This information is not for clinical use. These highlights do not include all the information needed to use Rytary safely and effectively. Before taking Rytary please consult with your doctor. See full prescribing information for Rytary.

Indications And Usage

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)

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Dosage And Administration

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 TIDa
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

Dosage Forms And Strengths

Extended-release capsules: 23.75 mg carbidopa and 95 mg levodopa: blue and white capsule imprinted with IPX066 on the capsule cap and 95 on the capsule body 36.25 mg carbidopa and 145 mg levodopa: blue and light blue capsule imprinted with IPX066 on the capsule cap and 145 on the capsule body 48.75 mg carbidopa and 195 mg levodopa: blue and yellow capsule imprinted with IPX066 on the capsule cap and 195 on the capsule body 61.25 mg carbidopa and 245 mg levodopa: blue capsule imprinted with IPX066 on the capsule cap and 245 on the capsule body Extended-release capsules: Carbidopa and levodopa 23.75 mg / 95 mg, 36.25 mg / 145 mg, 48.75 mg / 195 mg, 61.25 mg / 245 mg (3)

Contraindications

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)

Warning and Cautions

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) 5.1 Falling 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. 5.2 Withdrawal-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)]. 5.3 Cardiovascular 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 period of initial dosage adjustment. 5.4 Hallucinations/Psychosis There is an increased risk for hallucinations and psychosis in patients taking RYTARY. In a controlled clinical trial in patients with advanced Parkinson's disease, 9/201 (4%) of RYTARY-treated patients reported hallucinations or psychosis compared to 2/192 (1%) of oral immediate-release carbidopa-levodopa-treated patients. Hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Hallucinations may be accompanied by confusion, insomnia, and excessive dreaming. Abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Because of the risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with RYTARY. In addition, medications that antagonize the effects of dopamine used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of RYTARY [see Drug Interactions (7.2)]. 5.5 Impulse Control/Compulsive Behaviors Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including RYTARY, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with RYTARY. Consider a dose reduction or stopping the medication if a patient develops such urges while taking RYTARY. 5.6 Dyskinesia RYTARY can cause dyskinesias that may require a dosage reduction of RYTARY or other medications used for the treatment of Parkinson's disease. 5.7 Peptic Ulcer Disease Treatment with RYTARY may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer. 5.8 Glaucoma RYTARY may cause increased intraocular pressure in patients with glaucoma. Monitor intraocular pressure in patients with glaucoma after starting RYTARY. 5.9 Melanoma Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. Perform periodic skin examinations to monitor for melanoma in patients receiving RYTARY.

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)] Melanoma [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 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 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.

Drug Interactions

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.

Use In Specific Populations

Pregnancy: Based on animal data, may cause fetal harm (8.1) 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. In animal studies, carbidopa-levodopa has been shown to be developmentally toxic (including teratogenic effects) at clinically relevant doses. RYTARY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When administered to pregnant rabbits throughout organogenesis, carbidopa-levodopa caused both visceral and skeletal malformation in fetuses at all doses and ratios of carbidopa-levodopa tested. No teratogenic effects were observed when carbidopa-levodopa was administered to pregnant mice throughout organogenesis. There was a decrease in the number of live pups delivered by rats receiving carbidopa-levodopa during organogenesis. 8.3 Nursing Mothers Carbidopa is excreted in rat milk. In a study of one nursing mother with Parkinson's disease, excretion of levodopa in human milk was reported. Caution should be exercised when RYTARY is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In controlled clinical trials of RYTARY, 418 patients were 65 years or older and no overall differences in safety and efficacy were observed between these patients and those under 65 years of age.