Routine Monitoring for Patient Safety1

Obtain Prior to Initiation

Complete blood count (CBC) with lymphocyte count

Liver tests(serum aminotransferase, alkaline phosphatase, and total bilirubin)

After Initiation

At 6 months

Every 6-12 months thereafter, and as clinically indicated

Repeat as clinically indicated

Consider interruption of treatment in patients with lymphocyte counts <0.5x109/L persisting for >6 months. Discontinue treatment if significant liver injury is suspected.

See how MS experts help patients make the most of TECFIDERA

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 angioedema

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.

Lymphopenia1,2

TECFIDERA-Lymphocyte-Counts
TECFIDERA-Lymphocyte-Counts

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
  • 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 6 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 6 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

Please see Hepatic transaminases below for additional details.

Infections1

  • The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively
  • 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)
  • Consider withholding treatment from patients with serious infections until resolution

Hepatic transaminases1

  • 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 treatment
  • Discontinuations due to these elevations were <1% and similar in patients treated with TECFIDERA or placebo in clinical trials
  • Clinically significant cases of liver injury have been reported in patients treated with TECFIDERA in the postmarketing setting

Additional Considerations

Family planning1

Contraception

  • Coadministration of TECFIDERA with a combined oral contraceptive (norelgestromin and ethinyl estradiol) did not elicit any relevant effects in oral contraceptives exposure
  • No interaction studies have been performed with oral contraceptives containing other progestogens 

Pregnancy

  • There are no adequate data on the developmental risk associated with the use of TECFIDERA in pregnant woman 
  • Instruct patients that if they are pregnant or plan to become pregnant while taking TECFIDERA, they should inform their physician
  • Encourage patients to enroll in the TECFIDERA Pregnancy Registry by calling 1-866-810-1462 or visiting www.TECFIDERApregnancyregistry.com

Lactation

  • There are no data on the presence of TECFIDERA or monomethyl fumarate (MMF) in human milk. The effects on the breastfed infant and on milk production are unknown

Drug interaction studies1

  • TECFIDERA has no known drug interactions identified from in vitro CYP inhibition and induction studies, or in P-glycoprotein studies
  • Aspirin, when administered approximately 30 minutes before TECFIDERA, did not alter the pharmacokinetics of MMF

Half-life1

  • TECFIDERA has a short terminal half-life 
  • Terminal half-life of the active metabolite of TECFIDERA is approximately 1 hour, and there are no circulating metabolites at 24 hours in the majority of individuals 
  • Exhalation of CO2 is the primary route of elimination. Renal and fecal elimination are minor routes. Trace amounts of unchanged MMF were present in urine

*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.