dimethyl fumarate (Rx)

>10%

Flushing (40%)

Abdominal pain (18%)

Diarrhea (14%)

Nausea (12%)

1-10%

Vomiting (9%)

Pruritus (8%)

Rash (8%)

Albumin in urine (6%)

Erythema (5%)

Dyspepsia (5%)

Increased AST (4%)

Lymphopenia (2%)

Frequency Not Defined

Transient eosinophilia

Hepatobiliary disorders including liver function abnormalities (elevations in transaminases greater than or equal to 3 times ULN with concomitant elevations in total bilirubin > 2 times ULN)

Postmarketing Reports

Rhinorrhea

Alopecia

Herpes zoster and other serious opportunistic infections

Contraindications

Hypersensitivity to drug or components

Cautions

May cause lymphopenia; obtain a CBC including lymphocyte count before initiating therapy, after 6 months, and q6-12 months thereafter, and as clinically indicated; consider treatment interruption with lymphocyte counts <0.5 x 10^9/L persisting for >6 months; continue to obtain lymphocyte counts until their recovery if drug is discontinued or interrupted due to lymphopenia; consider withholding treatment from patients with serious infections until resolution; decisions about whether or not to restart dimethyl fumarate should be individualized based on clinical circumstances

Flushing (eg, warmth, redness, itching, and/or burning sensation) may occur; flushing symptoms generally may happen soon after initiating treatment and improve or resolve over time; in the majority of patients experiencing flushing, it is mild or moderate in severity

Progressive multifocal leukoencephalopathy (PML) resulting in death, in the postmarketing setting have occurred; withhold therapy at first sign or symptom suggestive of PML; perform appropriate diagnostic evaluation; cases have occurred predominantly in patients with lymphocyte counts <0.8x10^9/L persisting for more than 6 months; role of lymphopenia in PML cases uncertain

Do not restart therapy if anaphylaxis or angioedema occur

Clinically significant cases of liver injury reported; onset ranged from a few days to several months after treatment initiation; elevated hepatic transaminases (most not >3 x ULN) were observed during controlled trials and resolved upon treatment discontinuation; discontinue drug if clinically significant signs and symptoms of liver injury occur; obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment and during treatment, as clinically indicated; discontinue treatment if clinically significant liver injury induced by drug suspected

Opportunistic infections

• Serious cases of herpes zoster have occurred, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis
• Monitor patients for signs and symptoms of herpes zoster; if herpes zoster occurs, appropriate treatment should be administered; consider withholding treatment in patients with herpes zoster or other serious infections until 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; these infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC; these infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear
• Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment

Lymphopenia

• Drug may decrease lymphocyte counts; drug has not been studied in patients with pre­existing low lymphocyte counts
• Obtain a CBC, including lymphocyte count, before initiating treatment with drug, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated
• Consider interruption of drug in patients with lymphocyte counts less than 0.5 x 109/L persisting for more than six months; given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if drug is discontinued or interrupted due to lymphopenia
• Consider withholding treatment from patients with serious infections until resolution; decisions about whether or not to restart therapy should be individualized based on clinical circumstances

Pregnancy

There are no adequate data on developmental risk associated with use 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

Pregnancy registry

• Monitors pregnancy outcomes in women exposed to dimethyl fumarate during pregnancy; encourage patients to enroll by calling 1-866-810-1462 or visiting www.tecfiderapregnancyregistry.com

Lactation

There are no data on presence of DMF or MMF in human milk; effects on breastfed infant and on milk production are unknown

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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Exact mechanism is unknown

Methyl ester of fumaric acid that elicits immunomodulatory effects

Dimethyl fumarate and the metabolite (monomethyl fumarate [MMF]) activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, a transcription factor encoded by the NFE2L2 gene

The Nrf2 antioxidant response pathway is a cellular defense against oxidative stress

MMF has been identified as a nicotinic acid receptor agonist in vitro

Absorption

Peak Plasma Time: 2-2.5 hr (MMF)

Peak Plasma Concentration: 1.87 mg/L (MMF)

AUC: 8.21 mg•h/L (MMF)

High-fat, high-calorie meal did not affect AUC, but decreased Cmax by 40% and delayed Tmax to 5.5 hr (flushing decreased ~25%)

Distribution

Protein Bound: 27-45% (MMF)

Vd: 53-73 L

Metabolism

Metabolized rapidly by presystemic hydrolysis by esterases in GI tract, blood, and tissues (before it reaches systemic circulation) and is converted to its active metabolite, monomethyl fumarate (MMF)

Further metabolism of MMF occurs via tricarboxylic acid (TCA) cycle with no involvement of CYP450 system

Metabolites: MMF, fumaric acid, citric acid, and glucose

Elimination

Excretion: 60% by exhalation of CO2; 16% renal; 1% feces

Oral Administration

Swallow capsule whole and intact; do not chew, crush, or sprinkle on food

May take with or without food

Administration with food may reduce incidence of flushing by ~25%

Alternatively, administration of nonenteric coated aspirin (up to a dose of 325 mg) 30 minutes before each dose may reduce the incidence or severity of flushing

Storage

Capsules: Store at 15-30ºC (59-86ºF); protect the capsules from light; store in original container