Levodopa + Carbidopa + Entacapone

Approved Indications:

• Parkinson’s Disease (Idiopathic):
  Indicated for the treatment of adult patients with Parkinson’s disease experiencing end-of-dose motor fluctuations ("wearing-off") who are not stabilized on Levodopa and a DOPA decarboxylase inhibitor (Carbidopa).
• Advanced Parkinson’s Disease with Motor Fluctuations:
  Used to reduce "on-off" symptoms in patients already receiving a stable dose of Levodopa + Carbidopa.

Clinically Accepted Off-Label Uses:
Currently, there are no widely accepted off-label uses for this combination.

Route of Administration: Oral (tablet)

Adult Dosage:

• Each tablet contains:
• Levodopa: 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, or 200 mg
• Carbidopa: 12.5 mg or 25 mg
• Entacapone: 200 mg (fixed in all strengths)
• Initial Dose:
  Replace one dose of Levodopa + Carbidopa (with or without separate Entacapone) with a corresponding strength of the fixed combination. Administer as needed to match the patient’s current Levodopa regimen.
• Usual Frequency:
  Taken with each Levodopa dose, typically 3–10 times daily, depending on the previous Levodopa dosage.
• Maximum Dose:
  Do not exceed 8 tablets per day. Maximum Entacapone dose is 1600 mg/day.

Special Populations:

• Elderly:
  Initiate with lower strengths and titrate slowly. Monitor closely for hypotension, confusion, and hallucinations.
• Renal Impairment:
  No dose adjustment required for mild to moderate impairment. Use with caution in severe cases.
• Hepatic Impairment:
  Use is not recommended in patients with moderate to severe liver dysfunction due to Entacapone metabolism in the liver.
• Pediatrics:
  Not indicated for use in children or adolescents under 18 years of age.

Administration Notes:

• Tablets should be swallowed whole. Do not chew, divide, or crush.
• May be taken with or without food. Avoid high-protein meals close to dosing times to enhance Levodopa absorption.

This combination provides triple modulation of the dopaminergic pathway. Levodopa is a dopamine precursor that crosses the blood–brain barrier and is converted into dopamine, replenishing deficient levels in the striatum. Carbidopa inhibits the enzyme aromatic L-amino acid decarboxylase in peripheral tissues, reducing Levodopa metabolism before it reaches the brain and minimizing peripheral side effects. Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), another enzyme that breaks down Levodopa peripherally. By inhibiting COMT, Entacapone increases the bioavailability and plasma half-life of Levodopa, providing more sustained dopaminergic stimulation and reducing motor fluctuations.

• Absorption:
  Rapidly absorbed after oral administration. Food may delay Levodopa absorption but does not reduce bioavailability.
• Bioavailability:
• Levodopa: ~30%
• Carbidopa: ~40–70%
• Entacapone: ~35% (highly protein bound)
• Peak Plasma Concentration:
• Levodopa: 1–2 hours
• Entacapone: ~1 hour
• Distribution:
• Levodopa: Low protein binding
• Entacapone: >98% protein bound
• Metabolism:
• Levodopa: Decarboxylation (AADC) and COMT
• Carbidopa: Minimal hepatic metabolism
• Entacapone: Primarily by hepatic glucuronidation
• Half-life:
• Levodopa: 1.5 hours (extended to 2–3 hours with Entacapone)
• Carbidopa: ~2 hours
• Entacapone: 0.4–0.7 hours
• Elimination:
• Levodopa and Carbidopa: Mainly renal
• Entacapone: Fecal and renal

• Pregnancy:
  FDA Pregnancy Category C
  Animal studies have shown adverse fetal effects. No adequate human data. Use only if the potential benefit justifies the risk.
• Lactation:
  Levodopa is excreted into breast milk. Carbidopa and Entacapone excretion is unknown. The combination may suppress lactation and affect the infant’s dopaminergic system. Use with caution during breastfeeding.

• Primary Class: Anti-Parkinsonian Agent
• Subclass:
• Levodopa: Dopamine Precursor
• Carbidopa: Peripheral Decarboxylase Inhibitor
• Entacapone: COMT Inhibitor

• Known hypersensitivity to Levodopa, Carbidopa, Entacapone, or any excipients
• Narrow-angle glaucoma
• Severe hepatic impairment
• History of neuroleptic malignant syndrome or rhabdomyolysis
• Use with non-selective MAO inhibitors or within 14 days of discontinuation
• History of malignant melanoma or undiagnosed skin lesions

• Neuropsychiatric Risks: Confusion, hallucinations, delusions—especially in the elderly
• Impulse Control Disorders: Gambling, hypersexuality, compulsive eating or shopping
• Dyskinesia: May worsen or newly appear due to enhanced dopaminergic activity
• Orthostatic Hypotension: Especially during dose titration
• Diarrhea: Common with Entacapone; persistent diarrhea may indicate colitis
• Liver Toxicity: Avoid in moderate to severe hepatic impairment
• Melanoma Risk: Regular skin monitoring advised
• Withdrawal: Avoid abrupt discontinuation to prevent neuroleptic malignant syndrome

Common Adverse Effects:

• Neurologic: Dyskinesia, dizziness, headache, somnolence, hallucinations
• Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain
• Cardiovascular: Orthostatic hypotension
• Other: Discolored urine (reddish-brown)

Serious Adverse Effects:

• Neuroleptic malignant syndrome (with abrupt withdrawal)
• Rhabdomyolysis
• Severe or persistent diarrhea (may indicate colitis)
• Psychosis or severe behavioral changes
• Severe hepatic impairment (Entacapone-related)

• Non-selective MAO inhibitors: Contraindicated due to hypertensive crisis risk
• Dopamine antagonists (e.g., antipsychotics): May reduce therapeutic efficacy
• Iron supplements: Decrease Levodopa absorption; separate doses
• High-protein foods: Interfere with Levodopa transport in the gut
• Alcohol: May increase sedation and hypotension
• Warfarin: Entacapone may elevate INR; monitor closely
• CYP450: Entacapone does not significantly inhibit or induce CYP enzymes

• Guideline Endorsements (AAN, NICE):
  Recommended for patients with advanced Parkinson’s disease and end-of-dose wearing-off who require adjunct therapy beyond Levodopa/Carbidopa alone.
• Formulation Updates:
  Expanded availability of multiple fixed-dose strengths allows for individualized titration.
• Regulatory Warnings:
  Reinforced monitoring for impulse control disorders, severe diarrhea, and hepatotoxicity.

• Storage Temperature:
  Store at 20°C to 25°C (68°F to 77°F). Allowable excursions: 15°C to 30°C.
• Light and Moisture:
  Store in a tightly sealed container. Protect from moisture and light.
• Handling:
  Do not break, crush, or chew tablets.
• Refrigeration:
  Not required. No reconstitution necessary.