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Tecfidera

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Tecfidera

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Lymphopenia

TECFIDERA may decrease lymphocyte counts [see ADVERSE REACTIONS]. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA 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). 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.

Before initiating treatment with TECFIDERA, a recent CBC (i.e., within 6 months) should be available. A CBC is recommended annually, and as clinically indicated. Withholding treatment should be considered in patients with serious infections until the infection(s) is resolved. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.

Flushing

TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms generally began soon after initiating TECFIDERA and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued TECFIDERA for flushing and < 1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of TECFIDERA with food may reduce the incidence of flushing.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION)

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 [see DOSAGE AND ADMINISTRATION].

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, as taking TECFIDERA with food may help [see ADVERSE REACTIONS].

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. Advise patients to call 1-800-456-2255 for more information [see Use In Specific Populations].

Lymphocyte Counts

Inform patients that TECFIDERA may decrease lymphocyte counts. A recent blood test (i.e., within 6 months) should be available before they start therapy to identify patients with pre-existing low lymphocyte counts. Blood tests are also recommended annually, and as clinically indicated [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate (DMF) was administered during pregnancy and lactation at clinically relevant doses. TECFIDERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In rats administered DMF orally (25, 100, 250 mg/kg/day) throughout organogenesis, embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. This dose also produced evidence of maternal toxicity (reduced body weight). Plasma exposure (AUC) for monomethyl fumarate (MMF), the major circulating metabolite, at the no-effect dose is approximately three times that in humans at the recommended human dose (RHD) of 480 mg/day. In rabbits administered DMF orally (25, 75, and 150 mg/kg/day) throughout organogenesis, embryolethality and decreased maternal body weight were observed at the highest dose tested. The plasma AUC for MMF at the no-effect dose is approximately 5 times that in humans at the RHD.

Oral administration of DMF (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested. Neurobehavioral impairment was observed at all doses. A no-effect dose for developmental toxicity was not identified. The lowest dose tested was associated with plasma AUC for MMF lower than that in humans at the RHD.

Pregnancy Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to TECFIDERA during pregnancy. Encourage patients to enroll by calling 1-800-456-2255.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TECFIDERA is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

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

Last reviewed on RxList: 4/8/2013
This monograph has been modified to include the generic and brand name in many instances.

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Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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