RYTARY Carbidopa and Levodopa 145 mg; 36.25 mg Capsule, Extended Release, 100-count

5 WARNINGS AND PRECAUTIONS May cause falling asleep during activities of daily living. ( 5.1 ) Avoid sudden discontinuation or rapid dose reduction to reduce the risk of withdrawal-emergent hyperpyrexia and confusion. ( 5.2 ) Cardiovascular Events: Monitor patients with a history of cardiovascular disease.

( 5.3 ) Hallucinations/Psychosis may occur. ( 5.4 ) Impulse Control Disorders: Consider dose reduction or stopping RYTARY if occurs. ( 5.5 ) May cause or exacerbate dyskinesia: Consider dose reduction.

( 5.6 )

5.1Falling Asleep During Activities of Daily Living and Somnolence Patients treated with levodopa, a component of RYTARY, have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on levodopa, some perceived that they had no warning signs (sleep attack), such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported more than 1 year after initiation of treatment.

It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness in RYTARY-treated patients, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with RYTARY, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with RYTARY such as concomitant sedating medications or the presence of a sleep disorder. Consider discontinuing RYTARY in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If a decision is made to continue RYTARY, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent.

There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.2Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex that resembles 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 dopaminergic therapy. Avoid sudden discontinuation or rapid dose reduction in patients taking RYTARY. If the decision is made to discontinue RYTARY, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration (2.4) ] .

5.3Cardiovascular Ischemic Events Cardiovascular ischemic events have occurred in patients taking RYTARY. In a placebo controlled clinical study in patients with early Parkinson's disease, 7/289 (2.4%) of RYTARY-treated patients experienced cardiovascular ischemic adverse reactions compared to 1/92 (1.1%) of placebo-treated patients. In an active-controlled clinical study in patients with advanced Parkinson's disease, 3/450 (0.7%) of RYTARY-treated patients experienced cardiovascular ischemic adverse reactions compared to 0/471 oral immediate-release carbidopa-levodopa-treated patients.

These patients all had a previous history of ischemic heart disease or risk factors for ischemic heart disease. In patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias, cardiac function should be monitored in an intensive cardiac care facility during the p…

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) ] Vitamin B6 Deficiency and Seizures [see Warnings and Precautions (5.7) ] Peptic Ulcer Disease [see Warnings and Precautions (5.8) ] Glaucoma [see Warnings and Precautions (5.9) ] Early Parkinson's disease: Most common adverse reactions (incidence ≥ 5% and greater than placebo) are nausea, dizziness, headache, insomnia, abnormal dreams, dry mouth, dyskinesia, anxiety, constipation, vomiting, and orthostatic hypotension.

( 6.1 ) Advanced Parkinson's disease: Most common adverse reactions (incidence ≥ 5% and greater than oral immediate-release carbidopa-levodopa) are nausea and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 Conversion a % Maintenance % Dose Conve…

7 DRUG INTERACTIONS Iron salts and dopamine D2 antagonists including metoclopramide: May reduce the effectiveness of RYTARY. ( 7.2 , 7.3 )

7.1Monoamine Oxidase (MAO) Inhibitors The use of nonselective MAO inhibitors with RYTARY is contraindicated [see Contraindications (4) ] . Discontinue use of any nonselective MAO inhibitors at least two weeks prior to initiating RYTARY. The use of selective MAO-B inhibitors (e.g., rasagiline and selegiline) with RYTARY may be associated with orthostatic hypotension. Monitor patients who are taking these drugs concurrently.

7.2Dopamine D2 Receptor Antagonists and Isoniazid Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide) and isoniazid may reduce the effectiveness of levodopa. Monitor patients for worsening Parkinson's symptoms.

7.3Iron Salts Iron salts or multivitamins containing iron salts can form chelates with levodopa and carbidopa and can cause a reduction in the bioavailability of RYTARY. If iron salts or multivitamins containing iron salts are co-administered with RYTARY, monitor patients for worsening Parkinson's symptoms.