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.
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. 5). 8% of dimethyl fumarate-treated patients. There were no serious events of flushing or discontinuations due to flushing.
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 events 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 events. 4). 1. Hepatic function Based on data from placebo-controlled studies with dimethyl fumarate, the majority of patients with elevations had hepatic transaminases that were <3 times the upper limit of normal (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 x 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 […]