VUMERITY

Treatment should be initiated under supervision of a physician experienced in the treatment of multiple sclerosis. Posology The starting dose is 231 mg twice a day. 4). Temporary dose reductions to 231 mg twice a day may reduce the occurrence of flushing and gastrointestinal adverse reactions.

Within 1 month, the recommended dose of 462 mg twice a day should be resumed. 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.

Special populations Elderly Based on uncontrolled study data, the safety profile of diroximel fumarate in patients ≥55 years of age seems to be comparable to patients <55 years of age. 2). Based on the mechanism of action of the active substance there are no theoretical reasons for any requirement for dose adjustments in the elderly.

2). 2). 2). Diroximel fumarate has not been studied in patients with hepatic impairment. Paediatric population The safety and efficacy of Vumerity in children and adolescents aged 10 to less than 18 years have not yet been established.

There is no relevant use of Vumerity in children aged less than 10 years for the indication of relapsing remitting multiple sclerosis. Method of administration For oral use. Vumerity should be swallowed whole and intact. The capsules should not be crushed or chewed and the contents should not be sprinkled on food because the enteric- coating of the capsule contents prevents irritant effects on the gut.

2). 8).

Summary of the safety profile Upon oral administration, diroximel fumarate and dimethyl fumarate are rapidly metabolised to monomethyl fumarate before they reach the systemic circulation, adverse reactions are similar once metabolised.

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

Tabulated list of adverse reactions The adverse reactions which were more frequently reported in dimethyl fumarate-treated patients as compared to placebo-treated patients from two pivotal phase 3 placebo controlled clinical trials and post marketing experience are presented in Table 1.

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

Table 1:

Adverse reactions MedDRA System Organ Class Adverse reaction Frequency category Gastroenteritis Common Progressive multifocal leukoencephalopathy (PML)1 Not known Infections and infestations Herpes zoster1 Not known Lymphopenia1, 2 Common Leukopenia Common Blood and lymphatic system disorders Thrombocytopenia Uncommon Hypersensitivity Uncommon Anaphylaxis Not known Dyspnoea Not known Hypoxia Not known Hypotension Not known Immune system disorders Angioedema Not known Nervous system disorders Burning sensation Common Flushing1 Very commonVascular disorders Hot flush Common Respiratory, thoracic and mediastinal disorders Rhinorrhoea Not known Diarrhoea Very common Nausea Very common Abdominal pain upper Very common Abdominal pain Very common Vomiting Common Dyspepsia Common Gastritis Common Gastrointestinal disorders Gastrointestinal disorder Common Aspartate aminotransferase increased1 Common Alanine aminotransferase increased1 Common Hepatobiliary disorders Drug-induced liver injury Rare Pruritus Common Rash Common Erythema Common Skin and subcutaneous tissue disorders Alopecia Common Renal and urinary disorders Proteinuria Common General disorders and administration site conditions Feeling hot Common Ketones measured in urine Very common Albumin urine present Common Investigations White blood cell count decreased Common 1 See ‘Description of selected adverse reactions’ for further information 2 Lymphopenia was reported with the frequency “very common” in a phase 3, open-label, uncontrolled study with diroximel fumarate Description of selected adverse reactions Flushing In the placebo-controlled dimethyl fumarate studies, the incidence of flushing (34% versus 5%) and hot flush (7% versus 2%) was increased in patients treated with dimethyl fumarate 240 mg twice daily compared to placebo, respectively.

2). The risks associated with diroximel fumarate are expected to be similar to those reported for dimethyl fumarate even though not all the risks listed below have been observed specifically for diroximel fumarate. 8). The clinical implications of these changes are unknown.

g. creatinine, blood urea nitrogen and urinalysis) is recommended prior to treatment initiation with Vumerity, 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 x 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 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, a current complete blood count, including lymphocytes, must be performed. If the lymphocyte count is found to be below the normal range, a thorough assessment of possible causes should be completed prior to initiation of treatment.

Vumerity 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 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 that might further augment the individual PML risk should be considered (see subsection on PML). 1). Upon recovery and in the absence of alternative treatment options, decisions about whether or not to restart Vumerity after treatment discontinuation should be based on clinical judgement.

5). Suspected or confirmed Progressive Multifocal Leukoencephalopathy (PML).