Dimethyl

May cause rash, pruritus, or erythema. There are case reports of contact dermatitis resulting from dimethyl fumarate (DMF) exposure after use as a fungicide and desiccant in the shipping of furniture (Bruze 2011; Giménez-Arnau 2011; Ropper 2012).

Commonly causes mild to moderate flushing (eg, warmth, redness, itching, burning sensation); flushing generally appears soon after initiation, and improves or resolves with subsequent dosing. Administration with food may decrease flushing incidence. Administration of aspirin (nonenteric coated ≤325 mg) 30 minutes prior to dimethyl fumarate or a temporary dose reduction may also reduce the incidence and severity of flushing.

GI events (eg, nausea, vomiting, diarrhea, abdominal pain, dyspepsia) commonly occur with use; GI events generally occur in the first month of use and decrease thereafter. To improve tolerability, administer with food or temporarily reduce the dosage.

Clinically significant postmarketing cases of hepatic injury have been reported, with an onset ranging from a few days to several months after treatment initiation. Signs/symptoms of hepatic injury, including transaminase elevations >5 times the upper limit of normal (ULN) and total bilirubin elevations >2 times ULN have been observed. Some cases have required hospitalization; however, none of the cases were fatal or resulted in liver failure or transplant. Liver function test abnormalities resolved upon discontinuation. Drug-induced hepatocellular injury resulting in new-onset transaminase elevations combined with increased bilirubin levels is an important predictor of serious hepatic injury that may lead to acute hepatic failure, liver transplant, or death in some patients. Transaminase elevations (usually • Hypersensitivity reactions: Anaphylaxis and angioedema may occur after the first dose or at any time during treatment. Discontinue therapy if signs and symptoms of anaphylaxis or angioedema occur.

Decreased lymphocyte counts may occur. Obtain a CBC, including lymphocyte count, prior to initiation of therapy, after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider therapy interruption in patients with lymphocyte counts 3 persisting >6 months and in patients with serious infections. Due to a potential for delayed lymphocyte recovery following treatment interruption or discontinuation, monitor lymphocyte counts until lymphopenia is resolved. The decision to restart dimethyl fumarate should be individualized based on clinical circumstances. Dimethyl fumarate has not been studied in patients with preexisting low lymphocyte counts.

In clinical trials, proteinuria was reported at a slightly higher incidence than that observed with placebo; significance of these findings is unknown.

Cases of progressive multifocal leukoencephalopathy (PML) due to the JC virus (JCV), including fatality, have been reported, including cases in patients who were not immunocompromised and had no prior exposure to immunocompromised drugs, including natalizumab. The majority of PML cases occurred in patients with lymphocyte counts 3 (although the exact role of lymphopenia in PML is unknown). At the first sign or symptom suggestive of PML, perform a diagnostic evaluation and withhold therapy; symptoms progress over days to weeks and may include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, and mental status changes. Cases of PML have been diagnosed based on MRI findings and the detection of JCV DNA in the CSF without specific PML signs/symptoms. Monitoring with MRI for signs that may be consistent with PML may be beneficial and allow for an early diagnosis of PML. Concomitant drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling. Other warnings/precautions:

Dimethyl fumarate should only be prescribed by health care providers who are experienced in the diagnosis and management of multiple sclerosis.