6 ADVERSE REACTIONS

The following serious adverse reactions are discussed below and elsewhere in the labeling:

Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1)]
Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.2)]
Cardiovascular Ischemic Events [see Warnings and Precautions (5.3)]
Hallucinations/Psychosis [see Warnings and Precautions (5.4)]
Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.5)]
Dyskinesia [see Warnings and Precautions (5.6)]
Peptic Ulcer Disease [see Warnings and Precautions (5.7)]
Glaucoma [see Warnings and Precautions (5.8)

6.1 Clinical Trials 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 clinical practice.

The safety population consisted of a total of 978 Parkinson’s disease patients who received at least one dose of RYTARY, and had an average duration of exposure of 40 weeks.

Adverse Reactions in Early Parkinson’s Disease

In a placebo-controlled clinical study in patients with early Parkinson’s disease (Study 1), the most common adverse reactions with RYTARY (in at least 5% of patients and more frequently than in placebo) were nausea, dizziness, headache, insomnia, abnormal dreams, dry mouth, dyskinesia, anxiety, constipation, vomiting, and orthostatic hypotension.

Table 2 lists adverse reactions occurring in at least 5% of RYTARY-treated patients and at a higher rate than placebo in Study 1.

Table 2: Adverse Reactions in Study 1 in Patients with Early Stage Parkinson’s Disease

	Placebo	RYTARY 36.25 mg Carbidopa 145 mg Levodopa TID	RYTARY 61.25 mg Carbidopa 245 mg Levodopa TID	RYTARY 97.5 mg Carbidopa 390 mg Levodopa TID
	(N=92) %	(N=87) %	(N=104) %	(N=98) %
Nausea	9	14	19	20
Dizziness	5	9	19	12
Headache	11	7	13	17
Insomnia	3	2	9	6
Abnormal Dreams	0	2	6	5
Dry Mouth	1	3	2	7
Dyskinesia	0	2	4	5
Anxiety	0	2	3	5
Constipation	1	2	6	2
Vomiting	3	2	2	5
Orthostatic Hypotension	1	1	1	5

Adverse Reactions Leading to Discontinuation in Study 1

In Study 1, 12% of patients discontinued RYTARY early due to adverse reactions; a higher proportion of patients in the 61.25 mg / 245 mg RYTARY-treated group (14%) and in the 97.5 mg / 390 mg RYTARY-treated group (15%) experienced adverse reactions leading to early discontinuation compared to (4%) in the placebo group. The most common adverse reactions resulting in early discontinuation were nausea, dizziness, and vomiting.

Adverse Reactions in Advanced Parkinson’s Disease

In an active-controlled clinical study in patients with advanced Parkinson’s disease (Study 2), the most common adverse reactions with RYTARY that occurred during dose conversion or maintenance (in at least 5% of patients and more frequently than on oral immediate-release carbidopa-levodopa) were nausea and headache.

Table 3 lists adverse reactions occurring in at least 5% of RYTARY-treated patients and at a higher rate than oral immediate-release carbidopa-levodopa in Study 2.

Table 3: Adverse Reactions in Study 2 in Patients with Advanced Parkinson’s Disease

	RYTARY (N=201)		Immediate-Release Carbidopa-Levodopa (N=192)
Period	Dose Conversiona %	Maintenance %	Dose Conversiona %	Maintenance %
Nausea	4	3	6	2
Headache	5	1	3	2

a All patients were converted to RYTARY in the open-label Dose Conversion period and then received randomized treatment during maintenance.

Adverse Reactions Leading to Discontinuation in Study 2

In Study 2, 5% of patients discontinued treatment due to adverse reactions during conversion to RYTARY. The common adverse reactions leading to discontinuation during dose conversion were dyskinesia, anxiety, dizziness, and on and off phenomenon.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of RYTARY. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to RYTARY exposure.

Psychiatric: Suicide attempt, suicidal ideation.