DEMONSTRATED SAFETY PROFILE1

Contraindication

TECFIDERA is contraindicated in patients with known hypersensitivity to dimethyl fumarate or to any of the excipients of TECFIDERA. Reactions have included anaphylaxis and angioedema1

Warnings and Precautions

ANAPHYLAXIS AND ANGIOEDEMA1

Warning

  • Can occur after the first dose or anytime during treatment with TECFIDERA

Signs and symptoms

  • Include difficulty breathing, urticaria, and swelling of the throat and tongue

Guidance

  • Discontinue TECFIDERA and seek immediate medical care

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) 1

Warning

  • 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

Details

  • A fatal case of PML occurred in a patient who received TECFIDERA for 4 years while enrolled in a clinical trial
    • Patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years) while taking TECFIDERA
  • PML has also occurred in the postmarketing setting in the presence of lymphopenia (<0.8x109/L) persisting for more than 6 months
  • While the role of lymphopenia in these cases is uncertain, the majority of cases occurred in patients with lymphocyte counts <0.5x109/L

Signs and symptoms

  • Diverse and progress over days to weeks
  • 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
  • MRI findings may be apparent before clinical signs or symptoms

Guidance

  • At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation

For additional information, please see full Prescribing Information.

LYMPHOPENIA1

Warning

  • TECFIDERA may decrease lymphocyte counts

Details

  • During the first year in clinical trials, mean lymphocyte counts decreased by approximately 30% and then remained stable
  • Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline
  • Six percent (6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x109/L (lower limit of normal 0.91x109/L)
  • In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5x109/L for at least six months, and in this group, the majority of lymphocyte counts remained <0.5x109/L with continued therapy
  • TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts

Guidance

  • 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 <0.5x109/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
  • Restart TECFIDERA based on individual and clinical circumstances
  • Please see Infections below for additional details

LIVER INJURY1

Warning

  • 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 with TECFIDERA
  • None of the reported cases resulted in liver failure, liver transplant, or death. Some cases required hospitalization
  • 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

Signs and symptoms

  • Include elevation of serum aminotransferases to greater than 5-fold the upper limit of normal (ULN) and elevation of total bilirubin to greater than 2-fold the ULN

Guidance

  • Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment with TECFIDERA and during treatment, as clinically indicated
  • Discontinue TECFIDERA if clinically significant liver injury induced by TECFIDERA is suspected

FLUSHING1

Warning

  • May occur during treatment with TECFIDERA. In clinical trials, 40% experienced flushing
  • 3% of patients discontinued TECFIDERA because of flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization

Signs and symptoms

  • Generally began soon after initiating treatment and usually improved or resolved over time
  • Include warmth, redness, itching, and/or burning sensation

Guidance

  • Taking TECFIDERA with food may help with flushing
    • A high-fat, high-calorie meal did not affect overall exposure to TECFIDERA*
  • Alternatively, taking non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence and severity of flushing
  • Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing

TECFIDERA MAY DECREASE LYMPHOCYTE COUNTS1,2

INFECTIONS

  • The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively1
  • There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or 0.5x109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years)1
  • Consider withholding treatment from patients with serious infections until resolution1

HEPATIC TRANSAMINASES

  • In clinical trials, the majority of patients with elevations of hepatic transaminases had levels that were <3 times the upper limit of normal (ULN) and were primarily seen during the first 6 months of treatment1
  • Discontinuations due to these elevations were <1% and similar in patients treated with TECFIDERA or placebo1
  • Clinically significant cases of liver injury have been reported in patients treated with TECFIDERA in the postmarketing setting1

PREGNANCY

  • There are no adequate and well-controlled studies in pregnant women1
  • TECFIDERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus1
  • Encourage patients who become pregnant while taking TECFIDERA to enroll in the TECFIDERA pregnancy registry by calling 1-866-810-1462 or visiting www.TECFIDERApregnancyregistry.com1

For more information about animal data, please see full Prescribing Information.

Indication

Tecfidera® (dimethyl fumarate) is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

Important Safety Information

TECFIDERA is contraindicated in patients with known hypersensitivity to dimethyl fumarate or any of the excipients of TECFIDERA. TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Patients experiencing signs and symptoms of anaphylaxis and angioedema (which have included difficulty breathing, urticaria, and swelling of the throat and tongue) should discontinue TECFIDERA and seek immediate medical care.

Progressive multifocal leukoencephalopathy (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 in a clinical trial. PML has also occurred in the postmarketing setting in the presence of lymphopenia (<0.8x109/L) persisting for more than 6 months. While the role of lymphopenia in these cases is uncertain, the majority of cases occurred in patients with lymphocyte counts <0.5x109/L. The 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. At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms.

TECFIDERA may decrease lymphocyte counts; in clinical trials there was a mean decrease of ~30% in lymphocyte counts during the first year which then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but not to baseline. Six percent of TECFIDERA patients and <1% of placebo patients had lymphocyte counts <0.5x109/L. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.

There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or 0.5x109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years). In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5x109/L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5x109/L with continued therapy. A complete blood count including lymphocyte count should be obtained before initiating treatment, 6 months after starting, every 6 to 12 months thereafter and as clinically indicated. Consider treatment interruption if lymphocyte counts <0.5x109/L persist for more than six months and follow lymphocyte counts until lymphopenia is resolved. Consider withholding treatment in patients with serious infections until resolved. Decisions about whether or not to restart TECFIDERA should be based on clinical circumstances.

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.

TECFIDERA may cause flushing (e.g. warmth, redness, itching, and/or burning sensation). 40% 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 prior to dosing may reduce the incidence or severity of flushing.

TECFIDERA may cause gastrointestinal (GI) events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). Four percent of TECFIDERA patients and <1% of placebo patients discontinued due to GI events. The incidence of serious GI events was 1%. The most common adverse reactions associated with TECFIDERA versus placebo are flushing (40% vs 6%) and GI events: abdominal pain (18% vs 10%), diarrhea (14% vs 11%), nausea (12% vs 9%).

A transient increase in mean eosinophil counts was seen during the first two months.

TECFIDERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage patients who become pregnant while taking TECFIDERA to enroll in the TECFIDERA pregnancy registry by calling 1-866-810-1462 or visiting www.TECFIDERApregnancyregistry.com.

Please see full Prescribing Information and Patient Information for additional Important Safety Information.


*
A high-fat, high-calorie meal did not affect the overall exposure to MMF, a TECFIDERA metabolite, but decreased the maximal plasma concentration and increased the time until this concentration was reached. A high-fat, high-calorie meal reduced the incidence of flushing by approximately 25%.1

 

References: 1. TECFIDERA Prescribing Information, Biogen, Cambridge, MA. 2. Biogen, Data on file.