Dimethyl Fumarate (Page 2 of 6)

5.5 Liver Injury

Clinically significant cases of liver injury have been reported in patients treated with dimethyl fumarate delayed-release capsules in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment with dimethyl fumarate delayed-release capsules. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients.
Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials [see Adverse Reactions (6.1)]. Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment with dimethyl fumarate delayed-release capsules and during treatment, as clinically indicated. Discontinue dimethyl fumarate delayed-release capsules if clinically significant liver injury induced by dimethyl fumarate delayed-release capsules is suspected.

5.6 Flushing

Dimethyl fumarate delayed-release capsules may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of dimethyl fumarate delayed-release capsules treated patients experienced flushing. Flushing symptoms generally began soon after initiating dimethyl fumarate delayed-release capsules and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued dimethyl fumarate delayed-release capsules for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of dimethyl fumarate delayed-release capsules with food may reduce the incidence of flushing. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to dimethyl fumarate delayed-release capsules dosing may reduce the incidence or severity of flushing [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

6 ADVERSE REACTIONS

The following important adverse reactions are described elsewhere in labeling:
• Anaphylaxis and Angioedema [see Warnings and Precautions (5.1)].
• Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)].

• Herpes Zoster and Other Serious Opportunistic Infections [see Warnings and Precautions (5.3)].
• Lymphopenia [see Warnings and Precautions (5.4)].
• Liver Injury [see Warnings and Precautions (5.5)].
• Flushing [see Warnings and Precautions (5.6)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate delayed-release capsules were flushing, abdominal pain, diarrhea, and nausea.
Adverse Reactions in Placebo-Controlled Trials
In the two well-controlled studies demonstrating effectiveness, 1529 patients received dimethyl fumarate delayed-release capsules with an overall exposure of 2244 person-years [see Clinical Studies (14)].
The adverse reactions presented in the table below are based on safety information from 769 patients treated with dimethyl fumarate delayed-release capsules 240 mg twice a day and 771 placebo-treated patients.Table 1: Adverse Reactions in Study 1 and 2 reported for Dimethyl Fumarate Delayed-Release Capsules 240 mg BID at ≥ 2% higher incidence than placebo

Dimethyl Fumarate Delayed-Release Capsules N=769 % Placebo N=771 %
Flushing 40 6
Abdominal pain 18 10
Diarrhea 14 11
Nausea 12 9
Vomiting 9 5
Pruritus 8 4
Rash 8 3
Albumin urine present 6 4
Erythema 5 1
Dyspepsia 5 3
Aspartate aminotransferase increased 4 2
Lymphopenia 2 <1

Gastrointestinal
Dimethyl fumarate delayed-release capsules caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with dimethyl fumarate delayed-release capsules compared with placebo. Four percent (4%) of patients treated with dimethyl fumarate delayed-release capsules and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with dimethyl fumarate delayed-release capsules.
Hepatic Transaminases
An increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate delayed-release capsules was seen primarily during the first six months of treatment, and most patients with elevations had levels < 3 times the upper limit of normal (ULN) during controlled trials. Elevations of alanine aminotransferase and aspartate aminotransferase to ≥ 3 times the ULN occurred in a small number of patients treated with both dimethyl fumarate delayed-release capsules and placebo and were balanced between groups. There were no elevations in transaminases ≥ 3 times the ULN with concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic transaminases were < 1% and were similar in patients treated with dimethyl fumarate delayed-release capsules or placebo.
Eosinophilia
A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.
Adverse Reactions in Placebo-Controlled and Uncontrolled Studies In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received dimethyl fumarate delayed-release capsules and been followed for periods up to 4 years with an overall exposure of 4603 person-years. Approximately 1162 patients have received more than 2 years of treatment with dimethyl fumarate delayed-release capsules. The adverse reaction profile of Dimethyl fumarate delayed-release capsules in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.

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