DIMETHYL FUMARATE

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. 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.

2). 8). 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.

2). 4). Paediatric population The posology is the same in adults and in paediatric patients aged 13 years and older. 2. There are limited data available in children between 10 and 12 years old. The safety and efficacy of dimethyl fumarate in children aged less than 10 years have not yet been established.

Method of administration Dimethyl fumarate is 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 (present inside the capsule shell) prevents irritant effects on the gut.

8. The long-term safety of dimethyl fumarate in paediatric population has not yet been established. 5 Interaction with other medicinal products and other forms of interaction 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. Concomitant administration of non-live vaccines according to national vaccination schedules may be considered during dimethyl fumarate therapy.

In a clinical study involving a total of 71 patients with relapsing remitting multiple sclerosis, 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 titer) to tetanus toxoid (recall antigen) and a conjugated meningococcal C polysaccharide vaccine (neoantigen), while the immune response to different serotypes of an unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell independent antigen) varied in both treatment groups.

A positive immune response defined as a ≥4-fold increase in antibody titer to the three vaccines, was achieved by fewer subjects in both treatment groups. Small numerical differences in the response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were noted in favour of non-pegylated interferon.

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

During treatment with dimethyl fumarate, simultaneous use of other fumaric acid derivatives (topical or systemic) should be avoided. In humans, dimethyl fumarate is extensively metabolised by esterases before it reaches the systemic circulation and further metabolism occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450 (CYP) system.

Potential drug interaction risks were not identified from in vitro CYP- inhibition and induction studies, a p-glycoprotein study, or studies of the protein binding of dimethyl fumarate and monomethyl fumarate (a primary metabolite of dimethyl fumarate).

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

Evidence from healthy volunteer studies suggests that dimethyl fumarate- 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 in patients with Relapsing Remitting MS. 8). g. 4 Blood/laboratory tests). Consumption of alcoholic drinks should be avoided within two hours of taking dimethyl fumarate, as alcohol may lead to increased frequency of gastrointestinal adverse reactions.

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 estradiol) did not elicit any relevant change in oral contraceptive exposure.

No interaction studies have been performed with oral contraceptives containing other progestogens, however an effect of dimethyl fumarate on their exposure is not expected. Paediatric population Interaction studies have only been performed in adults.

6 Fertility, pregnancy and lactation Pregnancy There are no or limited amount of data from the use of dimethyl fumarate in pregnant women. 3). 5). 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 therapy.

The benefit of breast-feeding for the child and the benefit of therapy for the woman should be taken into account. Fertility There are no data on the effects of dimethyl fumarate on human fertility. 3). 7 Effects on ability to drive and use machines Dimethyl fumarate has no or negligible influence on the ability to drive and use machines.

No studies on the ability to drive and use machines have been conducted but no effects […]

8). The clinical implications of these changes are unknown. g. creatinine, blood urea nitrogen and urinalysis) is recommended prior to treatment initiation, after 3 and 6 months of treatment, every 6 to 12 months thereafter and as clinically indicated.

Drug-induced liver injury, including liver enzyme increase (≥3 upper limit of normal (ULN)) and elevation of total bilirubin levels (≥2 ULN) can result from treatment with dimethyl fumarate. The time to onset can be directly, several weeks or longer.

Resolution of the adverse reactions has been observed after treatment was discontinued. g. alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels are recommended prior to treatment initiation and during treatment as clinically indicated.

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 with this medicinal product.

Dimethyl fumarate has not been studied in patients with pre-existing low lymphocyte counts and caution should be exercised when treating these patients. 5 x 109/L). After starting therapy, complete blood counts, including lymphocytes, must be performed every 3 months.

5 x 109/L) persisting for more than 6 months. 8 x 109/L for more than 6 months, the benefit/risk of dimethyl fumarate treatment should be reassessed. - 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). 1). Upon recovery and in the absence of alternative treatment options, decisions about whether or not to restart dimethyl fumarate after treatment discontinuation should be based on clinical judgement.

Magnetic Resonance imaging (MRI) Before initiating treatment with dimethyl fumarate, 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. 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 for 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.

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 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 must be permanently discontinued. Prior treatment with immunosuppressive or […]

1. Suspected or confirmed Progressive Multifocal Leukoencephalopathy (PML)