Brand name: Lodosyn
Drug class: Dopamine Precursors
- Antiparkinsonian Agents
VA class: CN500
CAS number: 59-92-7

Levodopa/Carbidopa is also contained as an ingredient in the following combinations:
Carbidopa and Levodopa

Medically reviewed by Drugs.com on Oct 23, 2023. Written by ASHP.

Introduction

Antiparkinsonian agent; levodopa is the levorotatory isomer of dihydroxyphenylalanine and the metabolic precursor of dopamine, and carbidopa is a decarboxylase inhibitor that inhibits the peripheral decarboxylation of levodopa to dopamine.^{104 105 106 107 108 d}

Uses for Levodopa/Carbidopa

Parkinsonian Syndrome

Levodopa is used for symptomatic treatment of parkinsonian syndrome, including parkinson disease, postencephalitic parkinsonism, and symptomatic parkinsonian syndrome resulting from carbon monoxide intoxication or manganese intoxication.^{104 105 106 107 108 117 d} Available in various fixed-combination preparations with carbidopa for this use.^{104 105 107 117}

Carbidopa is used to inhibit decarboxylation of peripheral levodopa and increase the amount of levodopa available for transport to the brain.^{107 108} Available in fixed combination with levodopa and also as a single-entity preparation for use in patients receiving levodopa-carbidopa who require additional carbidopa to reduce nausea and vomiting and/or facilitate more rapid dosage titration.¹⁰⁸

Levodopa (in combination with carbidopa) is currently the most effective drug for relieving motor symptoms of parkinson disease.^{115 123 157 d} However, effectiveness decreases over time and most patients develop motor fluctuations and dyskinesias (drug-induced involuntary movements) with long-term use.^{101 105 115 157}

Strategies to reduce risk of motor complications include adjusting dosage of levodopa, adding other antiparkinsonian agents (e.g., dopamine receptor agonist [e.g., pramipexole, ropinirole, rotigotine], selective monoamine oxidase [MAO]-B inhibitor [e.g., rasagiline, safinamide, selegiline], catechol-O-methyltransferase [COMT] inhibitor [e.g., entacapone, tolcapone], amantadine), or initiating other agents first to delay use of levodopa.^{101 115 116 123 157}

Motor complications associated with long-term use of standard oral levodopa formulations are thought to result from fluctuating plasma concentrations due to short half-life, delayed gastric emptying, and erratic absorption.^{128 129 132 133} Several non-oral preparations of levodopa and carbidopa (e.g., levodopa oral inhalation powder, carbidopa-levodopa enteral suspension) are available for use in patients with advanced parkinson disease whose motor symptoms are not effectively controlled with oral therapies.^{118 126 129 130 133}

Levodopa oral inhalation powder is used for intermittent treatment of “off” episodes in patients receiving levodopa-carbidopa.^{126 128 129} Intended for use on an intermittent basis only in patients who are already receiving carbidopa-levodopa therapy.^{126 128} May be particularly useful in patients with severely delayed gastric emptying.¹²⁹

Carbidopa-levodopa enteral suspension is used for treatment of motor fluctuations in patients with advanced parkinson disease.^{118 130 131 132 133 134 135} Administered by continuous enteral infusion through a percutaneous endoscopic gastrojejunostomy (PEG-J) tube.^{118 130}

Levodopa/Carbidopa Dosage and Administration

Administration

Levodopa and carbidopa are administered orally as fixed-combination or single-entity (carbidopa only) conventional tablets, orally disintegrating tablets, extended-release tablets, or extended-release capsules.^{104 105 107 108 117} Levodopa also is available as a powder for oral inhalation.¹²⁶ Carbidopa-levodopa enteral suspension is administered through a nasojejunal (NJ) tube or a PEG-J tube.¹¹⁸

May continue therapy with other antiparkinsonian agents while carbidopa-levodopa is administered; however, dosage adjustments may be necessary.¹⁰⁸

If general anesthesia required, continue therapy as long as patient permitted to take oral medications.^{104 105 106 107} If therapy interrupted, observe patient for symptoms of neuroleptic malignant syndrome (NMS); resume as soon as patient is able to take oral medications.^{104 105 107} (See Hyperpyrexia and Confusion under Cautions.)

Oral Administration

Administer orally as fixed-combination or single-entity (carbidopa only) conventional (immediate-release) tablets, extended-release tablets, orally disintegrating tablets, or extended-release capsules.^{104 105 107 117}

Carbidopa-levodopa conventional tablets and orally disintegrating tablets contain a 1:4 or 1:10 ratio of carbidopa to levodopa.^{104 107} Carbidopa-levodopa extended-release tablets and capsules contain a 1:4 ratio of carbidopa to levodopa.^{105 117} Carbidopa and levodopa also are commercially available as fixed-combination tablets with entacapone (Stalevo) containing a 1:4 ratio of carbidopa to levodopa combined with 200 mg of entacapone.¹⁰⁶

Extended-release carbidopa-levodopa tablets: Administer as whole or half tablets; do not chew or crush.¹⁰⁵

Extended-release carbidopa-levodopa capsules: Swallow whole without regard to food; do not chew, divide, or crush.¹¹⁷ In patients with difficulty swallowing, may open capsules and sprinkle entire contents on a small amount (e.g., 1–2 tablespoons) of applesauce; administer mixture immediately and do not store for later use.¹¹⁷

Orally disintegrating carbidopa-levodopa tablets: Just prior to administration, gently remove tablet from the bottle with dry hands.¹⁰⁴ Place tablet on tongue to dissolve (usually within seconds) and swallow with saliva.¹⁰⁴ Administration with water is not necessary.¹⁰⁴

Fixed-combination carbidopa, levodopa, and entacapone tablets (Stalevo): Do not divide tablets; administer only one tablet per dosing interval.¹⁰⁶

Oral Inhalation

Administer levodopa powder with a special oral inhalation device (Inbrija inhaler) that delivers powdered drug from capsules.¹²⁶ A total of 2 capsules (each containing 42 mg of levodopa) is required for the recommended dose.¹²⁶ Do not swallow capsules as the intended effect will not be obtained.¹²⁶

To administer a dose, load first capsule into inhaler.¹²⁶ Before inhaling the dose, exhale completely as possible.¹²⁶ While keeping inhaler level, place mouthpiece of inhaler between the lips and inhale deeply and slowly through the inhaler; the patient should feel or hear a whirling sound, which is an indication that the inhaler is working.^{126 129} After inhaling contents of capsule, hold breath for 5 seconds before exhaling.^{126 129} Repeat these steps with the second capsule to complete full dose.¹²⁶

Use a new inhaler with each new carton of drug.^{126 129}

Consult manufacturer's prescribing information for additional details.¹²⁶

Enteral Administration

Administer carbidopa-levodopa enteral suspension (Duopa) as a 16-hour continuous infusion through a PEG-J tube using a portable infusion device (i.e., CADD Legacy 1400 pump).¹¹⁸ PEG-J tube placement and removal should be performed by a gastroenterologist or other experienced healthcare provider.¹¹⁸ May temporarily administer through an NJ tube (e.g., as a trial to determine whether patient responds to therapy and can manage device) until a permanent PEG-J tube can be established.^{118 133}

Enteral suspension is commercially available in single-use cassettes containing 4.63 mg of carbidopa and 20 mg of levodopa per mL.¹¹⁸

Store cassettes in freezer prior to use.¹¹⁸ (See Storage under Stability.) Prior to administration, remove cassette from refrigerator and allow to reach room temperature for 20 minutes.¹¹⁸ Failure to administer drug at room temperature may result in a subtherapeutic response.¹¹⁸ Cassettes are for single-use only; do not use for longer than 16 hours and discard cassette after this time period even if some drug remains.¹¹⁸

At end of the daily 16-hour administration period, disconnect PEG-J tube from the pump and flush with room temperature potable water.¹¹⁸

Consult manufacturer's prescribing information for additional details.¹¹⁸

Dosage

Dosage expressed in terms of levodopa and carbidopa.^{104 105 106 107 108 117 118 126}

Adjust dosage carefully according to individual requirements, response, and tolerance.^{104 105 106 107 108}

Daily dosage of carbidopa should be at least 70–100 mg daily; patients receiving <70–100 mg daily are likely to experience nausea and vomiting.^{104 105 107 108}

Observe patient closely if dosage is reduced abruptly or drug is discontinued; risk of precipitating a symptom complex resembling neuroleptic malignant syndrome (NMS).^{104 105 106 107} Gradually reduce dosage when treatment is discontinued.^{105 107 117} (See Hyperpyrexia and Confusion under Cautions.)

Adults

Parkinsonian Syndrome

Carbidopa-Levodopa Conventional Tablets or Orally Disintegrating Tablets

Oral

Initially, carbidopa 25 mg/levodopa 100 mg (as 1 tablet) 3 times daily.^{104 107} May increase dosage by 1 tablet (carbidopa 25 mg/levodopa 100 mg) daily or every other day until a daily dosage of carbidopa 200 mg/levodopa 800 mg is reached.^{104 107}

Alternatively, initiate with carbidopa 10 mg/levodopa 100 mg (as 1 tablet) 3 or 4 times daily; however, this dosage will not provide an adequate dose of carbidopa for most patients.^{104 107} May increase dosage by 1 tablet (carbidopa 10 mg/levodopa 100 mg) daily or every other day until a daily dosage of carbidopa 80 mg/levodopa 800 mg is reached.^{104 107}

Individualize maintenance dosage according to desired therapeutic response.^{104 107} Patients should receive at least 70–100 mg of carbidopa daily during maintenance therapy.^{104 107}

Use of combination preparations containing a 1:10 ratio of carbidopa to levodopa may not provide an adequate amount of carbidopa.^{104 107} If a greater proportion of carbidopa is required, may substitute 1 tablet of carbidopa 25 mg/levodopa 100 mg for 1 tablet of carbidopa 10 mg/levodopa 100 mg.^{104 107} If additional carbidopa is still required, may administer a 25-mg dose of carbidopa (as the single-entity tablet preparation) with each first daily dose of carbidopa-levodopa; may give additional 12.5-mg or 25-mg doses of carbidopa with each subsequent dose of carbidopa-levodopa as needed.¹⁰⁸

If patients require higher dosages of levodopa while receiving a combination preparation containing 100 mg of levodopa, switch patients to a preparation containing 250 mg of levodopa.^{104 107}

Carbidopa-Levodopa Extended-release Tablets

Oral

Extended-release tablets are not bioequivalent to immediate-release tablets; adjust dosage appropriately when converting patients between the formulations.¹⁰⁵ (See Bioavailability under Pharmacokinetics.)

Patients currently receiving immediate-release levodopa preparations: Convert to an appropriate dosage of the extended-release tablets that provides approximately 10% more levodopa daily than dosage previously received as the immediate-release preparation; levodopa dosage may need to be increased up to 30% more daily, depending on response.¹⁰⁵

Levodopa-naive patients: Initially, carbidopa 50 mg/levodopa 200 mg (as 1 extended-release tablet) twice daily; initial dosage should not be given at intervals <6 hours.¹⁰⁵ Adjust dose or dosing frequency based on response and tolerance at intervals ≥3 days.¹⁰⁵ Most patients are treated adequately with dosages that provide 400–1600 mg of levodopa, administered in divided doses at intervals ranging from 4–8 hours while awake.¹⁰⁵ Higher dosages (≥2400 mg of levodopa per day) and shorter intervals (<4 hours) have been used but usually are not recommended.¹⁰⁵ If the dosing interval is <4 hours and/or the divided doses are not equal, it is recommended that the smaller doses be given at the end of the day.¹⁰⁵

When additional levodopa is needed for symptomatic control, may consider adding doses of a conventional preparation of carbidopa-levodopa during brief periods of the day.¹⁰⁵

Carbidopa-Levodopa Extended-release Capsules

Oral

Extended-release capsules are not bioequivalent to immediate-release preparations; adjust dosage appropriately when converting patients between the formulations.¹¹⁷ (See Bioavailability under Pharmacokinetics.)

Patients currently receiving immediate-release levodopa preparations: Calculate patient's current total daily dosage of levodopa and convert to an appropriate starting dosage of the extended-release capsules (see Table 1).¹¹⁷ Following conversion, adjust dose and/or dosing interval as necessary based on patient tolerance and clinical response.¹¹⁷ In patients currently receiving carbidopa-levodopa in combination with a COMT inhibitor (e.g., entacapone), may need to increase total initial daily dose of levodopa in the extended-release capsule.¹¹⁷

Levodopa-naive patients: Initially, carbidopa 23.75 mg/levodopa 95 mg (as extended-release capsules) 3 times daily for the first 3 days.¹¹⁷ May increase to carbidopa 36.25 mg/levodopa 145 mg 3 times daily on the fourth day of treatment.¹¹⁷ Thereafter, may increase dosage based on patient tolerance and clinical response up to a maximum of carbidopa 97.5 mg/levodopa 390 mg 3 times daily; if needed, dosing frequency may be increased to a maximum of 5 times daily.¹¹⁷ Maintain patients on the lowest possible dosage necessary to achieve adequate symptom control while minimizing adverse effects.¹¹⁷

Carbidopa, Levodopa, and Entacapone Fixed-combination Tablets

Oral

Patients currently receiving carbidopa-levodopa conventional tablets with entacapone: May substitute with corresponding strength of the combination tablet containing same amounts of carbidopa and levodopa.¹⁰⁶ No experience transitioning patients receiving carbidopa-levodopa extended-release tablets or carbidopa-levodopa preparations not containing a 1:4 ratio.¹⁰⁶

Patients not currently receiving entacapone: Initially titrate to a tolerable and effective dose using separate carbidopa-levodopa and entacapone tablets.¹⁰⁶ Once optimum dosage established, may convert patients to a corresponding dosage of the carbidopa-levodopa-entacapone combination tablet.¹⁰⁶

Carbidopa Tablets

Oral

Carbidopa: 25 mg with first dose of carbidopa/levodopa each day for patients who need additional carbidopa; additional 12.5- or 25-mg doses may be given during the day with each dose of carbidopa/levodopa.¹⁰⁸

Levodopa Oral Inhalation Powder (Inbrija)

Oral Inhalation

Inhale contents of 2 capsules (total of 84 mg) as needed for “off” symptoms, up to 5 times daily.¹²⁶

Maximum recommended dose per “off” period is 84 mg and maximum daily dosage is 420 mg.¹²⁶

Carbidopa-Levodopa Enteral Suspension (Duopa)

Enteral

Dosage of carbidopa-levodopa enteral suspension consists of 3 components: a morning dose (administered usually over 10–30 minutes), a continuous infusion (administered over 16 hours), and additional doses (i.e., extra doses) as needed for breakthrough symptoms.^{118 133}

Prior to initiating treatment, convert patient from all forms of levodopa to oral immediate-release carbidopa-levodopa tablets (1:4 ratio).¹¹⁸ Dosage of enteral suspension is based on amount of oral levodopa taken the previous day.¹¹⁸

Determine initial morning dose of enteral suspension (in mL) as follows: calculate the total amount of levodopa (in mg) in the first dose of immediate-release carbidopa-levodopa taken the previous day.¹¹⁸ Convert this dose (in mg) to mL by multiplying by 0.8 and dividing by 20 mg/mL; add an additional 3 mL to account for priming volume.¹¹⁸

Determine initial continuous dose of enteral suspension (in mL) as follows: calculate the total amount of levodopa from oral immediate-release carbidopa-levodopa doses taken throughout the previous day (over 16 waking hours); do not use doses taken at night in the calculation.¹¹⁸ Subtract the first oral levodopa dose taken the previous day (determined in morning dose calculation) from the total oral levodopa dose taken over 16 hours; divide this value by 20 mg/mL to obtain the continuous dose that should be administered over 16 hours.¹¹⁸ Calculate hourly infusion rate (in mL/hour) by dividing continuous dose by 16 hours.¹¹⁸

After the first day of treatment, titrate daily morning dose and continuous dose based on individual response and tolerability until a stable dosage is obtained.¹¹⁸ (See Prescribing Limits.) If patient experiences persistent or numerous “off” periods during the 16-hour infusion period, may increase continuous dose or administer extra doses.¹¹⁸ In patients who require overnight treatment, an extended-release formulation of oral levodopa-carbidopa may be taken at bedtime after stopping the enteral infusion.¹³³ If dyskinesias or other adverse effects occur, may decrease continuous dose or temporarily interrupt therapy until adverse effects subside.¹¹⁸ Consult manufacturer's prescribing information for recommendations on dosage adjustments.¹¹⁸

Avoid sudden discontinuance of therapy or rapid dose reduction; when discontinuing therapy, taper dosage or switch patients to oral immediate-release carbidopa-levodopa therapy.¹¹⁸

Prescribing Limits

Adults

Parkinsonian Syndrome

Oral

Carbidopa: Experience with dosages >200 mg daily limited.^{104 105 107 108}

Carbidopa-levodopa extended-release capsules: Manufacturer recommends a maximum daily dose of carbidopa 612.5 mg and levodopa 2450 mg.¹¹⁷

Carbidopa-levodopa-entacapone fixed-combination tablets: If preparations containing carbidopa 12.5–37.5 mg, levodopa 50–150 mg, and entacapone 200 mg (Stalevo 50, 75, 100, 125, and 150) are used, maximum of 8 tablets daily.¹⁰⁶ If preparation containing carbidopa 50 mg, levodopa 200 mg, and entacapone 200 mg (Stalevo 200) is used, maximum of 6 tablets daily.¹⁰⁶

Levodopa oral inhalation: Maximum recommended dose per “off” period is 84 mg and maximum daily dosage is 420 mg.¹²⁶

Carbidopa-levodopa enteral suspension: Maximum recommended daily dose is 2000 mg of the levodopa component (i.e., one cassette per day).¹¹⁸

Cautions for Levodopa/Carbidopa

Contraindications

• Concomitant use with a nonselective MAO inhibitor.^{104 105 106 107 118 126} (See Specific Drugs and Foods under Interactions.)

• Angle-closure glaucoma.^{104 105 106 107}

• Known hypersensitivity to levodopa, carbidopa, or any ingredient in the formulation.^{104 105 106 107}

Warnings/Precautions

Warnings

Motor Complications

Therapy associated with dyskinesias; dosage reduction of levodopa-carbidopa or other antiparkinsonian agents may be needed.^{104 105 106 107 d}

Motor fluctuations also may occur with long-term use.^d May manifest as “end-of-dose” effect, sudden loss of effectiveness with abrupt onset of akinesia followed by sudden return of effectiveness (“on-off” phenomenon), or sudden hypotonic freezing (patient falls frequently while attempting to walk).^d

Neuropsychiatric Effects

Psychiatric disturbances reported.^{104 105 106 107 118 d} Observe patients carefully for depression with concomitant suicidal tendencies.^{104 105 106 107 118 d} Depression reported with increased frequency in patients receiving enteral carbidopa-levodopa suspension compared with oral immediate-release preparation.¹¹⁸

Hallucinations and abnormal thoughts or behavior (e.g., paranoia, confusion, psychotic disorder, agitation, delusions, delirium, psychotic-like behavior, disorientation, aggressive behavior) reported with dopaminergic drugs.¹⁰⁷ Hallucinations generally occur soon after initiation of levodopa therapy and may be alleviated by reducing dosage.¹⁰⁷

Generally avoid use in patients with major psychotic disorders.^{107 108}

Generalized neuropathy, most often characterized as sensory or sensorimotor, reported in patients receiving carbidopa-levodopa enteral suspension.¹¹⁸ Electrodiagnostic findings most consistent with axonal polyneuropathy.¹¹⁸ Evaluate patients for neuropathy prior to and during treatment, particularly in those with preexisting neuropathy or risk of neuropathy.¹¹⁸ Vitamin B supplementation reported to decrease incidence of neuropathy.^{133 136}

Cardiovascular Effects

Risk of orthostatic hypotension; usually asymptomatic and tolerance usually develops within a few months.^d

Cardiac ischemic events reported with use of some preparations.¹¹⁷

Use with caution in patients with a history of MI who have residual atrial, nodal, or ventricular arrhythmias; monitor cardiac function in a facility with intensive cardiac care during initial dosage adjustment.^{104 105 106 107 d}

Use with caution in patients with severe cardiovascular disease.^{104 105 106 107 d}

Respiratory Effects

Use with caution in patients with severe pulmonary disease (e.g., bronchial asthma).^{104 105 106 107 d}

Coughing is a frequent adverse effect of levodopa oral inhalation therapy.¹²⁶ Clinically important changes in pulmonary function not observed; however, this dosage form is not recommended in patients with COPD, asthma, or other chronic lung diseases.^{126 127}

GI Effects

Use with caution in patients with a history of peptic ulcers; possibility of upper GI hemorrhage in these patients.^{d 104 105 106 107}

Complications associated with the PEG-J procedure or device (e.g., bezoar; ileus; implant site erosion/ulcer; intestinal hemorrhage, ischemia, obstruction, or perforation; intussusception; pancreatitis; peritonitis; pneumoperitoneum; postoperative wound infection) may occur in patients receiving carbidopa-levodopa enteral suspension; may result in serious outcomes such as death or need for surgery.^{118 133} Instruct patients to notify a clinician immediately if they experience abdominal pain, prolonged constipation, nausea, vomiting, fever, or melanotic stool.¹¹⁸

Falling Asleep During Activities of Daily Living and Somnolence

Episodes of falling asleep while engaged in activities of daily living (e.g., driving) reported, sometimes resulting in accidents.^{105 107}

Some patients perceived no warning signs (e.g., excessive drowsiness) and believed they were alert immediately prior to the event.^{105 107}

Monitor patients for drowsiness or sleepiness.^{105 107} Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.^{105 107} Ask patients about any factors that may increase the risk of somnolence (e.g., concomitant sedating drugs, presence of sleep disorders).^{105 107}

Consider discontinuing therapy if a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating).^{105 107} If the drug is continued, advise patients not to drive and to avoid other potentially dangerous activities.^{105 107} (See Advice to Patients.) Insufficient information to establish whether dosage reduction will eliminate this adverse event.^{105 107}

Hyperpyrexia and Confusion

Symptom complex resembling neuroleptic malignant syndrome (NMS; e.g., elevated temperature, muscular rigidity, altered consciousness, autonomic instability) reported following dosage reduction or abrupt withdrawal of levodopa.^{104 105 106 107 d}

Observe patient closely when dosage is reduced or drug discontinued; especially important in patients receiving concomitant therapy with an antipsychotic agent.^{d 104 105 106 107}

General Precautions

Evaluate hepatic, hematopoietic, cardiovascular, and renal function periodically.^{d 104 105 106 107}

Use of Fixed Combinations

When the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo) is used, observe the usual precautions and contraindications associated with all drugs in the preparation.¹⁰⁶

Glaucoma

May increase IOP in patients with glaucoma; use with caution in patients with well-controlled open-angle glaucoma and monitor IOP.^{104 105 106 107 d} (See Contraindications under Cautions.)

Endocrine Disorders

Use with caution.^{104 105 106 107}

Closely monitor diabetic patients; levodopa may affect glycemic control.^d

Melanoma

Epidemiologic studies indicate patients with parkinsonian syndrome have a twofold to approximately sixfold higher risk of developing melanoma than the general population.^{105 106 107} Unclear whether increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat the disease).^{105 106 107}

Monitor for melanoma on a frequent and regular basis.^{105 106 107} Manufacturer recommends periodic skin examinations performed by appropriately qualified individuals (e.g., dermatologists).^{105 106 107}

Intense Urges

Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including levodopa-carbidopa).^{105 106 107} Urges stopped in some cases when dosage was reduced or drug was discontinued.^{105 106 107}

Consider reducing dosage or discontinuing therapy if a patient develops such urges.^{105 106 107}

Phenylketonuria with Orally Disintegrating Tablets

Levodopa-carbidopa orally disintegrating tablets contain aspartame (NutraSweet), which is metabolized in the GI tract to phenylalanine.^{104 110 111 112 113 114}

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women; in animal reproductive studies, decreased pup viability and teratogenic effects (e.g., visceral and skeletal malformations) observed.^{105 108}

Weigh risks versus benefits in women of childbearing potential.¹⁰⁷

Lactation

Levodopa is distributed into human milk; caution advised.^{104 105 106 107} Carbidopa is distributed into milk in rats;¹⁰⁶ not known whether carbidopa is distributed into human milk.¹⁰⁸

Use caution in nursing women.¹⁰⁵ Consider known benefits of breast-feeding along with mother's clinical need for the drug and any potential adverse effects on the infant from drug or underlying maternal condition.¹²⁶

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{104 105 106 107 126}

Geriatric Use

Oral preparations: No overall differences in safety or efficacy relative to younger adults.^{107 108 117}

Levodopa oral inhalation: Cough, upper respiratory tract infection, nausea, vomiting, extremity pain, and discolored nasal discharge were reported with higher frequency in geriatric patients ≥65 years of age than younger adults.¹²⁶

Hepatic Impairment

Use with caution.^{104 107}

Renal Impairment

Use with caution.^{104 107}

Common Adverse Effects

Dyskinesias, nausea, vomiting, headache, insomnia, abnormal dreams, dry mouth, anxiety, constipation, orthostatic hypotension.^{104 105 106 107 117}

Levodopa oral inhalation: Cough, nausea, upper respiratory tract infection, discolored sputum.¹²⁶

Carbidopa-levodopa enteral suspension: Complications from device insertion, nausea, depression, peripheral edema, hypertension, upper respiratory tract infection, oropharyngeal pain, atelectasis, incision site erythema.¹¹⁸

Drug Interactions

Specific Drugs and Foods

Levodopa/Carbidopa Pharmacokinetics

Absorption

Bioavailability

Levodopa is absorbed from the GI tract; peak plasma concentrations achieved within 0.5 or 2 hours following administration of conventional tablets or extended-release tablets, respectively.¹⁰⁵

Carbidopa-levodopa immediate-release preparations: Conventional tablets and orally disintegrating tablets begin to release the drugs within 30 minutes of administration.^{104 107 109} Pharmacokinetic values for orally disintegrating tablet and immediate-release tablet are similar.¹⁰⁹

Carbidopa-levodopa extended-release tablets: Bioavailability of levodopa from extended-release tablets 70–75% of that from conventional tablets.¹⁰⁵ Extended-release tablets result in less fluctuation in plasma concentrations between doses than conventional tablets.¹⁰⁵

Carbidopa-levodopa extended-release capsules: Formulated with both immediate-release and extended-release components.^{117 119} Following oral administration, plasma levodopa concentrations initially increase rapidly, followed by sustained plasma concentrations for about 4–5 hours; minimal peak to trough fluctuation.^{117 119} Bioavailability of levodopa from extended-release capsules approximately 70% relative to immediate-release preparations.¹¹⁷ Peak levodopa concentration is 30% of that achieved with immediate-release preparations at comparable doses.¹¹⁷

Levodopa oral inhalation: Following oral inhalation of a single dose, peak plasma concentrations obtained in approximately 0.5 hours.^{126 129} Bioavailability of levodopa from oral inhalation powder approximately 70% relative to immediate-release oral levodopa tablets.¹²⁶ Time to peak plasma concentration is approximately 15 minutes faster, but peak plasma concentrations and systemic exposure are substantially lower, compared with orally administered immediate-release levodopa-carbidopa tablets.¹²⁷

Carbidopa-levodopa enteral suspension: Following initiation of the 16-hour infusion, peak plasma concentrations of levodopa obtained in 2.5 hours.¹¹⁸ Bioavailability of enteral suspension comparable to conventional tablets.¹¹⁸ However, enteral suspension associated with less variability in plasma concentrations than conventional tablets.^{118 133} Absorption not influenced by gastric emptying rate.¹¹⁸

Food

Effects of food on levodopa pharmacokinetics are variable due to differences in formulations, dosages, and study designs.¹¹⁹

High protein diet may interfere with absorption of levodopa from conventional preparations.^{104 106 107 d}

Extended-release tablets: Food increases bioavailability and peak plasma concentrations of levodopa.¹⁰⁵

Extended-release capsules: Food decreased peak plasma concentration by 21% and increased AUC of levodopa by 13%; absorption delayed by approximately 2 hours.^{117 119}

Distribution

Extent

Widely distributed.^d

<1% of levodopa penetrates the CNS;^d carbidopa does not cross the blood-brain barrier.^{104 105 106 107}

Plasma Protein Binding

Levodopa: 10–30%.¹⁰⁶

Carbidopa: About 36%.^{106 d}

Elimination

Metabolism

Levodopa is metabolized in the stomach and intestine and on first pass through the liver; absorbed levodopa decarboxylated to dopamine.^d

Carbidopa inhibits peripheral decarboxylation of levodopa, thus increasing availability of levodopa for distribution into the CNS.^{104 105 106 107}

Elimination Route

Levodopa is excreted in urine as metabolites.^d

Half-life

Levodopa: 1.5 hours when administered with carbidopa.^{104 105}

Stability

Storage

Oral

Conventional Carbidopa-Levodopa Tablets

Tightly closed container at 25°C (may be exposed to 15–30°C).¹⁰⁷ Protect from light and moisture.¹⁰⁷

Extended-release Carbidopa-Levodopa Tablets

Tightly closed container at 25°C (may be exposed to 15–30°C); protect from light and moisture.¹⁰⁵

Orally Disintegrating Carbidopa-Levodopa Tablets

Tightly closed container at 20–25°C; protect from light and moisture.¹⁰⁴

Extended-release Carbidopa-Levodopa Capsules

Tightly closed container at 25°C (may be exposed to 15–30°C); protect from light and moisture.¹¹⁷

Levodopa Powder for Oral Inhalation

Store inhaler and capsules in a dry place at 20–25°C (may be exposed to 15–30°C).¹²⁶

Keep capsules in blister pack until ready to use.¹²⁶

Do not store capsules in inhalers.¹²⁶

Carbidopa-Levodopa Enteral Suspension

Store cassettes in freezer at -20°C.¹¹⁸ Thaw in refrigerator at 2–8°C prior to dispensing.¹¹⁸ Protect cassettes from light and keep in carton prior to use.¹¹⁸

Actions

• Manifestations of parkinsonian syndrome are related to depletion of dopamine in the corpus striatum.^{104 105 106 107}

• Levodopa relieves symptoms of parkinsonism presumably by increasing dopamine concentrations in the brain.^{104 105 106 107 d}

• Carbidopa inhibits the peripheral decarboxylation of levodopa by aromatic l-amino acid decarboxylase without affecting metabolism of the drug within CNS.^{104 105 106 107 d}

Advice to Patients

• Importance of taking levodopa/carbidopa as directed.^{104 105 106 107} Importance of not altering the prescribed dosage regimen or adding other antiparkinsonian drugs without consulting a clinician.^{104 105 106 107}

• Importance of informing patients with phenylketonuria that the orally disintegrating tablets contain aspartame.¹⁰⁴

• Advise patient to notify clinician if abnormal involuntary movements appear or get worse; dosage adjustment may be needed.^{104 105 106 107}

• Advise patient of expected onset and duration of effect.^{104 105 106 107}

• Possibility that dark color (red, brown, black) may appear in saliva, urine, or sweat; garments may be discolored.^{104 105 106 107}

• Advise patient that a change in diet to food high in protein may delay absorption of levodopa and reduce systemic availability.^{104 105 106 107} Excess acidity also may delay absorption.^{104 105 106 107}

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.^{104 105 106 107}

• Risk of somnolence and episodes of sudden sleep onset; importance of exercising caution when driving or operating machinery and of refraining from such activities if somnolence and/or an episode of sudden sleep onset occurs.^{105 107}

• Importance of instructing patients on proper administration of levodopa powder for oral inhalation using the specific inhaler provided by the manufacturer.¹²⁶ Instruct patients to take a dose when the return of their parkinsonian symptoms (“off” periods) first occurs.¹²⁶ Importance of reminding patients that the contents of Inbrija capsules are for oral inhalation only and must not be swallowed.¹²⁶

• Importance of instructing patients on proper administration of carbidopa-levodopa enteral suspension through the PEG-J tube and use of the ambulatory pump.^{118 136} Advise patients that if the pump is disconnected for short periods of time (e.g., <2 hours to swim, shower, or for a short medical procedure), no supplemental oral medication is needed, but an extra dose of the enteral suspension may be given before disconnecting.¹¹⁸ If the pump is disconnected for periods >2 hours, the patient should contact their clinician and take oral carbidopa-levodopa until the enteral infusion can be resumed.¹¹⁸

• Importance of asking patients whether they have developed any new or increased gambling urges, sexual urges, or other urges while receiving levodopa-carbidopa and of advising them of the importance of reporting such urges.^{105 106 107}

• Importance of frequent monitoring for melanoma and periodic dermatologic examinations by a dermatologist.^{105 106 107}

• Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.^{104 105 106 107}

• Importance of advising patients of other important precautionary information.^{104 105 106 107} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Frequently asked questions

• How long does it take carbidopa levodopa to work?
• How often should carbidopa/levodopa be taken?
• Can carbidopa/levodopa cause high blood pressure?
• What foods should be avoided when taking levodopa?
• Is Rytary better than Sinemet?
• What is the difference between carbidopa, levodopa, and Rytary?
• How long does it take for Rytary to start working?
• How long does Rytary stay in your system?

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