carbidopa/levodopa (Sinemet, Sinemet CR, Rytary, Duopa)
Classes: Antiparkinson Agents, Dopamine Agonists; Decarboxylase Inhibitors
Dosing and uses of Sinemet, Rytary, Duopa (carbidopa/levodopa)
Adult dosage forms and strengths
carbidopa/levodopa
tablet (Sinemet)
- 10mg/100mg
- 25mg/100mg
- 25mg/250mg
tablet, extended release (Sinemet CR)
- 25mg/100mg
- 50mg/200mg
capsule, extended release (Rytary)
- 23.75mg/95mg
- 36.25mg/145mg
- 48.75mg/195mg
- 61.25mg/245mg
enteral suspension, extended release (Duopa)
- (4.63mg/20mg)/mL in a single-use cassette
- Each cassette contains ~100 mL
Parkinson Disease & Parkinsonlike Disorders
Indicated for Parkinson disease, postencephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication
Maintain patients on the lowest dosage required to achieve symptomatic control and to minimize adverse reactions such as dyskinesia and nausea
Sinemet
- Immediate release: 25 mg/100 mg q8hr or 10 mg/100 mg PO q6-8hr initially; levodopa may be increased by 100 mg/day every 1-2 days
- Carbidopa should be 70-100 mg/day but not to exceed 200 mg/day; levodopa not to exceed 800 mg/day
- Sinemet CR: 50 mg/200 mg PO q12hr initially; may be increased up to 1600 mg/day of levodopa; doses must be given at least 6 hours apart
- Dosing considerations
- Immediate release (IR): When more carbidopa is required, substitute one 25 mg/100 mg tablet for each 10 mg/100 mg tablet; if necessary, dosage of 25 mg/250 mg tablet may be increased by one half or by 1 tablet every 1-2 days to maximum of 8 tablets daily; experience with total daily carbidopa doses higher than 200 mg is limited
- Extended release (ER): Doses and dosing intervals may be increased or decreased according to response; most patients are adequately treated with regimens providing levodopa 400-1600 mg/day divided q4-8hr while awake; higher levodopa dosages (≥2400 mg/day) and shorter intervals (<4 hours) are used but not usually recommended; if interval <4 hours is used or if divided doses are not equal, give smaller doses at end of day; allow at least 3 days between dosage adjustments
Conversion from immediate-release to Sinemet Cr
- 300-400 mg/day IR = 200 mg ER q12hr
- 500-600 mg/day IR = 300 mg ER q12hr or 200 mg ER q8hr
- 700-800 mg/day IR = 800 mg ER divided q8hr
- 900-1000 mg/day IR = 1000 ER divided q8hr
Rytary
- Contains immediate-release and extended-release beads
- Levodopa-naïve: 23.75 mg/95 mg PO TID initially; on treatment day 4, may increase to 36.25 mg/145 mg TID
- Dose may be increased up to a maximum recommended dose of 97.5 mg/390 mg TID
- The dosing frequency may be changed from 3x/day to a maximum of 5x/day if more frequent dosing is needed and if tolerated, up to a maximum recommended daily dose 612.5 mg/2450 mg
Converting from immediate-release (IR) to Rytary
- Doses of other carbidopa/levodopa products are not interchangeable
- For patients currently treated with carbidopa/levodopa plus catechol-O-methyl transferase (COMT) inhibitors (eg, entacapone), the initial total daily dose of levodopa in Rytary may need to be increased
- The dosing frequency may be changed from 3x/day to a maximum of 5x/day if more frequent dosing is needed and if tolerated, up to a maximum recommended daily dose 612.5 mg/2450 mg
- Dose conversion from IR
- 400-549 mg IR: 3 caps 23.75mg/95mg TID
- 550-749 mg IR: 4 caps 23.75mg/95mg TID
- 750-949 mg IR: 3 caps 36.25mg/145mg TID
- 950-1249 mg IR: 3 caps 48.75 mg/195 mg TID
- ≥1250 mg IR: 4 caps 48.75 mg/195 mg TID, OR 3 caps 61.25 mg/245 mg TID
Advanced Parkinson Disease (Duopa)
Duopa: Extended-release enteral solution for indicated for treatment of motor fluctuations in patients with advanced Parkinson disease
Administer enteral suspension by intrajejunal infusion over a 16-hr
Individualize daily dose by taking into consideration the morning dose, continuous dose, and extra doses that a patient is taking
Maximum daily dose 2000 mg of the levodopa component (ie, 1 cassette/day) administered over 16 hr; at the end of the daily 16-hr infusion, patients will disconnect the pump from jejunal tubing and take their night-time dose of oral immediate-release carbidopa-levodopa tablets
Treatment initiated in 3 steps
- Conversion of patients to oral immediate-release carbidopa-levodopa tablets in preparation for Duopa treatment
- Calculation and administration of the Duopa starting dose (ie, morning dose and continuous dose) for Day 1
- Titration of the dose as needed based on individual clinical response and tolerability
Extra doses
- Duopa has an extra dose function that can be used to manage acute “Off” symptoms that are not controlled by the morning dose and the continuous dose administered over 16 hr
- The extra dose function should be set at 1 mL (20 mg of levodopa) when starting Duopa
- If the amount of the extra dose needs to be adjusted, it is typically done in 0.2 mL increments
- The extra dose frequency should be limited to 1 extra dose q2hr
- Administration of frequent extra doses may cause or worsen dyskinesia
- Once no further adjustments are required to the morning dose, continuous dose, or extra dose, this dosing regimen should be administered daily
- Over time, additional changes may be necessary based on the patient’s clinical response and tolerability
Prepare for Duopa treatment
- Prior to initiating, convert patients from all other forms of levodopa to oral immediate-release carbidopa-levodopa tablets (1:4 ratio)
- Patients should remain on a stable dose of their concomitant medications taken for the treatment of Parkinson disease before initiation of Duopa enteral infusion
- Healthcare providers should ensure patients take their oral Parkinson disease medications the morning of the PEG-J procedure
Determine Duopa starting dose for Day 1
- Step 1: Calculate Duopa Morning Dose for Day 1
- a. Determine the total amount of levodopa (mg) in the first dose of PO immediate-release carbidopa-levodopa that was taken by the patient on the previous day
- b. Convert the PO levodopa dose from mg-to-mg by multiplying the PO dose by 0.8 and dividing by 20 mg/mL; this calculation will provide the Morning Dose of Duopa in mL
- c. Add 3 mL to the morning dose to fill (prime) the intestinal tube to obtain the ‘Total Morning Dose’
- d. The total morning dose is usually administered over 10-30 minutes
- e. Program the pump to deliver the total morning dose
- Step 2: Calculate and Administer the Duopa Continuous Dose for Day 1
- a. Determine the amount of PO immediate-release levodopa that the patient received from PO immediate-release carbidopa-levodopa doses throughout the previous day (ie, 16 waking hr), in mg; do not include the doses of PO immediate-release carbidopa-levodopa taken at night when calculating the levodopa amount
- b. Subtract the first PO levodopa dose in mg taken by the patient on the previous day (determined in Step 1a from the total PO levodopa dose in mg taken over 16 waking hr; divide the result by 20 mg/mL; this is the dose of Duopa administered as an enteral Continuous Dose (in mL) over 16 hr
- c. The hourly infusion rate (mL/hr) is obtained by dividing the Continuous Dose by 16 (hr); program this value into the pump as the continuous rate
- d. If persistent or numerous “Off” periods occur during the 16-hr infusion, consider increasing the Continuous Dose or using the Extra Dose function; if dyskinesia or levodopa-related adverse reactions occur, consider decreasing the Continuous Dose or stopping the infusion until the adverse reactions subside
Duopa titration
- In the controlled trial, the average number of titration days required to establish a stable Morning and Continuous Dose was 5 days
- Additional dose adjustments may be necessary over time based on the patient level of activity and disease progression
- Morning dose adjustment
- If the patient experienced dyskinesia or levodopa-related adverse reactions within 1 hr of the Morning Dose on the preceding day, decrease the Morning Dose by 1 mL
- For an inadequate clinical response within 1 hr of the Morning Dose on the preceding day, adjust the Morning Dose (excluding the 3 mL to fill the tube) as follows:
- a. If the Morning Dose on the preceding day was ≤6 mL: Increase the Morning Dose by 1 mL
- b. If the Morning Dose on the preceding day was >6 mL: Increase the Morning Dose by 2 mL
- Continuous dose adjustment
- Consider decreasing the Continuous Dose if the patient experienced troublesome dyskinesia, or other adverse reactions on the preceding day:
- a. Adverse reactions for a period lasting ≥ 1 hr: Decrease the Continuous Dose by 0.3 mL/hr
- b. Adverse reactions lasting for ≥2 periods of ≥1 hr: Decrease the Continuous Dose by 0.6 mL/hr
Dosage modifications
Renal impairment: Safety and efficacy not established; use with caution
Hepatic impairment: Safety and efficacy not established; use with caution
Pediatric dosage forms and strengths
Safety and efficacy not established
Sinemet, Rytary, Duopa (carbidopa/levodopa) adverse (side) effects
Frequency not defined
Edema
Agitation
Anxiety
Ataxia
Bruxism
Confusion
Daytime somnolence
Decreased attention span
Dyskinesia
Dystonia
Euphoria
Insomnia
Fainting
Fatigue
Increased trembling of hands
Insouciance
Malaise
Memory loss
Nightmares
Nervousness
Restlessness
Trismus
Vivid dreams
Alopecia
Hot flashes
Increased or dark perspiration
Skin eruptions
Abdominal pain and discomfort
Burning feeling in tongue
Constipation
Diarrhea
Dysgeusia
Dry mouth
Dysphagia
Hiccups
Meteorism
Sialorrhea
Nausea
Weight loss
Muscular spasms
Muscular cramp
Hematuria
Dark urine
Incontinence
Priapism
Urine retention
Blurred vision
Diplopia or dilated pupiL
Oculogyric problems
Warnings
Contraindications
Hypersensitivity
Narrow-angle glaucoma (tablets)
Concurrent administration of nonselective monoamine oxidase inhibitors (MAOIs) or use within last 14 days
Cautions
Use caution in history of MI with residual atrial, nodal, or ventricular arrhythmias, peptic ulcer, or seizure
Severe cardiovascular, respiratory disease, renal, hepatic, or endocrine disease; monitor disease parameters
Use caution in bronchial asthma patients taking sympathomimetics
Levodopa may cause patients to fall asleep while engaging in activities of daily living; caution regarding use of machinery and driving
Increases risk for hallucinations and psychosis when taking levodopa; other psychiatric symptoms include decreased impulse control and compulsive behaviors, depression, and suicidality
May exacerbate dyskinesia; reduce dose to control symptoms
Peripheral neuropathy reported with use; evaluate patients for history of neuropathyand known risk factors prior to initiating therapy; assess patients for peripheral neuropathy periodically during therapy
Orthostatic hypotension may occur (more common with immediate-release formulation)
Use caution in patients with glaucoma; monitor intraocular pressure carefully; some formulations are conraindicated in patients with narrow-angle glaucoma
Observe patients carefully if discontinued abruptly; risk of syndrome resembling neuroleptic malignant syndrome
Controlled-release formulation is less bioavailable than conventional formulation
Gastrointestinal complications from PEG-J or naso-jejunal tube can occur (eg, bezoar, ileus, implant site erosion/ulcer, intestinal hemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, pancreatitis, peritonitis, pneumoperitoneum, and post-operative wound infection); these complications may result in serious outcomes (eg,need for surgery, death)
Pregnancy and lactation
Pregnancy category: C
Lactation: Drug inhibits lactation; use with caution
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Sinemet, Rytary, Duopa (carbidopa/levodopa)
Mechanism of action
Carbidopa: Inhibits aromatic amino-acid decarboxylase in peripheral tissues; this, in turn, inhibits peripheral breakdown of levodopa, thereby increasing availability of levodopa at blood-brain barrier and allowing a lower levodopa dose
Carbidopa may also reduce nausea and vomiting and permit more rapid titration of levodopa
Levodopa: Metabolic precursor of dopamine, a neurotransmitter depleted in Parkinson disease; crosses blood-brain barrier to be converted by striatal enzymes to dopamine
Absorption
Duration: Short-duration improvement, 5 hr; long-duration response, 3-5 days
Peak plasma time: Immediate release (IR), 0.5 hr; extended release (ER), 2 hr
Peak plasma concentration: ER peak concentration is 35% of IR peak concentration
Distribution
Both drugs widely distributed; carbidopa does not cross blood-brain barrier; <1% of levodopa enters CNs
Protein bound: Carbidopa, 36%; levodopa, 10-30%
Vd: Levodopa, 0.9-1.6 L/kg in presence of carbidopa
Metabolism
Carbidopa not extensively metabolized; levodopa metabolized in small amounts in GI tract and undergoes first-pass hepatic metabolism
Metabolites: Dopamine, homovanillic acid
Elimination
Half-life: IR, 1.5 hr
Excretion: Carbidopa, urine (50%; PO); levodopa, urine (80-85%; increased in presence of carbidopa)
Administration
Extended-release Capsules (Rytary)
Swallow capsule whole with or without food
A high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hr
Do not chew, divide, or crush capsules
Difficulty swallowing: May open capsule and sprinkle entire contents on a small amount of applesauce and consume immediately
Extended-release enteral suspension (Duopa)
Bring to room temperature before administration; take 1 cassette out of the refrigerator and carton 20 minutes prior to use; failure to use the product at room temperature may result in the patient not receiving the right amount of medication (inaccurate infusion rate if too cold)
Administered as a 16-hr intrajejunal infusion via a naso-jejunal tube for short-term administration or through a PEG-J for long-term administration
Cassettes are for single-use only and should not be used for longer than 16 hr, even if some drug product remains; an opened cassette should not be re-used
The PEG-J should be disconnected from the pump at the end of the daily 16-hr administration period and flushed with room temperature potable water with a syringe
Long-term administration requires placement of a PEG-J outer transabdominal tube and inner jejunal tube by percutaneous endoscopic gastrostomy
The cassettes are specifically designed to be connected to the CADD-Legacy 1400 pump See prescribing information for appropriate tubing sets for long-term and short-term administration
Discontinuation
Avoid sudden discontinuation or rapid dose reduction; gradually taper at time of discontinuation
Duopa
- If patients need to discontinue, the dose should be tapered or patients should be switched to oral immediate-release carbidopa-levodopa tablets
- When using a PEG-J tube, discontinue by withdrawing the tube (by a qualified healthcare provider) and letting the stoma healthcare provider