Tecfidera

Delayed-release capsules: 120 mg and 240 mg

Capsules should be stored at 15 C to 30 C (59 F to 86 F). The capsules should be stored in the original container and protected from light.

Tecfidera is the brand name of the drug dimethyl fumarate, which is used to treat symptoms of relapsing-remitting multiple sclerosis.

Multiple sclerosis, or MS, is a neurological condition in which the immune system attacks the protective covering that surrounds nerve cells. Relapsing-remitting MS occurs when symptoms show up from time to time.

Tecfidera is in a class of drugs known as Nrf2 activators, which work by decreasing inflammation and preventing nerve damage associated with MS.

According to the drug's manufacturer, Biogen, the drug cuts MS relapses in half, reducing the risk of relapse by 49 percent in a two-year study.

The medicine is sometimes also used to treat psoriasis (a skin condition).

The Food and Drug Administration (FDA) approved Tecfidera in 2013.

Tecfidera Warnings

Tecfidera may cause a viral infection in the brain called progressive multifocal leukoencephalopathy (PML), which could lead to serious injury or death.

Call your doctor right away if you experience any of the following symptoms while taking this medicine:

• Decreased vision or vision problems
• A change in mental state
• Weakness on one side of the body
• Trouble with speaking or walking

Be sure to tell your doctor if you have an infection or a low white blood cell count before taking Tecfidera.

Also, let your physician know if you're allergic to Tecfidera or any other medication.

This drug may help symptoms of MS, but it won't cure the condition. Continue to take Tecfidera even if you feel well.

Don't stop taking this medicine without first talking to your doctor.

Pregnancy and Tecfidera

It's not known whether Tecfidera will harm an unborn baby.

Don't' take this medicine without first talking to a doctor if you're pregnant or plan to become pregnant.

It's also not known whether Tecfidera passes into breast milk or could harm a breastfeeding baby.

Tell your doctor if you're breastfeeding before taking this medicine.

Although appropriate studies on the relationship of age to the effects of dimethyl fumarate have not been performed in the geriatric population, geriatric-specific problems are not expected to limit the usefulness of dimethyl fumarate in the elderly.

Tecfidera is a prescription medication used to treat relapsing forms of multiple sclerosis, or MS. It is not known if eimethyl fumarate is safe and effective in children under 18 years of age.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Store at 15°C – 30°C (59-86°F).
• Protect the capsules from light. Store in original container.
• Once opened, discard bottles of Tecfidera after 90 days.
• Keep this and all medicines out of the reach of children.

Contraindications

• Known hypersensitivity to dimethyl fumarate or any excipients in the formulation.1 (See Anaphylaxis and Angioedema under Cautions.)

Warnings/Precautions

Anaphylaxis and Angioedema

May cause anaphylaxis or angioedema after the first dose or at any time during therapy.1 Signs and symptoms of hypersensitivity reactions have included difficulty breathing, urticaria, and swelling of the throat and tongue.1 (See Contraindications under Cautions and also see Advice to Patients.)

Progressive Multifocal Leukoencephalopathy (PML)

An FDA alert in November 2014 described a fatal case of PML (an opportunistic infection of the brain caused by the JC virus that usually leads to death or severe disability) in a patient with MS treated with dimethyl fumarate for 4 years in a clinical trial.1 15 19 The patient had prolonged lymphopenia (i.e., lymphocyte counts predominantly <500/mm3 for 3.5 years) during dimethyl fumarate therapy;1 15 19 the causative role of lymphopenia in this case is not known.1 19 The patient had no other known medical conditions resulting in compromised immune system function, had not received natalizumab, and was not concurrently receiving any immunosuppressive or immunomodulatory drugs.1 15 19

Several cases of PML have been reported in Europe in patients receiving other preparations containing dimethyl fumarate.15 17 20

At the first sign or symptom suggestive of PML (see Advice to Patients), immediately withhold dimethyl fumarate therapy and perform an appropriate diagnostic evaluation.1 15

Monitor lymphocyte counts in patients receiving dimethyl fumarate.1 15 (See Lymphopenia under Cautions.)

Lymphopenia

May decrease lymphocyte counts.1 2 16 In placebo-controlled clinical trials, mean lymphocyte counts decreased by approximately 30% during the first year of therapy and remained stable thereafter.1 2 Mean lymphocyte counts improved 4 weeks following discontinuance of the drug, but did not return to baseline values.1 (See Actions.)

Although an increased incidence of serious infections was not observed in patients with decreased lymphocyte counts in controlled trials, one case of PML developed during an extension study in the setting of prolonged lymphopenia.1 (See Progressive Multifocal Leukoencephalopathy [PML] under Cautions.)

Not studied in patients with preexisting low lymphocyte counts.1

Obtain a CBC, including lymphocyte count, prior to initiation of dimethyl fumarate, following 6 months of therapy, every 6–12 months during therapy thereafter, and as clinically indicated.1

In patients with lymphocyte counts <500/mm3 persisting for >6 months, consider interruption of therapy.1 Consider monitoring lymphocyte counts until lymphopenia has resolved since lymphocyte recovery may be delayed following drug discontinuance.1

In patients with serious infections, consider withholding treatment until the infection has resolved.1 Consider patient's clinical circumstances when deciding whether to restart dimethyl fumarate therapy.1

Flushing

May cause flushing (e.g., warmth, redness, itching, burning sensation).1 2 3 14 In clinical trials, 40% of dimethyl fumarate-treated patients experienced flushing.1 Symptoms generally are mild to moderate, begin soon after initiating therapy, and improve or resolve over time.1 3

Administration with food or pretreatment with non-enteric-coated aspirin may reduce incidence and/or severity of flushing.1 14 (See Administration under Dosage and Administration, see Specific Drugs under Interactions, and also see Actions.)

Specific Populations

Category C.1

Tecfidera pregnancy registry (for patients) at 866-810-1462 or .1

Not known whether dimethyl fumarate or its metabolites distribute into human milk.1 10 Use with caution in nursing women.1

Safety and efficacy not established in pediatric patients <18 years of age.1

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 (See Geriatric Patients under Dosage and Administration.)

Common Adverse Effects

Flushing,1 2 3 14 abdominal pain,1 2 3 diarrhea,1 2 3 nausea.1 2 3 Incidence of flushing and adverse GI effects generally higher early in therapy (mainly in the first month) and decreases with continued therapy (see Administration under Dosage and Administration).1 2 10 21

Proteinuria, pruritus, reduced lymphocyte counts, increased aminotransferase concentrations (e.g., ALT, AST), transient eosinophilia (during the first 2 months of therapy).1 2 3

No potential drug interactions with dimethyl fumarate or its main active metabolite, MMF, identified in CYP inhibition and induction studies, P-glycoprotein studies, or studies of protein binding.1

Specific Drugs

Dimethyl fumarate is used to treat the relapsing forms of multiple sclerosis (MS). This medicine will not cure MS, but it may slow some disabling effects and decrease the number of relapses of the disease.

This medicine is available only with your doctor's prescription.

• If you have an allergy to dimethyl fumarate or any other part of Tecfidera (dimethyl fumarate).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Tecfidera is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of dimethyl fumarate. The 120 mg capsules have a green cap and white body, printed with “BG-12 120 mg” in black ink on the body. The 240 mg capsules have a green cap and a green body, printed with “BG-12 240 mg” in black ink on the body.

The following important adverse reactions are described elsewhere in labeling:

• Anaphylaxis and Angioedema [see Warnings and Precautions (5.1)].
• Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)].
• Lymphopenia [see Warnings and Precautions (5.3)].
• Liver Injury [see Warnings and Precautions (5.4)].
• Flushing [see Warnings and Precautions (5.5)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for Tecfidera were flushing, abdominal pain, diarrhea, and nausea.

Adverse Reactions in Placebo-Controlled Trials

In the two well-controlled studies demonstrating effectiveness, 1529 patients received Tecfidera with an overall exposure of 2244 person-years [see Clinical Studies (14)].

The adverse reactions presented in the table below are based on safety information from 769 patients treated with Tecfidera 240 mg twice a day and 771 placebo-treated patients.

Gastrointestinal

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. Elevations of alanine aminotransferase and aspartate aminotransferase to ≥ 3 times the ULN occurred in a small number of patients treated with both Tecfidera and placebo and were balanced between groups. 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

A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.

Adverse Reactions in Placebo-Controlled and Uncontrolled Studies

In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received Tecfidera and been followed for periods up to 4 years with an overall exposure of 4603 person-years. Approximately 1162 patients have received more than 2 years of treatment with Tecfidera. The adverse reaction profile of Tecfidera in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.

Post Marketing Experience

The following adverse reaction has been identified during post approval use of Tecfidera. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Liver function abnormalities (elevations in transaminases ≥ 3 times ULN with concomitant elevations in total bilirubin > 2 times ULN) have been reported following Tecfidera administration in post marketing experience [See Warnings and Precautions (5.4)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of dimethyl fumarate (DMF) were conducted in mice and rats. In mice, oral administration of DMF (25, 75, 200, and 400 mg/kg/day) for up to two years resulted in an increase in nonglandular stomach (forestomach) and kidney tumors: squamous cell carcinomas and papillomas of the forestomach in males and females at 200 and 400 mg/kg/day; leiomyosarcomas of the forestomach at 400 mg/kg/day in males and females; renal tubular adenomas and carcinomas at 200 and 400 mg/kg/day in males; and renal tubule adenomas at 400 mg/kg/day in females. Plasma MMF exposure (AUC) at the highest dose not associated with tumors in mice (75 mg/kg/day) was similar to that in humans at the recommended human dose (RHD) of 480 mg/day.

In rats, oral administration of DMF (25, 50, 100, and 150 mg/kg/day) for up to two years resulted in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150 mg/kg/day. Plasma MMF AUC at the lowest dose tested was lower than that in humans at the RHD.

Mutagenesis

Dimethyl fumarate (DMF) and monomethyl fumarate (MMF) were not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. DMF and MMF were clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation. DMF was not clastogenic in the in vivo micronucleus assay in the rat.

Impairment of Fertility

In male rats, oral administration of DMF (75, 250, and 375 mg/kg/day) prior to and throughout the mating period had no effect on fertility; however, increases in non-motile sperm were observed at the mid and high doses. The no-effect dose for adverse effects on sperm is similar to the recommended human dose (RHD) of 480 mg/day on a body surface area (mg/m2) basis.

In female rats, oral administration of DMF (20, 100, and 250 mg/kg/day) prior to and during mating and continuing to gestation day 7 caused disruption of the estrous cycle and increases in embryolethality at the highest dose tested. The highest dose not associated with adverse effects (100 mg/kg/day) is twice the RHD on a mg/m2 basis.

Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of DMF, and in a chronic oral toxicity study evaluating a combination of four fumaric acid esters (including DMF) in rats.

Animal Toxicology and/or Pharmacology

Kidney toxicity was observed after repeated oral administration of dimethyl fumarate (DMF) in mice, rats, dogs, and monkeys. Renal tubule epithelia regeneration, suggestive of tubule epithelial injury, was observed in all species. Renal tubular hyperplasia was observed in rats with dosing for up to two years. Cortical atrophy and interstitial fibrosis were observed in dogs and monkeys at doses above 5 mg/kg/day. In monkeys, the highest dose tested (75 mg/kg/day) was associated with single cell necrosis and multifocal and diffuse interstitial fibrosis, indicating irreversible loss of renal tissue and function. In dogs and monkeys, the 5 mg/kg/day dose was associated with plasma MMF exposures less than or similar to that in humans at the recommended human dose (RHD).

A dose-related increase in incidence and severity of retinal degeneration was observed in mice following oral administration of DMF for up to two years at doses above 75 mg/kg/day, a dose associated with plasma MMF exposure (AUC) similar to that in humans at the RHD.

Before taking and while you take Tecfidera, tell your doctor if you have or have had a low white blood cell counts or an infection.

Tecfidera may cause a serious viral infection of the brain that can lead to disability or death. Call your doctor right away if you have any change in your mental state, decreased vision, weakness on one side of your body, or problems with speech or walking. These symptoms may start gradually and get worse quickly.