1 INDICATIONS AND USAGE Dimethyl fumarate delayed-release capsules are indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Dimethyl fumarate delayed-release capsules are indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults ( 1 )

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 )] • Serious Gastrointestinal Reactions [see Warnings and Precautions ( 5.7 )] Most common adverse reactions (incidence ≥10% and ≥2% placebo) were flushing, abdominal pain, diarrhea, and nausea.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Solco Healthcare US, LLC at 1-866-257-2597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

In placebo-controlled and uncontrolled clinical studies, a total of 2,513 patients have received dimethyl fumarate delayed-release capsules and been followed for periods up to 13 years with an overall exposure of 11,318 person-years.

Approximately 1,169 patients have received more than 5 years of treatment with dimethyl fumarate delayed-release capsules, and 426 patients have received at least 10 years of treatment with dimethyl fumarate delayed-release capsules.

Adverse Reactions in Placebo-Controlled Trials In the two well-controlled studies demonstrating effectiveness, 1,529 patients received dimethyl fumarate delayed-release capsules with an overall exposure of 2,244 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.

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.

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 Placebo N=769 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 clinical trial patients treated with dimethyl fumarate delayed-release capsules; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain (0.3%).

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.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dimethyl fumarate delayed-release capsules.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: Acute Pancreatitis; Gastrointestinal perforation, ulceration, obstruction, and hemorrhage [see Warnings and Precautions ( 5.7 )] Hepatobiliary Disorders: Liver function abnormalities (elevations in transaminases ≥ 3 times ULN with concomitant elevations in total bilirubin > 2 times ULN) [see Warnings and Precautions ( 5.5 )] Infections and Infestations: Herpes zoster infection and other serious opportunistic infections [see Warnings and Precautions ( 5.3 )] Respiratory, Thoracic, and Mediastinal Disorders: Rhinorrhea Skin and Subcutaneous: Alopecia