- Parkinsonism
- Restless Leg Syndrome (off-label)
- Dopa Responsive Dystonia (off-label)
- Levodopa is decarboxylated to Dopamine in the Central Nervous System (CNS)
- Dopamine is unable to cross the blood brain barrier
- Levodopa is combined with carbidopa, a peripheral decarboxylase inhibitor
- Carbidopa blocks the peripheral decarboxylation of Levodopa
- Without carbidopa, 99% of Levodopa would undergo peripheral decarboxylation and fail to reach the CNS
- Carbidopa also reduces peripheral Dopamine adverse effects (e.g. Orthostatic Hypotension, Nausea, Vomiting)
- Rapidly absorbed orally
- Half-Life (non-sustained release): 1 to 3 hours
- General pointers
- Levodopa/Carbidopa (Sinemet, regular release) is by far the single most effective agent in Parkinsonism
- This agent should be the first line and main agent used for Parkinsonism
- All other agents are adjuncts only
- Dosing Threshold
- Identify the individual patient's optimal dose and use this dose at each dosing interval
- Using a lower dose below threshold will be inadequate
-
Food Interactions
- Take at least one hour before a meal or 2 hours after a meal
- Levodopa is absorbed in the Small Intestine and impacted by gastric emptying
- However, patients may wish to initially take with food to reduce Nausea, and then space from food intake
- Wearing off of effect
- See frequency of dosing of Sinemet below
- Most common cause of Insomnia
- May cause anxiety, nocturnal cramps
- Duration of activity decreases with longterm use
- First 2 to 5 years of use: Consistent 5-6 hours of effect
- After 5-8 years: Motor fluctuations, Dyskinesia (on-off effect impacting mobility)
- Longterm: Progressive disorders of balance, gait, speech, Swallowing
-
Dyskinesia (e.g. Choreiform movements)
- Dyskinesia is more age related than that of duration of Levodopa use
- Reducing each Levodopa dose decreases this adverse effect
- Amantadine decreases Dyskinesia
- Adverse Effects: Educate patients about serious effects (most are reduced by tapering dose)
- Drowsiness
- Pathologic Gambling, Hypersexuality, Excessive shopping/spending
- Hallucinations or Delusions
- Swelling
- Carbidopa/Levodopa (Sinemet, Immediate Release)
- IR Tablet (Sinemet): 10/100 mg, 25/100 mg, 25/250 mg
- IR ODT Tablet (Parcopa): 10/100 mg, 25/100 mg, 25/250 mg
- Triple Scored IR Tablet (Dhivy)
- One tablet (25/100 mg) may be divided 1/4 (6.25/100), 1/2 (12.5/50) or 3/4 (18.75/75)
- Carbidopa/Levodopa Controlled Release (Sinemet CR)
- ER Tablet: 25/100 mg, 50/200 mg
- Carbidopa/Levodopa fast onset, sustained release (Rytary)
- IR/ER Capsule: 23.75/95 mg, 36.25/145 mg, 48.75/195 mg, 61.25/245 mg
- Capsules may be opened and contents sprinkled on food
- Carbidopa/Levodopa Biphasic Extended Release (Crexont)
- Biphasic ER Capsule: 35/140 mg, 52.5/210 mg, 70/280 mg, 87.5/350 mg
- Do not open biphasic capsule
- Carbidopa/Levodopa/Entacapone (Stalevo)
- Entacapone 200 mg combined with Immediate Release Carbidopa 12.5 to 50 mg, Levodopa 50 to 200 mg
- Carbidopa/Levodopa Enteral Suspension (Duopa)
- Inbrija (inhaled Levodopa)
- Carbidopa/Levodopa (Sinemet, Immediate Release)
- Preferred option over sustained release (first-line agent)
- Lower cost
- Better Pharmacokinetics
- Less Drug Interactions
- Dosing
- Start at 25 mg/100 mg (or 10 mg/100 mg) orally three times daily
- Increase by on half to one tablet every 1-2 days as needed
- Maximum : 3 tablets per dose, three times daily (no benefit to higher doses, but frequency may be increased)
- Frequency of dose
- Initially give dose three times daily
- Long term, dose may wear off early
- Frequency may need to be increased to every 6 hours (at same number of tablets at each dose)
- Emergency Dosing (rescue dose for hypomobility, "off" episode)
- Crushed Carbidopa/Levodopa tablets may be dissolved in carbonated beverage
- Preferred option over sustained release (first-line agent)
- Carbidopa/Levodopa Controlled Release (Sinemet CR)
- Start at 50/200 orally twice daily
- Convert 300-400 mg Levodopa immediate release/day to start CR 200 mg Levodopa twice daily
- Convert 500-600 mg Levodopa immediate release/day to start CR 300 mg Levodopa twice daily
- Convert 700-800 mg Levodopa immediate release/day to start CR 800 mg/day Levodopa divided three times daily
- Convert 900-1000 mg Levodopa immediate release/day to start CR 1000 mg/day Levodopa divided three times daily
- Increase by one tablet every 3 days as needed
- Maximum : 8 tablets daily
- No benefit over immediate release in motor function, and absorption may be sporadic in some patients
- Start at 50/200 orally twice daily
- Carbidopa/Levodopa fast onset, sustained release (Rytary)
- Start with lowest dose 23.75/95 mg orally three times daily
- May increase to 36.25/145 mg orally three times daily after 3 or more days
- Typical Dose: 3-4 caps three times daily
- Maximum: 97.5 mg/390 mg three times daily
- Onset within 1 hour, duration of 6 hours
- Costs 3-4 times more than generic Carbidopa/Levodopa
- May decrease "off time", the wearing off of activity between doses
- Consider in advanced Parkinsonism for "off time" problems despite four time daily dosing
- Requires higher dosing than other preparations due to lower Bioavailability
- (2015) Presc Lett 22(7): 41
- Start with lowest dose 23.75/95 mg orally three times daily
- Carbidopa/Levodopa/Entacapone (Stalevo)
- Start at 12.5/50/200 orally twice daily
- Increase slowly
- Maximum : 8 tablets daily
- Carbidopa/Levodopa Enteral Suspension (Duopa)
- Consider for refractory on-off effects with oral dosing (suspension may have more consistent absorption and sustained effects)
- Convert from immediate release dosing to administer over 16 hours (max daily dose 2000 mg)
- Enteral suspension delivered via GJ-Tube with portable infusion pump over 16 hours
- Consider following infusion with a nighttime oral immediate release dose
- Inbrija (inhaled Levodopa)
- Indicated in off-time motor rigidity or Tremor
- Rapid onset (10 min after inhalation) and duration of 1 hour used for prn "off time" rigidity or Tremor
- Less expensive ($30/dose) than Apokyn ($200/dose), an injectable option for off-time
- Requires dexterity to replace capsule in Inhaler
- Avoid in underlying lung disease (e.g. Asthma, COPD) due to bronchospasm risk
- (2019) Presc Lett 26(5)
- Non-Parkinsonism Indications
-
Restless Leg Syndrome
- Start Carbidopa/Levodopa (Immediate Release) 1/2 of a 25 mg/100 mg orally at bedtime
- Titrate to effect increasing by 1/2 tablet every 3-4 days to a maximum of 2 tablets (50 mg/200 mg) at bedtime
- May use a combination of immediate release and controlled release Carbidopa/Levodopa if symptomatic night awakenings
- Dopa Responsive Dystonia
- Start Carbidopa/Levodopa (Immediate Release) 25 mg/100 mg tablet orally daily
- Titrate to effect (maximum Levodopa 1000 mg/day)
- Nausea
- Somnolence
- Hallucinations
- Dizziness or Orthostasis
- Delusions
- Dyskinesias
- Lower Extremity Edema
- Major Depression and Suicidal Ideation
- Compulsive Gambling (or sexual activity)
-
Pyridoxine
- Stimulates decarboxylation (may prevent Levodopa from reaching CNS)
-
Antipsychotic agents
- Block Dopamine receptors
-
MAO Inhibitors
- MAO Inhibitors increase Sympathomimetic amine accumulation
- Stop non-selective MAO Inhibitors at least 2 weeks prior to Levodopa start
-
Anticholinergic Agents
- Anticholinergic Agents slow gastric emptying, delay absorption, but may increase overall Levodopa levels
- Pregnancy Category C
- Avoid in Lactation
- Carbidopa-Levodopa is the most effective of the Parkinsonism agents for Tremor, rigidity and slow movement
- Levodopa/Carbidopa (Dailymed)
- (2025) Presc Lett 32(1):3-4
- (2021) Med Lett Drugs Ther 63(1618): 25-32
- Ahlskog (2011) Mayo Internal Medicine Review Lecture
- Hamilton (2020) Tarascon Pocket Pharmacopoeia
- Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 46-7
- Schim (2001) CMEA Medicine Lecture, San Diego
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