IMPORTANT SAFETY INFORMATION

INDICATION

TECFIDERA® (dimethyl fumarate) is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Important Safety Information

CONTRAINDICATIONS

TECFIDERA® (dimethyl fumarate) is contraindicated in patients with known hypersensitivity to dimethyl fumarate or any of the excipients of TECFIDERA. Reactions have included anaphylaxis and angioedema.

WARNINGS AND PRECAUTIONS

Anaphylaxis and Angioedema

  • TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue TECFIDERA and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema

Progressive Multifocal Leukoencephalopathy (PML)

  • PML has occurred in patients with MS treated with TECFIDERA. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received TECFIDERA for 4 years while enrolled in a clinical trial
  • PML has occurred in the postmarketing setting in the presence of lymphopenia (<0.9 x 109/L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8 x 109/L persisting for more than 6 months
  • At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. 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
  • Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Monitoring with MRI for signs consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present

Herpes Zoster and Other Serious Opportunistic Infections

  • Serious cases of herpes zoster have occurred with TECFIDERA, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis. These events may occur at any time during treatment. Monitor patients on TECFIDERA for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered
  • Other serious opportunistic infections have occurred with TECFIDERA, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment
  • Consider withholding TECFIDERA treatment in patients with herpes zoster or other serious infections until the infection has resolved

Lymphopenia

  • TECFIDERA may decrease lymphocyte counts. In the MS placebo-controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. The incidence of infections and serious infections was similar in patients treated with TECFIDERA or placebo. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8 x 109/L or ≤0.5 x 109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 x 109/L for 3.5 years)
  • In controlled and uncontrolled clinical trials, 2% of patients experienced prolonged, severe lymphopenia (defined as lymphocyte counts <0.5 x 109/L for at least six months); in this group of patients, the majority of lymphocyte counts remained <0.5 x 109/L with continued therapy. In these patients with prolonged, severe lymphopenia, the median time for lymphocyte counts to return to normal after discontinuing TECFIDERA was 96.0 weeks
  • In these controlled and uncontrolled clinical studies, among patients who did not experience prolonged, severe lymphopenia during treatment, the median times for lymphocyte counts to return to normal after discontinuing TECFIDERA were as follows:
    • 4.3 weeks in patients with mild lymphopenia (lymphocyte count ≥0.8 x 109/L) at discontinuation,
    • 10.0 weeks in patients with moderate lymphopenia (lymphocyte count 0.5 to <0.8 x 109/L) at discontinuation, and
    • 16.7 weeks in patients with severe lymphopenia (lymphocyte count <0.5 x 109/L) at discontinuation.
  • TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts
  • Obtain a CBC, including lymphocyte count, before initiating treatment with TECFIDERA, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts less than 0.5 x 109/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if TECFIDERA is discontinued or interrupted due to lymphopenia. Consider withholding treatment from patients with serious infections until resolution

Liver Injury

  • Clinically significant cases of liver injury have been reported in patients treated with TECFIDERA in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients
  • Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials
  • Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating TECFIDERA and during treatment, as clinically indicated. Discontinue TECFIDERA if clinically significant liver injury induced by TECFIDERA is suspected

Flushing

  • TECFIDERA may cause flushing (e.g. warmth, redness, itching, and/or burning sensation). Forty percent of patients taking TECFIDERA reported flushing, which was mostly mild to moderate in severity. Three percent of patients discontinued TECFIDERA for flushing and <1% had serious flushing events that led to hospitalization. Taking TECFIDERA with food may reduce flushing. Alternatively, administration of non-enteric coated aspirin (up to 325mg) 30 minutes prior to dosing may reduce the incidence or severity of flushing

Serious Gastrointestinal Reactions

  • Serious gastrointestinal (GI) reactions, including perforation, ulceration, hemorrhage, and obstruction, some with fatal outcomes, have been reported in the postmarketing setting with the use of fumaric acid esters, including TECFIDERA, with or without concomitant aspirin use. The majority of these events have occurred within 6 months of fumaric acid ester treatment initiation. In controlled clinical trials, the incidence of serious gastrointestinal adverse events was 1% in patients treated with TECFIDERA; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain (0.3%)
  • Monitor patients, promptly evaluate, and discontinue TECFIDERA for new or worsening severe gastrointestinal signs and symptoms

ADVERSE REACTIONS

  • The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea
  • Gastrointestinal adverse reactions: TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA
  • Hepatic transaminases: An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels < 3 times the upper limit of normal (ULN) during controlled trials. There were no elevations in transaminases ≥3 times the ULN with concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic transaminases were < 1% and were similar in patients treated with TECFIDERA or placebo
  • Eosinophilia adverse reactions: A transient increase in mean eosinophil counts was seen during the first two months

PREGNANCY

  • Available data from the TECFIDERA Pregnancy Registry, observational studies, and pharmacovigilance with dimethyl fumarate use in pregnant women have not indicated an increased risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Most of the reported exposures to dimethyl fumarate occurred during the first trimester of pregnancy

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