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Carbidopa and Levodopa

Pronunciation

Pronunciation

(kar bi DOE pa & lee voe DOE pa)

Index Terms

  • Carbidopa/Levodopa
  • Levodopa and Carbidopa

Dosage Forms

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

Capsule Extended Release, Oral:

Rytary:

23.75/95: Carbidopa 23.75 mg and levodopa 95 mg

36.25/145: Carbidopa 36.25 mg and levodopa 145 mg

48.75/195: Carbidopa 48.75 mg and levodopa 195 mg

61.25/245: Carbidopa 61.25 mg and levodopa 245 mg

Suspension, Enteral:

Duopa: Carbidopa 4.63 mg and levodopa 20 mg per 1 mL (100 mL)

Tablet, Oral:

Sinemet:

10/100: Carbidopa 10 mg and levodopa 100 mg

25/100: Carbidopa 25 mg and levodopa 100 mg

25/250: Carbidopa 25 mg and levodopa 250 mg

Generic: 10/100: Carbidopa 10 mg and levodopa 100 mg; 25/100: Carbidopa 25 mg and levodopa 100 mg; 25/250: Carbidopa 25 mg and levodopa 250 mg

Tablet Extended Release, Oral:

Sinemet CR:

25/100: Carbidopa 25 mg and levodopa 100 mg

50/200: Carbidopa 50 mg and levodopa 200 mg

Generic: 25/100: Carbidopa 25 mg and levodopa 100 mg; 50/200: Carbidopa 50 mg and levodopa 200 mg

Tablet, orally disintegrating:

Parcopa:

10/100: Carbidopa 10 mg and levodopa 100 mg [contains phenylalanine 3.4 mg/tablet; mint flavor] [DSC]

25/100: Carbidopa 25 mg and levodopa 100 mg [contains phenylalanine 3.4 mg/tablet; mint flavor] [DSC]

25/250: Carbidopa 25 mg and levodopa 250 mg [contains phenylalanine 8.4 mg/tablet; mint flavor] [DSC]

Generic: 10/100: Carbidopa 10 mg and levodopa 100 mg; 25/100: Carbidopa 25 mg and levodopa 100 mg; 25/250: Carbidopa 25 mg and levodopa 250 mg

Brand Names: U.S.

  • Duopa
  • Parcopa [DSC]
  • Rytary
  • Sinemet
  • Sinemet CR

Pharmacologic Category

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

Pharmacology

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

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

Excretion

Urine

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

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.

Special Populations: Elderly

The AUC and Cmax of levodopa may be increased in elderly patients.

Special Populations: Gender

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

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).

Use: Unlabeled

Restless leg syndrome (Silber, 2004)

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: 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).

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% (~20% [Canadian labeling]) 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:

U.S. labeling: Increase by 1 tablet daily or every other day, as necessary, to 2 tablets 4 times daily

Canadian labeling: Increase by 1 tablet every 3 days

Carbidopa 25 mg/levodopa 100 mg:

U.S. labeling: Increase by 1 tablet daily or every other day

Canadian labeling: Increase by 1 tablet every 3 days

Carbidopa 25 mg/levodopa 250 mg:

U.S. labeling: Increase by 1/2 or 1 tablet daily or every other day

Canadian labeling: Increase by 1 tablet every day or every other day

Controlled-release tablet:

Patients not currently receiving levodopa: Initial:

U.S. labeling: Carbidopa 50 mg/levodopa 200 mg 2 times daily, at intervals not <6 hours

Canadian labeling: Carbidopa 25 to 50 mg/levodopa 100 to 200 mg 2 times daily, at intervals not <6 hours; initial dosing should not exceed levodopa 600 mg daily

Patients currently receiving levodopa: Note: Discontinue levodopa at least 12 hours (at least 8 hours [Canadian labeling]) 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 capsules are not interchangeable with other carbidopa/levodopa products.

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 extended-release capsules: Initial: Initial dose based off of total current daily dose of levodopa in immediate-release carbidopa/levodopa as follows (frequency of dosing may be increased to a maximum of 5 times daily if needed and tolerated):

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 (maximum dose: carbidopa 612.5 mg/levodopa 2,450 mg per day).

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

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 (RLS) (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 with RLS symptoms

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

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

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling; titrate dose cautiously in severe impairment. Use is contraindicated in uncompensated renal disease.

Dosing: Hepatic Impairment

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

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling; titrate dose cautiously in severe impairment. Use is contraindicated in uncompensated hepatic disease.

Dosing: Adjustment for Toxicity

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.

Reconstitution

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):333-7.11392406

Administration

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 naso-jejunal 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.

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 for future use).

Oral 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.

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

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).

Drug Interactions

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

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. Consider therapy modification

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

Antipsychotic Agents (First Generation [Typical]): Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). 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. 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. Consider therapy modification

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

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

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Levodopa. Monitor therapy

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

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

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

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

Fosphenytoin: May diminish the therapeutic effect of Levodopa. Monitor therapy

Glycopyrrolate (Systemic): May decrease the serum concentration of Levodopa. Monitor therapy

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

Iron Salts: 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 Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Isoniazid: May diminish the therapeutic effect of Levodopa. Monitor therapy

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

MAO Inhibitors: Levodopa may enhance the adverse/toxic effect of MAO Inhibitors. Of particular concern is the development of hypertensive reactions when levodopa is used with nonselective MAOI. Management: The concomitant use of nonselective monoamine oxidase inhibitors (MAOIs) and levodopa is contraindicated. Discontinue the nonselective MAOI at least two weeks prior to initiating levodopa. Monitor patients taking a selective MAOIs and levodopa. Consider therapy modification

Methionine: May diminish the therapeutic effect of Levodopa. Probably only with large doses of methionine. Data was generated using 4.5gm daily. Consider therapy modification

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

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

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

Multivitamins/Fluoride (with ADE): May diminish the therapeutic effect of Levodopa. Specifically, pyridoxine may diminish the effects of levodopa, when used in the absence of a dopa decarboxylase inhibitor. Management: Concurrent use of a multivitamin and levodopa (without carbidopa) should be avoided. 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. Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May diminish the therapeutic effect of Levodopa. Specifically, pyridoxine may diminish the effects of levodopa, when used in the absence of a dopa decarboxylase inhibitor. Management: Concurrent use of a multivitamin and levodopa (without carbidopa) should be avoided. Consider therapy modification

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

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

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

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. 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. Consider therapy modification

Papaverine: May enhance the hypotensive effect of Levodopa. Papaverine may diminish the therapeutic effect of Levodopa. Monitor therapy

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

Phenytoin: May diminish the therapeutic effect of Levodopa. Monitor therapy

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

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

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

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

Sapropterin: May enhance the adverse/toxic effect of Levodopa. Monitor therapy

Sulpiride: May diminish the therapeutic effect of Levodopa. Levodopa may diminish the therapeutic effect of Sulpiride. Avoid combination

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

Adverse Reactions

Frequency not always defined.

Cardiovascular: Orthostatic hypotension (≤73%), peripheral edema (Duopa 8%), hypertension (≤8%), ischemia (≤2%), cardiac arrhythmia, chest pain, edema, flushing, hypotension, myocardial infarction, palpitations, phlebitis, syncope

Central nervous system: Dizziness (6% to 19%), headache (13% to 17%; oral 1% to 5%), depression (with or without suicidal tendencies; Duopa 11%), insomnia (6% to 9%), anxiety (2% to 8%), confusion (2% to 8%), abnormal dreams (2% to 6%), polyneuropathy (Duopa 5%), sleep disorder (Duopa 5%), hallucination (1% to 5%), psychosis (1% to 5%), abnormal behavior, abnormal gait, abnormality in thinking, agitation, ataxia, decreased mental acuity, delirium, delusions, dementia, disorientation, drowsiness, euphoria, extrapyramidal reaction, falling, fatigue, glossopyrosis, Horner syndrome (reactivation), impulse control disorder, malaise, memory impairment, narcolepsy, nervousness, neuroleptic malignant syndrome, nightmares, numbness, on-off phenomenon, paranoia, paresthesia, pathological gambling, peripheral neuropathy, seizure (causal relationship not established), trismus

Dermatologic: Excessive granulation tissue (Duopa, 5%), skin rash (≤5%), alopecia, diaphoresis, discoloration of sweat

Endocrine & metabolic: Abnormal alanine aminotransferase, abnormal alkaline phosphatase, abnormal aspartate transaminase, abnormal lactate dehydrogenase, glycosuria, hot flash, hyperglycemia, hypokalemia, increased libido (including hypersexuality), increased uric acid, weight gain, weight loss

Gastrointestinal: Nausea (3% to 30%), constipation (≤22%), hiatal hernia (6% to 8%), xerostomia (7%), intestinal obstruction (Duopa 5%), diarrhea (≤5%), dyspepsia (≤5%), ileus (≤5%), vomiting (≤5%), abdominal distress, abdominal pain, anorexia, bruxism, discoloration of saliva, duodenal ulcer, dysgeusia, dysphagia, flatulence, gastrointestinal hemorrhage, heartburn, hiccups, sialorrhea, sore throat

Genitourinary: Bacteriuria (1% to 5%), difficulty in micturition, priapism, proteinuria, urinary frequency, urinary incontinence, urinary retention, urinary tract infection, urine discoloration

Hematologic & oncologic: Leukocyturia (1% to 5%), agranulocytosis, anemia, decreased hematocrit, decreased hemoglobin, hemolytic anemia, IgA vasculitis, leukopenia, malignant melanoma

Hepatic: Abnormal bilirubin levels

Hypersensitivity: Hypersensitivity reaction (angioedema, bullous lesions [including pemphigus-like reactions], pruritus, urticaria)

Immunologic: Abnormal Coombs test

Local: Erythema at injection site (Duopa 19%), application site discharge (Duopa 11%)

Neuromuscular & skeletal: Dyskinesia (12% to 17%; Rytary 2% to 5%; including choreiform, dystonic and other involuntary movements), increased creatine phosphokinase (≤17%), back pain, excessive tremors, leg pain, muscle cramps, muscle twitching, shoulder pain, weakness

Ophthalmic: Blepharospasm, blurred vision, diplopia, glaucoma, increased intraocular pressure, mydriasis, oculogyric crisis (may be associated with acute dystonic reactions)

Renal: Increased blood urea nitrogen (≤13%)

Respiratory: Atelectasis (Duopa 8%), oropharyngeal pain (Duopa 8%), upper respiratory tract infection (Duopa 8%; Sinemet and Sinemet CR ≤2%), cough, dyspnea, hoarseness

Miscellaneous: Procedural complications (from device insertion: Duopa 57%), fever (≤5%)

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. The Canadian labeling contraindicates use in patients with suspicious, undiagnosed skin lesions or history of melanoma.

• 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; use in hepatic disease is contraindicated in Canadian labeling.

• 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. Duodopa Canadian labeling recommends obtaining vitamin B12, vitamin B6, folic acid, homocysteine, and methylmalonic acid levels prior to initiation and regularly thereafter during therapy (Duodopa Canadian product monograph, 2014).

• 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; use in renal disease is contraindicated in Canadian labeling.

• 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.

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, 2014).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies using this combination. 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 information related to the use of carbidopa/levodopa in pregnant women is limited (Ball, 1995; Cook, 1985; Golbe, 1987; Serikawa, 2011; Shulman, 2000). 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).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nightmares, fatigue, dry mouth, insomnia, vomiting, or nausea. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion); confusion; behavioral changes; hallucinations; uncontrollable urges; narcolepsy; skin growth; mole changes; abnormal movements; severe headache; jaundice; 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; severe constipation; abdominal pain; angina; tachycardia; abnormal heartbeat; chills; pharyngitis; bruising; bleeding; severe dizziness; passing out; severe loss of strength and energy; or signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, tachycardia, abnormal heartbeat, or sweating a lot) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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