SPL UNCLASSIFIED SECTION.

container1. container2. carton1. carton2.

ADVERSE REACTIONS SECTION.

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)]. 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)]. Most common adverse reactions (incidence >=10% and >=2% placebo) were flushing, abdominal pain, diarrhea, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddys Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of 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 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 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 240 mg twice day and 771 placebo-treated patients. Table 1: Adverse Reactions in Study and reported for Dimethyl Fumarate 240 mg BID at >= 2% higher incidence than placebo Dimethyl Fumarate N=769 Placebo N=771 Flushing 40 Abdominal pain 18 10 Diarrhea 14 11 Nausea 12 Vomiting 5 Pruritus 4 Rash 3 Albumin urine present 4 Erythema 1 Dyspepsia 3 Aspartate aminotransferase increased 2 Lymphophenia <1 Gastrointestinal Dimethyl fumarate 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 compared with placebo. Four percent (4%) of patients treated with dimethyl fumarate 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. Hepatic Transaminases An increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate 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 >= times the ULN occurred in small number of patients treated with both dimethyl fumarate and placebo and were balanced between groups. There were no elevations in transaminases >= 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 or placebo. Eosinophilia transient increase in mean eosinophil counts was seen during the first months of therapy. Adverse Reactions in Placebo-Controlled and Uncontrolled Studies In placebo-controlled and uncontrolled clinical studies, total of 2513 patients have received dimethyl fumarate and been followed for periods up to years with an overall exposure of 4603 person-years. Approximately 1162 patients have received more than years of treatment with dimethyl fumarate. The adverse reaction profile of dimethyl fumarate in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.. 6.2Post Marketing Experience. The following adverse reaction has been identified during post-approval use of dimethyl fumarate. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Liver function abnormalities (elevations in transaminases >= times ULN with concomitant elevations in total bilirubin 2 times ULN) have been reported following dimethyl fumarate administration in postmarketing experience See Warnings and Precautions (5.5) ]. Herpes zoster infection and other serious opportunistic infections have has been reported with dimethyl fumarate administration in postmarketing experience [See Warnings and Precautions (5.3)].Rhinorrhea has been reported with dimethyl fumarate administration in post marketing experience.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Kidney toxicity was observed after repeated oral administration of dimethyl fumarate (DMF) in mice, rats, dogs, and monkeys. Renal tubule epithelia regeneration, suggestive of tubule epithelial injury, was observed in all species. Renal tubular hyperplasia was observed in rats with dosing for up to two years. Cortical atrophy and interstitial fibrosis were observed in dogs and monkeys at doses above mg/kg/day. In monkeys, the highest dose tested (75 mg/kg/day) was associated with single cell necrosis and multifocal and diffuse interstitial fibrosis, indicating irreversible loss of renal tissue and function. In dogs and monkeys, the mg/kg/day dose was associated with plasma MMF exposures less than or similar to that in humans at the recommended human dose (RHD).A dose-related increase in incidence and severity of retinal degeneration was observed in mice following oral administration of DMF for up to two years at doses above 75 mg/kg/day, dose associated with plasma MMF exposure (AUC) similar to that in humans at the RHD.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis Carcinogenicity studies of dimethyl fumarate (DMF) were conducted in mice and rats. In mice, oral administration of DMF (25, 75, 200, and 400 mg/kg/day) for up to two years resulted in an increase in nonglandular stomach (forestomach) and kidney tumors: squamous cell carcinomas and papillomas of the forestomach in males and females at 200 and 400 mg/kg/day; leiomyosarcomas of the forestomach at 400 mg/kg/day in males and females; renal tubular adenomas and carcinomas at 200 and 400 mg/kg/day in males; and renal tubule adenomas at 400 mg/kg/day in females. Plasma MMF exposure (AUC) at the highest dose not associated with tumors in mice (75 mg/kg/day) was similar to that in humans at the recommended human dose (RHD) of 480 mg/day. In rats, oral administration of DMF (25, 50, 100, and 150 mg/kg/day) for up to two years resulted in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150 mg/kg/day. Plasma MMF AUC at the lowest dose tested was lower than that in humans at the RHD. Mutagenesis Dimethyl fumarate (DMF) and monomethyl fumarate (MMF) were not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. DMF and MMF were clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation. DMF was not clastogenic in the in vivo micronucleus assay in the rat. Impairment of Fertility In male rats, oral administration of DMF (75, 250, and 375 mg/kg/day) prior to and throughout the mating period had no effect on fertility; however, increases in non-motile sperm were observed at the mid and high doses. The no-effect dose for adverse effects on sperm is similar to the recommended human dose (RHD) of 480 mg/day on body surface area (mg/m2) basis. In female rats, oral administration of DMF (20, 100, and 250 mg/kg/day) prior to and during mating and continuing to gestation day caused disruption of the estrous cycle and increases in embryolethality at the highest dose tested. The highest dose not associated with adverse effects (100 mg/kg/day) is twice the RHD on mg/m2 basis. Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of DMF, and in chronic oral toxicity study evaluating combination of four fumaric acid esters (including DMF) in rats.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism by which dimethyl fumarate (DMF) exerts its therapeutic effect in multiple sclerosis is unknown. DMF and the metabolite, monomethyl fumarate (MMF), have been shown to activate the Nuclear factor (erythroid-derived 2)-like (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. MMF has been identified as nicotinic acid receptor agonist in vitro.. 12.2 Pharmacodynamics. Potential to prolong the QT interval In placebo controlled thorough QT study performed in healthy subjects, there was no evidence that dimethyl fumarate caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).. 12.3 Pharmacokinetics. After oral administration of dimethyl fumarate, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Dimethyl fumarate is not quantifiable in plasma following oral administration of dimethyl fumarate. Therefore all pharmacokinetic analyses related to dimethyl fumarate were performed with plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers. Absorption The median Tmax of MMF is 2-2.5 hours. The peak plasma concentration (Cmax) and overall exposure (AUC) increased approximately dose proportionally in the dose range studied (120 mg to 360 mg). Following administration of dimethyl fumarate 240 mg twice day with food, the mean Cmax of MMF was 1.87 mg/L and AUC was 8.21 mg.hr/L in MS patients. high-fat, high-calorie meal did not affect the AUC of MMF but decreased its Cmax by 40%. The Tmax was delayed from 2.0 hours to 5.5 hours. In this study, the incidence of flushing was reduced by approximately 25% in the fed state. Distribution The apparent volume of distribution of MMF varies between 53 and 73 in healthy subjects. Human plasma protein binding of MMF is 27 to 45% and independent of concentration. Metabolism In humans, dimethyl fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Further metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. MMF, fumaric and citric acid, and glucose are the major metabolites in plasma. Elimination Exhalation of CO2 is the primary route of elimination, accounting for approximately 60% of the dimethyl fumarate dose. Renal and fecal elimination are minor routes of elimination, accounting for 16% and 1% of the dose respectively.Trace amounts of unchanged MMF were present in urine. The terminal half-life of MMF is approximately hour and no circulating MMF is present at 24 hours in the majority of individuals. Accumulation of MMF does not occur with multiple doses of dimethyl fumarate. Specific Populations Body weight, gender, and age do not require dosage adjustment. No studies have been conducted in subjects with hepatic or renal impairment. However, neither condition would be expected to affect exposure to MMF and therefore no dosage adjustment is necessary. Drug Interaction Studies No potential drug interactions with dimethyl fumarate or MMF were identified in in vitro CYP inhibition and induction studies, or in P-glycoprotein studies. Single doses of interferon beta-1a or glatiramer acetate did not alter the pharmacokinetics of MMF. Aspirin, when administered approximately 30 minutes before dimethyl fumarate, did not alter the pharmacokinetics of MMF.Oral Contraceptives The coadministration of dimethyl fumarate with combined oral contraceptive (norelgestromin and ethinyl estradiol) did not elicit any relevant effects in oral contraceptives exposure. No interaction studies have been performed with oral contraceptives containing other progestogens.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy and safety of dimethyl fumarate were demonstrated in two studies (Studies and 2) that evaluated dimethyl fumarate taken either twice or three times day in patients with relapsing- remitting multiple sclerosis (RRMS). The starting dose for dimethyl fumarate was 120 mg twice or three times day for the first days, followed by an increase to 240 mg twice or three times day. Both studies included patients who had experienced at least relapse over the year preceding the trial or had brain Magnetic Resonance Imaging (MRI) scan demonstrating at least one gadolinium-enhancing (Gd+) lesion within weeks of randomization. The Expanded Disability Status Scale (EDSS) was also assessed and patients could have scores ranging from to 5. Neurological evaluations were performed at baseline, every months, and at the time of suspected relapse. MRI evaluations were performed at baseline, month 6, and year and in subset of patients (44% in Study and 48% in Study 2). Study 1: Placebo-Controlled Trial in RRMS Study was 2-year randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. The primary endpoint was the proportion of patients relapsed at years. Additional endpoints at years included the number of new or newly enlarging T2 hyperintense lesions, number of new T1 hypointense lesions, number of Gd+ lesions, annualized relapse rate (ARR), and time to confirmed disability progression. Confirmed disability progression was defined as at least 1 point increase from baseline EDSS (1.5 point increase for patients with baseline EDSS of 0) sustained for 12 weeks. Patients were randomized to receive dimethyl fumarate 240 mg twice day (n=410), dimethyl fumarate 240 mg three times day (n=416), or placebo (n=408) for up to years. The median age was 39 years, median time since diagnosis was years, and median EDSS score at baseline was 2. The median time on study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks on study drug per treatment group were 69% for patients assigned to dimethyl fumarate 240 mg twice day, 69% for patients assigned to dimethyl fumarate 240 mg three times day and 65% for patients assigned to placebo groups. Dimethyl fumarate had statistically significant effect on all of the endpoints described above and the 240 mg three times daily dose showed no additional benefit over the dimethyl fumarate 240 mg twice daily dose. The results for this study (240 mg twice day vs. placebo) are shown in Table and Figure 1.Table 2: Clinical and MRI Results of Study Dimethyl Fumarate 240 mg BID Placebo P-value Clinical Endpoints N=410 N=408 Proportion relapsing (primary endpoint) Relative risk reduction 27% 49% 46% <0.0001 Annualized relapse rate Relative reduction 0.172 53% 0.364 <0.0001 Proportion with disability progression Relative risk reduction 16% 38% 27% 0.0050 MRI Endpoints N=152 N=165 Mean number of new or newly enlarging T2 lesions over years 2.6 17 <0.0001 Percentage of subjects with no new or newly enlarging lesions 45% 27% Number of Gd+ lesions at years Mean (median) 0.1 (0) 1.8(0) Percentage of subjects with lesions 93% 62% lesion 5% 10% lesions <1% 8% to lesions 9% or more lesions <1% 11% Relative odds reduction (percentage) 90% <0.0001 Mean number of new T1 hypointense lesions over years 1.5 5.6 <0.0001 Figure 1: Time to 12-Week Confirmed Progression of Disability (Study 1) Study 2: Placebo-Controlled Trial in RRMS Study was 2-year multicenter, randomized, double-blind, placebo-controlled study that also included an open-label comparator arm in patients with RRMS. The primary endpoint was the annualized relapse rate at years. Additional endpoints at years included the number of new or newly enlarging T2 hyperintense lesions, number of T1 hypointense lesions, number of Gd+ lesions, proportion of patients relapsed, and time to confirmed disability progression as defined in Study 1. Patients were randomized to receive dimethyl fumarate 240 mg twice day (n=359), dimethyl fumarate 240 mg three times day (n=345), an open-label comparator (n=350), or placebo (n=363) for up to years. The median age was 37 years, median time since diagnosis was years, and median EDSS score at baseline was 2.5. The median time on study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks on study drug per treatment group were 70% for patients assigned to dimethyl fumarate 240 mg twice day, 72% for patients assigned to dimethyl fumarate 240 mg three times day and 64% for patients assigned to placebo groups. Dimethyl fumarate had statistically significant effect on the relapse and MRI endpoints described above. There was no statistically significant effect on disability progression. The dimethyl fumarate 240 mg three times daily dose resulted in no additional benefit over the dimethyl fumarate 240 mg twice daily dose. The results for this study (240 mg twice day vs. placebo) are shown in Table 3. Table 3: Clinical and MRI Results of Study Dimethyl Fumarate 240 mg BID Placebo P-value Clinical Endpoints N= 359 N=363 Annualized relapse rate Relative reduction 0.224 44% 0.401 <0.0001 Proportion relapsing Relative risk reduction 29% 34% 41% 0.0020 Proportion with disability progression Relative risk reduction 13% 21% 17% 0.25 MRI Endpoints N=147 N=144 Mean number of new or newly enlarging T2 lesions over years 5.1 17.4 <0.0001 Percentage of subjects with no new or newly enlarging lesions 27% 12% Number of Gd+ lesions at years Mean (median) 0.5 (0.0) 2.0 (0.0) Percentage of subjects with lesions 80% 61% lesion 11% 17% lesions 3% 6% to lesions 3% 2% or more lesions 3% 14% Relative odds reduction (percentage) 74% <0.0001 Mean number of new T1 hypointense lesions over years 3.0 7.0 <0.0001 figure1.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Dimethyl fumarate is 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. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Dimethyl fumarate delayed-release capsule contains dimethyl fumarate which is also known by its chemical name, dimethyl (E) butenedioate, (C6H8O4). It has the following structure: Dimethyl fumarate is white to off-white powder that is freely soluble in dichloromethane and very slightly soluble in water with molecular mass of 144.13. Dimethyl fumarate is provided as hard gelatin delayed-release capsules for oral administration, containing 120 mg or 240 mg of dimethyl fumarate consisting of the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, methacrylic acid-ethyl acrylate copolymer, methacrylic acid methyl methacrylate copolymer, microcrystalline cellulose, polysorbate 80, sodium lauryl sulfate, talc and triethyl citrate. The capsule shell contains the following inactive ingredients: gelatin and titanium dioxide and is imprinted with black ink, Black imprinting ink contains shellac, propylene glycol, black iron oxide and potassium hydroxide. structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Starting dose: 120 mg twice day, orally, for days (2.1)Maintenance dose after days: 240 mg twice 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 capsule with or without food (2.1). Starting dose: 120 mg twice day, orally, for days (2.1). Maintenance dose after days: 240 mg twice 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 capsule with or without food (2.1). 2.1 Dosing Information. The starting dose for dimethyl fumarate delayed-release capsules is 120 mg twice day orally. After days, the dose should be increased to the maintenance dose of 240 mg twice day orally. Temporary dose reductions to 120 mg twice day may be considered for individuals who do not tolerate the maintenance dose. Within weeks, the recommended dose of 240 mg twice 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 dose of 325 mg) 30 minutes prior to dimethyl fumarate delayed-release capsule 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 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Dimethyl fumarate is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of dimethyl fumarate. The 120 mg capsules are white to off white colored enteric coated mini tablets filled in size 0 empty hard gelatin capsule shell with white opaque cap and white opaque body imprinted with 120 mg with black ink. The 240 mg capsules are white to off white colored enteric coated mini tablets filled in size 0 empty hard gelatin capsule shell with white opaque cap and white opaque body imprinted with 240 mg with black ink.. Delayed-release capsules: 120 mg and 240 mg (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of dimethyl fumarate did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Dimethyl fumarate is available as hard gelatin delayed-release capsules in two strengths containing either 120 mg or 240 mg of dimethyl fumarate. The 120 mg capsules are white to off white colored enteric coated mini tablets filled in size 0 empty hard gelatin capsule shell with white opaque cap and white opaque body imprinted with 120 mg with black ink. The 240 mg capsules are white to off white colored enteric coated mini tablets filled in size 0 empty hard gelatin capsule shell with white opaque cap and white opaque body imprinted with 240 mg with black ink. Dimethyl fumarate delayed-release capsules are available as follows: 120 mg capsules:bottle of 14 capsules (NDC 43598-429-52) Store in original container240 mg capsules:bottle of 60 capsules (NDC 43598-430-60) Store in original containerStore at 15C to 30C (59 to 86F). Protect the capsules from light.. bottle of 14 capsules (NDC 43598-429-52) Store in original container. bottle of 60 capsules (NDC 43598-430-60) Store in original container.

INDICATIONS & USAGE SECTION.

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 is 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information) Dosage Inform patients that they will be provided two strengths of dimethyl fumarate when starting treatment: 120 mg capsules for the day starter dose and 240 mg capsules for the maintenance dose, both to be taken twice daily. Inform patients to swallow dimethyl fumarate capsules whole and intact. Inform patients to not crush, chew, or sprinkle capsule contents on food. Inform patients that dimethyl fumarate can be taken with or without food [see Dosage and Administration (2.1)]. Anaphylaxis and Angioedema Advise patients to discontinue dimethyl fumarate and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema [see Warnings and Precautions (5.1)]. Progressive Multifocal Leukoencephalopathy Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in patients who received dimethyl fumarate. Inform the patient that PML is characterized by progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that 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 [see Warnings and Precautions (5.2)]. Herpes Zoster and Other Serious Opportunistic Infections Inform patients that herpes zoster and other serious opportunistic infections have occurred in patients who received dimethyl fumarate. Instruct the patient of the importance of contacting their doctor if they develop any signs or symptoms associated with herpes zoster or other serious opportunistic infections [see Warnings and Precautions (5.3)]. Lymphocyte Counts Inform patients that dimethyl fumarate may decrease lymphocyte counts. blood test should be obtained before they start therapy. Blood tests are also recommended after months of treatment, every to 12 months thereafter, and as clinically indicated [see Warnings and Precautions (5.4), Adverse Reactions (6.1)]. Liver Injury Inform patients that dimethyl fumarate may cause liver injury. Instruct patients treated with dimethyl fumarate to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. blood test should be obtained before patients start therapy and during treatment, as clinically indicated see Warnings and Precautions (5.5)]. Flushing and Gastrointestinal (GI) Reactions Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are the most common reactions, especially at the initiation of therapy, and may decrease over time. Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI reactions. Advise patients experiencing flushing that taking dimethyl fumarate with food or taking non-enteric coated aspirin prior to taking dimethyl fumarate may help [see Adverse Reactions (6.1)]. Pregnancy Instruct patients that if they are pregnant or plan to become pregnant while taking dimethyl fumarate they should inform their physician.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The mechanism by which dimethyl fumarate (DMF) exerts its therapeutic effect in multiple sclerosis is unknown. DMF and the metabolite, monomethyl fumarate (MMF), have been shown to activate the Nuclear factor (erythroid-derived 2)-like (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. MMF has been identified as nicotinic acid receptor agonist in vitro.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis Carcinogenicity studies of dimethyl fumarate (DMF) were conducted in mice and rats. In mice, oral administration of DMF (25, 75, 200, and 400 mg/kg/day) for up to two years resulted in an increase in nonglandular stomach (forestomach) and kidney tumors: squamous cell carcinomas and papillomas of the forestomach in males and females at 200 and 400 mg/kg/day; leiomyosarcomas of the forestomach at 400 mg/kg/day in males and females; renal tubular adenomas and carcinomas at 200 and 400 mg/kg/day in males; and renal tubule adenomas at 400 mg/kg/day in females. Plasma MMF exposure (AUC) at the highest dose not associated with tumors in mice (75 mg/kg/day) was similar to that in humans at the recommended human dose (RHD) of 480 mg/day. In rats, oral administration of DMF (25, 50, 100, and 150 mg/kg/day) for up to two years resulted in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150 mg/kg/day. Plasma MMF AUC at the lowest dose tested was lower than that in humans at the RHD. Mutagenesis Dimethyl fumarate (DMF) and monomethyl fumarate (MMF) were not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. DMF and MMF were clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation. DMF was not clastogenic in the in vivo micronucleus assay in the rat. Impairment of Fertility In male rats, oral administration of DMF (75, 250, and 375 mg/kg/day) prior to and throughout the mating period had no effect on fertility; however, increases in non-motile sperm were observed at the mid and high doses. The no-effect dose for adverse effects on sperm is similar to the recommended human dose (RHD) of 480 mg/day on body surface area (mg/m2) basis. In female rats, oral administration of DMF (20, 100, and 250 mg/kg/day) prior to and during mating and continuing to gestation day caused disruption of the estrous cycle and increases in embryolethality at the highest dose tested. The highest dose not associated with adverse effects (100 mg/kg/day) is twice the RHD on mg/m2 basis. Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of DMF, and in chronic oral toxicity study evaluating combination of four fumaric acid esters (including DMF) in rats.. 13.2 Animal Toxicology and/or Pharmacology. Kidney toxicity was observed after repeated oral administration of dimethyl fumarate (DMF) in mice, rats, dogs, and monkeys. Renal tubule epithelia regeneration, suggestive of tubule epithelial injury, was observed in all species. Renal tubular hyperplasia was observed in rats with dosing for up to two years. Cortical atrophy and interstitial fibrosis were observed in dogs and monkeys at doses above mg/kg/day. In monkeys, the highest dose tested (75 mg/kg/day) was associated with single cell necrosis and multifocal and diffuse interstitial fibrosis, indicating irreversible loss of renal tissue and function. In dogs and monkeys, the mg/kg/day dose was associated with plasma MMF exposures less than or similar to that in humans at the recommended human dose (RHD).A dose-related increase in incidence and severity of retinal degeneration was observed in mice following oral administration of DMF for up to two years at doses above 75 mg/kg/day, dose associated with plasma MMF exposure (AUC) similar to that in humans at the RHD.

OVERDOSAGE SECTION.

10 OVERDOSE. Cases of overdose with dimethyl fumarate have been reported. The symptoms described in these cases were consistent with the known adverse event profile of dimethyl fumarate.There are no known therapeutic interventions to enhance elimination of dimethyl fumarate nor is there known antidote. In the event of overdose, initiate symptomatic supportive treatment as clinically indicated.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Dimethyl Fumarate Capsules, 120 mg Container.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Potential to prolong the QT interval In placebo controlled thorough QT study performed in healthy subjects, there was no evidence that dimethyl fumarate caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. After oral administration of dimethyl fumarate, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Dimethyl fumarate is not quantifiable in plasma following oral administration of dimethyl fumarate. Therefore all pharmacokinetic analyses related to dimethyl fumarate were performed with plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers. Absorption The median Tmax of MMF is 2-2.5 hours. The peak plasma concentration (Cmax) and overall exposure (AUC) increased approximately dose proportionally in the dose range studied (120 mg to 360 mg). Following administration of dimethyl fumarate 240 mg twice day with food, the mean Cmax of MMF was 1.87 mg/L and AUC was 8.21 mg.hr/L in MS patients. high-fat, high-calorie meal did not affect the AUC of MMF but decreased its Cmax by 40%. The Tmax was delayed from 2.0 hours to 5.5 hours. In this study, the incidence of flushing was reduced by approximately 25% in the fed state. Distribution The apparent volume of distribution of MMF varies between 53 and 73 in healthy subjects. Human plasma protein binding of MMF is 27 to 45% and independent of concentration. Metabolism In humans, dimethyl fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Further metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. MMF, fumaric and citric acid, and glucose are the major metabolites in plasma. Elimination Exhalation of CO2 is the primary route of elimination, accounting for approximately 60% of the dimethyl fumarate dose. Renal and fecal elimination are minor routes of elimination, accounting for 16% and 1% of the dose respectively.Trace amounts of unchanged MMF were present in urine. The terminal half-life of MMF is approximately hour and no circulating MMF is present at 24 hours in the majority of individuals. Accumulation of MMF does not occur with multiple doses of dimethyl fumarate. Specific Populations Body weight, gender, and age do not require dosage adjustment. No studies have been conducted in subjects with hepatic or renal impairment. However, neither condition would be expected to affect exposure to MMF and therefore no dosage adjustment is necessary. Drug Interaction Studies No potential drug interactions with dimethyl fumarate or MMF were identified in in vitro CYP inhibition and induction studies, or in P-glycoprotein studies. Single doses of interferon beta-1a or glatiramer acetate did not alter the pharmacokinetics of MMF. Aspirin, when administered approximately 30 minutes before dimethyl fumarate, did not alter the pharmacokinetics of MMF.Oral Contraceptives The coadministration of dimethyl fumarate with combined oral contraceptive (norelgestromin and ethinyl estradiol) did not elicit any relevant effects in oral contraceptives exposure. No interaction studies have been performed with oral contraceptives containing other progestogens.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary There are no adequate data on the developmental risk associated with the use of dimethyl fumarate in pregnant women. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate (DMF) was administered during pregnancy and lactation at clinically relevant doses. [see Data] In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal DataIn rats administered DMF orally (25, 100, 250 mg/kg/day) throughout organogenesis, embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. This dose also produced evidence of maternal toxicity (reduced body weight). Plasma exposure (AUC) for monomethyl fumarate (MMF), the major circulating metabolite, at the no-effect dose is approximately three times that in humans at the recommended human dose (RHD) of 480 mg/day. In rabbits administered DMF orally (25, 75, and 150 mg/kg/day) throughout organogenesis, embryolethality and decreased maternal body weight were observed at the highest dose tested. The plasma AUC for MMF at the no-effect dose is approximately times that in humans at the RHD. Oral administration of DMF (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested. Neurobehavioral impairment was observed at all doses. no-effect dose for developmental toxicity was not identified. The lowest dose tested was associated with plasma AUC for MMF lower than that in humans at the RHD.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information. Dimethyl fumarate (dye-METH-il FUE-ma-rate) delayed-release capsules What are dimethyl fumarate delayed-release capsules Dimethyl fumarate delayed-release capsules are prescription medicine used to treat relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. It is not known if dimethyl fumarate delayed-release capsules are safe and effective in children under 18 years of ageWho should not take dimethyl fumarate delayed-release capsulesDo not use dimethyl fumarate delayed-release capsules if you have had an allergic reaction (such as welts, hives, swelling of the face, lips, mouth or tongue, or difficulty breathing) to dimethyl fumarate delayed-release capsules or any of its ingredients. See below for complete list of ingredients.Before taking and while you take dimethyl fumarate delayed-release capsules, tell your doctor if you have or have had:low white blood cell counts or an infectionany other medical conditionsTell your doctor if you are:pregnant or plan to become pregnant. It is not known if dimethyl fumarate delayed-release capsules will harm your unborn baby breastfeeding or plan to breastfeed. It is not known if dimethyl fumarate passes into your breast milk. You and your doctor should decide if you will take dimethyl fumarate or breastfeed.taking prescription or over-the-counter medicines, vitamins, or herbal supplementsHow should take dimethyl fumarate delayed-release capsulesTake dimethyl fumarate delayed-release capsules exactly as your doctor tells you to take itThe recommended starting dose is one 120 mg capsule taken by mouth times day for daysThe recommended dose after days is one 240 mg capsule taken by mouth times dayDimethyl fumarate delayed-release capsules can be taken with or without foodSwallow dimethyl fumarate delayed-release capsules whole. Do not crush, chew, or sprinkle capsule contents on food.Protect dimethyl fumarate delayed-release capsules from light. You can do this by storing the capsules in their original container.If you take too much dimethyl fumarate delayed-release capsules, call your doctor or go to the nearest hospital emergency room right away. What are the possible side effects of dimethyl fumarate delayed-release capsules Dimethyl fumarate delayed-release capsules may cause serious side effects including:allergic reaction (such as welts, hives, swelling of the face, lips, mouth or tongue, or difficulty breathing)PML rare brain infection that usually leads to death or severe disabilitydecreases in your white blood cell count Your doctor should do blood test before you start treatment with dimethyl fumarate delayed-release capsules and while on therapy.liver problems. Your doctor should do blood tests to check your liver function before you start taking dimethyl fumarate delayed-release capsules and during treatment if needed. Tell your doctor right away if you get any of these symptoms of liver problem during treatment. severe tirednessloss of appetitepain on the right side of your stomachhave dark or brown (tea color) urineyellowing of your skin or the white part of your eyesherpes zoster infections (shingles), including central nervous system infections other serious infections The most common side effects of dimethyl fumarate delayed-release capsules include:flushing, redness, itching, or rashnausea, vomiting, diarrhea, stomach pain, or indigestionFlushing and stomach problems are the most common reactions, especially at the start of therapy, and may decrease over time. Taking dimethyl fumarate delayed-release capsules with food may help reduce flushing. Call your doctor if you have any of these symptoms and they bother you or do not go away. Ask your doctor if taking aspirin before taking dimethyl fumarate delayed-release capsules may reduce flushing.These are not all the possible side effects of dimethyl fumarate delayed-release capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. General Information about the safe and effective use of dimethyl fumarate delayed-release capsulesMedicines are sometimes prescribed for purposes other than those listed in this Patient Information. Do not use dimethyl fumarate delayed-release capsules for condition for which it was not prescribed. Do not give dimethyl fumarate delayed-release capsules to other people, even if they have the same symptoms that you have. It may harm them.If you would like more information, talk to your doctor or pharmacist. You can ask your doctor or pharmacist for information about dimethyl fumarate delayed-release capsules that is written for healthcare professionals. What are the ingredients in dimethyl fumarate delayed-release capsules Active ingredient: dimethyl fumarateInactive ingredients: Colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, methacrylic acid-ethyl acrylate copolymer, methacrylic acid methyl methacrylate copolymer, microcrystalline cellulose, polysorbate 80, sodium lauryl sulfate, talc and triethyl citrate. The capsule shell contains the following inactive ingredients: gelatin and titanium dioxide and is imprinted with black ink, Black imprinting ink contains shellac, propylene glycol, black iron oxide and potassium hydroxide. This Patient Information has been approved by the U.S. Food and Drug Administration.To reorder additional Patient Information Sheets, contact Dr. Reddys Customer Service at 1-866-733-3952.Rx OnlyDistributor:Dr. Reddys Laboratories Inc.,Princetone, NJ 08540Made in IndiaRevised: 0521. Dimethyl fumarate delayed-release capsules are prescription medicine used to treat relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. It is not known if dimethyl fumarate delayed-release capsules are safe and effective in children under 18 years of age. Do not use dimethyl fumarate delayed-release capsules if you have had an allergic reaction (such as welts, hives, swelling of the face, lips, mouth or tongue, or difficulty breathing) to dimethyl fumarate delayed-release capsules or any of its ingredients. See below for complete list of ingredients.. low white blood cell counts or an infection. any other medical conditions. pregnant or plan to become pregnant. It is not known if dimethyl fumarate delayed-release capsules will harm your unborn baby breastfeeding or plan to breastfeed. It is not known if dimethyl fumarate passes into your breast milk. You and your doctor should decide if you will take dimethyl fumarate or breastfeed.. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Take dimethyl fumarate delayed-release capsules exactly as your doctor tells you to take it. The recommended starting dose is one 120 mg capsule taken by mouth times day for days. The recommended dose after days is one 240 mg capsule taken by mouth times day. Dimethyl fumarate delayed-release capsules can be taken with or without food. Swallow dimethyl fumarate delayed-release capsules whole. Do not crush, chew, or sprinkle capsule contents on food.. Protect dimethyl fumarate delayed-release capsules from light. You can do this by storing the capsules in their original container.. If you take too much dimethyl fumarate delayed-release capsules, call your doctor or go to the nearest hospital emergency room right away.. allergic reaction (such as welts, hives, swelling of the face, lips, mouth or tongue, or difficulty breathing). PML rare brain infection that usually leads to death or severe disability. decreases in your white blood cell count Your doctor should do blood test before you start treatment with dimethyl fumarate delayed-release capsules and while on therapy.. liver problems. Your doctor should do blood tests to check your liver function before you start taking dimethyl fumarate delayed-release capsules and during treatment if needed. Tell your doctor right away if you get any of these symptoms of liver problem during treatment. severe tirednessloss of appetitepain on the right side of your stomachhave dark or brown (tea color) urineyellowing of your skin or the white part of your eyes. severe tiredness. loss of appetite. pain on the right side of your stomach. have dark or brown (tea color) urine. yellowing of your skin or the white part of your eyes. herpes zoster infections (shingles), including central nervous system infections other serious infections. flushing, redness, itching, or rash. nausea, vomiting, diarrhea, stomach pain, or indigestion. Flushing and stomach problems are the most common reactions, especially at the start of therapy, and may decrease over time. Taking dimethyl fumarate delayed-release capsules with food may help reduce flushing. Call your doctor if you have any of these symptoms and they bother you or do not go away. Ask your doctor if taking aspirin before taking dimethyl fumarate delayed-release capsules may reduce flushing.. Medicines are sometimes prescribed for purposes other than those listed in this Patient Information. Do not use dimethyl fumarate delayed-release capsules for condition for which it was not prescribed. Do not give dimethyl fumarate delayed-release capsules to other people, even if they have the same symptoms that you have. It may harm them.. If you would like more information, talk to your doctor or pharmacist. You can ask your doctor or pharmacist for information about dimethyl fumarate delayed-release capsules that is written for healthcare professionals.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm.( 8.1) 8.1 Pregnancy. Risk Summary There are no adequate data on the developmental risk associated with the use of dimethyl fumarate in pregnant women. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate (DMF) was administered during pregnancy and lactation at clinically relevant doses. [see Data] In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal DataIn rats administered DMF orally (25, 100, 250 mg/kg/day) throughout organogenesis, embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. This dose also produced evidence of maternal toxicity (reduced body weight). Plasma exposure (AUC) for monomethyl fumarate (MMF), the major circulating metabolite, at the no-effect dose is approximately three times that in humans at the recommended human dose (RHD) of 480 mg/day. In rabbits administered DMF orally (25, 75, and 150 mg/kg/day) throughout organogenesis, embryolethality and decreased maternal body weight were observed at the highest dose tested. The plasma AUC for MMF at the no-effect dose is approximately times that in humans at the RHD. Oral administration of DMF (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested. Neurobehavioral impairment was observed at all doses. no-effect dose for developmental toxicity was not identified. The lowest dose tested was associated with plasma AUC for MMF lower than that in humans at the RHD.. 8.2 Lactation. Risk Summary There are no data on the presence of DMF or MMF in human milk. The effects on the breastfed infant and on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for dimethyl fumarate and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. Clinical studies of dimethyl fumarate did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Anaphylaxis and angioedema: Discontinue and do not restart dimethyl fumarate if these occur. (5.1)Progressive multifocal leukoencephalopathy (PML): Withhold dimethyl fumarate at the first sign or symptom suggestive of PML. (5.2)Herpes zoster and other serious opportunistic infections: Consider withholding dimethyl fumarate in cases of serious infection until the infection has resolved. (5.3)Lymphopenia: Obtain CBC including lymphocyte count before initiating dimethyl fumarate, after months, and every to 12 months thereafter. Consider interruption of dimethyl fumarate if lymphocyte counts <0.5 109/L persist for more than six months. (5.4)Liver injury: Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating dimethyl fumarate and during treatment, as clinically indicated. Discontinue dimethyl fumarate if clinically significant liver injury induced by dimethyl fumarate is suspected. (5.5). Anaphylaxis and angioedema: Discontinue and do not restart dimethyl fumarate if these occur. (5.1). Progressive multifocal leukoencephalopathy (PML): Withhold dimethyl fumarate at the first sign or symptom suggestive of PML. (5.2). Herpes zoster and other serious opportunistic infections: Consider withholding dimethyl fumarate in cases of serious infection until the infection has resolved. (5.3). Lymphopenia: Obtain CBC including lymphocyte count before initiating dimethyl fumarate, after months, and every to 12 months thereafter. Consider interruption of dimethyl fumarate if lymphocyte counts <0.5 109/L persist for more than six months. (5.4). Liver injury: Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating dimethyl fumarate and during treatment, as clinically indicated. Discontinue dimethyl fumarate if clinically significant liver injury induced by dimethyl fumarate is suspected. (5.5). 5.1Anaphylaxis and Angioedema. Dimethyl fumarate can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue dimethyl fumarate 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. 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. fatal case of PML occurred in patient who received dimethyl fumarate for years while enrolled in clinical trial. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5 109/L for 3.5 years) while taking dimethyl fumarate [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 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 (<0.9x109/L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8 109/L persisting for more than months.At the first sign or symptom suggestive of PML, withhold dimethyl fumarate 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 absenceof 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 PML, if present. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.. 5.3 Herpes Zoster and Other Serious Opportunistic Infections. Serious cases of herpes zoster have occurred with dimethyl fumarate, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis. These events may occur at any time during treatment. Monitor patients on dimethyl fumarate for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered. Other serious opportunistic infections have occurred with dimethyl fumarate, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment. Consider withholding dimethyl fumarate treatment in patients with herpes zoster or other serious infections until the infection has resolved [see Adverse Reactions (6.2)].. 5.4 Lymphopenia. Dimethyl fumarate may decrease lymphocyte counts. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with dimethyl fumarate and then remained stable. Four weeks after stopping dimethyl fumarate, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of dimethyl fumarate patients and <1% of placebo patients experienced lymphocyte counts <0.5 109/L (lower limit of normal 0.91 109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with dimethyl fumarate or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts<0.8 109/L or <=0.5 109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 109/L for 3.5 years) [see Warnings and Precautions (5.2)]. In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5 109/L for at least six months, and in this group the majority of lymphocyte counts remained <0.5 109/L with continued therapy. Dimethyl fumarate has not been studied in patients with pre-existing low lymphocyte counts. Obtain CBC, including lymphocyte count, before initiating treatment with dimethyl fumarate, months after starting treatment, and then every to 12 months thereafter, and as clinically indicated. Consider interruption of dimethyl fumarate in patients with lymphocyte counts less than 0.5 109/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if dimethyl fumarate is discontinued or interrupted due to lymphopenia. Consider withholding treatment from patients with serious infections until resolution.Decisions about whether or not to restart dimethyl fumarate should be individualized based on clinical circumstances.. 5.5 Liver Injury. Clinically significant cases of liver injury have been reported in patients treated with dimethyl fumarate in the postmarketing setting. The onset has ranged from few days to several months after initiation of treatment with dimethyl fumarate. 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 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 and during treatment, as clinically indicated. Discontinue dimethyl fumarate if clinically significant liver injury induced by dimethyl fumarate is suspected.. 5.6 Flushing. Dimethyl fumarate may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of dimethyl fumarate treated patients experienced flushing. Flushing symptoms generally began soon after initiating dimethyl fumarate 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 for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of dimethyl fumarate with food may reduce the incidence of flushing. Alternatively, administration of non-enteric coated aspirin (up to dose of 325 mg) 30 minutes prior to dimethyl fumarate dosing may reduce the incidence or severity of flushing [see Dosing and Administration (2.1)and Clinical Pharmacology (12.3)].