Tecfidera dimethyl fumarate 240 mg Capsule, 60-count — NDC 64406-006-02 (Billing 64406-0006-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 2 (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 a nicotinic acid receptor agonist in vitro .

12.2Pharmacodynamics Potential to prolong the QT interval In a 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).

12.3Pharmacokinetics After oral administration of TECFIDERA, 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 TECFIDERA. Therefore all pharmacokinetic analyses related to TECFIDERA were performed with plasma MMF concentrations.

Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers. Absorption The median T max of MMF is 2-2.5 hours. The peak plasma concentration (C max ) and overall exposure (AUC) increased approximately dose proportionally in the dose range studied (120 mg to 360 mg).

Following administration of TECFIDERA 240 mg twice a day with food, the mean C max of MMF was 1.87 mg/L and AUC was 8.21 mg.hr/L in MS patients. A high-fat, high-calorie meal did not affect the AUC of MMF but decreased its C max by 40%. The T max 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 L in healthy subjects. Human plasma protein binding of MMF is 27-45% 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 CO 2 is the primary route of elimination, accounting for approximately 60% of the TECFIDERA 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 1 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 TECFIDERA. 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 TECFIDERA, did not alter the pharmacokinetics of MMF. Oral Contraceptives The coadministration of dimethyl fumarate with a 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 progesto… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 2 (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 a nicotinic acid receptor agonist in vitro .

12.3Pharmacokinetics After oral administration of TECFIDERA, 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 TECFIDERA. Therefore all pharmacokinetic analyses related to TECFIDERA were performed with plasma MMF concentrations.

Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers. Absorption The median T max of MMF is 2-2.5 hours. The peak plasma concentration (C max ) and overall exposure (AUC) increased approximately dose proportionally in the dose range studied (120 mg to 360 mg).

Following administration of TECFIDERA 240 mg twice a day with food, the mean C max of MMF was 1.87 mg/L and AUC was 8.21 mg.hr/L in MS patients. A high-fat, high-calorie meal did not affect the AUC of MMF but decreased its C max by 40%. The T max 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 L in healthy subjects. Human plasma protein binding of MMF is 27-45% 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 CO 2 is the primary route of elimination, accounting for approximately 60% of the TECFIDERA 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 1 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 TECFIDERA. 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 TECFIDERA, did not alter the pharmacokinetics of MMF. Oral Contraceptives The coadministration of dimethyl fumarate with a 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. Vaccines A randomized, open-label study examined the concomitant use of TECFIDERA and several non-live vaccines in adults 27-55 years of age with relapsing forms of MS (38 subjects undergoing treatment with TECFIDERA at the time of vaccination and 33 subjects undergoing treatment with non-pegylated interferon at the time of vaccination). Concomitant exposure to TECFIDERA did not attenuate antibody responses to tetanus toxoid-containing vaccine, pneumococcal polysaccharide, and meningococcal vaccines relative to antibody responses in interferon-treated patients.

The impact of these findings on vaccine effectiveness in this patient population is unknown. The safety and effectiveness of live or live-attenuated vaccines administered concomitantly with TECFIDERA have not been assessed.

12.2Pharmacodynamics Potential to prolong the QT interval In a 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).

14 CLINICAL STUDIES The efficacy and safety of TECFIDERA were demonstrated in two studies (Studies 1 and 2) that evaluated TECFIDERA taken either twice or three times a day in patients with relapsing-remitting multiple sclerosis (RRMS). The starting dose for TECFIDERA was 120 mg twice or three times a day for the first 7 days, followed by an increase to 240 mg twice or three times a day. Both studies included patients who had experienced at least 1 relapse over the year preceding the trial or had a brain Magnetic Resonance Imaging (MRI) scan demonstrating at least one gadolinium-enhancing (Gd+) lesion within 6 weeks of randomization.

The Expanded Disability Status Scale (EDSS) was also assessed and patients could have scores ranging from 0 to 5. Neurological evaluations were performed at baseline, every 3 months, and at the time of suspected relapse. MRI evaluations were performed at baseline, month 6, and year 1 and 2 in a subset of patients (44% in Study 1 and 48% in Study 2).

Study 1: Placebo-Controlled Trial in RRMS Study 1 was a 2-year randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. The primary endpoint was the proportion of patients relapsed at 2 years. Additional endpoints at 2 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 a 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 TECFIDERA 240 mg twice a day (n=410), TECFIDERA 240 mg three times a day (n=416), or placebo (n=408) for up to 2 years. The median age was 39 years, median time since diagnosis was 4 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 TECFIDERA 240 mg twice a day, 69% for patients assigned to TECFIDERA 240 mg three times a day and 65% for patients assigned to placebo groups. TECFIDERA had a statistically significant effect on all of the endpoints described above and the 240 mg three times daily dose showed no additional benefit over the TECFIDERA 240 mg twice daily dose.

The results for this study (240 mg twice a day vs. placebo) are shown in Table 2 and Figure 1 . Table 2: Clinical and MRI Results of Study 1 TECFIDERA 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 0.172 0.364 <0.0001 Relative reduction 53% Proportion with disability progression 16% 27% 0.0050 Relative risk reduction 38% MRI Endpoints N=152 N=165 Mean number of new or newly enlarging 2.6 17 <0.0001 T2 lesions over 2 years Percentage of subjects with no new or newly enlarging lesions 45% 27% Number of Gd+ lesions at 2 years 0.1 (0) 1.8 (0) Mean (median) Percentage of subjects with 0 lesions 93% 62% 1 lesion 5% 10% 2 lesions <1% 8% 3 to 4 lesions 0 9% 5 or more lesions <1% 11% Relative odds reduction 90% <0.0001 (percentage) Mean number of new T1 hypointense 1.5 5.6 <0.0001 lesions over 2 years Figure 1: Time to 12-Week Confirmed Progression of Disability (Study 1) Figure 1 Study 2: Placebo-Controlled Trial in RRMS Study 2 was a 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 2 years. Additional endpoints at 2 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 TECFIDERA 240… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 a body surface area (mg/m 2 ) 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 7 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 a mg/m 2 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 a chronic oral toxicity study evaluating a combination of four fumaric acid esters (including DMF) in rats.

13.2Animal 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 5 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 5 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, a dose associated with plasma MMF exposure (AUC) similar to that in humans at the RHD.