GOCOVRI

GOCOVRI contains amantadine in an extended-release formulation. The active ingredient in GOCOVRI is amantadine hydrochloride. The chemical name for amantadine hydrochloride is tricyclo [3.3.1.1 3,7 ] decan-1-amine, hydrochloride or 1-adamantanamine hydrochloride with the following structural formula: The molecular formula is C 10 H 17 N∙HCl and the molecular weight is 187.71 (g/mol). Amantadine hydrochloride is a white crystalline powder and is non-hygroscopic, practically insoluble in ether, sparingly soluble in methylene chloride, soluble in chloroform, and freely soluble in water, ethanol, and methanol. GOCOVRI capsules are for oral use. Each capsule contains 68.5 mg or 137 mg amantadine (as 85 mg or 170 mg amantadine hydrochloride, respectively). Capsules also contain the following inactive ingredients: copovidone, ethylcellulose, hypromellose, magnesium stearate, medium-chain triglycerides, microcrystalline cellulose, povidone, and talc in a hard gelatin capsule. chemical structure

GOCOVRI ® is indicated: For the treatment of dyskinesia in patients with Parkinson's disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications As adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing "off" episodes GOCOVRI ® is indicated: For the treatment of dyskinesia in patients with Parkinson's disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications ( 1 ) As adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing "off" episodes ( 1 )

Administer orally once daily at bedtime ( 2.1 , 2.3 ) The initial daily dosage is 137 mg; after 1 week, increase to the recommended daily dosage of 274 mg ( 2.1 ) Swallow whole; may sprinkle contents on soft food ( 2.2 ) May be taken with or without food; avoid use with alcohol ( 2.2 ) A lower dosage is recommended for patients with moderate or severe renal impairment ( 2.3 ) 2.1 Dosing Information The initial daily dosage of GOCOVRI is 137 mg, administered orally once daily at bedtime. After one week, increase to the recommended dosage of 274 mg (two 137 mg capsules) once daily at bedtime. GOCOVRI is not substitutable with other amantadine immediate- or extended-release products. 2.2 Administration Information GOCOVRI should be swallowed whole. Do not crush, chew or divide capsules. If needed, GOCOVRI may be administered by carefully opening and sprinkling the entire contents on a small amount (teaspoonful) of soft food, such as applesauce. The drug/food mixture should be swallowed immediately without chewing. Do not store mixture for future use. GOCOVRI can be taken with or without food [see Clinical Pharmacology ( 12.3 )]. Concomitant use of GOCOVRI with alcohol is not recommended [see Drug Interactions ( 7.4 )]. It is recommended to avoid sudden discontinuation of GOCOVRI [see Dosage and Administration ( 2.4 )]. 2.3 Dosing in Patients with Renal Impairment The initial and maximum recommended daily dosage of GOCOVRI for patients with renal impairment (creatinine clearance estimated by Modification of Diet in Renal Disease (MDRD) method) is provided below. 1 Increase, if needed, after one week of the initial dosage Creatinine Clearance Dosage Mild renal impairment (60 to 89 mL/min/1.73 m 2 ) Initial dosage: 137 mg once daily at bedtime. After one week, increase to recommended dosage of 274 mg once daily at bedtime. Moderate renal impairment (30 to 59 mL/min/1.73 m 2 ) Initial dosage: 68.5 mg once daily at bedtime Maximum recommended dosage: 137 mg once daily at bedtime 1 Severe renal impairment (15 to 29 mL/min/1.73 m 2 ) 68.5 mg once daily at bedtime End Stage Renal Disease (below 15 mL/min/1.73 m 2 ) Contraindicated 2.4 Discontinuation and Missed Dose Rapid dose reduction or withdrawal of GOCOVRI may cause adverse reactions [see Warnings and Precautions ( 5.5 )]. Therefore, to discontinue GOCOVRI in patients who have been on the drug for more than 4 weeks, GOCOVRI dosage should, if possible, be reduced by half for the final week of dosing. If a dose of GOCOVRI is missed, the next dose should be taken as scheduled.

GOCOVRI is contraindicated in patients with end-stage renal disease (i.e., creatinine clearance below 15 mL/min/1.73 m 2 ) [see Clinical Pharmacology ( 12.3 )]. GOCOVRI is contraindicated in patients with end-stage renal disease ( 4 )

The following serious adverse reactions are described in more detail elsewhere in the labeling: Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions ( 5.1 )] Suicidality and Depression [see Warnings and Precautions ( 5.2 )] Hallucinations/Psychotic Behavior [see Warnings and Precautions ( 5.3 )] Dizziness and Orthostatic Hypotension [see Warnings and Precautions ( 5.4 )] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions ( 5.5 )] Corneal Edema [see Warnings and Precautions ( 5.6 )] Impulse Control/Compulsive Behaviors [see Warnings and Precautions ( 5.7 )] The most commonly observed adverse reactions occurring at a frequency of >10% and greater than placebo were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Adamas Pharma, LLC at 1-833-223-2627 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Placebo-Controlled Trials GOCOVRI was evaluated in two double-blind, placebo-controlled efficacy trials of similar design and population: Study 1 (123 patients) and Study 2 (75 patients) [see Clinical Studies ( 14 )] . The study population was approximately 56% male and 94% white, with a mean age of 65 years (age range from 34 years to 82 years). The mean duration of levodopa-induced dyskinesia was 4 years (range 0.1 to 14 years). Active treatment started at 137 mg once daily for one week, followed by a dose increase to 274 mg once daily. The treatment duration was 25 weeks for Study 1 and 13 weeks for Study 2. Of the 100 patients in the safety population described below, 39 patients were treated with GOCOVRI for 24 weeks. The safety data for these trials were pooled. The most common adverse reactions reported in >10% of GOCOVRI-treated patients and more frequently than on placebo were: hallucinations, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension. The overall rate of discontinuation because of adverse reactions for GOCOVRI-treated patients was 20%, compared to 8% for placebo-treated patients. Adverse reactions that led to treatment discontinuation in at least 2% of patients were hallucinations (8% GOCOVRI vs. 0% placebo), dry mouth (3% GOCOVRI vs. 0% placebo), peripheral edema (3% GOCOVRI vs. 0% placebo), blurred vision (GOCOVRI 3% vs. 0% placebo), postural dizziness and syncope (GOCOVRI 2% vs. 0% placebo), abnormal dreams (GOCOVRI 2% vs. 1% placebo), dysphagia (GOCOVRI 2% vs. 0% placebo), and gait disturbance (GOCOVRI 2% vs. 0% placebo). Table 1: Adverse Reactions Reported for ≥ 3% of Patients Treated with 274 mg GOCOVRI in Study 1 and Study 2 (Pooled Analysis) a=Includes visual hallucinations and auditory hallucinations b=Includes anxiety and generalized anxiety c=Includes orthostatic hypotension, postural dizziness, syncope, presyncope, and hypotension d=The denominator is all male patients in the safety population randomized to GOCOVRI (n=54) or placebo (n=57) Adverse Reactions GOCOVRI 274 mg N=100 % Placebo N=98 % Psychiatric disorders Hallucinations a 21 3 Anxiety b 7 3 Insomnia 7 2 Depression/Depressed mood 6 1 Abnormal dreams 4 2 Confusional state 3 2 Nervous system disorders Dizziness 16 1 Headache 6 4 Dystonia 3 1 Gastrointestinal disorders Dry mouth 16 1 Constipation 13 3 Nausea 8 3 Vomiting 3 0 General disorders and administration site conditions Peripheral edema 16 1 Gait disturbance 3 0 Injury, poisoning and procedural complications Fall 13 7 Contusion 6 1 Infections and infestations Urinary tract infection 10 5 Skin and subcutaneous tissue disorders Livedo reticularis 6 0 Pigmentation disorder 3 0 Metabolism and nutrition disorders Decreased appetite 6 1 Vascular disorders Orthostatic hypotension c 13 1 Eye disorders Blurred vision 4 1 Cataract 3 1 Dry eye 3 0 Musculoskeletal and connective tissue disorders Joint swelling 3 0 Muscle spasms 3 0 Reproductive system and breast disorders Benign prostatic hyperplasia d 6 2 Respiratory, thoracic and mediastinal disorders Cough 3 0 Other clinically relevant adverse reactions observed at <3% included somnolence, fatigue, suicide ideation or attempt, apathy, delusions, illusions, and paranoia [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )]. Difference in the Frequency of Adverse Reactions by Gender Adverse reactions reported more frequently in women treated with 274 mg of GOCOVRI (n=46), compared to men (n=54), were: dry mouth (22% women, 11% men), nausea (13% women, 4% men), livedo reticularis (13% women, 0% men), abnormal dreams (9% women, 0% men) and cataracts (7% women, 0% men). Men treated with 274 mg of GOCOVRI reported the following adverse reactions more frequently than women: dizziness (20% men, 11% women), peripheral edema (19% men, 11% women), anxiety (11% men, 2% women), orthostatic hypotension (7% men, 2% women) and gait disturbance (6% men, 0% women). Difference in the Frequency of Adverse Reactions by Age Hallucinations (visual or auditory) were reported in 31% of GOCOVRI-treated patients age 65 years and over (n=52), compared to 10% in patients below the age of 65 years (n=48). Falls were reported in 17% of GOCOVRI-treated patients age 65 and over, compared to 8% of patients below age 65. Orthostatic hypotension was reported in 8% of patients age 65 and over, compared to 2% of patients below age 65. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of GOCOVRI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders: Seizure. Vision: Corneal edema

Other Anticholinergic Drugs: Doses should be reduced if atropine-like effects occur ( 7.1 ) Drugs Affecting Urinary pH: Excretion increases with acidic urine; possible accumulation with urine change towards alkaline ( 7.2 ) Live Attenuated Influenza Vaccines: Not recommended during use ( 7.3 ) Alcohol: Concomitant use not recommended ( 7.4 ) 7.1 Other Anticholinergic Drugs Products with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. The dose of anticholinergic drugs or of GOCOVRI should be reduced if atropine-like effects appear when these drugs are used concurrently. 7.2 Drugs Affecting Urinary pH The pH of the urine has been reported to influence the excretion rate of amantadine. Urine pH is altered by diet, drugs (e.g., carbonic anhydrase inhibitors, sodium bicarbonate), and clinical state of the patient (e.g., renal tubular acidosis or severe infections of the urinary tract). Since the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. Alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse reactions. Monitor for efficacy or adverse reactions under conditions that alter the urine pH to more acidic or alkaline, respectively. 7.3 Live Attenuated Influenza Vaccines Because of its antiviral properties, amantadine may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live vaccines are not recommended during treatment with GOCOVRI. Inactivated influenza vaccines may be used, as appropriate. 7.4 Alcohol Concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension [see Warnings and Precautions ( 5.4 )] , and may result in dose-dumping [see Clinical Pharmacology ( 12.3 )] .

16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].