of patients who experienced gastrointestinal events, it was mild or moderate in severity. Four per cent (4%) of patients treated with dimethyl fumarate discontinued due to gastrointestinal adverse reactions. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% of patients treated with dimethyl fumarate (see section 4.2).

Hepatic function

Based on data from placebo-controlled studies, the majority of patients with elevations had hepatic transaminases that were < 3 times the ULN. The increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate relative to placebo was primarily seen during the first 6 months of treatment. Elevations of alanine aminotransferase and aspartate aminotransferase ≥ 3 times ULN, respectively, were seen in 5% and 2% of patients treated with placebo and 6% and 2% of patients treated with dimethyl fumarate. Discontinuations due to elevated hepatic transaminases were < 1% and similar in patients treated with dimethyl fumarate or placebo. Elevations in transaminases ≥ 3 times ULN with concomitant elevations in total bilirubin > 2 times ULN, were not observed in placebo-controlled studies.

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

Lymphopenia

In the placebo-controlled studies most patients (> 98%) had normal lymphocyte counts prior to initiating treatment. Upon treatment with dimethyl fumarate, mean lymphocyte counts decreased over the first year with a subsequent plateau. On average, lymphocyte counts decreased by approximately 30% of baseline value. Mean and median lymphocyte counts remained within normal limits. Lymphocyte counts < 0.5×109/L were observed in < 1% of patients treated with placebo and 6% of patients treated with dimethyl fumarate. A lymphocyte count < 0.2×109/L was observed in 1 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 fumarate had lymphopenia (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 group with severe lymphopenia, the majority of lymphocyte counts remained < 0.5×109/L with continued therapy.

In addition, in an uncontrolled, prospective, post-marketing study, at week 48 of treatment with dimethyl fumarate (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 more frequently 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 dimethyl fumarate therapy with lymphocyte counts below the LLN were monitored for recovery of lymphocyte count to the LLN (see section 5.1).

Progressive multifocal leukoencephalopathy (PML) Cases of infections with John Cunningham virus (JCV) causing PML have been reported with dimethyl fumarate (see section 4.4). PML may be fatal or result in severe disability. In one of the clinical trials, 1 patient taking dimethyl fumarate 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 cells counts were variable (ranging from < 0.05 – 0.5×109/L) and correlated more with the overall severity of lymphopenia (< 0.5×109/L to < LLN). Consequently, the CD4+/CD8+ ratio was increased in these patients.

Prolonged moderate to severe lymphopenia appears to increase the risk of PML with dimethyl fumarate. However, PML also occurred in patients with mild lymphopenia. Additionally, the majority of PML cases in the post-marketing setting have occurred in patients > 50 years.

Herpes zoster infections

Herpes zoster infections have been reported with dimethyl fumarate. In the long-term extension study, in which 1,736 MS patients were treated, approximately 5% experienced one or more events of herpes zoster, of which 42% were mild, 55% were moderate,and 3% were severe. The time to onset from first dimethyl fumarate dose ranged from approximately 3 months to 10 years. Four patients experienced serious events, all of which resolved. Most subjects, including those who experienced a serious herpes zoster infection, had lymphocyte counts above the lower 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 zoster infection were non-serious and resolved with treatment. Limited data are available on absolute lymphocyte 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) or severe (< 0.5 x 109/L to 0.2×109/L) lymphopenia (see section 4.4).

Laboratory abnormalities

In the placebo-controlled studies, measurement of urinary ketones (1+ or greater) was higher in patients treated with dimethyl fumarate (45%) compared to placebo (10%). No untoward 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 of parathyroid 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 values for both parameters remained within normal range.

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

Paediatric population

In a 96-week open label, randomised active controlled trial, paediatric patients with RRMS (n=7 aged 10 to less than 13 years and n=71 aged 13 to less than 18 years were treated with (120 mg twice a day for 7 days followed by 240 mg twice a day for the remainder of treatment; the safety profile in paediatric 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 paediatric and adult populations, cannot be excluded. Gastrointestinal disorders as well as respiratory, thoracic and mediastinal disorders and the adverse events of headache and dysmenorrhea were more frequently reported (≥10%) in the paediatric population than in the adult population.

These adverse events were reported in the following percentages in paediatric patients:

• Headache was reported in 28% of patients treated with dimethyl fumarate versus 36% in patients treated with interferon beta-1a.

• Gastrointestinal disorders were reported in 74% of patients treated with dimethyl fumarate versus 31% in patients treated with interferon beta-1a. Among them, abdominal pain and vomiting were the most frequently reported with dimethyl fumarate.

• Respiratory, thoracic and mediastinal disorders were reported in 32% of patients treated with dimethyl fumarate versus 11% in patients treated with interferon beta-1a. Among them, oropharyngeal pain and cough were the most frequently reported with dimethyl fumarate.

• Dysmenorrhea was reported in 17% of patients treated with dimethyl fumarate versus 7% of patients treated with interferon beta-1a.

In a small 24-week open-label uncontrolled study in paediatric patients with RRMS aged 13 to 17 years (120 mg twice a day for 7 days followed by 240 mg twice a day for the remainder of treatment; n = 22), followed by a 96-week extension study (240 mg twice per day; n = 20), the safety profile appeared similar to that observed in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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