dimethyl fumarate

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.

2 DOSAGE AND ADMINISTRATION Starting dose: 120 mg twice a day, orally, for 7 days ( 2.1 ) Maintenance dose after 7 days: 240 mg twice a day, orally ( 2.1 ) Swallow dimethyl fumarate delayed-release capsules whole and intact. Do not crush, chew, or sprinkle capsule contents on food ( 2.1 ) Take dimethyl fumarate delayed-release with or without food ( 2.1 ) 2.1 Dosing Information The starting dose for dimethyl fumarate delayed-release capsules are 120 mg twice a day orally. After 7 days, the dose should be increased to the maintenance dose of 240 mg twice a day orally. Temporary dose reductions to 120 mg twice a day may be considered for individuals who do not tolerate the maintenance dose. Within 4 weeks, the recommended dose of 240 mg twice a day should be resumed. Discontinuation of dimethyl fumarate delayed-release capsules should be considered for patients unable to tolerate return to the maintenance dose. The incidence of flushing may be reduced by administration of dimethyl fumarate delayed-release capsules with food. 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 Clinical Pharmacology ( 12.3 )] . Dimethyl fumarate delayed-release capsules should be swallowed whole and intact. Dimethyl fumarate delayed-release capsules should not be crushed or chewed and the capsule contents should not be sprinkled on food. Dimethyl fumarate delayed-release capsules can be taken with or without food. 2.2 Blood Tests Prior to Initiation of Therapy Obtain a complete blood cell count (CBC) including lymphocyte count before initiation of therapy [see Warnings and Precautions ( 5.4 )]. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment with dimethyl fumarate delayed-release capsules [see Warnings and Precautions ( 5.5 )] .

5 WARNINGS AND PRECAUTIONS Anaphylaxis and Angioedema: Discontinue and do not restart dimethyl fumarate delayed-release capsules if these occur. ( 5.1 ) Progressive multifocal leukoencephalopathy (PML): Withhold dimethyl fumarate delayed-release capsules at the first sign or symptom suggestive of PML. ( 5.2 ) Herpes Zoster and Other Serious Opportunistic Infections: Consider withholding dimethyl fumarate delayed-release capsules in cases of serious infection until the infection has resolved. ( 5.3 ) Lymphopenia: Obtain a CBC including lymphocyte count before initiating dimethyl fumarate delayed-release capsules, after 6 months, and every 6 to 12 months thereafter. Consider interruption of dimethyl fumarate delayed-release capsules if lymphocyte counts <0.5 x 109/L persist for more than 6 months. ( 5.4 ) Liver Injury: Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating 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. ( 5.5 ) 5.1 Anaphylaxis and Angioedema Dimethyl fumarate delayed-release capsules can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, uticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue dimethyl fumarate delayed-release capsules and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema. 5.2 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with dimethyl fumarate delayed-release capsules. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received dimethyl fumarate delayed-release capsules for 4 years while enrolled in a clinical trial. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) while taking dimethyl fumarate delayed-release capsules [see Warnings and Precautions ( 5. 4)] . The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly. PML has also occurred in the postmarketing setting in the presence of lymphopenia (<0.9x10 9 /L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8x 10 9 /L persisting for more than 6 months. At the first sign or symptom suggestive of PML, withhold dimethyl fumarate delayed-release capsules and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PM…

4 CONTRAINDICATIONS Dimethyl fumarate delayed-release capsules are contraindicated in patients with known hypersensitivity to dimethyl fumarate or to any of the excipients of dimethyl fumarate delayed-release capsules. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions ( 5.1 )] . Known hypersensitivity to dimethyl fumarate or any of the excipients of dimethyl fumarate delayed-release capsules.

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 Upsher-Smith Laboratories, LLC at 1-855-899-9180 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 2513 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 1169 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, 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. 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 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 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…