Tecfidera

— THERAPEUTIC DISORDERS TREATED —
  • Multiple sclerosis
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Tecfidera Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Dimethyl fumarate 120mg, 240mg; del-rel caps.

    How Supplied

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

    How Supplied

    Tecfidera is available as hard gelatin delayed-release capsules in two strengths containing either 120 mg or 240 mg of dimethyl fumarate. The green and white 120 mg capsules are printed with “BG-12 120 mg” in black ink. The green 240 mg capsules are printed with “BG-12 240 mg” in black ink.

    Tecfidera is available as follows:

    • 30-day Starter Pack: 7-day bottle 120 mg capsules, quantity 14; 23-day bottle 240 mg capsules, quantity 46.

    • 120 mg capsules: 7-day bottle of 14 capsules.

    • 240 mg capsules: 30-day bottle of 60 capsules.

    Storage

    Store at 15°C to 30°C (59 to 86°F). Protect the capsules from light. Store in original container.

    Manufacturer

    Biogen

    Generic Availability

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

    Tecfidera Indications

    Indications

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

    Tecfidera Dosage and Administration

    Prior to Treatment Evaluations

    Obtain a complete blood cell count (CBC) including lymphocyte count before initiation of therapy.

    Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment with Tecfidera.

    Adult

    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.

    Adult

    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.

    May reduce flushing if taken with food. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to Tecfidera dosing may reduce the incidence or severity of flushing.

    Children

    Not established.

    Tecfidera Contraindications

    Not Applicable

    Tecfidera Boxed Warnings

    Not Applicable

    Tecfidera Warnings/Precautions

    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.

    Warnings/Precautions

    Anaphylaxis and Angioedema

    • May 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.

    • Discontinue and seek immediate medical care if signs and symptoms of anaphylaxis or angioedema occur.

    Progressive Multifocal Leukoencephalopathy (PML)

    • 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.

    • Withhold treatment and perform an appropriate diagnositc evaluation at the first sign or symptom suggestive of PML.

    • MRI findings may be apparent before clinical signs or symptoms. Monitoring with MRI for signs that may be 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

    • Monitor for signs and symptoms of herpes zoster. 

    • Administer appropriate treatment if herpes zoster occurs and consider withholding Tecfidera in patients with herpes zoster or other serious infections until the infection has resolved.

    • Other serious opportunistic infections have occurred, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. Perform prompt diagnostic evaluation and receive appropriate treatment if symptoms and signs consistent with any of these infections occur.

    Lymphopenia

    • Tecfidera may decrease lymphocyte counts. 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 interrupting Tecfidera if lymphocyte counts less than 0.5 x 109 /L persisting for more than 6 months. 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. Decisions about whether or not to restart Tecfidera should be individualized based on clinical circumstances.

    Liver Injury

    • Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to and during treatment, as clinically indicated. Discontinue treatment if clinically significant liver injury induced by Tecfidera is suspected.

    Flushing

    • Administration of Tecfidera with food may reduce the incidence of flushing. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to Tecfidera dosing may reduce the incidence or severity of flushing.

    Pregnancy Considerations

    Pregnancy Exposure Registry 

    • There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Tecfidera during pregnancy. Encourage patients to enroll by calling 1-866-810-1462 or visiting www.tecfiderapregnancyregistry.com.

    Risk Summary

    • There are no adequate data on the developmental risk associated with the use of Tecfidera in pregnant women. The background risk of major birth defects and miscarriage for the indicated population is unknown.

    Nursing Mother Considerations

    Risk Summary

    • There are no data on the presence of DMF or MMF in human milk. The effects on the breastfed infant and on milk production are unknown. 

    • The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Tecfidera and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition. 

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established.

    Geriatric Considerations

    Clinical studies of Tecfidera did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

    Tecfidera Pharmacokinetics

    Absorption

    The median Tmax of MMF is 2-2.5 hours. The peak plasma concentration (Cmax) and overall exposure (AUC) increased approximately dose proportionally in the dose range studied (120 mg to 360 mg). Following administration of Tecfidera 240 mg twice a day with food, the mean Cmax of MMF was 1.87 mg/L and AUC was 8.21 mg.hr/L in MS patients.

    A high-fat, high-calorie meal did not affect the AUC of MMF but decreased its Cmax by 40%. The Tmax was delayed from 2.0 hours to 5.5 hours. In this study, the incidence of flushing was reduced by approximately 25% in the fed state. 

    Distribution

    The apparent volume of distribution of MMF varies between 53 and 73 L in healthy subjects. Human plasma protein binding of MMF is 27-45% and independent of concentration.

    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.

    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.

    Tecfidera Interactions

    Tecfidera Adverse Reactions

    Adverse Reactions

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

    Tecfidera Clinical Trials

    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)

    Tecfidera Note

    Notes

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

    Tecfidera Patient Counseling

    Patient Counseling

    Dosage

    • Inform patients that they will be provided two strengths of Tecfidera when starting treatment: 120 mg capsules for the 7-day starter dose and 240 mg capsules for the maintenance dose, both to be taken twice daily.
    • Inform patients to swallow Tecfidera capsules whole and intact. Inform patients to not crush, chew, or sprinkle capsule contents on food. Inform patients that Tecfidera can be taken with or without food.

    Anaphylaxis and Angioedema 

    • Advise patients to discontinue Tecfidera and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema.

    Progressive Multifocal Leukoencephalopathy

    • Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in patients who received Tecfidera. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML.
    • Inform the patient that 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.

    Herpes Zoster and Other Serious Opportunistic Infections 

    • Inform patients that herpes zoster and other serious opportunistic infections have occurred in patients who received Tecfidera.
    • Instruct the patient of the importance of contacting their doctor if they develop any signs or symptoms associated with herpes zoster or other serious opportunistic infections.

    Lymphocyte 

    • Counts Inform patients that Tecfidera may decrease lymphocyte counts.
    • A blood test should be obtained before they start therapy. Blood tests are also recommended after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated.

    Liver Injury 

    • Inform patients that Tecfidera may cause liver injury. Instruct patients treated with Tecfidera to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
    • A blood test should be obtained before patients start therapy and during treatment, as clinically indicated. 

    Flushing and Gastrointestinal (GI) Reactions 

    • Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are the most common reactions, especially at the initiation of therapy, and may decrease over time.
    • Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI reactions. Advise patients experiencing flushing that taking Tecfidera with food or taking a non-enteric coated aspirin prior to taking Tecfidera may help.

    Pregnancy and Pregnancy Registry 

    • 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 if they become pregnant while taking Tecfidera.

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