Introduction
Rytary (carbidopa-levodopa extended-release capsules) is a prescription medication approved by the FDA in 2015 for the treatment of Parkinson's disease and parkinsonism secondary to cerebral injury or encephalitis. It represents an advanced formulation combining immediate-release and extended-release components of carbidopa and levodopa in a single capsule, designed to provide more continuous dopaminergic stimulation and reduce motor fluctuations associated with standard levodopa therapy.
Mechanism of Action
Rytary contains two active components: carbidopa, a peripheral dopa decarboxylase inhibitor, and levodopa, a metabolic precursor of dopamine. Levodopa crosses the blood-brain barrier and is converted to dopamine in the striatum, compensating for the dopamine deficiency characteristic of Parkinson's disease. Carbidopa inhibits the peripheral conversion of levodopa to dopamine, allowing more levodopa to reach the central nervous system and reducing peripheral side effects. The extended-release formulation provides both immediate release (approximately 25-30% of total levodopa) and extended release (approximately 70-75% of total levodopa) components, resulting in more sustained plasma concentrations.
Indications
- Treatment of Parkinson's disease
- Treatment of post-encephalitic parkinsonism
- Symptomatic treatment of parkinsonism following carbon monoxide intoxication or manganese intoxication
- Treatment of parkinsonism secondary to cerebral vascular disease
Dosage and Administration
Initial Therapy: The recommended starting dose is one capsule of Rytary 23.75/95 mg (carbidopa/levodopa) three times daily while awake, with intervals of approximately 4-8 hours between doses. Conversion from Immediate-Release Carbidopa-Levodopa: Dosing should be individualized based on patient's current levodopa regimen. Generally, the total daily dose of Rytary may need to be increased by approximately 10% more levodopa than the previous immediate-release formulation. Dose Titration: May be adjusted as frequently as every 1-2 days based on therapeutic response and tolerability. Administration: Should be swallowed whole. May be opened and sprinkled on applesauce for patients with swallowing difficulties. Should be taken with food to reduce nausea. Special Populations:- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: Use with caution; no specific dosage recommendations
- Geriatric patients: Start at lower end of dosing range
Pharmacokinetics
Absorption: Levodopa absorption occurs primarily in the small intestine. The extended-release component demonstrates biphasic release with an initial peak at approximately 1 hour and a second peak at approximately 4 hours. Distribution: Levodopa distributes into various body tissues, including the brain. Protein binding is minimal. Metabolism: Levodopa is extensively metabolized primarily via decarboxylation to dopamine and via O-methylation to 3-O-methyldopa. Carbidopa is metabolized to two main metabolites. Elimination: The elimination half-life of levodopa is approximately 1.5 hours. Approximately 70-80% of the drug is excreted in urine within 24 hours as metabolites.Contraindications
- Hypersensitivity to any component of the formulation
- Concomitant use with nonselective monoamine oxidase (MAO) inhibitors (must allow至少14 days between therapies)
- Narrow-angle glaucoma
- History of melanoma or undiagnosed skin lesions
- Patients with suspicious, undiagnosed skin lesions or a history of melanoma
Warnings and Precautions
Falling Asleep During Activities of Daily Living: Patients may fall asleep without warning during activities including driving, which sometimes results in accidents. Hypotension: Orthostatic hypotension can occur, particularly when titrating dosage. Hallucinations/Psychotic Behavior: May occur at recommended doses, with higher risk in elderly patients and those with pre-existing psychotic disorders. Impulse Control Disorders: Pathological gambling, increased libido, hypersexuality, compulsive spending or eating may occur. Dopamine Dysregulation Syndrome: Compulsive use of dopaminergic medications despite potentially harmful consequences. Withdrawal-Emergent Hyperpyrexia and Confusion: A symptom complex resembling neuroleptic malignant syndrome may occur with rapid dose reduction or withdrawal. Melanoma: Patients have increased risk of melanoma and should undergo periodic dermatologic examination.Drug Interactions
MAO Inhibitors: Concomitant use with nonselective MAO inhibitors may precipitate hypertensive crisis. Dopamine D2 Receptor Antagonists: May diminish effectiveness of Rytary (e.g., phenothiazines, butyrophenones, risperidone). Antihypertensive Agents: May potentiate hypotensive effects. Iron Salts: May reduce bioavailability of levodopa. Protein-rich meals: May interfere with absorption of levodopa. Isoniazid: May decrease effectiveness of levodopa.Adverse Effects
Most Common Adverse Reactions (≥5%):- Nausea (15%)
- Dizziness (12%)
- Headache (11%)
- Insomnia (10%)
- Abnormal dreams (8%)
- Dry mouth (7%)
- Dyspepsia (6%)
- Constipation (6%)
- Anxiety (6%)
- Orthostatic hypotension (5%)
- Falling asleep during activities of daily living
- Orthostatic hypotension
- Hallucinations/psychosis
- Impulse control disorders
- Dyskinesia
- Depression with suicidal ideation
- Withdrawal-emergent hyperpyrexia and confusion
Monitoring Parameters
- Motor function and Parkinson's symptoms assessment (UPDRS)
- Blood pressure (standing and supine)
- Mental status and psychiatric symptoms
- Signs of impulse control disorders
- Dyskinesia monitoring
- Nutritional status (protein intake)
- Dermatologic examinations for melanoma
- Renal and hepatic function (periodically)
- Hemoglobin and hematocrit (periodically)
Patient Education
- Take with food to minimize gastrointestinal upset
- Do not suddenly stop taking medication
- Be aware of potential for drowsiness and avoid driving if affected
- Rise slowly from sitting or lying position to prevent dizziness
- Report any unusual urges or behaviors (gambling, shopping, sexual urges)
- Report hallucinations, confusion, or significant mood changes
- Maintain regular dermatologic examinations
- Be consistent with protein intake timing relative to medication administration
- Do not crush or chew capsules (may open and sprinkle on applesauce if needed)
- Keep medication in original container with desiccant
References
1. FDA Prescribing Information: Rytary (carbidopa and levodopa) extended-release capsules. Revised January 2020. 2. Pahwa R, Lyons KE, Hauser RA, et al. Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson's disease. Parkinsonism Relat Disord. 2014;20(2):142-148. 3. Stocchi F, Hsu A, Khanna S, et al. Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients. Parkinsonism Relat Disord. 2014;20(12):1335-1340. 4. Hauser RA, Hsu A, Kell S, et al. Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol. 2013;12(4):346-356. 5. Olanow CW, Kieburtz K, Odin P, et al. Continuous dopaminergic stimulation (CDS)-based treatment strategies for Parkinson's disease. Parkinsonism Relat Disord. 2014;20 Suppl 1:S85-S88.