Tecfidera Adverse Reactions

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 Tecfidera. 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 Tecfidera for periods of 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 Tecfidera, and 426 patients have received at least 10 years of treatment with Tecfidera. 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 as follows.
The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ Class. The incidence of the adverse reactions as follows 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). (See Table 5.)

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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 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 Tecfidera 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 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 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 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. Discontinuations due to elevated hepatic transaminases were <1% and similar in patients treated with Tecfidera 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 Tecfidera 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 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 <0.5x10⁹/L were observed in <1% of patients treated with placebo and 6% of patients treated with Tecfidera. A lymphocyte count <0.2x10⁹/L was observed in 1 patient treated with Tecfidera and in no patients treated with placebo.
In clinical studies (both controlled and uncontrolled), 41% of patients treated with Tecfidera had lymphopenia (defined in these studies as <0.91x10⁹/L). Mild lymphopenia (counts ≥0.8x10⁹/L to <0.91 x10⁹/L) was observed in 28% of patients; moderate lymphopenia (counts ≥0.5x10⁹/L to <0.8x10⁹/L) persisting for at least six months was observed in 11% of patients; severe lymphopenia (counts <0.5x10⁹/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 <0.5x10⁹/L with continued therapy.
In addition, in an uncontrolled, prospective, post-marketing study, at week 48 of treatment with Tecfidera (n=185), CD4+ T cells were moderately (counts ≥0.2x10⁹/L to <0.4x10⁹/L) or severely (<0.2x10⁹/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 <0.2x10⁹/L and 25% of patients at counts <0.1x10⁹/L. In controlled and uncontrolled clinical studies, patients who discontinued Tecfidera therapy with lymphocyte counts below the LLN were monitored for recovery of lymphocyte count to the LLN (see Pharmacology: Pharmacodynamics under Actions).
Progressive multifocal leukoencephalopathy (PML): Cases of infections with John Cunningham virus (JCV) causing PML have been reported with Tecfidera (see Precautions). PML may be fatal or result in severe disability. In one of the clinical trials, 1 patient taking Tecfidera developed PML in the setting of prolonged severe lymphopenia (lymphocyte counts predominantly <0.5x10⁹/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 (>0.5x10⁹/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 <0.1x10⁹/L, whereas reductions in CD4+ T cells counts were variable (ranging from <0.05 to 0.5x10⁹/L) and correlated more with the overall severity of lymphopenia (<0.5 x10⁹/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 Tecfidera. 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 Tecfidera. 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 Tecfidera 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 subjects 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 × 10⁹/L to <0.8 × 10⁹/L) or severe (<0.5 × 10⁹/L to 0.2 × 10⁹/L) lymphopenia (see Precautions).
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.
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 following adverse events were reported in the following percentage in paediatric patients: Headache was reported in 28% of patients treated with Tecfidera versus 36% in patients treated with interferon beta-1a.
Gastrointestinal disorders were reported in 74% of patients treated with Tecfidera versus 31% in patients treated with interferon beta-1a. Among them, abdominal pain and vomiting were the most frequently reported with Tecfidera.
Respiratory, thoracic and mediastinal disorders were reported in 32% of patients treated with Tecfidera versus 11% in patients treated with interferon beta-1a. Among them, oropharyngeal pain and cough were the most frequently reported with Tecfidera.
Dysmenorrhea was reported in 17% of patients treated with Tecfidera 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.