Gocovri Amantadine 137 mg Capsule, Coated Pellets, 60-count — NDC 70482-170-60 (Billing 70482-0170-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism by which amantadine exerts efficacy in the treatment of dyskinesia in patients with Parkinson's disease or as adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing "off" episodes is unknown. Amantadine is a weak uncompetitive antagonist of the NMDA receptor. Amantadine has not been shown to possess direct anticholinergic activity in animal studies; however, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation in humans.

Amantadine may have direct and indirect effects on dopamine neurons; it exerts dopaminergic-like side effects such as hallucinations and dizziness in humans.

12.2Pharmacodynamics The effect of amantadine on QT prolongation was not studied in a dedicated thorough QT study. Alcohol consumption may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension [see Drug Interactions ( 7.4 )] .

12.3Pharmacokinetics GOCOVRI is an extended-release formulation. The pharmacokinetics of amantadine from 68.5 mg, 137 mg, and 274 mg of GOCOVRI are dose proportional in healthy subjects. Absorption After a single dose bedtime administration of GOCOVRI, the median T max for plasma amantadine was around 12 hours (range 6-20 hours).

The steady-state concentrations of GOCOVRI were achieved 4 days after the dose initiation. The steady-state total exposures (AUC 0-tau ) were 20-30% higher than after single dose, suggesting an accumulation ratio of 1.2-1.3. Effect of Food A single dose crossover study of GOCOVRI established the lack of effect of high-fat, high-calorie meal on plasma amantadine pharmacokinetics; additionally, administration of entire capsule contents sprinkled on applesauce also did not affect plasma amantadine pharmacokinetics.

Distribution The volume of distribution determined after the intravenous administration of amantadine to 15 healthy subjects was 3 to 8 L/kg, suggesting potential extravascular distribution. Amantadine is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL. Elimination In a study with healthy volunteers after oral administration, the apparent plasma clearance of amantadine was estimated to be 0.27 ± 0.094 L/hr/kg (range 0.13 to

0.57L/hr/kg). Amantadine is primarily excreted unchanged in the urine, and in a study of six healthy volunteers, the ratio of amantadine renal clearance to apparent plasma clearance was 0.79 ± 0.17 (mean ± SD). The mean plasma amantadine half-life at steady-state was approximately 16 hours.

Metabolism Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 0-15% of the administered dose in multiple studies. The contribution of this metabolite to efficacy or toxicity is not known.

Excretion Amantadine is primarily excreted unchanged in the urine by both glomerular filtration and tubular secretion. Specific Population Male/Female Patients In an integrated analysis of five studies in healthy volunteers (n=147), the mean total amantadine clearance following administration of GOCOVRI, adjusted for body weight in kilograms, was 1.2 fold higher in males compared to females (95% CI: 1.1, 1.3, P=0.007). No dose adjustment by gender is warranted.

Renal Impairment The renal clearance of amantadine is significantly lower in adult patients with moderate or severe renal impairment, compared to healthy adults. Since the renal pathway is a major elimination pathway, impairment in renal function can result in significant accumulation in the plasma, warranting dose adjustment. The impact of renal impairment on dose adjustment was not investigated in a dedicated study.

Based on PK simulations, the range of the total exposures (AUC 0-tau ) in subjects with normal renal function (creatinine clearance >90 mL/min/1.73 m 2 ) or mild renal impairment (c… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The mechanism by which amantadine exerts efficacy in the treatment of dyskinesia in patients with Parkinson's disease or as adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing "off" episodes is unknown. Amantadine is a weak uncompetitive antagonist of the NMDA receptor. Amantadine has not been shown to possess direct anticholinergic activity in animal studies; however, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation in humans.

Amantadine may have direct and indirect effects on dopamine neurons; it exerts dopaminergic-like side effects such as hallucinations and dizziness in humans.

12.3Pharmacokinetics GOCOVRI is an extended-release formulation. The pharmacokinetics of amantadine from 68.5 mg, 137 mg, and 274 mg of GOCOVRI are dose proportional in healthy subjects. Absorption After a single dose bedtime administration of GOCOVRI, the median T max for plasma amantadine was around 12 hours (range 6-20 hours).

The steady-state concentrations of GOCOVRI were achieved 4 days after the dose initiation. The steady-state total exposures (AUC 0-tau ) were 20-30% higher than after single dose, suggesting an accumulation ratio of 1.2-1.3. Effect of Food A single dose crossover study of GOCOVRI established the lack of effect of high-fat, high-calorie meal on plasma amantadine pharmacokinetics; additionally, administration of entire capsule contents sprinkled on applesauce also did not affect plasma amantadine pharmacokinetics.

Distribution The volume of distribution determined after the intravenous administration of amantadine to 15 healthy subjects was 3 to 8 L/kg, suggesting potential extravascular distribution. Amantadine is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL. Elimination In a study with healthy volunteers after oral administration, the apparent plasma clearance of amantadine was estimated to be 0.27 ± 0.094 L/hr/kg (range 0.13 to

0.57L/hr/kg). Amantadine is primarily excreted unchanged in the urine, and in a study of six healthy volunteers, the ratio of amantadine renal clearance to apparent plasma clearance was 0.79 ± 0.17 (mean ± SD). The mean plasma amantadine half-life at steady-state was approximately 16 hours.

Metabolism Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 0-15% of the administered dose in multiple studies. The contribution of this metabolite to efficacy or toxicity is not known.

Excretion Amantadine is primarily excreted unchanged in the urine by both glomerular filtration and tubular secretion. Specific Population Male/Female Patients In an integrated analysis of five studies in healthy volunteers (n=147), the mean total amantadine clearance following administration of GOCOVRI, adjusted for body weight in kilograms, was 1.2 fold higher in males compared to females (95% CI: 1.1, 1.3, P=0.007). No dose adjustment by gender is warranted.

Renal Impairment The renal clearance of amantadine is significantly lower in adult patients with moderate or severe renal impairment, compared to healthy adults. Since the renal pathway is a major elimination pathway, impairment in renal function can result in significant accumulation in the plasma, warranting dose adjustment. The impact of renal impairment on dose adjustment was not investigated in a dedicated study.

Based on PK simulations, the range of the total exposures (AUC 0-tau ) in subjects with normal renal function (creatinine clearance >90 mL/min/1.73 m 2 ) or mild renal impairment (creatinine clearance between 60 and 89 mL/min/1.73 m 2 ) were comparable for the same dosing regimen. However, patients with moderate renal impairment (creatinine clearance between 30 and 59 mL/min/1.73 m 2 ) had higher exposures relative to patients with normal renal function or mild renal impairment. Severe renal impairment (creatinine clearance between 15 and 29 mL/min/1.73 m 2 ) resulted in even higher total exposures.

Dosage adjustment is recommended in patients with moderate and severe renal impairment [see Use in Special Populations ( 8.6 ) and Dosage and Administration ( 2.3 )]. GOCOVRI is contraindicated in patients with end stage renal disease (creatinine clearance less than 15 mL/min/1.73 m 2 ). Amantadine is inefficiently removed by hemodialysis.

Drug Interaction Studies The in-vitro dissolution-release profiles showed 52% drug release after 45 minutes, and up to 95% after 2 hours, at concentrations of 40% alcohol/0.1N HCl. In vitro studies indicate that amantadine has negligible or no inhibitor… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The effect of amantadine on QT prolongation was not studied in a dedicated thorough QT study. Alcohol consumption may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension [see Drug Interactions ( 7.4 )] .

14 CLINICAL STUDIES Overview of Studies The efficacy of GOCOVRI for the treatment of dyskinesia in patients with Parkinson's disease and for the adjunctive treatment to levodopa/carbidopa in patients with Parkinsons's disease experiencing "off" episodes was assessed in two randomized, double-blind, placebo-controlled efficacy trials: Study 1 and Study 2. Key inclusion criteria in both studies included at least 1 hour of troublesome dyskinesia time during the day and at least mild functional impact because of dyskinesia.

Study 1 was conducted in 121 (modified Intention to Treat (mITT) population) Parkinson's disease patients with dyskinesia in the United States (US) and Canada. The duration of treatment in Study 1 was up to 25 weeks. Study 2 was conducted in 75 (mITT population) patients with dyskinesia in the US, Germany, France, Spain, and Austria.

The duration of treatment was 13 weeks. In both studies, the primary efficacy endpoint was the change in total score of the Unified Dyskinesia Rating Scale (UDysRS) between baseline and Week 12. Key secondary endpoints derived from a Parkinson's disease home diary included changes from baseline to Week 12 in ON time without troublesome dyskinesia and OFF time.

Study Population In Study 1 and Study 2, the mean age of patients at the time of Parkinson's disease diagnosis was 55 years (range: 29-75 years). At baseline, patients had a mean UDysRS total score of 40.1 (range: 8-76), a mean duration of ON time without troublesome dyskinesia (Parkinson's disease home diary) of 8.4 hours (range: 0-15.3), and a mean duration of OFF time of 2.8 hours (range: 0-9.5). Patients in Study 1 and Study 2 were treated with a stable dose of levodopa, with 32% of patients on levodopa monotherapy.

Patients were also treated with concomitant dopamine agonists (54%) and/or MAO-B inhibitors (44%). Study 1 In Study 1, a significant decrease in mean UDysRS total score (reduction in dyskinesia) was observed at Week 12 in patients treated with GOCOVRI, compared with placebo (Table 2). Study 2 In Study 2, a significant decrease in mean UDysRS total score (reduction in dyskinesia) was observed at Week 12 in patients treated with GOCOVRI, compared with placebo (Table 2).

Table 2: UDysRS Total Score at Week 12 for Study 1 and Study 2 mITT Population Study 1 Study 2 Placebo (N=58) GOCOVRI 274 mg (N=63) Placebo (N=38) GOCOVRI 274 mg (N=37) UDysRS total score, LS Mean (SE) Change from Baseline -8.0 (1.64) -15.9 (1.62) -6.3 (2.08) -20.7 (2.20) Treatment Difference -7.9 (2.30) -14.4 (3.03) P-value 0.0009 <0.0001 In Study 1 and Study 2, there was a significant increase in ON time without troublesome dyskinesia, and a significant decrease in OFF time between baseline and Week 12 in patients treated with GOCOVRI, compared with placebo (Table 3).

Table 3: PD Home Diary Results at Week 12 for Study 1 and Study 2 mITT Population Study 1 Study 2 Placebo (N=58) GOCOVRI 274 mg (N=63) Placebo (N=38) GOCOVRI 274 mg (N=37) ON Time w/o Troublesome Dyskinesia, LS Mean (SE) Change from Baseline 0.8 (0.43) 3.6 (0.43) 2.1 (0.53) 4.0 (0.56) Treatment Difference 2.7 (0.61) 1.9 (0.78) P-value <0.0001 0.0168 OFF Time, LS Mean (SE) Change from Baseline 0.3 (0.26) -0.6 (0.27) 0.6 (0.31) -0.5 (0.34) Treatment Difference -0.9 (0.37) -1.1 (0.46) P-value 0.0171 0.0199

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies designed to evaluate the carcinogenic potential of amantadine have not been conducted. Mutagenesis Amantadine was negative for genotoxicity in in vitro (Ames and mammalian cell [Chinese Hamster ovary and human peripheral blood lymphocytes]) assays in the presence or absence of metabolic activation and in an in vivo mouse bone marrow micronucleus assay. Impairment of Fertility The effects of amantadine on fertility have not been adequately tested in a study in animals conducted according to current standards.

In a reproduction study reported in the literature, oral administration of amantadine to male and female rats at a dose of 32 mg/kg/day resulted in impaired fertility. The no-effect dose for adverse effects on fertility (10 mg/kg/day) is less than the recommended human dose of 274 mg/day on a mg/m 2 basis.