Multiple sclerosis:

Indications for: TECFIDERA

Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Clinical Trials:

The efficacy and safety of Tecfidera was evaluated in two studies (Studies 1 and 2) in patients with relapsing-remitting multiple sclerosis (RRMS). 

 

Study 1

Study 1 was a 2-year randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. Patients were randomly assigned to receive Tecfidera 240 mg twice a day (n=410), Tecfidera 240 mg three times a day (n=416), or placebo (n=408) for up to 2 years. The primary endpoint was the proportion of patients relapsed at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of new T1 hypointense lesions, number of Gd+ lesions, annualized relapse rate (ARR), and time to confirmed disability progression.

Results showed that treatment with Tecfidera achieved a statistically significant effect on all of the endpoints described above and the 240 mg three times daily dose showed no additional benefit over the Tecfidera 240 mg twice daily dose. The following results are for Tecfidera 240 mg twice daily vs placebo, respectively:

  • Proportion relapsing (primary endpoint): 27% vs 46% (relative risk reduction, 49%; P <.0001)

  • ARR: 0.172 vs 0.364 (relative reduction, 53%; P <.0001)

  • Proportion with disability progression: 16% vs 27% (relative risk reduction, 38%; P =.005)

  • Mean number of new or newly enlarging T2 lesions over 2 years: 2.6 vs 17 (P <.0001)

  • Percentage of patients with no new or newly enlarging lesions: 45% vs 27%

  • Number of Gd+ lesions at 2 years: 0.1 vs 1.8 (relative odds reduction, 90%; P <.0001)

  • Mean number of new T1 hypointense lesions over 2 years: 1.5 vs 5.6 (P <.0001)

Study 2

Study 2 was a 2-year randomized, double-blind, placebo-controlled study that also included an open-label comparator arm in patients with RRMS. Patients were randomly assigned to receive Tecfidera 240 mg twice a day (n=359), Tecfidera 240 mg three times a day (n=345), an open-label comparator (n=350), or placebo (n=363) for up to 2 years. The primary endpoint was the annualized relapse rate (ARR) at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of T1 hypointense lesions, number of Gd+ lesions, proportion of patients relapsed, and time to confirmed disability progression.

Results showed that treatment with Tecfidera achieved a statistically significant effect on the relapse and MRI endpoints described above and the 240 mg three times daily dose showed no additional benefit over the Tecfidera 240 mg twice daily dose. The following results are for Tecfidera 240 mg twice daily vs placebo, respectively:

  • ARR: 0.224 vs 0.364 (relative reduction, 44%; P <.0001)

  • Proportion relapsing: 29% vs 41% (relative risk reduction, 34%; P =.002)

  • Proportion with disability progression: 13% vs 17% (relative risk reduction, 21%; P =.25)

  • Mean number of new or newly enlarging T2 lesions over 2 years: 5.1 vs 17.4 (P <.0001)

  • Percentage of patients with no new or newly enlarging lesions: 27% vs 12%

  • Number of Gd+ lesions at 2 years: 0.5 vs 2.0 (relative odds reduction, 74%; P <.0001)

  • Mean number of new T1 hypointense lesions over 2 years: 3.0 vs 7.0 (P <.0001)

Adult Dosage:

Swallow whole. Initially 120mg twice daily for 7 days, then increase to maintenance dose of 240mg twice daily. If maintenance dose not tolerated, temporarily reduce back to initial dose. Within 4 weeks, resume maintenance dose; if not tolerated, consider discontinuing.

Children Dosage:

Not established.

TECFIDERA Warnings/Precautions:

Obtain a CBC including lymphocyte count prior to initiation, after 6 months, and every 6–12 months thereafter; consider interruption if lymphocyte counts <0.5×109/L persist for >6 months. Pre-existing low lymphocyte counts: not studied. Monitor for herpes zoster, other serious opportunistic infections; evaluate and treat if occurs; consider withholding until infection resolved. Monitor serum aminotransferase, alkaline phosphatase, and total bilirubin prior to initiation and during treatment; discontinue if significant liver injury is suspected. Discontinue if anaphylaxis or angioedema occurs. Withhold and evaluate at first sign/symptom suggestive of PML. Administration with non-enteric coated aspirin (up to 325mg) or food may reduce incidence/severity of flushing. Pregnancy. Nursing mothers.

Adverse Reactions:

Flushing, abdominal pain, diarrhea, nausea; anaphylaxis, lymphopenia, liver injury.

Note:

Enroll pregnant patients exposed to Tecfidera by calling (866) 810-1462.

Metabolism:

In humans, dimethyl fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Further metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. MMF, fumaric and citric acid, and glucose are the major metabolites in plasma.

Drug Elimination:

Exhalation of CO2 is the primary route of elimination, accounting for approximately 60% of the Tecfidera dose. Renal and fecal elimination are minor routes of elimination, accounting for 16% and 1% of the dose respectively. Terminal half-life: ~1 hour.

Generic Drug Availability:

Del-rel caps (YES); Starter Pack (NO)

How Supplied:

Starter Pack (30-day)—1 (120mg × 14 + 240mg × 46); Del-rel caps 120mg—14; 240mg—60