Applies to diroximel fumarate: oral capsule delayed release.

Serious side effects of Diroximel fumarate

Along with its needed effects, diroximel fumarate 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 diroximel fumarate:

Less common

• Cough or hoarseness
• fever or chills
• lower back or side pain
• painful or difficult urination

Incidence not known

• Back pain
• bloating of the stomach
• blurred vision
• confusion
• dark urine
• difficulty with swallowing
• dizziness
• drowsiness
• fast heartbeat
• headache
• hives, itching, or skin rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• nausea
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• seizures
• stomach pain
• tightness in the chest
• unusual tiredness or weakness
• vomiting
• yellow eyes or skin

Other side effects of Diroximel fumarate

Some side effects of diroximel 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
• feeling of warmth
• redness of the face, neck, arms and occasionally, upper chest

Less common

• Acid or sour stomach
• belching
• heartburn
• indigestion
• stomach discomfort or upset

For Healthcare Professionals

Applies to diroximel fumarate: oral delayed release capsule.

General

Upon oral administration, this drug and dimethyl fumarate are rapidly metabolized to monomethyl fumarate before reaching systemic circulation; adverse reactions were similar once metabolized. The most common adverse reactions for dimethyl fumarate were flushing and gastrointestinal (GI) events (i.e., diarrhea, nausea, abdominal pain, upper abdominal pain); the most common adverse reactions leading to discontinuation of dimethyl fumarate were flushing and GI events. This drug had fewer and less severe GI adverse events than dimethyl fumarate.^[Ref]

Cardiovascular

Very common (10% or more): Flushing (up to 32.8%)

Common (1% to 10%): Hot flush

Frequency not reported: Serious flushing (generalized erythema, rash, pruritus)

Dimethyl fumarate:

-Very common (10% or more): Flushing (e.g., warmth, redness, itching, burning sensation; up to 40.2%)

-Common (1% to 10%): Hot flush

-Frequency not reported: Hypotension

In clinical trials of dimethyl fumarate, 40% of dimethyl fumarate-treated patients 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 dimethyl fumarate for flushing and less than 1% had serious flushing symptoms that were probable hypersensitivity/anaphylactoid reactions and not life-threatening but led to hospitalization.

Dermatologic

Dimethyl fumarate:

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

-Frequency not reported: Angioedema

-Postmarketing reports: Alopecia

Endocrine

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

Dimethyl fumarate:

-Frequency not reported: Increased parathyroid hormone levels

Gastrointestinal

Very common (10% or more): GI adverse reactions (up to 34.8%), diarrhea (up to 15.4%), nausea (up to 14.6%)

Common (1% to 10%): Upper abdominal pain, abdominal pain, vomiting, lower abdominal pain

Postmarketing reports: Acute pancreatitis

Dimethyl fumarate:

-Very common (10% or more): GI adverse reactions (up to 49%), diarrhea (up to 22.3%), abdominal pain (up to 18%), nausea (up to 20.7%), upper abdominal pain (up to 15.5%)

-Common (1% to 10%): Vomiting, dyspepsia, gastritis, GI disorder, gastroenteritis, lower abdominal pain

In a clinical study evaluating GI tolerability, overall GI adverse reactions were observed in 34.8% of patients treated with this drug and in 49% of dimethyl fumarate-treated patients. Treatment discontinuations for GI tolerability reasons were 0.8% and 4.8% for this drug and dimethyl fumarate, respectively. Treatment-emergent GI adverse reactions for this drug and dimethyl fumarate, respectively, included diarrhea (15.4% and 22.3%), nausea (14.6% and 20.7%), upper abdominal pain (6.7% and 15.5%), abdominal pain (6.3% and 9.6%), lower abdominal pain (5.9% and 6.8%), and vomiting (3.6% and 8.8%).

The incidence of GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, upper abdominal pain, dyspepsia) was increased in patients treated with dimethyl fumarate compared to placebo. GI events began early during therapy (primarily in the first month) and usually decreased over time in patients treated with dimethyl fumarate 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 dimethyl fumarate.

Genitourinary

Dimethyl fumarate:

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

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

Hematologic

Very common (10% or more): Lymphopenia

Dimethyl fumarate:

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

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

-Uncommon (0.1% to 1%): Thrombocytopenia

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

In an uncontrolled, prospective, postmarketing study, at week 48 of treatment with dimethyl fumarate, CD4+ T cells were moderately (counts 0.2 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 with dimethyl fumarate, mean lymphocyte counts decreased by about 30% during the first year of therapy and then remained stable; 4 weeks after stopping dimethyl fumarate, 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 dimethyl fumarate patients 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 dimethyl fumarate 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 dimethyl fumarate 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 with dimethyl fumarate, 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 0.5 to less than 0.8 x 10[9] cells/L) persisting for at least 6 months was observed in 11% 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 dimethyl fumarate therapy.

Hepatic

In clinical studies, high postbaseline values were observed mostly for ALT and AST, and more often with this drug (29.5% and 15.8%) vs dimethyl fumarate (16.4% and 9%), respectively.

Most patients with elevated hepatic transaminases had levels less than 3 times the upper limit of normal (3 x ULN). Elevated hepatic aminotransferase at least 3 x ULN and at least 5 x ULN, respectively, were seen in 0.8% and 0.4% of patients taking this drug and 1.6% and 0.4% of patients taking dimethyl fumarate. Elevated transaminases at least 3 x ULN with concomitant elevated total bilirubin greater than 2 x ULN have not been observed with this drug.

An increased incidence of elevated hepatic transaminases in patients treated with dimethyl fumarate was seen mainly during the first 6 months of therapy; most patients with elevations had levels less than 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 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 dimethyl fumarate administration 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 dimethyl fumarate during postmarketing experience; onset ranged from a few days to several months after starting dimethyl fumarate. 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.

Very common (10% or more): Increased ALT (up to 25.9%), increased AST (up to 15.8%)

Frequency not reported: Elevated hepatic transaminases

Dimethyl fumarate:

-Very common (10% or more): Increased ALT (up to 16.4%)

-Common (1% to 10%): Increased AST, elevated hepatic transaminases

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

-Postmarketing reports: Liver function abnormalities, liver injury

Hypersensitivity

Dimethyl fumarate:

-Uncommon (0.1% to 1%): Hypersensitivity

-Postmarketing reports: Hypersensitivity reactions (including urticaria, angioedema, difficulty breathing), anaphylaxis

Metabolic

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

Dimethyl fumarate:

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

Nervous system

Dimethyl fumarate:

-Common (1% to 10%): Burning sensation

Other

A fatal case of PML occurred in a patient taking dimethyl fumarate 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 dimethyl fumarate. 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 dimethyl fumarate administration 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 dimethyl fumarate use (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. 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 with dimethyl fumarate. 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 (0.5 to less than 0.8 x 10[9] cells/L) or severe (0.2 to less than 0.5 x 10[9] cells/L) lymphopenia.

Other serious opportunistic infections were reported with dimethyl fumarate, 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, gastrointestinal tract, lungs, skin, eye, and ear.

Frequency not reported: Herpes zoster infection

Dimethyl fumarate:

-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])

Renal

Dimethyl fumarate-containing product:

-Frequency not reported: Fanconi syndrome

Respiratory

Dimethyl fumarate:

-Frequency not reported: Dyspnea, hypoxia

-Postmarketing reports: Rhinorrhea