carbidopa/levodopa (Sinemet, Sinemet CR, Rytary, Duopa)

Dosing and uses of Sinemet, Rytary, Duopa (carbidopa/levodopa)

• Adult
• Pediatric

 

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