Usage
- Medical Conditions: Carbidopa/levodopa/entacapone is prescribed for the treatment of Parkinson’s disease in patients experiencing motor fluctuations (“wearing-off” phenomenon) while taking carbidopa/levodopa. It’s specifically indicated when these patients are experiencing “off” episodes and aren’t responding well to carbidopa/levodopa alone.
- Pharmacological Classification: Antiparkinsonian agent, Dopamine precursor, Catechol-O-methyltransferase (COMT) inhibitor, Decarboxylase inhibitor.
- Mechanism of Action: This combination therapy addresses Parkinson’s disease by increasing dopamine levels in the brain. Levodopa is a precursor to dopamine, converting into dopamine in the brain. Carbidopa prevents levodopa’s peripheral conversion to dopamine, allowing more levodopa to reach the brain. Entacapone, a COMT inhibitor, further enhances levodopa’s availability by blocking an enzyme that breaks it down. This results in more stable and sustained dopamine levels in the brain, mitigating motor fluctuations.
Alternate Names
- International/Regional Variations: The combination itself doesn’t have alternate names, but individual components do. Levodopa is sometimes called L-DOPA.
- Brand Names: Stalevo is the most common brand name.
How It Works
- Pharmacodynamics: Levodopa improves Parkinsonian symptoms by replenishing depleted dopamine in the brain. Carbidopa enhances levodopa’s central nervous system penetration by inhibiting peripheral decarboxylation. Entacapone, a COMT inhibitor, increases levodopa’s half-life and bioavailability by reducing its metabolism, further improving its efficacy.
- Pharmacokinetics:
- Absorption: Levodopa is rapidly absorbed from the small intestine. Carbidopa and entacapone have good oral bioavailability. Food, particularly high-protein meals, can affect levodopa absorption and delay the onset of action. High-fat meals may also delay the medicine’s effect.
- Metabolism: Levodopa is metabolized peripherally to dopamine by dopa decarboxylase (which carbidopa inhibits) and to 3-O-methyldopa by COMT (which entacapone inhibits). Entacapone is extensively metabolized, primarily by glucuronidation. Carbidopa undergoes minimal metabolism.
- Elimination: Levodopa and its metabolites are primarily excreted renally. Entacapone and its metabolites are eliminated in both urine and feces. Carbidopa is primarily excreted in the urine.
- Mode of Action: Levodopa crosses the blood-brain barrier and converts to dopamine, stimulating dopamine receptors. Carbidopa does not cross the blood-brain barrier, confining its action to the periphery. Entacapone reversibly inhibits COMT, primarily in the periphery.
- Receptor Binding/Enzyme Inhibition: Levodopa activates dopamine receptors in the brain. Carbidopa inhibits dopa decarboxylase. Entacapone inhibits COMT.
- Elimination Pathways: Primarily renal excretion for levodopa and carbidopa, both renal and hepatic (via glucuronidation) for entacapone.
Dosage
Standard Dosage
Adults:
- Starting dose is individualized based on patient’s current carbidopa/levodopa regimen and symptoms.
- If switching from carbidopa/levodopa and entacapone taken separately, the starting dose is typically the same as the previous levodopa dose.
- If switching from carbidopa/levodopa without entacapone, adjustments may be needed (either reducing or slightly increasing levodopa depending on presence of dyskinesias).
- Dosage adjustments are made by changing tablet strength or dosing interval. Administer one tablet per dose, up to a maximum of 8 times daily for strengths containing 50mg to 150mg of levodopa, and up to 6 times daily for the 200mg levodopa strength.
- Patients receiving less than 70-100 mg of carbidopa daily are more prone to nausea and vomiting.
Children:
- Use and dose must be determined by a doctor. Safety and efficacy have not been established in pediatric patients.
Special Cases:
- Elderly Patients: No specific dose adjustment is recommended based on age alone.
- Patients with Renal Impairment: No dose adjustment is generally required.
- Patients with Hepatic Dysfunction: Dose reduction may be necessary in patients with mild to moderate hepatic impairment. The drug is contraindicated in severe hepatic impairment.
- Patients with Comorbid Conditions: Caution is advised in patients with cardiovascular disease, asthma, peptic ulcer disease, glaucoma, and psychoses. Dosage adjustments may be necessary.
Clinical Use Cases
Carbidopa/levodopa/entacapone is not indicated for:
- Intubation
- Surgical Procedures
- Mechanical Ventilation
- Intensive Care Unit (ICU) Use
- Emergency Situations (e.g., status epilepticus, cardiac arrest)
Dosage Adjustments
Dose modifications may be required based on individual patient factors, including renal/hepatic function, comorbid conditions, and the presence of adverse effects.
Side Effects
Common Side Effects
- Dyskinesia (involuntary movements)
- Nausea
- Diarrhea
- Dizziness
- Hallucinations
- Sleepiness (somnolence)
- Urine discoloration (harmless)
Rare but Serious Side Effects
- Neuroleptic Malignant Syndrome (NMS)
- Rhabdomyolysis
- Severe hypotension
- Syncope
- Impulse control disorders (e.g., gambling, compulsive shopping)
Long-Term Effects
- Dyskinesias can worsen with long-term treatment.
- Impulse control disorders may persist.
Adverse Drug Reactions (ADR)
- Angioedema
- Depression with suicidal ideation
- Severe dyskinesias
Contraindications
- Hypersensitivity to carbidopa, levodopa, or entacapone.
- Narrow-angle glaucoma.
- Pheochromocytoma.
- Concurrent use of nonselective MAO inhibitors or within 14 days of discontinuing them.
- History of NMS and/or non-traumatic rhabdomyolysis.
- Severe hepatic impairment.
Drug Interactions
- MAO Inhibitors: Concomitant use with nonselective MAOIs is contraindicated. Use with selective MAO-B inhibitors requires careful monitoring.
- Antihypertensives: May enhance hypotensive effects.
- Iron Salts: Reduce levodopa absorption.
- Dopamine D2 receptor antagonists (antipsychotics): May diminish levodopa efficacy.
- Other drugs metabolized by COMT: May require dosage adjustments.
- High-protein meals: May decrease levodopa absorption.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C (FDA classification) - use only if benefit outweighs risk. Animal studies have shown adverse effects.
- Fetal Risks: Potential for fetal malformations based on animal studies.
- Breastfeeding: Levodopa is excreted in breast milk. Breastfeeding is not recommended during treatment.
Drug Profile Summary
- Mechanism of Action: Replenishes dopamine in the brain; carbidopa prevents peripheral levodopa breakdown; entacapone inhibits COMT, prolonging levodopa’s action.
- Side Effects: Dyskinesia, nausea, diarrhea, dizziness, hallucinations, somnolence, urine discoloration. Rarely: NMS, rhabdomyolysis.
- Contraindications: Hypersensitivity, narrow-angle glaucoma, pheochromocytoma, concurrent use of nonselective MAOIs, history of NMS/rhabdomyolysis, severe hepatic impairment.
- Drug Interactions: MAOIs, antihypertensives, iron salts, antipsychotics, drugs metabolized by COMT, high-protein foods.
- Pregnancy & Breastfeeding: Use cautiously in pregnancy only if the potential benefit justifies the risk to the fetus. Not recommended while breastfeeding.
- Dosage: Individualized based on the patient’s condition and response; up to 8 tablets/day for certain strengths, 6 tablets/day for others.
- Monitoring Parameters: Blood pressure, motor symptoms, signs of dyskinesia, psychiatric status, liver function.
Popular Combinations
This medication is itself a combination of three active ingredients.
Precautions
- General Precautions: Monitor for hypotension, dyskinesia, psychiatric adverse events, and hepatic dysfunction. Evaluate for pre-existing conditions such as cardiac disease, asthma, and glaucoma.
- Specific Populations: Caution in pregnant women and breastfeeding mothers. Monitor elderly patients for side effects.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Carbidopa + Entacapone + Levodopa?
A: The dosage is individualized and depends on the patient’s current levodopa/carbidopa regimen and tolerability. The starting dose is usually equivalent to the patient’s prior levodopa dose. The maximum daily dose can vary based on the tablet strength (up to 8 tablets/day for some strengths, 6 tablets/day for others).
Q2: What are the common side effects?
A: Common side effects include dyskinesia, nausea, diarrhea, dizziness, hallucinations, daytime sleepiness, and discoloration of urine.
Q3: What are the serious side effects to watch out for?
A: Rare but serious side effects include neuroleptic malignant syndrome (NMS), rhabdomyolysis, severe hypotension and syncope, and impulse control disorders (compulsive gambling, shopping, etc.).
Q4: Can this medication be used in patients with hepatic or renal impairment?
A: It’s contraindicated in patients with severe hepatic impairment. Caution is advised in mild to moderate hepatic impairment and severe renal impairment.
Q5: What are the contraindications to using this medication?
A: Contraindications include hypersensitivity, narrow-angle glaucoma, pheochromocytoma, concurrent use of non-selective MAO inhibitors, a history of NMS or rhabdomyolysis.
Q6: How should patients transition to carbidopa/levodopa/entacapone from carbidopa/levodopa?
A: It depends on their current therapy. If already taking entacapone separately, patients can usually switch to the combined tablet of equivalent levodopa strength. If not previously on entacapone, the levodopa dose may need to be adjusted, particularly if they have dyskinesias.
Q7: Are there any dietary restrictions when taking carbidopa/levodopa/entacapone?
A: High-protein meals should be avoided as they interfere with levodopa absorption. High-fat meals can delay the onset of action.
Q8: Can Carbidopa/levodopa/entacapone be crushed or chewed?
A: No. Swallow the tablet whole. Crushing or chewing can affect drug absorption and may cause staining of the mouth and teeth.
Q9: Can Carbidopa/levodopa/entacapone be used during pregnancy or breastfeeding?
A: Its use during pregnancy should be carefully weighed against the potential risks to the fetus. It is generally not recommended during breastfeeding.
