Dosing and uses of Tecfidera, BG-12 (dimethyl fumarate)
Adult dosage forms and strengths
capsule, delayed-release
- 120mg
- 240mg
Multiple Sclerosis
Indicated for treatment of relapsing forms of multiple sclerosis
120 mg PO BID initially; after 7 days, increase to maintenance dose of 240 mg BId
Dosing Considerations
Recent CBC (ie, within 6 months) recommended before initiation to identify patients with pre-existing low lymphocyte counts
Consider withholding treatment in patients with serious infections until the infection(s) is resolved
Friedreich's Ataxia (Orphan)
Orphan designation for treatment of Friedreich's ataxia
Orphan sponsor
- Gino Cortopassi; 608 12th Street; Davis, CA 95616
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%
Pediatric dosage forms and strengths
Safety and efficacy not established
Tecfidera, BG-12 (dimethyl fumarate) adverse (side) effects
>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
Warnings
Contraindications
Hypersensitivity to drug or ingredients
Cautions
May cause lymphopenia; in clinical trials, mean lymphocyte counts decreased ~30% during the first year of treatment, and then remained stable; obtain a CBC including lymphocyte count before initiating therapy, after 6 months, and every 6 to 12 months thereafter
Flushing (eg, warmth, redness, itching, and/or burning sensation) may occur
One confirmed case of progressive multifocal leukoencephalopathy (PML) resulting in death reported; withhold therapy at first sign or symptom suggestive of PML; perform appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms
Do not restart therapy if anaphylaxis or angioedema occur
Obtain a CBC, including lymphocyte count, before initiating treatment, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated; consider interruption of dimethyl fumarate in patients with lymphocyte counts less than 0.5 x 109/L persisting for more than six months; continue to obtain lymphocyte counts until their recovery if dimethyl fumarate 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
Pregnancy and lactation
Pregnancy category: C
There is a pregnancy registry that 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: Unknown whether distributed in breast milk
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.
Pharmacology of Tecfidera, BG-12 (dimethyl fumarate)
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
