Levodopa + Carbidopa

Pharmacologic Category

Anti-Parkinson Agent, Decarboxylase Inhibitor; Anti-Parkinson Agent, Dopamine Precursor

Dosing: Adult

Parkinson disease:

Oral:

Immediate-release tablet, orally disintegrating tablet: Note: Carbidopa/levodopa tablets are available in a 1:4 ratio of carbidopa to levodopa as well as 1:10 ratio. Tablets of the two ratios may be given separately or combined as needed to provide the optimum dosage.

Initial: Carbidopa 25 mg/levodopa 100 mg 3 times daily (preferred) or carbidopa 10 mg/levodopa 100 mg 3 to 4 times daily (typically does not provide an adequate amount of carbidopa for most patients)

Patients previously treated with levodopa <1,500 mg daily: Carbidopa 25 mg/levodopa 100 mg 3 or 4 times daily

Patients previously treated with levodopa >1,500 mg daily: Carbidopa 25 mg/levodopa 250 mg 3 or 4 times daily

Note: Discontinue levodopa at least 12 hours before starting therapy with carbidopa/levodopa. Substitute the combination drug at a dosage that will provide approximately 25% of the previous levodopa dosage.

Dosage adjustment: Alternate tablet strengths may be substituted according to individual carbidopa/levodopa requirements. Use of more than 1 dosage strength or dosing 4 times daily may be required (maximum: 8 tablets of any strength daily or 200 mg of carbidopa and 2,000 mg of levodopa).

Carbidopa 10 mg/levodopa 100 mg: Increase by 1 tablet daily or every other day, as necessary, to 2 tablets 4 times daily.

Carbidopa 25 mg/levodopa 100 mg: Increase by 1 tablet daily or every other day.

Carbidopa 25 mg/levodopa 250 mg: Increase by ¹/₂ or 1 tablet daily or every other day.

Controlled-release tablet:

Patients not currently receiving levodopa: Initial: Carbidopa 50 mg/levodopa 200 mg 2 times daily, at intervals not <6 hours

Patients currently receiving levodopa: Note: Discontinue levodopa at least 12 hours before starting carbidopa/levodopa therapy. Initial: Substitute at a dosage that will provide approximately 25% of the previous levodopa dosage; usual initial dose in mild to moderate disease is carbidopa 50 mg/levodopa 200 mg 2 times daily

Patients converting from immediate-release formulation to controlled release: Initial: Dosage should be substituted at an amount that provides ~10% more of levodopa/day; total calculated dosage is administered in divided doses 2 to 3 times/day (or ≥3 times/day for patients maintained on levodopa ≥700 mg). Intervals between doses should be 4 to 8 hours while awake; when divided doses are not equal, smaller doses should be given toward the end of the day. Depending on clinical response, dosage may need to be increased to provide up to 30% more levodopa/day.

Dosage adjustment: May adjust every 3 days; intervals should be >4 hours during the waking day (maximum dose: 8 tablets/day)

Extended-release capsule: Note: Carbidopa/levodopa extended-release (ER) capsules are not interchangeable with other carbidopa/levodopa products on a 1:1 basis.

Patients not currently receiving levodopa: Initial: Carbidopa 23.75 mg/levodopa 95 mg 3 times daily for 3 days; on day 4, increase to carbidopa 36.25 mg/levodopa 145 mg 3 times daily. May increase dose up to carbidopa 97.5 mg/levodopa 390 mg 3 times a day; frequency of dosing may be increased to a maximum of 5 times daily if needed and tolerated (maximum: carbidopa 612.5 mg/levodopa 2,450 mg per day).

Patients converting from immediate-release formulation to ER capsules: Note: For patients currently treated with immediate-release carbidopa/levodopa plus catechol-O-methyl transferase (COMT) inhibitors (eg, entacapone) and converting to ER capsules, the initial total daily dose of carbidopa/levodopa ER capsules may need to be increased. Use of carbidopa/levodopa ER capsules in combination with other levodopa products has not been studied.

Initial: Initial dose based off of total current daily dose of levodopa in immediate-release carbidopa/levodopa as follows:

If total daily dose of levodopa is between 400 mg to 549 mg: 3 capsules of carbidopa 23.75 mg/levodopa 95 mg 3 times daily (levodopa total daily dose: 855 mg).

If total daily dose of levodopa is between 550 mg to 749 mg: 4 capsules of carbidopa 23.75 mg/levodopa 95 mg 3 times daily (levodopa total daily dose: 1,140 mg).

If total daily dose of levodopa is between 750 mg to 949 mg: 3 capsules of carbidopa 36.25 mg/levodopa 145 mg 3 times daily (levodopa total daily dose: 1,305 mg).

If total daily dose of levodopa is between 950 mg to 1249 mg: 3 capsules of carbidopa 48.75 mg/levodopa 195 mg 3 times daily (levodopa total daily dose: 1,755 mg).

If total daily dose of levodopa is ≥1,250 mg: 4 capsules of carbidopa 48.75 mg/levodopa 195 mg 3 times daily (levodopa total daily dose: 2,340 mg) or 3 capsules of carbidopa 61.25/levodopa 245 mg 3 times daily (levodopa total daily dose: 2,205 mg).

Dosage adjustment: Adjust dose as needed; frequency of dosing may be increased to a maximum of 5 times daily if needed and tolerated (maximum dose: carbidopa 612.5 mg/levodopa 2,450 mg per day). Adjust dose and frequency in response to any motor complications that arise (Espay 2017).

Intestinal infusion via PEG-J tube:

Intestinal suspension (Duopa): Initial: Note: Prior to initiation of therapy, convert patients from all forms of levodopa to oral immediate-release carbidopa/levodopa tablets (1:4 ratio). Total daily dose (expressed in terms of levodopa) consists of a morning dose, a continuous dose and extra doses. Maximum dose is 2,000 mg of the levodopa component (ie, one cassette per day) over 16 hours. Patients should receive their routine night-time dosage of oral immediate-release carbidopa/levodopa after discontinuation of daily infusion.

Morning dose and continuous dose: Refer to manufacturer’s labeling for morning dose and continuous dose calculations and titration instructions.

Extra doses: Can be used to manage acute "off" symptoms that are not controlled by the morning and continuous dose. Set extra dose function at 1 mL (20 mg of levodopa) initially; adjust in 0.2 mL increments if needed. Maximum: One extra dose every 2 hours. Note: Frequent extra doses may cause or worsen dyskinesias.

Discontinuation: Avoid sudden discontinuation or rapid dose reduction; taper dose or switch patients to oral immediate-release carbidopa-levodopa.

Intestinal gel (Duodopa [Canadian product]): Note: Conversion to/from oral levodopa tablet formulations and the intestinal gel formulation can be done on a 1:1 ratio. Total daily dose (expressed in terms of levodopa) consists of a morning bolus dose, a continuous maintenance dose, and additional bolus doses when necessary. Nighttime dosing may be necessary in certain rare situations (eg, nocturnal akinesia). Dosage adjustments should be carried out over a period of a few weeks. Patients should receive their routine night-time dosage of oral levodopa/carbidopa after discontinuation of daily infusion

Morning bolus dose:

Day 1: Based on a percentage of the previous morning levodopa intake and volume to fill intestinal tubing:

Previous morning dose of levodopa ≤200 mg: Administer Duodopa at 80% of dose

Previous morning dose of levodopa 201 to 399 mg: Administer Duodopa at 70% of dose

Previous morning dose of levodopa ≥400 mg: Administer Duodopa at 60% of dose

Day 2 and beyond till dose is stable: Adjust dose based on response to the previous morning levodopa intake and volume to fill intestinal tubing): Usual: Levodopa 100 to 200 mg (5 to 10 mL); Maximum: Levodopa 300 mg (15 mL)

Continuous maintenance dose: Adjustable in increments of 2 mg/hour (0.1 mL/hour) and based on previous daily intake of levodopa: Usual: Levodopa 40 to 120 mg/hour (2 to 6 mL/hour) infused up to 16 hours; Range: Levodopa 20 to 200 mg/hour (1 to 10 mL/hour). Higher doses may be necessary in exceptional cases.

Additional bolus doses: Usual: Levodopa: 10 to 40 mg (0.5 to 2 mL), if needed for rapid deterioration of motor functions (eg, hypokinesia); may give additional doses hourly until stable dose is established then give every 2 hours as needed. In patients requiring >5 additional boluses/day, consider increasing the maintenance dose

Restless legs syndrome, intermittent (off-label use) (Silber 2004): Oral:

Immediate-release tablet: Carbidopa 25 mg/levodopa 100 mg (0.5 to 1 tablet) given in the evening, at bedtime, or upon waking during the night as needed for restless legs syndrome (RLS) symptoms.

Controlled-release tablet: Carbidopa 25 mg/levodopa 100 mg (1 tablet) before bedtime as needed for RLS symptoms that awaken patient during the night.

Note: Due to risk of augmentation, some guidelines recommend limiting the frequency to 2 to 3 administrations per week (IRLSSG/EURLSSG/RLS-F [Garcia-Borreguero 2016]).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dosing: Adjustment for Toxicity: Adult

Intestinal suspension (Duopa):

Dyskinesias or levodopa-related adverse reactions within 1 hour of morning dose on preceding day: Decrease morning dose by 1 mL.

Dyskinesias or adverse reactions lasting ≥1 hour on the preceding day: Decrease the continuous dose by 0.3 mL per hour.

Dyskinesias or adverse reactions lasting for 2 or more periods of ≥1 hour on the preceding day: Decrease the continuous dose by 0.6 mL per hour.

Use: Labeled Indications

Parkinson disease: Treatment of Parkinson disease, postencephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide and/or manganese intoxication; treatment of motor fluctuations in advanced Parkinson disease (intestinal suspension [Duopa] only).

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Restless leg syndrome, intermittentLevel of Evidence [G]

Based on the American Academy of Sleep Medicine (AASM) practice parameters for the treatment of restless legs syndrome and periodic limb movement, the use of carbidopa and levodopa is an effective and recommended alternative treatment option in patients with intermittent restless leg syndrome (RLS) that does not require daily therapy; however, a risk of RLS symptom augmentation and early morning rebound symptoms exists with this therapy (AASM [Aurora 2012]).

The European Federation of Neurological Societies/European Neurological Society/European Sleep Research Society (EFNS/ENS/ESRS) Task Force guidelines for the management of restless leg syndrome consider levodopa effective in reducing RLS symptoms as an on-demand treatment in intermittent RLS (EFNS/ENS/ESRS [Garcia-Borreguero 2012]).

Based on the International Restless Legs Syndrome Study Group, European Restless Legs Syndrome Study Group, and RLS Foundation (IRLSSG/EURLSSG/RLS-F) guidelines for the prevention and treatment of dopaminergic augmentation in restless legs syndrome, levodopa may be effective for intermittent RLS limiting the frequency to only 2 to 3 administrations per week due to the risk of augmentation (IRLSSG/EURLSSG/RLS-F [Garcia-Borreguero 2016]).

Clinical experience also suggests the utility of carbidopa and levodopa in the management of RLS ^Ref.

Level of Evidence Definitions

Level of Evidence Scale

Comparative Efficacy

• CARBIDOPA/LEVODOPA INTESTINAL GEL

Clinical Practice Guidelines

Parkinson Disease:

American Academy of Neurology (AAN) Consensus on Conversion From Standard Therapy, "Optimizing Extended-Release Carbidopa/Levodopa in Parkinson Disease," 2017

Canadian Neurological Sciences Federation, “Canadian Guidelines on Parkinson’s Disease,” 2012

National Institute for Health and Care Excellence (NICE), "Parkinson's Disease in Adults," 2017

Restless Legs Syndrome:

American Academy of Neurology, "Treatment of Restless Legs Syndrome in Adults," 2016

American Academy of Neurology Practice Guideline, "Treatment of Restless Legs Syndrome in Adults," 2016

American Academy of Sleep Medicine, "The Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder in Adults - An Update for 2012: Practice Parameters With an Evidence-Based Systematic Review and Meta-Analysis," 2012

European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society, “European Guidelines on Management of Restless Legs Syndrome: Report of a Joint Task Force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society," November 2012

International Restless Legs Syndrome Study Group (IRLSSG), European Restless Legs Syndrome Study Group (ERLSSG), and Restless Legs Syndrome Foundation, "Guidelines for the First-Line Treatment of Restless Legs Syndrome/Willis-Ekbom Disease, Prevention and Treatment of Dopaminergic Augmentation: A Combined Task Force of the IRLSSG, ERLSSG and the RLS Foundation," May 2016

Administration: Oral

Extended-release capsule: Administer with or without food; a high-fat, high-calorie meal may delay the absorption of levodopa by ~2 hours. Swallow capsules whole; do not chew, divide, or crush capsules. Patients who have difficulty swallowing intact capsules may open the capsule, sprinkle entire contents on a small amount of applesauce (1 to 2 tablespoons) and consume immediately (do not store the for future use).

Tablet formulations: Space doses evenly over the waking hours. Administer with meals to decrease GI upset. Controlled release product should not be chewed or crushed. Orally disintegrating tablets do not require water; the tablet should disintegrate on the tongue's surface before swallowing.

Administration: Other

Intestinal suspension (Duopa): Remove one cassette from refrigerator 20 minutes prior to use (failure to use at room temperature may result in inaccurate dosage). Administer as a 16-hour infusion through either a nasojejunal tube (temporary administration) or through a percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) tube (long-term administration) connected to the CADD-Legacy 1400 pump. At the end of administration, disconnect the tube from the pump at the end of the infusion and flush with room-temperature drinking water with a syringe. Following discontinuation of the daily infusion, patients should administer their routine night-time dosage of oral immediate-release carbidopa/levodopa.

Intestinal gel (Duodopa [Canadian product]): Gel is administered directly to the jejunum via a portable infusion pump (CADD-legacy Duodopa pump). Administer through a temporary nasojejunal tube for a short-term test period to evaluate patient response and for dose optimization. Long-term administration requires placement of PEG-J tube for intestinal infusion. Continuous maintenance dose is infused throughout the day for up to 16 hours; if necessary may administer at night (eg, nocturnal akinesia). Disconnect PEG-J tube from infusion pump at end of infusion and flush with room temperature water to prevent occlusion of tubing. Following discontinuation of the daily infusion, patients should administer their routine night-time dosage of oral levodopa/carbidopa.

Dietary Considerations

Avoid high protein diets (>2 g/kg) which may decrease the efficacy of levodopa via competition with amino acids in crossing the blood-brain barrier. Some products may contain phenylalanine.

Storage/Stability

Oral formulations: Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from light and moisture.

Intestinal suspension (Duopa): Store in freezer at -20°C (-4°F). Fully thaw in refrigerator at 2°C to 8°C (36°F to 46°F) prior to use; protect from light. To ensure controlled thawing, remove the cartons containing the seven individual cassettes from the transport box and separate the cartons from each other. Assign a 12-week, use-by date based on the time the cartons are put in the refrigerator to thaw (may take up to 96 hours to thaw). Once thawed, the individual cartons may be packed in a closer configuration within the refrigerator. Cassettes are for single use only and should be discarded daily following infusion (up to 16 hours). Do not re-use opened cassettes.

Intestinal gel (Duodopa [Canadian product]): Store in refrigerator at 2°C to 8°C (36°F to 46°F). Keep in outer carton to protect from light. Cassettes are for single use only and should be discarded daily following infusion (up to 16 hours).

Preparation for Administration: Adult

Intestinal suspension (Duopa): Fully thaw in refrigerator prior to use. To ensure controlled thawing, take the cartons containing the seven individual cassettes out of the transport box and separate the cartons from each other. Assign a 12-week, use-by date based on the time the cartons are put into the refrigerator to thaw (may take up to 96 hours to thaw). Once thawed, the individual cartons may be packed in a closer configuration within the refrigerator. Remove one cassette from refrigerator 20 minutes prior to administration (failure to use at room temperature may result in inaccurate dosage).

Extemporaneously Prepared

An oral suspension containing carbidopa 1.25 mg and levodopa 5 mg per mL may be made with tablets. Crush ten tablets each containing carbidopa 25 mg and levodopa 100 mg and reduce to a fine powder. Add small portions of a 1:1 mixture of Ora-Sweet® and Ora-Plus® and mix to a uniform paste; mix while adding the vehicle in equal proportions to almost 200 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add sufficient quantity of vehicle to make 200 mL. Label "shake well" and "refrigerate". Stable 42 days under refrigeration. Also stable 28 days at room temperature.

Nahata MC, Morosco RS, and Leguire LE, "Development of Two Stable Oral Suspensions of Levodopa-Carbidopa for Children With Amblyopia," J Pediatr Ophthalmol Strabismus, 2000, 37(6):333-7.[PubMed 11392406]

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat Parkinson's disease.

• It is used to treat signs like Parkinson's disease caused by other health problems.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nightmares

• Fatigue

• Dry mouth

• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Depression like thoughts of suicide, anxiety, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion

• Confusion

• Behavioral changes

• Sensing things that seem real but are not

• Uncontrollable urges

• Narcolepsy

• Skin growth

• Mole changes

• Abnormal movements

• Severe headache

• Dark urine

• Yellow skin or eyes

• Vision changes

• Eye pain

• Severe eye irritation

• Shortness of breath

• Burning or numbness feeling

• Swelling of arms or legs

• Vomiting blood

• Black, tarry, or bloody stools

• Persistent constipation

• Nausea

• Vomiting

• Abdominal pain

• Chest pain

• Fast heartbeat

• Abnormal heartbeat

• Chills

• Sore throat

• Bruising

• Bleeding

• Severe dizziness

• Passing out

• Severe loss of strength and energy

• Neuroleptic malignant syndrome like fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

International issues:

Prescribing and Access Restrictions

Duodopa intestinal gel [Canadian product]: In Canada, the Duodopa Education Program is a risk mitigation program established to provide safe and effective use of Duodopa in advanced Parkinson patients. The program involves:

- Education of prescribing neurologists and other health care providers on suitable candidates for treatment, surgical procedures (PEG tube placement), and follow-up care including infusion device education.

- Distribution of educational materials to patients and caregivers describing Duodopa intestinal gel and its proper use, PEG tube placement, and complications associated with the mode of administration and/or PEG tube placement.

Contraindications

Hypersensitivity to levodopa, carbidopa, or any component of the formulation; concurrent use with nonselective monoamine oxidase inhibitors (MAOIs) or use within the last 14 days

Tablets: Additional contraindications: Narrow angle glaucoma

Canadian labeling: Additional contraindications (not in US labeling): Clinical or laboratory evidence of uncompensated cardiovascular, endocrine, hepatic, hematologic or pulmonary disease (eg, including bronchial asthma), or renal disease; when administration of a sympathomimetic amine (eg, epinephrine, norepinephrine, isoproterenol) is contraindicated; in the presence of a suspicious, undiagnosed skin lesion or history of melanoma; intestinal gel therapy in patients with any condition preventing the required placement of a PEG tube for administration (ie, pathological changes of gastric wall, inability to bring gastric and abdominal wall together, blood coagulation disorders, peritonitis, acute pancreatitis, paralytic ileus).

Warnings/Precautions

Concerns related to adverse effects:

• Abnormal thinking/behavioral changes: Abnormal thinking and behavior changes have been reported and may include aggressive behavior, agitation, confusion, delirium, delusions, disorientation, paranoid ideation, and psychotic-like behavior.

• Dyskinesias: May cause or exacerbate dyskinesias; may require dosage reduction.

• Hallucinations: Hallucinations may occur and be accompanied by confusion and to a lesser extent sleep disorder and excessive dreaming; typically presents shortly after initiation of therapy and may require dose reduction.

• Impulse control disorders: Dopamine agonists used for Parkinson disease or restless legs syndrome have been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases.

• Melanoma: Risk for melanoma development is increased in Parkinson disease patients; drug causation or factors contributing to risk have not been established. Patients should be monitored closely and periodic skin examinations should be performed.

• Neuroleptic malignant syndrome: A symptom complex resembling neuroleptic malignant syndrome (NMS) has been reported in association with rapid dose reduction, or abrupt withdrawal. Identification of more severe NMS-like reactions (eg, altered consciousness, hyperthermia, involuntary movements, muscle rigidity, autonomic instability, mental status changes) can be complex; monitor patients closely for this reaction and when the dosage of levodopa is reduced abruptly or discontinued. Discontinue treatment immediately if signs/symptoms arise.

• Orthostatic hypotension: May cause orthostatic hypotension; Parkinson disease patients appear to have an impaired capacity to respond to a postural challenge. Use with caution in patients at risk of hypotension (such as those receiving antihypertensive drugs) or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Parkinson patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and should be informed of this risk.

• Somnolence: Somnolence and falling asleep while engaged in activities of daily living (including operation of motor vehicles) have been reported; some cases reported that there were no warning signs for the onset of symptoms. Symptom onset may occur well after initiation of treatment; some events have occurred more than 1 year after start of therapy. Prior to treatment initiation, evaluate for factors that may increase these risks such as concomitant sedating medications, and the presence of sleep disorders. Monitor for drowsiness or sleepiness. If significant daytime sleepiness or episodes of falling asleep during activities that require active participation occurs (eg, driving, conversations, eating), discontinue the medication. There is insufficient information to suggest that dose reductions will eliminate these symptoms. If therapy is continued, advise patient to avoid driving and other potentially dangerous activities.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with severe cardiovascular disease, including a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias.

• Endocrine disease: Use with caution in patients with endocrine disease and when interpreting plasma/urine catecholamine levels; falsely diagnosed pheochromocytoma has been rarely reported.

• Glaucoma: Use with caution in patients with glaucoma; monitor IOP carefully; some formulations are contraindicated in patients with narrow-angle glaucoma.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Neuropathy: Peripheral neuropathy has been reported with use; prior to initiation, evaluate patients for history of neuropathy and known risk factors (eg, deficiency of vitamin B₆ and/or B₁₂, diabetes mellitus, hypothyroidism). Assess patients for peripheral neuropathy periodically during therapy.

• Peptic ulcer disease: Oral products: Use with caution in patients with a history of peptic ulcer disease; risk of GI hemorrhage may be increased.

• Psychotic disorders: Avoid use in patients with a major psychotic disorder. Use with extreme caution in patients with psychotic disorders because of the risk of exacerbating psychosis; observe patients closely for development of depression with concomitant suicidal tendencies.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution in patients with respiratory disease.

Special populations:

• Elderly: Use with caution in elderly patients; may be more sensitive to CNS effects (eg, hallucinations) of levodopa.

Concurrent drug therapy concerns:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage forms specific issues:

• Intestinal suspension (Duopa): GI complications (eg, bezoar, ileus, implant-site erosion/ulcer, intestinal hemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, pancreatitis, peritonitis, pneumoperitoneum, postoperative wound infection) may occur (may be fatal). Patients should notify their health care provider immediately if abdominal pain, prolonged constipation, nausea, vomiting, fever, and/or melanotic stool occur.

• Intestinal gel (Duodopa [Canadian product]): Product should be prescribed only by neurologists experienced in the treatment of Parkinson disease and who have completed the Duodopa Education Program. Response to levodopa/carbidopa intestinal gel therapy should be assessed with a short-term test period of administration via a temporary nasojejunal tube prior to placement of a percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) tube for permanent access and administration. Sudden deterioration in therapy response with recurring motor symptoms may indicate PEG-J tube complications (eg, displacement) or obstruction of the infusion device. Tube or infusion device complications may require initiation of oral levodopa/carbidopa therapy until complications are resolved.

Other warnings/precautions:

• Body fluid discoloration: Urine, saliva, or sweat may appear dark in color (red, brown, black) during therapy.

• Dietary protein: Distribute dietary protein throughout the day to avoid fluctuations in levodopa absorption. A high-protein diet may reduce the effectiveness of the enteral formulations.

• Discontinuation of therapy: Dopaminergic agents have been associated with a syndrome resembling neuroleptic malignant syndrome on abrupt withdrawal, rapid dose reduction, significant dosage reduction after long-term use, or changes in dopaminergic therapy. Avoid sudden discontinuation or rapid dose reduction; taper dose to reduce the risk of hyperpyrexia and confusion.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

The elderly may be more sensitive to the CNS effects of levodopa.

Pregnancy Considerations

Carbidopa can be detected in the umbilical cord, but absorption in fetal tissue is minimal. Levodopa crosses the placenta and can be metabolized by the fetus and detected in fetal tissue (Merchant 1995).

The incidence of Parkinson disease in pregnancy is relatively rare, and although information related to the use of carbidopa/levodopa in pregnant women is limited (Ball 1995; Cook 1985; Golbe 1987; Serikawa 2011; Shulman 2000; Tüfekçioğlu 2018; Zlotnik 2014), this combination has the most outcome information available for the treatment of pregnant women (Seier 2017). Current guidelines note that the available information is insufficient to make a recommendation for the treatment of restless legs syndrome in pregnant women (Aurora 2012).

Breast-Feeding Considerations

Levodopa is present in breast milk.

A study was done in one breastfeeding woman at 4.5 months postpartum who had been taking carbidopa/levodopa for several years. Regardless of the formulation (sustained release or immediate release), peak levodopa concentrations in the breast milk were found ~3 hours after the maternal dose and returned to baseline ~6 hours after the dose. The highest milk concentration (3.47 nmol/L) was found following the immediate release tablet, and this was 27% of the peak maternal plasma concentration (occurring 30 minutes after the dose) and ~40% of the simultaneous plasma concentration. Carbidopa was not evaluated (Thulin 1998).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Lactation may be inhibited by levodopa.

Briggs' Drugs in Pregnancy & Lactation

• Carbidopa
• Levodopa

Adverse Reactions

>10%:

Cardiovascular: Orthostatic hypotension (enteral suspension: 70% to 73%; oral: 1% to 5%)

Central nervous system: Dizziness (2% to 19%), headache (oral : 1% to 17%), depression (enteral suspension: 11%; oral: 1% to 2%)

Gastrointestinal: Nausea (enteral suspension: 30%; oral: 3% to 20%), constipation (enteral suspension: 22%; oral: ≤6%)

Neuromuscular & skeletal: Dyskinesia (2% to 17%), increased creatine phosphokinase (enteral suspension: ≤17%)

Renal: Increased blood urea nitrogen (enteral suspension: ≤13%)

1% to 10%:

Cardiovascular: Hypertension (enteral suspension: 8%), peripheral edema (enteral suspension: 8%), ischemia (oral: ≤2%), chest pain (oral: ≤1%)

Central nervous system: Insomnia (oral: 1% to 9%), anxiety (2% to 8%), confusion (2% to 8%), abnormal dreams (oral: ≤6%), polyneuropathy (enteral suspension: 5%), sleep disorder (enteral suspension: 5%), hallucination (≤5%), psychosis (≤5%), dystonia (oral: ≤2%), on-off phenomenon (oral: 1% to 2%), paresthesia (oral: ≤1%)

Dermatologic: Skin rash (enteral suspension: 5%)

Endocrine & metabolic: Increased serum glucose (≥1%)

Gastrointestinal: Xerostomia (oral: 1% to 7%), diarrhea (≤5%), dyspepsia (≤5%), vomiting (oral: 2% to 5%), anorexia (oral: 1%)

Genitourinary: Bacteriuria (enteral suspension: 5%; oral: ≥1%), urinary tract infection (oral: 2%), hematuria (oral: ≥1%), urinary frequency (oral: ≤1%)

Hematologic & oncologic: Leukocyturia (enteral suspension: 5%; oral: ≥1%), decreased hematocrit (oral: ≥1%), decreased hemoglobin (oral: ≥1%)

Neuromuscular & skeletal: Back pain (oral: ≤2%), muscle cramps (oral: ≤1%), shoulder pain (oral: ≤1%)

Respiratory: Atelectasis (enteral suspension: 8%), oropharyngeal pain (enteral suspension: 8%), upper respiratory tract infection (enteral suspension: 8%; oral: 1% to 2%), dyspnea (oral: ≤2%)

Miscellaneous: Fever (enteral suspension: 5%)

<1%, postmarketing, and/or case reports: Abdominal distress, abdominal pain, abnormal behavior, abnormal gait, abnormality in thinking, agitation, agranulocytosis, alopecia, anemia, angioedema, asthenia, ataxia, blepharospasm, blurred vision, bruxism, bullous rash (including pemphigus-like reactions), cardiac arrhythmia, common cold, cough, decreased mental acuity, decreased serum potassium, delirium, delusions, dementia, diaphoresis, diplopia, discoloration of saliva, discoloration of sweat, disorientation, drowsiness, duodenal ulcer, dysgeusia, dysphagia, edema, euphoria, extrapyramidal reaction, falling, fatigue, flatulence, flushing, gastrointestinal hemorrhage, glossopyrosis, glycosuria, heartburn, hemolytic anemia, Henoch-Schonlein purpura, hiccups, hoarseness, Horner syndrome (reactivation), hot flash, hypotension, impulse control disorder, increased lactate dehydrogenase, increased libido (including hypersexuality), increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate transaminase, increased serum bilirubin, increased tremors, increased uric acid, leukopenia, lower extremity pain, malaise, malignant melanoma, memory impairment, muscle twitching, mydriasis, myocardial infarction, narcolepsy, nervousness, neuroleptic malignant syndrome, nightmares, numbness, oculogyric crisis, palpitations, paranoia, pathological gambling, peripheral neuropathy, phlebitis, positive direct Coombs test, priapism, proteinuria, pruritus, seizure, sense of stimulation, sialorrhea, suicidal ideation, suicidal tendencies, syncope, thrombocytopenia, trismus, urinary incontinence, urinary retention, urine discoloration, urticaria, weight gain, weight loss

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Carbidopa Allergy
• Levodopa and Carbidopa Allergy

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Alizapride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Amisulpride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Amisulpride. Risk X: Avoid combination

Antipsychotic Agents (First Generation [Typical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Management: Avoid concomitant therapy if possible and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Risk D: Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Risk D: Consider therapy modification

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Biperiden: May enhance the adverse/toxic effect of Levodopa-Containing Products. Specifically, the risk of choreic movements or dyskinesias may be increased. Risk C: Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Bromopride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Risk X: Avoid combination

BuPROPion: Anti-Parkinson Agents (Dopamine Agonist) may enhance the adverse/toxic effect of BuPROPion. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Droxidopa: Carbidopa may diminish the therapeutic effect of Droxidopa. Carbidopa may decrease serum concentrations of the active metabolite(s) of Droxidopa. Carbidopa may increase the serum concentration of Droxidopa. Risk C: Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

Fosphenytoin-Phenytoin: May diminish the therapeutic effect of Levodopa-Containing Products. Risk C: Monitor therapy

Glycopyrrolate (Systemic): May decrease the serum concentration of Levodopa-Containing Products. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Iron Preparations: May decrease the serum concentration of Levodopa. Only applies to oral iron preparations. Management: Consider separating doses of the agents by 2 or more hours to minimize the effects of this interaction. Monitor for decreased therapeutic effects of levodopa during concomitant therapy, particularly if doses cannot be separated. Exceptions: Ferric Carboxymaltose; Ferric Derisomaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk D: Consider therapy modification

Isoniazid: May diminish the therapeutic effect of Levodopa-Containing Products. Risk C: Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Macimorelin: Levodopa-Containing Products may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination

Methionine: May diminish the therapeutic effect of Levodopa-Containing Products. Management: Avoid large daily doses of methionine in patients receiving levodopa (clinical studies showing interaction used 4.5 g methionine daily). More typical doses of methionine (eg, 500 mg) may not cause a problem. Risk D: Consider therapy modification

Methylphenidate: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy

Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: Levodopa-Containing Products may enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Of particular concern is the development of hypertensive reactions when levodopa is used with nonselective MAOI. Exceptions: Rasagiline; Safinamide; Selegiline. Risk X: Avoid combination

Monoamine Oxidase Inhibitors (Type B): Levodopa-Containing Products may enhance the orthostatic hypotensive effect of Monoamine Oxidase Inhibitors (Type B). Risk C: Monitor therapy

Multivitamins/Fluoride (with ADE): May diminish the therapeutic effect of Levodopa-Containing Products. Management: Concurrent use of a multivitamin and levodopa (without carbidopa) should be avoided. Risk D: Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May diminish the therapeutic effect of Levodopa. Multivitamins/Minerals (with ADEK, Folate, Iron) may decrease the serum concentration of Levodopa. Only applies to oral iron-containing preparations. Management: Separate doses of these agents by 2 or more hours. Monitor for decreased levodopa effects, particularly if doses cannot be separated. Concurrent use of a multivitamin and levodopa (without carbidopa) should be avoided. Risk D: Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May diminish the therapeutic effect of Levodopa-Containing Products. Management: Concurrent use of a multivitamin and levodopa (without carbidopa) should be avoided. Risk D: Consider therapy modification

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification

Papaverine: May enhance the hypotensive effect of Levodopa-Containing Products. Papaverine may diminish the therapeutic effect of Levodopa-Containing Products. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Pyridoxine: May diminish the therapeutic effect of Levodopa-Containing Products. Management: The concomitant use of pyridoxine and levodopa (in the absence of a dopa decarboxylase inhibitor (DDI)) should be avoided. Use of a DDI (eg, carbidopa) with levodopa will essentially eliminate the risk of this interaction. Risk D: Consider therapy modification

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Sapropterin: May enhance the adverse/toxic effect of Levodopa-Containing Products. Risk C: Monitor therapy

Solriamfetol: Anti-Parkinson Agents (Dopamine Agonist) may enhance the hypertensive effect of Solriamfetol. Risk C: Monitor therapy

Spiramycin: May decrease the serum concentration of Carbidopa. And thus may decrease the effectiveness of levodopa. Risk C: Monitor therapy

Sulpiride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination

Food Interactions

High protein diets have the potential to impair levodopa absorption; levodopa competes with certain amino acids for transport across the gut wall or across the blood-brain barrier. Management: Avoid high protein diets.

Test Interactions

False-positive reaction for urinary glucose; false-negative reaction using glucose-oxidase tests for glucosuria; false-positive urine ketones; false diagnosis for pheochromocytoma (rare) based on plasma and urine levels of catecholamines

Monitoring Parameters

Signs and symptoms of Parkinson disease; periodic hepatic function tests, BUN, creatinine, and CBC; periodic skin examinations; blood pressure, standing and sitting/supine; symptoms of dyskinesias, mental status changes; cardiac function (particularly during initial dosage adjustment), IOP (in patients with glaucoma); signs and symptoms of neuroleptic malignant syndrome if abrupt discontinuation required (as with surgery); drowsiness or sleepiness; signs of depression (including suicidal thoughts); signs and symptoms of peripheral neuropathy prior to therapy and periodically during therapy.

Additional Canadian labeling recommendations include vitamin B₁₂, vitamin B₆, folic acid, homocysteine, and methylmalonic acid levels prior to initiation and regularly thereafter (Duodopa Canadian product monograph).

Nursing Physical Assessment/Monitoring

Monitor therapeutic response (eg, activities of daily living, involuntary movements) at beginning of therapy and periodically throughout therapy.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release, Oral:

Rytary: Carbidopa 23.75 mg and levodopa 95 mg, Carbidopa 36.25 mg and levodopa 145 mg, Carbidopa 48.75 mg and levodopa 195 mg, Carbidopa 61.25 mg and levodopa 245 mg [contains fd&c blue #2 (indigotine)]

Suspension, Enteral:

Duopa: Carbidopa 4.63 mg and levodopa 20 mg per mL (100 mL)

Tablet, Oral:

Sinemet: Carbidopa 10 mg and levodopa 100 mg, Carbidopa 25 mg and levodopa 250 mg [contains fd&c blue #2 aluminum lake]

Sinemet: Carbidopa 25 mg and levodopa 100 mg [contains fd&c yellow #10 aluminum lake]

Generic: Carbidopa 10 mg and levodopa 100 mg, Carbidopa 25 mg and levodopa 100 mg, Carbidopa 25 mg and levodopa 250 mg

Tablet Disintegrating, Oral:

Generic: Carbidopa 10 mg and levodopa 100 mg, Carbidopa 25 mg and levodopa 100 mg, Carbidopa 25 mg and levodopa 250 mg

Tablet Extended Release, Oral:

Sinemet CR: Carbidopa 25 mg and levodopa 100 mg, Carbidopa 50 mg and levodopa 200 mg [contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake]

Generic: Carbidopa 25 mg and levodopa 100 mg, Carbidopa 50 mg and levodopa 200 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Gel, Enteral:

Duodopa: Carbidopa 5 mg and levodopa 20 mg per mL (100 mL)

Tablet, Oral:

Sinemet 100/10: Carbidopa 10 mg and levodopa 100 mg [DSC]

Sinemet 250/25: Carbidopa 25 mg and levodopa 250 mg [contains fd&c blue #2 (indigotine)]

Sinemet 100/25: Carbidopa 25 mg and levodopa 100 mg [contains fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Generic: Carbidopa 10 mg and levodopa 100 mg, Carbidopa 25 mg and levodopa 100 mg, Carbidopa 25 mg and levodopa 250 mg

Tablet Extended Release, Oral:

Sinemet CR: Carbidopa 25 mg and levodopa 100 mg [DSC]

Sinemet CR 200/50: Carbidopa 50 mg and levodopa 200 mg [DSC] [contains fd&c yellow #10 aluminum lake]

Generic: Carbidopa 25 mg and levodopa 100 mg, Carbidopa 50 mg and levodopa 200 mg

Anatomic Therapeutic Chemical (ATC) Classification

• N04BA02

Generic Available (US)

May be product dependent

Pricing: US

Capsule, controlled release (Rytary Oral)

23.75-95 mg (per each): $3.85

36.25-145 mg (per each): $3.85

48.75-195 mg (per each): $3.85

61.25-245 mg (per each): $4.83

Suspension (Duopa Enteral)

4.63-20 mg/mL (per mL): $2.42

Tablet, controlled release (Carbidopa-Levodopa ER Oral)

25-100 mg (per each): $0.93 - $0.99

50-200 mg (per each): $1.74 - $1.90

Tablet, controlled release (Sinemet CR Oral)

25-100 mg (per each): $1.57

50-200 mg (per each): $3.02

Tablet, orally-disintegrating (Carbidopa-Levodopa Oral)

10-100 mg (per each): $1.21 - $1.22

25-100 mg (per each): $1.37 - $1.38

25-250 mg (per each): $1.75

Tablets (Carbidopa-Levodopa Oral)

10-100 mg (per each): $0.38 - $0.77

25-100 mg (per each): $0.16 - $0.87

25-250 mg (per each): $0.53 - $1.11

Tablets (Sinemet Oral)

10-100 mg (per each): $1.25

25-100 mg (per each): $1.40

25-250 mg (per each): $1.79

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Parkinson disease symptoms are due to a lack of striatal dopamine; levodopa circulates in the plasma to the blood-brain-barrier (BBB), where it crosses, to be converted by striatal enzymes to dopamine; carbidopa inhibits the peripheral plasma breakdown of levodopa by inhibiting its decarboxylation, and thereby increases available levodopa at the BBB

Pharmacodynamics/Kinetics

Absorption: Absorption of levodopa may be decreased with high-fat, high-calorie or high-protein meal.

Distribution: Levodopa: 0.9 to 1.6 L/kg (in presence of carbidopa), crosses the blood-brain barrier; Carbidopa: Does not cross the blood-brain barrier

Metabolism: Levodopa has two major pathways (decarboxylation and O-methylation) and two minor pathways (transamination and oxidation) of metabolism; Carbidopa inhibits the decarboxylation of levodopa to dopamine in the peripheral tissue to allow greater levodopa distribution into the CNS

Bioavailability:

Controlled and extended release: Levodopa: Bioavailability is ~70% to 75% relative to availability from immediate release formulation; Carbidopa: Bioavailability is ~50% to 58% relative to availability from immediate release formulation

Intestinal gel [Canadian product]: Levodopa: Similar bioavailability relative to oral administration of tablet formulations (81% to 98%)

Intestinal suspension: Levodopa: 97% relative to oral immediate release tablets

Half-life elimination: Immediate release: Levodopa (in presence of carbidopa): 1.5 hours; Half-life may be prolonged with controlled and extended release formulations due to continuous absorption

Time to peak: Immediate release: 0.5 hours; Controlled and extended release: 2 hours; Intestinal gel [Canadian product]: Therapeutic plasma levels reached 10 to 30 minutes following morning bolus dose; Intestinal suspension: 2.5 hours

Excretion: Urine

Pharmacodynamics/Kinetics: Additional Considerations

Geriatric: The AUC and C_max of levodopa may be increased in elderly patients.

Gender: Increased carbidopa and levodopa peak concentrations and systemic exposure in females compared with males.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and taste alterations; Dopaminergic therapy in Parkinson's disease (ie, treatment with levodopa and carbidopa combination) is associated with orthostatic hypotension. Patients may experience orthostatic hypotension as they stand up after treatment; especially if lying in dental chair for extended periods of time. Use caution with sudden changes in position during and after dental treatment.

Effects on Bleeding

No information available to require special precautions

Related Information

• Oral Medications That Should Not Be Crushed or Altered

Pharmacotherapy Pearls

To block the peripheral conversion of levodopa to dopamine, ≥70 mg/day of carbidopa is needed. “On-off” (a clinical syndrome characterized by sudden periods of drug activity/inactivity), can be managed by giving smaller, more frequent doses of Sinemet or adding a dopamine agonist or selegiline; when adding a new agent, doses of Sinemet can usually be decreased. Protein in the diet should be distributed throughout the day to avoid fluctuations in levodopa absorption. Levodopa is the drug of choice when rigidity is the predominant presenting symptom.

Conversion from levodopa to carbidopa/levodopa: Note: Levodopa must be discontinued at least 12 hours prior to initiation of levodopa/carbidopa:

Initial dose: Levodopa portion of carbidopa/levodopa should be at least 25% of previous levodopa therapy.

Levodopa <1,500 mg/day: Sinemet or Parcopa (levodopa 25 mg/carbidopa 100 mg) 3-4 times/day

Levodopa ≥1,500 mg/day: Sinemet or Parcopa (levodopa 25 mg/carbidopa 250 mg) 3-4 times/day

Conversion from immediate release carbidopa/levodopa (Sinemet or Parcopa) to Sinemet CR (50/200):

Sinemet or Parcopa [total daily dose of levodopa]/Sinemet CR:

Sinemet or Parcopa (levodopa 300-400 mg/day): Sinemet CR (50/200) 1 tablet twice daily

Sinemet or Parcopa (levodopa 500-600 mg/day): Sinemet CR (50/200) 1¹/₂ tablets twice daily or 1 tablet 3 times/day

Sinemet or Parcopa (levodopa 700-800 mg/day): Sinemet CR (50/200) 4 tablets in 3 or more divided doses

Sinemet or Parcopa (levodopa 900-1,000 mg/day): Sinemet CR (50/200) 5 tablets in 3 or more divided doses

Intervals between doses of Sinemet CR should be 4-8 hours while awake; when divided doses are not equal, smaller doses should be given toward the end of the day

Index Terms

Carbidopa/Levodopa; Levodopa and Carbidopa; Parcopa

References

Aurora RN, Kristo DA, Bista SR, et al, "The Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder in Adults-An Update for 2012: Practice Parameters With an Evidence-Based Systematic Review and Meta-analyses: An American Academy of Sleep Medicine Clinical Practice Guideline," Sleep, 2012, 35(8):1039-62.[PubMed 22851801]

Ball MC and Sagar HJ, "Levodopa in Pregnancy," Mov Disord, 1995, 10(1):115.[PubMed 7885346]

Cook DG and Klawans HL, "Levodopa During Pregnancy," Clin Neuropharmacol, 1985, 8(1):93-5.[PubMed 3978654]

Devos D, “Patient Profile, Indications, Efficacy and Safety of Duodenal Levodopa Infusion in Advanced Parkinson’s Disease,” Mov Disord, 2009, 24(7):993-1000.[PubMed 19253412]

Duodopa (carbidopa/levodopa intestinal gel) [product monograph]. St. Laurent, Quebec, Canada: AbbVie Corporation; February 2018.

Duopa (carbidopa and levodopa) [prescribing information]. North Chicago, IL: AbbVie Inc; December 2019.

Espay AJ, Pagan FL, Walter BL, et al. Optimizing extended-release carbidopa/levodopa in Parkinson disease: consensus on conversion from standard therapy. Neurol Clin Pract. 2017;7(1):86-93. doi: 10.1212/CPJ.0000000000000316.[PubMed 28243505]

Factor SA, “Current Status of Symptomatic Medical Therapy in Parkinson’s Disease,” Neurotherapeutics, 2008, 5(2):164-80.[PubMed 18394561]

Garcia-Borreguero D, Ferini-Strambi L, Kohnen R, et al; European Federation of Neurological Societies; European Neurological Society; European Sleep Research Society. European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society. Eur J Neurol. 2012;19(11):1385-1396. doi: 10.1111/j.1468-1331.2012.03853.x.[PubMed 22937989]

Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1-11. doi: 10.1016/j.sleep.2016.01.017.[PubMed 27448465]

Golbe LI, "Parkinson's Disease and Pregnancy," Neurology, 1987, 37(7):1245-9.[PubMed 3601093]

Lee K, Kang H, Yu H, et al. Thrombocytopenia associated with levodopa treatment. Journal of Movement Disorder. 2013;6:21-22.[PubMed 24868421]

Merchant CA, Cohen G, Mytilineou C, et al, "Human Transplacental Transfer of Carbidopa/Levodopa," J Neural Transm Park Dis Dement Sect, 1995, 9(2-3):239-42.[PubMed 8527007]

Molina JA, Sàinz-Artiga MJ, Fraile A, et al, “Pathologic Gambling in Parkinson's Disease: A Behavioral Manifestation of Pharmacologic Treatment,” Mov Disord, 2000, 15(5):869-72.[PubMed 11009192]

Olanow CW, Watts RL, and Koller WC, “An Algorithm (Decision Tree) for the Management of Parkinson's Disease (2001): Treatment Guidelines,” Neurology, 2001, 56(11 Suppl 5):1-88.[PubMed 11402154]

Rytary (carbidopa and levodopa) [prescribing information]. Hayward, CA: Impax Pharmaceuticals; April 2016.

Rytary (carbidopa and levodopa) [prescribing information]. Bridgewater, NJ: Amneal Specialty, a division of Amneal Pharmaceuticals LLC; December 2019.

Seier M, Hiller A. Parkinson's disease and pregnancy: an updated review. Parkinsonism Relat Disord. 2017;40:11-17. doi: 10.1016/j.parkreldis.2017.05.007.[PubMed 28506531]

Serikawa T, Shimohata T, Akashi M, et al, "Successful Twin Pregnancy in a Patient With Parkin-Associated Autosomal Recessive Juvenile Parkinsonism," BMC Neurol, 2011, 11:72.[PubMed 21682904]

Shulman LM, Minagar A, and Weiner WJ, "The Effect of Pregnancy in Parkinson's Disease," Mov Disord, 2000, 15(1):132-5.[PubMed 10634252]

Silber MH, Ehrenberg BL, Allen RP, et al, “An Algorithm for the Management of Restless Legs Syndrome,” Mayo Clin Proc, 2004, 79(7):916-22.[PubMed 15244390]

Sinemet (carbidopa/levodopa) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; April 2018.

Sinemet (carbidopa/levodopa) [product monograph]. Kirkland, Quebec, Canada: Merck Canada Inc; September 2018.

Sinemet CR (carbidopa/levodopa extended release tablets) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; April 2018.

Sinemet CR ((carbidopa/levodopa extended release tablets) [product monograph]. Kirkland, Quebec, Canada: Merck Canada Inc; September 2018.

Stern MB, “Contemporary Approaches to the Pharmacotherapeutic Management of Parkinson's Disease: An Overview,” Neurology, 1997, 49(1 Suppl 1):2-9.[PubMed 9222162]

Thulin PC, Woodward WR, Carter JH, et al, "Levodopa in Human Breast Milk: Clinical Implications," Neurology, 1998, 50(6):1920-1.[PubMed 9633767]

Tüfekçioğlu Z, Hanağası H, Yalçın Çakmaklı G, et al. Use of anti-Parkinson medication during pregnancy: a case series. J Neurol. 2018;265(8):1922-1929. doi: 10.1007/s00415-018-8937-1.[PubMed 29926223]

Walker SW, Fina A, and Kryger MH, “L-Dopa/Carbidopa for Nocturnal Movement Disorders in Uremia,” Sleep, 1996, 19(3):214-8.[PubMed 8723378]

Weintraub D, Siderowf AD, Potenza MN, et al, “Association of Dopamine Agonist Use With Impulse Control Disorders in Parkinson Disease,” Arch Neurol, 2006, 63(7):969-73.[PubMed 16831966]

Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016;87(24):2585-2593.[PubMed 27856776]

Vignatelli L, Billiard M, Clarenbach P, et al, “EFNS Guidelines on Management of Restless Leg Syndrome and Periodic Limb Movement Disorder in Sleep,” Eur J Neurol, 2006, 13(10):1049-65.[PubMed 16987157]

Zlotnik Y, Giladi N, Hilel A, Shapira Y, Goldstein S, Gurevich T. Levodopa-carbidopa intestinal gel (LCIG) infusion during pregnancy and delivery: first documented case. Parkinsonism Relat Disord. 2014;20(11):1317-1318. doi: 10.1016/j.parkreldis.2014.09.018.[PubMed 25262534]

Brand Names: International

Aldopa (BD); Apo-Levotard (MY); Apodespan (IE); Bidopar (TW); Carbidel (PH); Carbidol (BR); Carbilev (ZA); Cardopar (SG); Carlevod (AR); Cinemet CR (BD); Conrayen (EG); Corbilta (BE); Credanil (MT); Dopadura (DE); Dopicar (IL); Duodopa (AU, HR, IL, JP, RO, TH); DuoDopa (BE, GB, IE); Enpalevo (TW); Grifoparkin (CL, PE); Half Sinemet (IE); Istonil (PY); Kinson (AU); Lavida (PH); Lebocar (AR); Ledocar (PH); Levocar (EG, JO); Levomed (MY); Levomet (HK, SG, TH); Levopa (BD); Nakom (EE, HR, PL, RO, RU, SI, SK); Numient (BE); Pardopa (IN); Parken (CO); Parkimet (PH); Parkimet CR (PH); Parkomet (AE, BH, CY, IQ, IR, JO, KW, LY, OM, SY, YE); Perkin (KR); Racovel (MX); Saniter (CL); Sindopa (NZ); Sinedin (PH); Sinedopa (HK, MY); Sinedopa Mite (MY); Sinemet (AT, AU, BB, BR, CH, CY, CZ, DE, DK, EC, EE, EG, ES, FI, FR, GB, GR, HK, IE, IS, IT, JO, KR, KW, LB, LT, MT, MX, MY, NL, NO, NZ, PK, PL, PT, PY, RU, SA, SE, SK, TH, TR, TW, UY, VE); Sinemet 25 100 (HK, MY, PH); Sinemet CR (AU, BB, BG, CH, CN, CY, CZ, EG, GB, GR, HK, IL, IT, KR, KW, LT, MY, NL, NZ, PE, PH, PT); Sinemet Retard (ES); Sulconar (PE); Syndopa (BD, VN); Tidomet (PH, TH); Tidomet CR (PH); Tidomet Forte (IN); Tidomet L.S. (IN); Tidomet Plus (IN); Vedilma (VN); Wendica (VN); Zuades (BE)

Last Updated 2/27/20