RYTARY

RYTARY is a combination of carbidopa, an inhibitor of aromatic amino acid decarboxylation, and levodopa, an aromatic amino acid, in extended-release capsules for oral use. Carbidopa is a white to creamy white powder, slightly soluble in water, with a molecular weight of 244.2. It is designated chemically as (-)-L-α-hydrazino-3, 4-dihydroxy-α-methylhydrocinnamic acid monohydrate. Its molecular formula is C 10 H 14 N 2 O 4 • H 2 O and its structural formula is: Capsule content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.2. Levodopa is a white to off-white, crystalline powder, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (−)-3-(3, 4-Dihydroxyphenyl)-L-alanine. Its molecular formula is C 9 H 11 NO 4 and its structural formula is: Each extended-release capsule contains 23.75 mg carbidopa, USP and 95 mg levodopa USP, 36.25 mg carbidopa, USP and 145 mg levodopa USP, 48.75 mg carbidopa, USP and 195 mg levodopa USP, or 61.25 mg carbidopa, USP and 245 mg levodopa USP. The inactive ingredients are microcrystalline cellulose, mannitol, tartaric acid, ethyl cellulose, hypromellose, sodium starch glycolate, sodium lauryl sulfate, povidone, talc, methacrylic acid copolymers, triethyl citrate, croscarmellose sodium, and magnesium stearate. All capsule shells contain gelatin and titanium dioxide. In addition, all blue capsule shells contain FD&C Blue #2 and yellow iron oxide. All yellow capsule shells contain yellow iron oxide. All capsules imprinted with blue pharmaceutical ink contain FD&C Blue #2, butyl alcohol, dehydrated alcohol, isopropyl alcohol, propylene glycol, shellac and strong ammonia solution. 1 2

RYTARY is indicated for the treatment of Parkinson's disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. RYTARY is a combination of carbidopa (an aromatic amino acid decarboxylation inhibitor) and levodopa (an aromatic amino acid) indicated for the treatment of Parkinson's disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. ( 1 )

Levodopa-naïve patients: Starting dose is 23.75 mg/95 mg three times daily; may increase to 36.25 mg/145 mg three times daily on the fourth day of treatment. ( 2.1 ) See Table 1 for instructions for converting patients taking immediate-release carbidopa-levodopa to an initial dose of RYTARY. Dosages of RYTARY are not interchangeable with other carbidopa-levodopa products. ( 2.2 ) The maximum recommended daily dose of RYTARY is 612.5 mg/2,450 mg. ( 2.1 , 2.2 ) RYTARY may be taken with or without food; do not chew, divide or crush. ( 2.4 , 12.3 ) 2.1 Dosage in Patients Naïve to Levodopa Therapy The recommended starting dosage of RYTARY in levodopa-naïve patients is 23.75 mg/95 mg taken orally three times a day for the first 3 days. On the fourth day of treatment, the dosage of RYTARY may be increased to 36.25 mg/145 mg taken three times a day. Based upon individual patient clinical response and tolerability, the RYTARY dose may be increased up to a maximum recommended dose of 97.5 mg/390 mg taken three times a day. The dosing frequency may be changed from three times a day to a maximum of five times a day if more frequent dosing is needed and if tolerated. Maintain patients on the lowest dosage required to achieve symptomatic control and to minimize adverse reactions such as dyskinesia and nausea. The maximum recommended daily dose of RYTARY is 612.5 mg/2,450 mg. 2.2 Converting from Immediate-Release Carbidopa-Levodopa to RYTARY The dosages of other carbidopa and levodopa products are not interchangeable on a 1:1 basis with the dosages of RYTARY. To convert patients from immediate-release carbidopa-levodopa to RYTARY, first calculate the patient’s current total daily dose of levodopa. The starting total daily dose of RYTARY is as recommended in Table 1. After conversion, any combination of the four RYTARY dosage strengths can be used to achieve an optimal dosing. Adjust the dose and dosing frequency as necessary to maintain patient tolerance and sufficient symptomatic control. Administration of concomitant Parkinson’s disease medications should remain stable while adjusting the RYTARY dose. In clinical trials, RYTARY was administered in divided doses of three to five times a day. The maximum recommended total daily dose of RYTARY is 612.5 mg/2,450 mg. For patients currently treated with carbidopa and levodopa plus a catechol-O-methyl transferase (COMT) inhibitor (such as entacapone), the initial total daily dose of levodopa in RYTARY described in Table 1 may need to be increased. Use of RYTARY in combination with other levodopa products has not been studied. Table 1 : Conversion from Immediate-Release Carbidopa-Levodopa to RYTARY Total Daily Dose of Levodopa in Immediate-Release Carbidopa-Levodopa Recommended Starting Dosage of RYTARY Total Daily Dose of Levodopa in RYTARY RYTARY Dosing Regimen 400 mg to 549 mg 855 mg 3 capsules RYTARY 23.75 mg/95 mg taken TID a 550 mg to 749 mg 1,140 mg 4 capsules RYTARY 23.75 mg/95 mg taken TID 750 mg to 949 mg 1,305 mg 3 capsules RYTARY 36.25 mg/145 mg taken TID 950 mg to 1,249 mg 1,755 mg 3 capsules RYTARY 48.75 mg/195 mg taken TID Equal to or greater than 1,250 mg 2,340 mg or 4 capsules RYTARY 48.75 mg/195 mg taken TID or 2,205 mg 3 capsules RYTARY 61.25 mg/245 mg taken TID a TID: three times a day 2.3 Discontinuation of RYTARY Avoid sudden discontinuation or rapid dose reduction of RYTARY. The daily dose of RYTARY should be tapered at the time of treatment discontinuation [see Warnings and Precautions (5.2) ] . 2.4 Administration Information Swallow RYTARY whole with or without food. A high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours [see Clinical Pharmacology (12.3) ] . Do not chew, divide or crush RYTARY capsules. For patients who have difficulty swallowing intact capsules, administer RYTARY by carefully twisting apart both halves of the capsule. Sprinkle the entire contents of both halves of the capsule on a small amount of applesauce (1 to 2 tablespoons) and consume the mixture immediately. Do not store the drug/food mixture for future use.

RYTARY is contraindicated in patients: Currently taking a nonselective monoamine oxidase (MAO) inhibitor (e.g., phenelzine and tranylcypromine) or have recently (within 2 weeks) taken a nonselective MAO inhibitor. Hypertension can occur if these drugs are used concurrently [see Drug Interactions (7.1) ] . Nonselective MAO inhibitors. ( 4 )

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) ] 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. 6.1 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 Conversion a % Maintenance % Dose Conversion a % 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 Post-marketing 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.

Iron salts and dopamine D2 antagonists including metoclopramide: May reduce the effectiveness of RYTARY. ( 7.2 , 7.3 ) 7.1 Monoamine 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. 7.2 Dopamine 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. 7.3 Iron 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.

16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in a tightly closed container, protected from light and moisture. Dispense in a tightly closed, light-resistant container.