Note: This document contains side effect information about dimethyl fumarate. Some dosage forms listed on this page may not apply to the brand name Tecfidera.

Summary

Common side effects of Tecfidera include: infection, abdominal pain, and flushing. Other side effects include: increased serum aspartate aminotransferase, pruritus, skin rash, vomiting, lymphocytopenia, and erythema of skin. Continue reading for a comprehensive list of adverse effects.

Applies to dimethyl fumarate: oral capsule delayed release.

Serious side effects of Tecfidera

Along with its needed effects, dimethyl fumarate (the active ingredient contained in Tecfidera) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking dimethyl fumarate:

More common

• Chills
• cough
• feeling of warmth
• fever
• hoarseness
• lower back or side pain
• painful or difficult urination
• redness of the face, neck, arms, and occasionally, upper chest

Incidence not known

• Black, tarry stools
• chest pain
• difficulty with swallowing
• dizziness
• fast heartbeat
• hives, itching, or skin rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
• painful blisters on the trunk of the body
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swollen glands
• tightness in the chest
• trouble breathing
• unusual bleeding or bruising
• unusual tiredness or weakness

Other side effects of Tecfidera

Some side effects of dimethyl fumarate may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Diarrhea
• nausea
• stomach pain
• vomiting

Less common

• Belching
• heartburn
• indigestion
• stomach discomfort or upset

For Healthcare Professionals

Applies to dimethyl fumarate: oral delayed release capsule.

General

The most common adverse reactions associated with the capsule formulation were flushing and gastrointestinal (GI) events (e.g., abdominal pain, diarrhea, nausea, upper abdominal pain). The most common adverse reactions associated with the tablet formulation were GI events followed by flushing and lymphopenia.

Unless otherwise indicated, the adverse reactions have been reported with the capsule formulation.^[Ref]

Cardiovascular

In clinical trials, 40% of patients treated with this drug reported flushing; symptoms generally began soon after starting treatment and usually improved/resolved over time. In most patients with flushing, it was of mild or moderate severity; 3% of patients discontinued this drug for flushing and less than 1% had serious flushing symptoms that were probable hypersensitivity/anaphylactoid reactions and not life-threatening but led to hospitalization.

Tablet formulation: Flushing was most likely to occur during the early weeks of therapy and tended to lessen with time. In the clinical study, 20.8% of patients receiving this drug experienced flushing, which was mild in most cases. Individual episodes of flushing usually began shortly after taking the tablets and resolved within a few hours.

Very common (10% or more): Flushing (e.g., warmth, redness, itching, burning sensation; up to 40%)

Common (1% to 10%): Hot flush

Frequency not reported: Hypotension

Tablet formulation:

-Very common (10% or more): Flushing (up to 20.8%)

Dermatologic

Common (1% to 10%): Pruritus, rash, erythema, alopecia

Frequency not reported: Angioedema

Postmarketing reports: Alopecia

Tablet formulation:

-Common (1% to 10%): Erythema, skin burning sensation, pruritus

-Rare (0.01% to 0.1%): Allergic skin reaction

Endocrine

Levels of parathyroid hormone increased in patients treated with this drug relative to placebo (median percentage increase from baseline at 2 years of 29% vs 15%, respectively); mean values remained within normal range.

Frequency not reported: Increased parathyroid hormone levels

Gastrointestinal

Very common (10% or more): Abdominal pain (up to 18%), diarrhea (up to 14%), nausea (up to 12%), upper abdominal pain

Common (1% to 10%): Vomiting, dyspepsia, gastritis, GI disorder, gastroenteritis

Postmarketing reports: Acute pancreatitis

Tablet formulation:

-Very common (10% or more): Diarrhea (up to 36.9%), abdominal distension, abdominal pain, nausea

-Common (1% to 10%): Vomiting, dyspepsia, constipation, abdominal discomfort, flatulence

The incidence of GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, upper abdominal pain, dyspepsia) was increased in patients treated with this drug compared to placebo. GI events began early during therapy (primarily in the first month) and usually decreased over time in patients treated with this drug compared to placebo. In most patients who experienced GI events, these events were of mild or moderate severity. Serious GI events (including gastroenteritis, gastritis) were reported in 1% of patients treated with this drug.

Tablet formulation: GI disorders were most likely to occur during the first 2 to 3 months after starting therapy. Diarrhea was reported in 36.9% of patients; most of these diarrhea events were of mild to moderate severity.

Genitourinary

Very common (10% or more): Ketones measured in urine (up to 45%)

Common (1% to 10%): Albumin urine present, proteinuria

Frequency not reported: Dysmenorrhea

Tablet formulation:

-Uncommon (0.1% to 1%): Proteinuria

Hematologic

Very common (10% or more): Decreased CD8+ T cells (up to 59%), lymphopenia (up to 41%), decreased CD4+ T cells (up to 37%)

Common (1% to 10%): Leukopenia, decreased WBC count, decreased lymphocyte counts

Uncommon (0.1% to 1%): Thrombocytopenia

Frequency not reported: Increased eosinophil counts, increased CD4+/CD8+ ratio

Tablet formulation:

-Very common (10% or more): Lymphopenia, leukopenia

-Common (1% to 10%): Eosinophilia, leukocytosis

Related product containing dimethyl fumarate (the active ingredient contained in Tecfidera) with other fumaric acid esters:

-Very rare (less than 0.01%): Acute lymphatic leukemia, irreversible pancytopenia

In an uncontrolled, prospective, postmarketing study, at week 48 of treatment with this drug, CD4+ T cells were moderately (counts at least 0.2 x 10[9] cells/L to less than 0.4 x 10[9] cells/L) or severely (less than 0.2 x 10[9] cells/L) decreased in up to 37% or 6% of patients, respectively; CD8+ T cells were decreased in up to 59% of patients at counts less than 0.2 x 10(9) cells/L and 25% of patients at counts less than 0.1 x 10(9) cells/L.

In multiple sclerosis trials, mean lymphocyte counts decreased by about 30% during the first year of therapy and then remained stable; 4 weeks after stopping this drug, mean lymphocyte counts increased but did not return to baseline. Lymphocyte counts less than 0.5 x 10(9) cells/L (lower limit of normal [LLN]: 0.91 x 10[9] cells/L) were reported in 6% of patients treated with this drug and less than 1% of placebo patients; a lymphocyte count less than 0.2 x 10(9) cells/L was seen in 1 patient treated with this drug and in no patients treated with placebo. Occurrence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with this drug or placebo, respectively; no increased incidence of serious infections was observed in patients with lymphocyte counts less than 0.8 x 10(9) cells/L or less than 0.5 x 10(9) cells/L in controlled trials.

In controlled and uncontrolled clinical trials, 41% of patients had lymphopenia (defined as lymphocyte counts less than LLN). Mild lymphopenia (counts at least 0.8 x 10[9] cells/L to less than LLN) was observed in 28% of patients; moderate lymphopenia (counts at least 0.5 x 10[9] cells/L to less than 0.8 x 10[9] cells/L) persisting for at least 6 months was observed in 10% of patients. Severe lymphopenia (counts less than 0.5 x 10[9] cells/L) persisting for at least 6 months was seen in 2% of patients; in this group, most lymphocyte counts remained less than 0.5 x 10(9) cells/L with continued therapy.

A transient increase in mean eosinophil counts was observed during the first 2 months of therapy.

Tablet formulation: Changes in hematological parameters were most likely to occur during the first 3 months after starting therapy. In the clinical study, mean lymphocyte counts began to decrease slightly between weeks 3 and 5 and reached a maximum in week 12 where about a third of patients had lymphocyte values less than 1 x 10(9) cells/L; these values remained within the normal range during the clinical study. At week 16 (end of treatment), there was no further decline in lymphocyte counts; at this time, 13/175 patients had lymphocyte levels less than 0.7 x 10(9) cells/L. During posttherapy follow up, lymphocyte levels less than 0.7 x 10(9) cells/L were observed in 1/29 patients at 6 months and no patients at 12 months after stopping therapy. At 12 months after stopping therapy, 3/28 patients had lymphocyte values less than 1 x 10(9) cells/L, which represented 3/279 patients started on this drug.

Tablet formulation: A decline in total leukocyte count became apparent at week 12 of therapy; it slowly increased again at week 16 (end of treatment). At 12 months after stopping therapy, all patients had values above 3 x 10(9) cells/L.

Tablet formulation: A transient increase in mean eosinophils was observed as early as week 3, peaked at week 5 and 8, and returned to baseline at week 16.

Hepatic

An increased incidence of elevated hepatic transaminases in patients treated with this drug was seen mainly during the first 6 months of therapy; most patients with elevations had levels less than 3 times the upper limit of normal (3 x ULN) during controlled trials. Elevated ALT and AST to at least 3 x ULN, respectively, occurred in 6% and 2% of patients treated with dimethyl fumarate (the active ingredient contained in Tecfidera) and 5% and 2% of patients treated with placebo; no elevated transaminases at least 3 x ULN with concomitant elevated total bilirubin greater than 2 x ULN were reported during clinical trials. However, liver function abnormalities (elevated transaminases at least 3 x ULN with concomitant elevated total bilirubin greater than 2 x ULN) have been reported after administration of this drug during postmarketing experience; these abnormalities resolved upon discontinuation of therapy over a varying period of time.

Clinically significant cases of liver injury have been reported in patients treated with this drug during postmarketing experience; onset ranged from a few days to several months after starting this drug. Signs/symptoms of liver injury (including elevated serum aminotransferases to greater than 5-fold ULN and elevated total bilirubin to greater than 2-fold ULN) have been observed; these abnormalities resolved upon discontinuation of therapy. Some cases required hospitalization, but none of the reported cases resulted in liver failure, liver transplant, or death.

Common (1% to 10%): Increased AST, increased ALT

Frequency not reported: Increased serum aminotransferases, increased total bilirubin, increased hepatic transaminases, drug-induced liver injury

Postmarketing reports: Liver function abnormalities, liver injury

Tablet formulation:

-Common (1% to 10%): Increased hepatic enzymes

Hypersensitivity

Uncommon (0.1% to 1%): Hypersensitivity

Postmarketing reports: Hypersensitivity reactions (including urticaria, angioedema, difficulty breathing), anaphylaxis/anaphylactoid reaction

Metabolic

Frequency not reported: Decreased 1,25-dihydroxy vitamin D levels

Tablet formulation:

-Common (1% to 10%): Decreased appetite

Levels of 1,25-dihydroxy vitamin D decreased in patients treated with this drug relative to placebo (median percentage decrease from baseline at 2 years of 25% vs 15%, respectively); mean values remained within normal range.

Nervous system

Common (1% to 10%): Burning sensation

Frequency not reported: Headache

Tablet formulation:

-Common (1% to 10%): Headache, paresthesia

Related product containing dimethyl fumarate (the active ingredient contained in Tecfidera) with other fumaric acid esters:

-Uncommon (0.1% to 1%): Dizziness

Other

A fatal case of PML occurred in a patient taking this drug for 4 years while enrolled in a clinical trial; during the trial, the patient had prolonged lymphopenia (lymphocyte counts mainly less than 0.5 x 10[9] cells/L for 3.5 years) while taking this drug. The patient had no other identified systemic medical conditions that compromised immune system function and was not previously treated with natalizumab (known to be associated with PML); in addition, the patient was not taking any immunosuppressive or immunomodulatory agents concomitantly.

In several PML cases where T cell subsets were determined at time of PML diagnosis, CD8+ T cell counts were decreased to less than 0.1 x 10(9) cells/L, whereas reductions in CD4+ T cells counts were variable (ranging from less than 0.05 to 0.5 x 10[9] cells/L) and correlated more with overall severity of lymphopenia (less than 0.5 x 10[9] cells/L to less than LLN); thus, the CD4+/CD8+ ratio was increased in these patients.

PML has occurred in the setting of lymphopenia (lymphocyte count less than LLN) after administration of this drug during postmarketing experience; these PML cases have occurred mainly in the setting of prolonged moderate to severe lymphopenia (e.g., lymphocyte counts less than 0.8 x 10[9] cells/L for more than 6 months) but also occurred in patients with mild lymphopenia. The majority of PML cases in the postmarketing setting were reported in patients older than 50 years.

Herpes zoster infections have been reported with use of this drug (including during postmarketing experience); in a long-term extension study, 5% of patients reported 1 or more events of herpes zoster, most of which were of mild to moderate severity. Most patients (including those who had a serious herpes zoster infection) had lymphocyte counts above LLN; in a majority of patients with concurrent lymphocyte counts below LLN, lymphopenia was rated moderate or severe. Most cases of herpes zoster infection during postmarketing experience were nonserious and resolved with treatment; however, serious cases of herpes zoster (including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster oticus, herpes zoster infection neurological, herpes zoster meningoencephalitis, herpes zoster meningomyelitis) have been reported. Limited data were available on absolute lymphocyte count (ALC) in patients with herpes zoster infection during postmarketing experience; however, when reported, most patients had moderate (at least 0.5 x 10[9] cells/L to less than 0.8 x 10[9] cells/L) or severe (less than 0.5 x 10[9] cells/L to 0.2 x 10[9] cells/L) lymphopenia.

Other serious opportunistic infections were reported, including cases of serious viral (herpes simplex virus, West Nile virus, CMV), fungal (Candida, Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections; such infections have occurred in patients with reduced ALC, as well as in those with normal ALC, and have affected the brain, meninges, spinal cord, GI tract, lungs, skin, eye, and ear.

Very common (10% or more): Infections (up to 60%)

Common (1% to 10%): Serious infections, feeling hot, herpes zoster infection

Frequency not reported: Progressive multifocal leukoencephalopathy (PML), John Cunningham virus (JCV) infections

Postmarketing reports: PML (in the setting of lymphopenia), herpes zoster infection (including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster oticus, herpes zoster infection neurological, herpes zoster meningoencephalitis, herpes zoster meningomyelitis), other serious opportunistic infections (including viral infections [herpes simplex virus, West Nile virus, CMV], fungal infections [Candida, Aspergillus], bacterial infections [Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis])

Tablet formulation:

-Common (1% to 10%): Fatigue, feeling hot, asthenia

-Frequency not reported: PML

-Postmarketing reports: Herpes zoster

Renal

Frequency not reported: Fanconi syndrome

Tablet formulation:

-Uncommon (0.1% to 1%): Increased serum creatinine

-Frequency not reported: Renal failure

Related product containing dimethyl fumarate (the active ingredient contained in Tecfidera) with other fumaric acid esters:

-Frequency not reported: Fanconi syndrome

Respiratory

Frequency not reported: Dyspnea, hypoxia, oropharyngeal pain, cough

Postmarketing reports: Rhinorrhea