Gocovri Drug Information

® 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 As adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing "off" episodes

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) . 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. 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.

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 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.

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.

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.

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 , and may result in dose-dumping .

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.

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.

Pediatric Use The safety and effectiveness of GOCOVRI in pediatric patients have not been established.

is contraindicated in patients with end-stage renal disease (i.e., creatinine clearance below 15 mL/min/1.73 m 2 ). GOCOVRI is contraindicated in patients with end-stage renal disease

Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 1 gram of amantadine hydrochloride (equivalent to 0.8 g amantadine). Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal, or central nervous system toxicity.

Pulmonary edema and respiratory distress (including adult respiratory distress syndrome, ARDS) have been reported with amantadine; renal dysfunction, including increased BUN and decreased creatinine clearance, can occur. Central nervous system effects that have been reported with overdose include agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, tremor, disorientation, depersonalization, fear, delirium, psychotic reactions, lethargy, and coma. Seizures may be exacerbated in patients with prior history of seizure disorders.

Hyperthermia has occurred with amantadine overdose. For acute overdosing, general supportive measures should be employed along with immediate gastric decontamination if appropriate. Give intravenous fluids if necessary.

The excretion rate of amantadine increases with acidification of urine, which may increase the elimination of the drug. Monitor patients for arrhythmias and hypotension. Electrocardiographic monitoring may be needed after ingestion because arrhythmias have been reported after overdose, including arrhythmias with fatal outcomes.

Adrenergic agents, such as isoproterenol, in patients with an amantadine overdose has been reported to induce arrhythmias. Monitor blood electrolytes, urine pH, and urinary output. Although amantadine is not efficiently removed by hemodialysis, this procedure may be useful in the treatment of amantadine toxicity in patients with renal failure.