dimethyl fumarate (Rx)

Brand and Other Names:Tecfidera, BG-12
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule, delayed-release

  • 120mg
  • 240mg
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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) resolved

Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating treatment

Friedreich's Ataxia (Orphan)

Orphan designation for treatment of Friedreich's ataxia

Orphan sponsor

  • Gino Cortopassi; 608 12th Street; Davis, CA 95616

Safety and efficacy not established

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Adverse 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

Liver injury

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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 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

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

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

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Pregnancy & 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.

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Pharmacology

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

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Administration

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%

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Formulary

FormularyPatient Discounts

Adding plans allows you to compare formulary status to other drugs in the same class.

To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

Adding plans allows you to:

  • View the formulary and any restrictions for each plan.
  • Manage and view all your plans together – even plans in different states.
  • Compare formulary status to other drugs in the same class.
  • Access your plan list on any device – mobile or desktop.

The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
QL Quantity Limits
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
ST Step Therapy
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
OR Other Restrictions
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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