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)]
Impulse Control/Compulsive Behaviors [see Warnings and Precautions ( 5.6)]

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.