GOCOVRI

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION 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.

4 CONTRAINDICATIONS 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 )

5 WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living : Advise patients prior to treatment; ordinarily discontinue if occurs ( 5.1 ) Suicidality and Depression : Monitor patients for depressed mood, depression, or suicidal ideation or behavior ( 5.2 ) Hallucinations/Psychotic Behavior: Patients with major psychotic disorder should ordinarily not be treated with GOCOVRI; observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases ( 5.3 ) Dizziness and Orthostatic Hypotension : Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose ( 5.4 ) Withdrawal-Emergent Hyperpyrexia and Confusion : Avoid sudden discontinuation ( 5.5 ) Corneal Edema : Monitor patients for new changes in vision, including blurred vision, with or without eye pain, or vision loss. Taper and discontinue if corneal edema occurs ( 5.6 ) Impulse Control/Compulsive Behaviors : Ask patients about increased gambling urges, sexual urges, uncontrolled spending or other urges; consider dose reduction or discontinuation if occurs ( 5.7 ) 5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated for Parkinson's disease have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. In controlled clinical trials, somnolence and fatigue were reported as adverse reactions in 4% of patients treated with GOCOVRI 274 mg and 1% for placebo. Before initiating treatment with GOCOVRI, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with GOCOVRI, such as concomitant sedating medications or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued. If a decision is made to continue GOCOVRI, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living or daytime somnolence. 5.2 Suicidality and Depression In controlled clinical trials, suicidal ideation or suicide attempt was reported in 2% of GOCOVRI-treated patients and 0% of placebo-treated patients. Depression or depressed mood was reported in 6% of GOCOVRI-treated patients and 1% of placebo-treated patients. Confusional state was reported in 3% of GOCOVRI-treated patients and 2% of placebo-treated patients. Apathy was reported in 2% of GOCOVRI-treated patients and 0% of placebo-treated patients. Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression. 5.3 Hallucinations/Psychotic Behavior Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. In controlled trials, the incidence of patients who experienced visual hallucinations, auditory hallucinations, delusions, illusions, or paranoia was 25% in patients treated with GOCOVRI 274 mg, and 3% in placebo-treated patients. Hallucinations caused discontinuation of treatment in 8% of GOCOVRI-treated patients, and in 0% of placebo-treated patients. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation, and after dose increases. 5.4 Dizziness and Orthostatic Hypotension In controlled clinical trials, 29% of GOCOVRI-treated patients and 2% of placebo-treated patients experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness or hypotension. In GOCOVRI-treated patients, 3% discontinued study treatment because of dizziness, postural dizziness, or syncope, compared to 0% of placebo-treated patients. Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Concomitant use of alcohol when using GOCOVRI is not recommended [see Drug Interactions ( 7.4 )]. 5.5 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. Abrupt discontinuation of GOCOVRI may cause an increase in the symptoms of Parkinson's disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. It is recommended to avoid sudden discontinuation of GOCOVRI [see Dosing Information ( 2.4 )] . 5.6 Corneal Edema Corneal edema has been reported in patients taking amantadine. Symptoms include sudden onset of blurry vision, or progressive vision loss, with or without eye pain. Corneal involvement is usually bilateral. Onset can occur from a few weeks to several years after starting amantadine. Resolution of symptoms typically begins within weeks of amantadine cessation. However, corneal grafts have been required in some patients when the condition is not recognized. Permanent damage can occur if amantadine is continued. Ask patients if their vision has changed and obtain ophthalmologic examinations to rule out corneal edema should vision changes occur after initiation of therapy with GOCOVRI. If corneal edema occurs, taper and discontinue GOCOVRI [see Dosage and Administration ( 2.4 )] . 5.7 Impulse Control/Compulsive Behaviors Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including GOCOVRI, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with GOCOVRI. Consider dose reduction or stopping the medication if a patient develops such urges while taking GOCOVRI.

7 DRUG INTERACTIONS 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 )] .

6 ADVERSE REACTIONS 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 Supernus Pharmaceuticals, Inc. 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

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of amantadine in pregnant women. Animal studies suggest a potential risk for fetal harm with amantadine. In mice and rats, adverse developmental effects (embryolethality, increased incidence of malformations, and reduced fetal body weight) were observed when amantadine was administered to pregnant animals 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 for major birth defects and miscarriage in patients with Parkinson's disease is unknown. Data Animal Data The effects of amantadine on development have not been tested in studies conducted in animals using currently recommended methodology; however, developmental toxicity studies of amantadine have been reported in the published literature. In mice, oral administration of amantadine (0, 10, or 40 mg/kg/day) to pregnant animals during organogenesis (gestation days 7-12) resulted in embryolethality and reduced fetal body weight at the highest dose tested, which was associated with maternal toxicity. The no-effect dose for developmental toxicity in mice (10 mg/kg/day) is less than the recommended human dose (RHD) of 274 mg/day, based on body surface area (mg/m 2 ). In rats, oral administration of amantadine (0, 40 or 120 mg/kg/day) to pregnant animals during organogenesis (gestation days 7-12) resulted in embryolethality and reduced fetal body weight at the highest dose. The no-effect dose for developmental toxicity in this study (40 mg/kg/day) is approximately equal to the RHD on a mg/m 2 basis. In another study in pregnant rats, oral administration of amantadine during organogenesis (gestation days 7-14) resulted in an increase in visceral and skeletal malformations at oral doses of 50 and 100 mg/kg/day. The no-effect dose for teratogenicity in this study (37 mg/kg/day) is approximately equal to the RHD on a mg/m 2 basis. Evaluation of parturition, lactation, and post-natal development in a limited number of litters from the mouse and rat studies described above revealed reductions in live litter size and pup weights at birth at 40 mg/kg/day in mice and 120 mg/kg/day in rats.