Tecfidera Adverse Reactions

Summary of the Safety Profile: The most common adverse reactions (incidence ≥10%) for patients treated with Tecfidera were flushing and gastrointestinal events (i.e. diarrhoea, nausea, abdominal pain, abdominal pain upper). 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 Tecfidera. The most commonly reported adverse reactions leading to discontinuation (incidence >1%) in patients treated with Tecfidera were flushing (3%) and gastrointestinal events (4%).
In placebo-controlled and uncontrolled clinical studies, a total of 2,468 patients have received Tecfidera and been followed for periods up to 4 years with an overall exposure equivalent to 3,588 person-years. Approximately 1,056 patients have received more than 2 years of treatment with Tecfidera. The experience in uncontrolled clinical trials is consistent with the experience in the placebo-controlled clinical trials.
Tabulated Summary of Adverse Reactions: Adverse reactions, which were more frequently reported in Tecfidera versus placebo-treated patients, are presented in the table as follows. These data were derived from 2 pivotal Phase 3 placebo-controlled, double-blind clinical trials with a total of 1,529 patients treated with Tecfidera and for up to 24 months with an overall exposure of 2,371 person-years (see Pharmacology: Pharmacodynamics under Actions). The frequencies described in Table 2 are based on 769 patients treated with Tecfidera 240 mg twice a day and 771 patients treated with placebo.
The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ Class. The incidence of the adverse reactions in Table 2 are 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 (cannot be estimated from the available data). (See Table 2.)

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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 Tecfidera 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 Tecfidera. In patients with flushing, the majority had flushing events that were mild or moderate in severity. Overall, 3% of patients treated with Tecfidera 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 Tecfidera (see Dosage & Administration, Precautions and Interactions).
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 Tecfidera 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 Tecfidera. In the majority of patients who experienced gastrointestinal events, it was mild or moderate in severity. Four percent (4%) of patients treated with Tecfidera discontinued due to gastrointestinal events. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% of patients treated with Tecfidera (see Dosage & Administration).
Hepatic Transaminases: In placebo-controlled studies, elevations of hepatic transaminases were observed. 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 Tecfidera 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 Tecfidera. There were no elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN. Discontinuations due to elevated hepatic transaminases were <1% and similar in patients treated with Tecfidera or placebo.
Renal: In placebo-controlled studies, the incidence of proteinuria was higher in patients treated with Tecfidera (9%) compared to placebo (7%). The overall incidence of renal and urinary adverse eventswas similar for Tecfidera and placebo-treated patients. There were no reports of serious renal failure. On urinalysis, the percentage of patients with protein values of 1+ or greater was similar for Tecfidera (43%) and placebo-treated patients (40%). Typically, laboratory observations of proteinuria were not progressive. Compared to patients treated with placebo, estimated glomerular filtration rate (eGFR) was observed to increase in patients treated with Tecfidera, including those patients with 2 consecutive occurrences of proteinuria (≥1+).
Haematological: In the placebo-controlled studies, most patients (>98%) had normal lymphocyte values prior to initiating treatment. Upon treatment with Tecfidera, 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 x 10⁹/L were observed in <1% of patients treated with placebo and 6% of patients treated with Tecfidera. A lymphocyte count <0.2 x 10⁹/L was observed in 1 patient treated with Tecfidera and in no patients treated with placebo. In uncontrolled and controlled clinical studies, 2% of patients experienced lymphocyte counts <0.5 x 10⁹/L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5 x 10⁹/L with continued therapy. The incidence of infections (58% versus 60%) and serious infections (2% versus 2%) was similar in patients treated with placebo or Tecfidera. An increased incidence of infections and serious infections was not observed in patients with lymphocyte counts <0.8 x 10⁹/L or <0.5 x 10⁹/L. PML has occurred in the setting of prolonged moderate to severe lymphopenia (see Precautions). A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.
Laboratory Abnormalities: In the placebo-controlled studies, measurement of urinary ketones (1+ or greater) was higher in patients treated with Tecfidera (45%) compared to placebo (10%). No untoward clinical consequences were observed in clinical trials.
Levels of 1,25-dihydroxyvitamin D decreased in Tecfidera 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 Tecfidera 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.
In post marketing experience, hypersensitivity reactions such as urticaria, angioedema, and difficulty breathing have been reported following Tecfidera administration.
Progressive multifocal leukoencephalopathy has occurred in the setting of prolonged moderate to severe lymphopenia following Tecfidera administration.
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.