Dosing & Uses
Dosage Forms & Strengths
capsule, delayed-release
- 95mg
- 190mg of monomethyl fumarate is bioequivalent to 240mg of the prodrug dimethyl fumarate
Multiple sclerosis
Indicated for relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
Starting dose: 95 mg PO BID for 7 days
Maintenance dose after 7 days: 190 mg PO BID
Unable to tolerate the maintenance dose
- Consider temporarily reducing dosage to 95 mg PO BID; within 4 weeks, resume at 190 mg PO BID
- Unable to tolerate return to the maintenance dose: Consider discontinuing treatment
- Administration of nonenteric-coated aspirin (up to a 325-mg dose) 30 min before administration may reduce the incidence or severity of flushing
Dosage Modifications
Renal or hepatic impairment
- No studies have been conducted
- However, neither condition would be expected to affect plasma exposure to monomethyl fumarate (MMF); therefore, no dosage adjustment is necessary
Dosing Considerations
Laboratory parameters
- Obtain a CBC count, including lymphocyte count, before initiation, 6 months after initiation, and then every 6-12 months thereafter, as clinically indicated
- Obtain AST/ALT, alkaline phosphatase, and total bilirubin levels before initiation, during treatment, as clinically indicated
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (6)
- axicabtagene ciloleucel
monomethyl fumarate, axicabtagene ciloleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- brexucabtagene autoleucel
monomethyl fumarate, brexucabtagene autoleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- ciltacabtagene autoleucel
monomethyl fumarate, ciltacabtagene autoleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- idecabtagene vicleucel
monomethyl fumarate, idecabtagene vicleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- lisocabtagene maraleucel
monomethyl fumarate, lisocabtagene maraleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- tisagenlecleucel
monomethyl fumarate, tisagenlecleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
Monitor Closely (3)
- isavuconazonium sulfate
monomethyl fumarate and isavuconazonium sulfate both decrease immunosuppressive effects; risk of infection. Use Caution/Monitor.
- ozanimod
ozanimod, monomethyl fumarate. Either increases effects of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Coadministration with immunosuppressive therapies may increase the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs in order to avoid unintended additive immunosuppressive effects.
- ublituximab
ublituximab and monomethyl fumarate both increase immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Owing to potential additive immunosuppressive effects, consider duration of effect and mechanism of action of these therapies if coadministered
Minor (0)
Adverse Effects
Data obtained from clinical trials of prodrug dimethyl fumarate (DMF), which is metabolized to MMF
>10%
Flushing (40%)
Abdominal pain (18%)
Diarrhea (14%)
Nausea (12%)
1-10%
Vomiting (9%)
Pruritus (8%)
Rash (8%)
Albumin urine present (6%)
Erythema (5%)
Dyspepsia (5%)
AST increased (4%)
Lymphopenia (2%)
Frequency Not Defined
A transient increase in mean eosinophil counts during first 2 months of treatment
Postmarketing Reports
Liver function abnormalities: AST/ALT ≥3x ULN with concomitant elevations in total bilirubin >2x ULN
Infections: Herpes zoster infection, other serious opportunistic infections
Gastrointestinal disorders: Acute pancreatitis
Respiratory, thoracic, and mediastinal disorders: Rhinorrhea
Skin and subcutaneous: Alopecia
Warnings
Contraindications
Hypersensitivity to MMF, DMF, diroximel fumarate, or to any of its excipients
Taking DMF or diroximel fumarate
Cautions
Clinically significant cases of liver injury reported; onset ranges from a few days to several months after initiating; discontinue if clinically significant drug-induced liver injury is suspected
May cause flushing (eg, warmth, redness, itching, and/or burning sensation)
Anaphylaxis and angioedema
- Anaphylaxis and angioedema after initial dose or at any time during treatment may occur
- Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue
Progressive multifocal leukoencephalopathy
- Progressive multifocal leukoencephalopathy (PML) has occurred with DMF
- Withhold dose at first sign or symptom suggestive of PML and perform diagnostic evaluation
- Typical symptoms (eg, progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, changes in thinking, memory changes, orientation leading to confusion, personality changes) may progress over days to weeks
- Monitor with MRI for signs consistent with PML and investigate any suspicious findings to allow for an early diagnosis of PML, if present
Herpes zoster and other serious opportunistic infections
- Serious cases of herpes zoster reported; these events may occur at any time during treatment
- Monitor for signs and symptoms of herpes zoster
- If herpes zoster occurs, administer appropriate treatment
- Other serious opportunistic infections reported, including serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections
- Consider withholding treatment in patients with herpes zoster or other serious infections until the infection has resolved
Lymphopenia
- May decrease lymphocyte counts
- Consider interrupting dose in patients with lymphocyte counts <0.5 x 109/L persisting for >6 months
- Continue to monitor CBC count until their recovery if therapy is discontinued or interrupted because of lymphopenia
- Consider withholding treatment from patients with serious infections until resolution
- Decide whether or not to restart treatment based on clinical circumstances
Drug interaction overview
-
DMF or diroximel fumarate
- Both DMF and diroximel fumarate are metabolized to MMF
- Therefore, coadministration of MMF with DMF or diroximel fumarate is contraindicated
- MMF may initiate the day following discontinuation of either of these drugs
Pregnancy & Lactation
Pregnancy
No adequate data available on the use of MMF or its prodrug in pregnant females
Animal data
- In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when DMF was administered during pregnancy and lactation at clinically relevant doses
Lactation
No data available on presence of DMF or MMF in human milk
Effects on breastfed infants and on milk production are unknown
Consider the mother’s clinical need and any potential adverse effects on the breastfed infants from the drug or from the 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.Pharmacology
Mechanism of Action
Monomethyl fumarate (MMF) is the active moiety of dimethyl fumarate (DMF) and diroximel fumarate
Mechanism by which MMF exerts its therapeutic effect in MS is unknown
Activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans
The Nrf2 pathway is involved in the cellular response to oxidative stress; MMF has been identified as a nicotinic acid receptor agonist in vitro
Absorption
Peak plasma time: 4.03 hr (MMF)
Effects of food
- Administration with high-fat, high-calorie meal: No significant change at AUC; decreased peak plasma concentration by 20%; delayed peak plasma time by 7 hr
Distribution
Protein bound: 27-45% (MMF)
Vd: 53-73 L (MMF)
Metabolism
In humans, metabolism of MMF occurs through the tricarboxylic acid cycle, with no involvement of the CYP450 system
Major metabolites in plasma: MMF, fumaric and citric acid, and glucose
Elimination
Half-life: ~0.5 hr
Excretion
- Exhalation of CO2: ~ 60%
- Renal: 16%
- Feces: 1%
Administration
Oral Administration
May take with or without food
Swallow capsules whole and intact; do not crush, chew or mix contents with food
Administration of nonenteric-coated aspirin (up to a 325-mg dose) 30 min before administration may reduce the incidence or severity of flushing
Storage
Unopened bottle
- Refrigerate at 2-8ºC (35-46ºF); do not freeze
Opened bottle
- Store at 20-25ºC (68-77ºF); excursions permitted at 15-30ºC (59-86ºF) for up to 3 months
- Protect from light
- Store in original container
- Capsules may become deformed if kept at high temperatures
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