VA Class:CN500

AHFS Class:

• Dopamine Precursors 28:36.16

Generic Name(s):

• Levodopa

• Carbidopa

• Carbidopa and Levodopa

Levodopa is the levorotatory isomer of dihydroxyphenylalanine and the metabolic precursor of dopamine, and carbidopa is a decarboxylase inhibitor that inhibits the peripheral decarboxylation of levodopa to dopamine.

Parkinsonian Syndrome

Levodopa is used in the symptomatic treatment of parkinsonian syndrome, including parkinson disease (paralysis agitans) and parkinsonism resulting from encephalitis (postencephalitic parkinsonism), carbon monoxide intoxication, or manganese intoxication. Levodopa is commercially available in various fixed-combination preparations with carbidopa for this use.104,105,107,117

Carbidopa is used to inhibit the decarboxylation of peripheral levodopa and increase the amount of levodopa available for transport to the brain.107,108 Concomitant administration of levodopa and carbidopa generally decreases levodopa dosage requirements by 70-80%, reduces the adverse peripheral effects of levodopa decarboxylation (e.g., nausea and vomiting), allows for more rapid dosage titration, and may provide a smoother response to levodopa. Certain patients who responded poorly to levodopa alone have improved when carbidopa was administered concomitantly; however, patients with markedly irregular “on-off” responses to levodopa (see Nervous System and Muscular Effects under Cautions) usually have not benefited from the addition of carbidopa. Carbidopa has no therapeutic effect when given alone to patients with parkinsonian syndrome and should be used only in conjunction with levodopa. A single-entity carbidopa preparation is commercially available for use in patients who are already receiving levodopa and carbidopa, but require additional carbidopa to reduce nausea and vomiting and/or facilitate more rapid dosage titration.108

Levodopa (in combination with carbidopa) currently is the most effective drug for relieving the motor symptoms of parkinsonian syndrome and is considered by many clinicians to be the drug of choice for this use. Levodopa completely or partially relieves akinesia, rigidity, and tremor in about 80% of patients treated, and improves functional ability and other secondary motor manifestations such as those affecting gait, postural stability, facial expression, swallowing, speech, and handwriting. Levodopa also may be useful in the management of other symptoms of parkinsonian syndrome including dysphagia, sialorrhea, and seborrhea. Levodopa therapy often produces a general alerting response, increased vigor, and a sense of well-being. However, the effectiveness of levodopa decreases over time and most patients develop motor complications such as motor fluctuations (e.g., end-of-dose failure, “on-off” phenomenon, akinesia) and dyskinesias (drug-induced involuntary movements) with long-term use.101,105,115,157 Strategies for reducing the risk of motor complications include adjusting the dosage of levodopa or adding other antiparkinsonian agents such as a dopamine receptor agonist (e.g., pramipexole, ropinirole, rotigotine), selective monoamine oxidase (MAO)-B inhibitor (e.g., rasagiline, safinamide, selegiline), catechol- O -methyltransferase (COMT) inhibitor (e.g., entacapone), or amantadine.101,115,157 Alternatively, a levodopa-sparing strategy may be used in which other antiparkinsonian agents are initiated first and then levodopa is added when these other therapies no longer provide adequate symptom control.101,115,116,123,157 This delayed approach is often used in younger patients who have a higher risk of developing motor complications and a longer life expectancy.101,116,123,157 The appropriate treatment approach should be individualized based on the patient's age, symptoms, cognitive status, disease severity, adverse effects, and cost of therapy.101,120,122,123,124,125

Motor complications associated with long-term use of standard oral formulations of levodopa are thought to result from fluctuating plasma concentrations of the drug due to its short half-life, delayed gastric emptying, and erratic absorption.128,129,132,133 Several non-oral preparations of levodopa have been developed to overcome these challenges and may be useful alternatives in patients with advanced parkinson disease whose motor symptoms are not effectively controlled with oral therapies.118,126,129,130,133 One such preparation is levodopa powder for oral inhalation, which is indicated for use as adjunctive therapy to levodopa-carbidopa for the intermittent treatment of “off” episodes in patients with parkinson disease.126 Inhaled levodopa has been shown to be effective only in patients who are already receiving levodopa-carbidopa therapy.126,128 Some clinicians state that this form of levodopa may be particularly useful in patients with severely delayed gastric emptying.129 Efficacy of levodopa oral inhalation powder has been established in a 12-week randomized, double-blind, placebo-controlled study in patients with parkinson disease who were experiencing at least 2 hours of “off” time per day while receiving levodopa-carbidopa therapy.126,128 Improvement in motor function (assessed by the change in Unified Parkinson Disease Rating Scale [UPDRS] motor score from predose to 30 minutes postdose) was substantially greater in patients receiving inhaled levodopa (84 mg) compared with those receiving placebo; in addition, 58% of levodopa-treated patients returned to an “on” state, which was sustained through 60 minutes postdose.126,128

Another non-oral preparation of levodopa that may be used in advanced parkinson disease patients experiencing motor complications is carbidopa-levodopa enteral suspension.118,130 The enteral suspension is delivered continuously over a 16-hour period daily through a percutaneous endoscopic gastrojejunostomy (PEG-J) tube; this delivery method bypasses the stomach and eliminates the variability associated with gastric emptying, providing a more stable plasma concentration of levodopa.118,130 Efficacy of carbidopa-levodopa enteral infusion has been evaluated in several controlled prospective studies and observational studies.118,130,131,132,133,134,135 These studies have consistently demonstrated that treatment with the enteral suspension decreases total daily “off” time and increases “on” time without troublesome dyskinesia in patients with advanced parkinson disease; some studies also demonstrated improvements in nonmotor symptoms and quality of life measures.118,131,132,133,134,135 In a 12-week randomized, double-dummy, double-blind, active-controlled study, mean “off” time decreased by 4 hours following treatment with carbidopa-levodopa enteral suspension compared with a decrease of 2 hours with a standard oral immediate-release carbidopa-levodopa preparation.118,131 Results of longer-term studies suggest that the benefits of enterally administered continuous carbidopa-levodopa therapy are sustained over time; the longest reported duration of therapy is 16 years.132,133,134,135

Other Uses

Although levodopa is not effective in the management of extrapyramidal effects induced by antipsychotic agents and is not generally useful in the management of other neurologic diseases, the drug may be of some benefit in conditions in which marked akinesia is present. Levodopa is not useful in the treatment of psychiatric disorders.

Administration

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

In patients with moderate to severe motor fluctuations, better global improvement may be achieved in some patients when extended-release rather than conventional tablet preparations of carbidopa-levodopa are used. However, some studies have not found a substantial difference in “off” time between extended-release and immediate-release tablet preparations in such patients. In patients without motor fluctuations, the preparations were comparably effective but less frequent dosing was required with the extended-release preparation. Use of the extended-release capsule formulation of carbidopa-levodopa has been shown to improve “off” time compared with immediate-release preparations in patients with advanced parkinson disease.117,119 (See Absorption under Pharmacokinetics.)

Patients receiving other antiparkinsonian agents may continue taking these drugs while carbidopa-levodopa is administered; however, dosage adjustments of these drugs may be necessary.108

Whenever a general anesthetic is required, levodopa may be continued as long as the patient is able to take fluids and medication orally.104,105,107 If therapy is interrupted, the patient should be observed for neuroleptic malignant syndrome and the usual daily dose may be given as soon as the patient can take oral medication.104,105,107

Oral Administration

Fixed-combination carbidopa-levodopa oral dosage forms include conventional tablets, orally disintegrating tablets, extended-release tablets, and extended-release capsules.104,105,107,117 Carbidopa-levodopa conventional tablets and orally disintegrating tablets contain a 1:4 or 1:10 ratio of carbidopa to levodopa.104,107 Carbidopa-levodopa extended-release tablets and capsules contain a 1:4 ratio of carbidopa to levodopa.105,117 Carbidopa and levodopa also are commercially available in fixed combination with entacapone (Stalevo^®) in a tablet preparation containing a 1:4 ratio of carbidopa to levodopa combined with 200 mg of entacapone.106 Carbidopa also is commercially available as single-entity conventional tablets.108

Orally Disintegrating Carbidopa-Levodopa Tablets

Patients receiving carbidopa-levodopa orally disintegrating tablets should be instructed to gently remove a tablet from the bottle with dry hands just prior to administration.104 The tablet should then be immediately placed on the tongue to dissolve (usually within seconds) and swallowed with saliva; administration with liquid is not necessary.104

Extended-release Carbidopa-Levodopa Tablets

Extended-release tablets of carbidopa-levodopa can be administered as whole or halved tablets; the tablets should be swallowed intact and not chewed or crushed.105 Patients should be advised that the extended-release tablets are designed to release the drugs over a 4- to 6-hour period and of the importance of taking the drug at regular intervals according to the prescribed schedule.105 Patients also should be advised that the onset of effect with the morning dose of extended-release tablets occasionally may be delayed up to 1 hour compared with that experienced with conventional tablets.105

Extended-release Carbidopa-Levodopa Capsules

Extended-release carbidopa-levodopa capsules may be administered orally with or without food; however, administration with a high-fat, high-calorie meal may delay absorption of levodopa by about 2 hours.117 The capsules should be swallowed whole without chewing, dividing, or crushing.117 Patients with difficulty swallowing may open the capsules and sprinkle the entire contents on a small amount of applesauce (e.g., 1-2 tablespoons); the mixture should be administered immediately and not stored for later use.117

Carbidopa, Levodopa, and Entacapone Fixed Combination (Stalevo®)

The fixed-combination preparation containing carbidopa, levodopa, and entacapone (Stalevo^®) generally is used in patients receiving stable dosages of carbidopa, levodopa, and entacapone equivalent to those in the combination preparation.106 The fixed-combination preparation also may be used in certain patients receiving stable dosages of carbidopa and levodopa equivalent to those in the fixed-combination preparation when a decision has been made to add entacapone to the regimen.106 Stalevo^® tablets should not be divided, and only one tablet should be administered per dosing interval.106

Oral Inhalation

Levodopa powder is administered by oral inhalation using a special inhalation device (Inbrija^® inhaler).126 The drug is commercially available as 42-mg capsules for oral inhalation; a total of 2 capsules should be administered (one at a time) to obtain the recommended dose.126 The capsules are for oral inhalation only and must not be swallowed as the intended effect will not be obtained.126 Inhaled levodopa is intended to be administered on an intermittent basis only in patients who are already receiving treatment with a carbidopa-levodopa combination.126

The inhalers and capsules should be stored in a dry place at room temperature; capsules should not be stored in the inhalers.126 The capsules should not be removed from their foil-sealed blister packaging until immediately prior to use.126 To administer a dose, the first capsule should be loaded into the inhaler.126,129 Before inhaling the dose, the patient should exhale as completely as possible.126 While keeping the inhaler upright, the patient should place the mouthpiece of the inhaler between the lips and inhale deeply and slowly through the inhaler until a whirling sound is felt or heard; this is an indication that the inhaler is working.126,129 After inhaling the contents of a capsule, the patient should hold their breath for 5 seconds before exhaling.126,129 These steps should be repeated with the second capsule to complete the full dose.126 Patients should use a new inhaler with each new carton of levodopa inhalation powder.126,129 The manufacturer's prescribing information should be consulted for additional details on administration of levodopa powder for oral inhalation.126

Enteral Administration

Carbidopa-levodopa enteral suspension is administered as a 16-hour continuous enteral infusion through a PEG-J tube using a portable infusion device (i.e., CADD^® Legacy 1400 pump).118 Placement and removal of the PEG-J tube should be performed by a gastroenterologist or other experienced healthcare provider.118 A nasojejunal (NJ) tube may be used for short-term administration of the drug (e.g., as a trial to determine whether the patient responds to therapy and can manage the device) until a permanent PEG-J tube can be established.118,133 At the end of the daily 16-hour administration period, the patient's PEG-J tube should be disconnected from the pump and flushed with room temperature potable water.118

The enteral suspension is commercially available in single-use cassettes containing 4.63 mg of carbidopa and 20 mg of levodopa per mL.118 Cassettes should be stored in the freezer (-20°C) and thawed in the refrigerator (2-8°C) prior to dispensing.118 Cassettes should be protected from light and kept in their cartons prior to use.118 Prior to administration, the cassette should be removed from the refrigerator and allowed to reach room temperature for 20 minutes; failure to administer the drug at room temperature may result in a subtherapeutic response.118 Cassettes are for single-use only and should not be used for longer than 16 hours; the cassette should be discarded after this time period even if some drug product remains.118

The manufacturer's labeling should be consulted for more detailed information on administration of carbidopa-levodopa enteral suspension.118

Dosage

Parkinsonian Syndrome

Dosage of carbidopa-levodopa must be carefully adjusted according to individual requirements, response, and tolerance.104,105,106,107,108 Because patients receiving carbidopa dosages lower than 70-100 mg daily are likely to experience levodopa-induced nausea and vomiting, the minimum recommended daily dosage of carbidopa is 70-100 mg.104,105,107,108

Because of the risk of precipitating a symptom complex resembling neuroleptic malignant syndrome (NMS), patients should be observed closely if levodopa dosage is reduced abruptly or the drug is discontinued; when discontinuing treatment, dosage should be reduced gradually.105,107,117 (See Precautions and Contraindications under Cautions.)

Immediate-release Oral Carbidopa-Levodopa Preparations

When immediate-release conventional tablets or orally disintegrating tablets of carbidopa and levodopa are used in patients with parkinsonian syndrome, therapy usually is initiated with a preparation containing 25 mg of carbidopa and 100 mg of levodopa; an initial dosage of 1 tablet (25 mg carbidopa/100 mg levodopa) 3 times daily is recommended.104,107 Dosage may be increased by 1 tablet every 1 or 2 days until a maximum dosage of 8 tablets daily (200 mg of carbidopa and 800 mg of levodopa) is reached.104,107 If an immediate-release combination preparation containing 10 mg of carbidopa and 100 mg of levodopa is used, therapy usually is initiated with 1 tablet 3 or 4 times daily; however, this dosage will not provide an adequate amount of carbidopa for many patients.104,107 Dosage may be increased by 1 tablet every 1 or 2 days until a maximum dosage of 8 tablets daily (80 mg of carbidopa and 800 mg of levodopa) is reached.104,107

Maintenance therapy should be individualized and adjusted according to the desired therapeutic response.104,107 Patients should receive at least 70-100 mg of carbidopa daily during maintenance therapy, since peripheral aromatic l-amino acid decarboxylase is saturated at this dosage and patients receiving a lower daily dosage of carbidopa are likely to experience nausea and vomiting.104,107 Use of combination preparations containing a 1:10 ratio of carbidopa to levodopa may not provide an adequate amount of carbidopa.104,107 If a greater proportion of carbidopa is required in the combination, one tablet of an immediate-release preparation containing 25 mg of carbidopa and 100 mg of levodopa may be substituted for one tablet of the preparation containing 10 mg of carbidopa and 100 mg of levodopa.104,107 If additional carbidopa is still required, a 25-mg dose of carbidopa (as the single-entity tablet preparation) may be given with each first daily dose of carbidopa-levodopa, and additional 12.5-mg or 25-mg doses of carbidopa may be administered with each subsequent dose of carbidopa-levodopa as needed.108 If patients require higher dosages of levodopa while receiving an immediate-release combination preparation containing 100 mg of levodopa, patients should be switched to a combination preparation containing 250 mg of levodopa.104,107

In general, the single-entity carbidopa preparation may be given with any dose of carbidopa-levodopa as required for optimum therapeutic response.108 Because experience with carbidopa daily dosages greater than 200 mg is limited, dosage of carbidopa should not exceed 200 mg daily.108

Extended-release Carbidopa-Levodopa Tablets

Bioavailability of levodopa from the extended-release tablet formulation of carbidopa-levodopa is approximately 70-75% of immediate-release preparations; increased daily dosages may therefore be required to achieve the same level of symptomatic relief provided by immediate-release preparations.105 Dosage should be individualized based on patient tolerance and clinical response.105

Patients being transferred from an immediate-release carbidopa-levodopa preparation should receive an initial dosage of the extended-release tablets that provides approximately 10% more levodopa daily than they previously were receiving with the immediate-release preparation.105 In some patients, up to 30% more levodopa daily may be required initially depending on clinical response.105

For patients in whom levodopa therapy is initiated with extended-release carbidopa-levodopa tablets (i.e., those not being switched from existing levodopa therapy), an initial dosage of carbidopa 50 mg and levodopa 200 mg (as 1 extended-release tablet) twice daily is recommended.105 Initial dosage in such patients should not be given at intervals of less than 6 hours.105

Following initiation of therapy, doses and/or dosing intervals can be increased or decreased according to patient tolerance and clinical response.105 Most patients are treated adequately with dosages providing 400-1600 mg of levodopa daily, administered in divided doses at intervals ranging from 4-8 hours while awake.105 Higher dosages (600 mg of carbidopa and 2400 mg or more of levodopa) and shorter intervals (less than 4 hours) have been used with the extended-release tablets but usually are not recommended.105 If the dosing interval is shorter than 4 hours and/or the divided doses are not equal, it is recommended that the smaller doses be given at the end of the day.105 Dosage of the extended-release tablets generally should be adjusted no more frequently than at 3-day intervals.105 Some patients with advanced disease may benefit from the addition of doses of a conventional preparation of carbidopa-levodopa during brief periods of the day when additional levodopa is needed for symptomatic control.105

Extended-release Carbidopa-Levodopa Capsules

The extended-release capsule formulation of carbidopa-levodopa is less bioavailable than immediate-release preparations and increased daily dosages generally are required to achieve the same level of symptomatic relief provided by immediate-release preparations.117 Dosage should be individualized based on patient tolerance and clinical response.117

In patients transferring from therapy with immediate-release carbidopa-levodopa preparations to the extended-release capsules, the patient's current total daily dosage of levodopa should be calculated and used to determine an appropriate starting dosage of the extended-release capsules (see Table 1).117

Following conversion, the dose and/or dosing intervals can be increased or decreased as necessary based on patient tolerance and clinical response.117 In patients currently receiving carbidopa-levodopa in combination with a catechol- O -methyltransferase (COMT) inhibitor (e.g., entacapone), the total initial daily dose of levodopa in the extended-release capsule may need to be increased.117

If extended-release capsules of carbidopa-levodopa are used in levodopa-naive patients (i.e., those not being switched from existing carbidopa-levodopa therapy), the recommended initial dosage is carbidopa 23.75 mg and levodopa 95 mg administered 3 times daily for the first 3 days.117 Dosage may be increased to carbidopa 36.25 mg and levodopa 145 mg 3 times daily on the fourth day of treatment.117 Thereafter, dosage may be increased based on patient tolerance and clinical response up to a maximum recommended dosage of carbidopa 97.5 mg and levodopa 390 mg 3 times daily; if needed, dosing frequency may be increased to a maximum of 5 times daily.117 Patients should be maintained on the lowest possible dosage necessary to achieve adequate symptom control while minimizing adverse effects.117

The manufacturer recommends a maximum daily dose of carbidopa 612.5 mg and levodopa 2450 mg when using the extended-release capsules.117

Carbidopa, Levodopa, and Entacapone Fixed Combination

For patients transferring from therapy with carbidopa-levodopa to the fixed-combination preparation containing carbidopa, levodopa, and entacapone (Stalevo^®), recommendations are available for transferring patients currently receiving carbidopa-levodopa preparations containing a 1:4 ratio of carbidopa to levodopa.106

Patients who are currently receiving entacapone 200 mg with each dose of carbidopa-levodopa (as a conventional tablet preparation) can be switched to the corresponding strength of the fixed-combination preparation containing the same amounts of carbidopa and levodopa.106 The manufacturer states that there is no experience to date in transitioning patients currently receiving extended-release preparations of carbidopa-levodopa or carbidopa-levodopa preparations not containing a 1:4 ratio to the fixed-combination preparation Stalevo^®.106

For patients initiating entacapone therapy, recommendations regarding use of the fixed-combination preparation Stalevo^® should be individualized according to the current levodopa dosage and the presence of dyskinesias.106 Patients treated with carbidopa-levodopa conventional tablets who are receiving more than 600 mg of levodopa daily or have a history of moderate or severe dyskinesias before initiation of entacapone therapy are likely to require a reduction in levodopa dosage.106 In such patients, dosage should first be adjusted by administering carbidopa-levodopa (1:4 ratio) and entacapone as separate preparations.106 If it is determined that optimum maintenance dosages of levodopa, carbidopa, and entacapone correspond to the doses in the commercial combination product, the fixed-combination preparation containing carbidopa, levodopa, and entacapone (Stalevo^®) may be used.106 For patients receiving levodopa dosages of 600 mg or less daily (conventional tablets, 1:4 ratio) and who do not have dyskinesias, an attempt can be made to initiate entacapone therapy with the fixed-combination preparation containing carbidopa, levodopa, and entacapone.106 The initial dosage of the fixed-combination preparation of carbidopa, levodopa and entacapone should provide the same dosage of carbidopa and levodopa that the patient currently is taking.106 However, a reduction in the dosage of carbidopa-levodopa or entacapone may be necessary.106 Because dosage of carbidopa, levodopa, or entacapone cannot be adjusted individually using the fixed-combination preparation, administration of carbidopa-levodopa and entacapone as separate preparations may be necessary.106

Because there is limited clinical experience with entacapone dosages exceeding 1.6 g daily, the maximum recommended dosage of fixed-combination preparations containing carbidopa 12.5-37.5 mg, levodopa 50-150 mg, and entacapone 200 mg (Stalevo^® 50, 75, 100, 125, and 150) is 8 tablets daily.106 Because there is limited clinical experience with carbidopa dosages exceeding 300 mg daily, the maximum recommended dosage of the fixed-combination preparation containing carbidopa 50 mg, levodopa 200 mg, and entacapone 200 mg (Stalevo^® 200) is 6 tablets daily.106

Levodopa Oral Inhalation

The recommended dosage of levodopa oral inhalation powder for the intermittent treatment of “off” episodes in adults with parkinson disease is 84 mg (contents of two 42-mg capsules) as needed, up to 5 times daily.126 The maximum recommended dose per “off” period is 84 mg and the maximum recommended daily dosage is 420 mg.126

Carbidopa-Levodopa Enteral Suspension

Dosage of carbidopa-levodopa enteral suspension consists of 3 components: a morning dose (administered usually over 10-30 minutes), a continuous infusion (administered over 16 hours), and additional doses (i.e., extra doses) as needed for breakthrough symptoms.118,133 Prior to initiating treatment with the enteral suspension, patients should be converted from all forms of levodopa to oral immediate-release carbidopa-levodopa tablets (1:4 ratio).118 The initial dosage of the enteral suspension is based on the patient's previous daily dosage of oral levodopa (taken the day prior to initiation of enteral therapy).118

The initial morning dose of carbidopa-levodopa enteral suspension (in mL) should be determined as follows.118 The total amount of levodopa (in mg) in the first dose of immediate-release carbidopa-levodopa taken the previous day should be calculated.118 This dose (in mg) should then be converted to mL by multiplying the dose by 0.8 and dividing by 20 mg/mL; an additional 3 mL should be added to account for priming volume.118

The initial continuous dose of carbidopa-levodopa enteral suspension (in mL) should be determined as follows.118 The total amount of levodopa from oral immediate-release carbidopa-levodopa doses throughout the previous day (over 16 waking hours) should be calculated; doses taken at night should not be used in the calculation.118 The first oral levodopa dose taken the previous day (determined in the morning dose calculation) should be subtracted from the total oral levodopa dose taken over 16 hours; the resulting value should be divided by 20 mg/mL to obtain the continuous dose that should be administered over 16 hours.118 The hourly infusion rate (in mL/hour) is then calculated by dividing the continuous dose by 16 hours.118

After the first day of treatment, the daily morning dose and continuous dose of carbidopa-levodopa should be titrated based on individual response and tolerability until a stable dosage is obtained.118 The maximum recommended daily dose is 2000 mg of levodopa (i.e., one cassette per day).118 If the patient experiences persistent or numerous “off” periods during the 16-hour infusion period, an increase in the continuous dose or extra doses may be given.118 In patients who require overnight treatment, an extended-release formulation of oral levodopa-carbidopa may be taken at bedtime after stopping the enteral infusion.133 If dyskinesias or other adverse effects occur, a decrease in the continuous dose or temporary interruption in therapy may be considered until adverse effects subside.118 The manufacturer's prescribing information should be consulted for recommendations on dosage adjustments.118

Sudden discontinuance of therapy or rapid dose reduction should be avoided; when discontinuing therapy with the enteral suspension, dosage should be tapered or patients may be switched to oral immediate-release carbidopa-levodopa therapy.118

Adverse effects occur in most patients who receive levodopa (with or without carbidopa). Adverse effects of levodopa are numerous and are usually dose dependent and reversible. The incidence of levodopa-induced nausea and vomiting is generally less when carbidopa is used in conjunction with the drug. However, concomitant administration of carbidopa does not decrease adverse reactions resulting from the central effects of levodopa; some CNS effects may occur at a lower dosage and more rapidly during therapy with levodopa-carbidopa combinations than with levodopa alone. The adverse effect profile of extended-release carbidopa-levodopa tablets is similar to conventional (immediate-release) preparations.105

Whenever the fixed-combination preparation containing carbidopa, levodopa, and entacapone (Stalevo^®) is used, consideration should be given to the possible adverse effects reported with the individual components.106

Nervous System and Muscular Effects

The most common adverse effects of levodopa are dyskinesias including choreiform, dystonic, dyskinetic, and other involuntary movements. Involuntary movements occur in about 50% of patients on long-term therapy and may consist of grimacing, bruxism, gnawing, chewing, twisting and protrusion of the tongue, rhythmic opening and closing of the mouth, bobbing and wave-like motions of the head with or without gesticulation, slow rhythmic movements of the neck, hands or feet, jerky movements of the shoulder or pelvic girdle, and opisthotonos or ballismus. Intermittent myoclonic body jerks during sleep, ataxia, increased hand tremor, and muscle twitching and blepharospasm (which may be an early sign of excessive dosage) may also occur. Dyskinesias usually are dose related and may require reduction of dosage. They do not usually occur in nonparkinsonian patients such as those with chronic manganese intoxication. Because carbidopa allows more levodopa to reach the brain, dyskinesias may occur at lower dosages and more rapidly when levodopa is used in conjunction with carbidopa than when levodopa is used alone.

Several types of motor fluctuations also may occur in patients receiving long-term levodopa therapy. In one form, a gradual return of parkinsonian symptoms may occur toward the end of an inter-dose period. This can be minimized by more frequent administration of the drug. In the “on-off” phenomenon, a sudden loss of effectiveness with an abrupt onset of akinesia (“off” effect) which may last from 1 minute to an hour followed by an equally sudden return of effectiveness (“on” effect) may occur many times daily. This occasionally can be minimized by increasing the number of doses per day. Akinesia paradoxica (“start hesitation”), a sudden hypotonic freezing in which the patient frequently falls because he becomes akinetic just as he starts to walk, may be relieved by reducing the dosage of levodopa. Although the cause of these episodes has not been precisely determined, it appears that they may result from a combination of progression of the disease and excessive levodopa dosage.

Numerous mild to severe CNS and psychiatric disturbances may be produced by levodopa and may include decreased attention span, memory loss, insouciance, nervousness, anxiety, agitation, restlessness, confusion, insomnia, vivid dreams, nightmares, daytime somnolence, euphoria, malaise, fatigue, pathologic gambling, increased libido (including hypersexuality), and symptoms related to impulse control. (See Precautions and Contraindications under Cautions.) Hallucinations and abnormal thoughts or behavior (e.g., paranoia, confusion, psychotic disorder, delusions, delirium, psychotic-like behavior, disorientation, aggressive behavior) have been reported in some patients receiving dopaminergic drugs.107,108,117 Hallucinations generally present soon after initiation of levodopa therapy and may be alleviated by reducing dosage of the drug.107,108,117 Serious psychiatric disturbances requiring reduction of dosage or complete withdrawal of levodopa have included severe depression with or without suicidal tendencies, dementia, toxic delirium, paranoid delusions, hallucinations, and hypomania with inappropriate or excessive sexual behavior. In clinical studies, depression was reported with increased frequency in patients receiving the enteral carbidopa-levodopa suspension compared with those receiving oral immediate-release preparations of the drug.118

A symptom complex resembling neuroleptic malignant syndrome (NMS; characterized by elevated temperature, muscular rigidity, altered consciousness, autonomic instability) has been reported in association with rapid dosage reduction of, withdrawal of, or changes in dopaminergic therapy.107,117 (See Precautions and Contraindications under Cautions.)

Generalized neuropathy, most often characterized as sensory or sensorimotor, has been reported in patients receiving carbidopa-levodopa enteral suspension.118 Electrodiagnostic findings were most consistent with an axonal polyneuropathy.118

GI Effects

Nausea, vomiting, and anorexia (which may be accompanied by weight loss) occur frequently in patients receiving levodopa. Adverse GI effects of levodopa generally occur early in therapy while dosage is being increased and may be relieved by temporary reduction of dosage or administration of the drug with food. Other adverse GI effects which have been reported less frequently include duodenal ulcer, GI bleeding, constipation, diarrhea, epigastric and abdominal distress and pain, flatulence, hiccups, sialorrhea, dry mouth, dysphagia, change in taste sensation (including bitter taste), burning of the tongue, and trismus.

Cardiovascular Effects

Orthostatic hypotension occurs frequently following therapeutic doses of levodopa; however, it is usually asymptomatic and tolerance usually develops within a few months.

Cardiac irregularities occur infrequently with levodopa and may include palpitation, sinus tachycardia, ventricular tachycardia or extrasystole, atrial flutter or fibrillation, or block of atrioventricular conduction. Other reported adverse cardiovascular effects of levodopa include flushing and hypertension.

Cardiac ischemic events have been reported with some preparations of levodopa-carbidopa (e.g., extended-release fixed-combination capsules).117

Respiratory Effects

Adverse respiratory effects of levodopa have included episodic hyperventilation, bizarre breathing patterns, hoarseness, and excessive nasal discharge.

Coughing is a frequent adverse effect of levodopa oral inhalation therapy.126 Temporary, asymptomatic reductions in forced expiratory volume in 1 second (FEV₁) have been reported in healthy individuals receiving this dosage form.125 In patients receiving levodopa oral inhalation therapy, spirometric testing did not reveal any clinically important changes in pulmonary function; however, patients with a recent history of chronic obstructive pulmonary disease (COPD), asthma, or other chronic respiratory conditions were not evaluated.126

Other Adverse Effects

Adverse reactions affecting the urinary tract include urinary frequency, retention, incontinence, and dark urine. Adverse ocular effects include blurred vision, diplopia, mydriasis or miosis, widening of the palpebral fissures, activation of latent Horner's syndrome, and oculogyric crises. However, levodopa has been reported to reduce the incidence and severity of oculogyric crises in some patients with postencephalitic parkinsonian syndrome. Rarely, phlebitis, leukopenia, hemolytic or nonhemolytic anemia, thrombocytopenia, agranulocytosis, and decreased hemoglobin and hematocrit have occurred. If leukopenia occurs during levodopa therapy, the drug should be discontinued, at least temporarily.

Other adverse effects reported to occur in patients receiving levodopa include muscle cramps, a sense of stimulation, headache, weakness, numbness, increased sweating, dark sweat or other body fluids (e.g., saliva), pigmentation of the skin and teeth, rash, hot flashes, postmenopausal bleeding, weight gain or loss, priapism, edema, and alopecia. The development or exacerbation of malignant melanoma has been reported rarely in patients receiving levodopa therapy; however, a causal relationship to the drug has not been fully established to date.

Transient elevations in serum alkaline phosphatase, AST, ALT, LDH, bilirubin, and BUN concentrations may occur in patients receiving levodopa therapy. Rarely, positive direct antiglobulin (Coombs') test results have been reported during prolonged therapy with levodopa. In controlled clinical trials, the incidence of patients experiencing increased BUN and CPK was increased with carbidopa-levodopa enteral suspension compared with oral immediate-release carbidopa-levodopa preparations.118

Precautions and Contraindications

Levodopa-carbidopa should be used with caution in patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias; when initiating therapy in these patients, cardiac function should be monitored in an intensive coronary care facility.107 Levodopa also should be administered with caution to patients with severe cardiovascular, pulmonary (e.g., bronchial asthma), renal, hepatic, or endocrine disease.107

Levodopa should be administered with caution to patients with a history of active peptic ulcer because there is a possibility that the drug may cause upper GI hemorrhage in such patients. Complications associated with the PEG-J procedure or device may occur in patients receiving carbidopa-levodopa enteral suspension and can sometimes result in serious outcomes including death and the need for surgery; these complications may include bezoar; ileus; implant site erosion/ulcer; intestinal hemorrhage, ischemia, obstruction, or perforation; intussusception; pancreatitis; peritonitis; pneumoperitoneum; and postoperative wound infection.118,133 Patients should be instructed to notify their clinician immediately if they experience abdominal pain, prolonged constipation, nausea, vomiting, fever, or melanotic stool while receiving the enteral suspension.118

Patients receiving carbidopa-levodopa enteral suspension should be instructed on proper administration of the drug through the PEG-J tube and use of the ambulatory pump.118,136 Patients should be advised that if the pump is disconnected for short periods of time (e.g., less than 2 hours to swim, shower, or for a short medical procedure), no supplemental oral medication is needed, but an extra dose of the enteral suspension may be given before disconnecting.118 If the pump is disconnected for periods longer than 2 hours, the patient should contact their clinician and take oral carbidopa-levodopa until the enteral infusion can be resumed.118

Patients receiving levodopa powder for oral inhalation should be instructed on proper use of the specific inhaler provided by the manufacturer.126 Patients should be instructed to take a dose when the return of their parkinsonian symptoms (“off” periods) first occurs.126 Patients should also be reminded that the contents of Inbrija^® capsules are for oral inhalation only and must not be swallowed.126

Since psychiatric changes have been reported with dopaminergic agents, levodopa and carbidopa generally should not be used in patients with major psychotic disorders.107,108 Because the incidence of depression was increased in patients receiving the enteral suspension of carbidopa-levodopa compared with those receiving oral immediate-release formulations, patients receiving the enteral suspension should be monitored for the development of depression and concomitant suicidal tendencies.118 Patients also should be cautioned about the possibility of developing hallucinations and instructed to notify a clinician promptly should these manifestations occur.107

Because peripheral neuropathy has been reported in patients receiving the enteral suspension, such patients should be monitored for signs and symptoms of neuropathy prior to and during treatment, particularly in those with preexisting neuropathy or risk of neuropathy.118 Vitamin B supplementation has been reported to decrease the incidence of neuropathy.133,136

Patients should be observed closely when levodopa dosage is reduced abruptly or the drug is discontinued, especially in patients receiving an antipsychotic agent concomitantly, since a symptom complex resembling NMS has occurred following abrupt withdrawal of antiparkinsonian agents.117,118 (See Nervous System and Muscular Effects under Cautions.) Sudden discontinuance or rapid dosage reduction of carbidopa-levodopa should be avoided, and dosage should be gradually reduced when treatment is being discontinued.117,118

Patients receiving dopaminergic agents have reported falling asleep while engaged in activities of daily living, including operating a motor vehicle (which has sometimes resulted in accidents).105,107 Although many patients reported somnolence while receiving dopaminergic agents, some patients did not perceive warning signs, such as excessive drowsiness, and believed they were alert prior to the episode of falling asleep.105,107 Falling asleep while engaged in such activities usually occurs in a setting of preexisting somnolence, although some patients may not give such a history.105,107 Patients may not acknowledge drowsiness or sleepiness until directly questioned about these adverse effects during specific activities.105,107 Prior to initiating levodopa-carbidopa therapy, patients should be advised of the potential to develop drowsiness and specifically asked about any factors that may increase the risk of somnolence (e.g., concomitant use of sedating drugs, presence of sleep disorders).105,107 Patients should be continually reassessed for drowsiness or sleepiness during therapy, especially since some of the episodes of falling asleep occur well after starting treatment.105,107 Patients receiving therapy with dopaminergic agents, including levodopa, must be informed of this risk and advised to exercise caution when driving or operating machinery.105,107 Patients should be advised that they must refrain from these activities if they experience somnolence and/or an episode of sudden sleep onset.105,107 If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), discontinuance of levodopa-carbidopa therapy should be considered.105,107 If a decision is made to continue therapy, the patient should be advised not to drive and to avoid other potentially dangerous activities.105 There is insufficient information to establish whether dosage reduction will eliminate this adverse event.105,107

Data from epidemiologic studies indicate that patients with parkinsonian syndrome have a twofold to approximately sixfold greater risk of developing melanoma than the general population.105,106,107 It is unclear whether this increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat the disease).105,106,107 Because of these findings, patients should be monitored for melanoma on a frequent and regular basis.105,106,107 The manufacturer recommends that dermatologic examinations be performed periodically by qualified clinicians (e.g., dermatologists).105,106,107

Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges have been reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including levodopa-carbidopa).105,106,107 These urges stopped in some cases when dosage was reduced or the drug was discontinued.105,106,107 Clinicians should ask patients whether they have developed new or increased gambling urges, sexual urges, or other urges while receiving levodopa-carbidopa and should advise them of the importance of reporting such urges.105,106,107 If a patient develops such urges while receiving levodopa-carbidopa, consideration should be given to reducing the dosage or discontinuing the drug.105,106,107

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that levodopa-carbidopa orally disintegrating tablets contain aspartame (NutraSweet^®), which is metabolized in the GI tract to provide phenylalanine following oral administration.104,110,111,112,113,114

Because of the risk of bronchospasm, use of levodopa powder for oral inhalation (Inbrija^®) is not recommended in patients with asthma, COPD, or other chronic lung diseases.126

When the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo^®) is used, the precautions and contraindications associated with all the drugs in the formulation must be considered.106

Patients should be advised of the possibility that dark color (red, brown, black) may appear in saliva, urine, or sweat after ingestion of levodopa-carbidopa, and that garments may become discolored.107

Periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function should be performed in all patients receiving prolonged levodopa therapy.107 Because some patients receiving levodopa have experienced abnormal bleeding episodes following prostatectomy, it has been recommended that hematologic studies be performed during the postoperative evaluation of all patients receiving the drug.

Levodopa and carbidopa are contraindicated in patients receiving nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine).107,108,118,126 Levodopa and carbidopa also are contraindicated in patients with known hypersensitivity to the drugs.107 Some manufacturers state that levodopa or levodopa-carbidopa products are contraindicated in patients with angle closure glaucoma, but patients with chronic wide-angle glaucoma may be treated cautiously with the drugs if intraocular pressure is monitored and remains well controlled.107,108

Pediatric Precautions

Safety and efficacy of levodopa and carbidopa preparations in patients <18 years of age have not been established.104,107,108,117,126

Geriatric Precautions

No overall differences in response have been observed between geriatric patients >65 years of age and younger adults receiving oral levodopa and carbidopa preparations, but greater sensitivity of some older individuals to adverse reactions such as hallucinations cannot be ruled out.107,108,117 In clinical studies evaluating levodopa powder for oral inhalation, cough, upper respiratory tract infection, nausea, vomiting, extremity pain, and discolored nasal discharge were reported with higher frequency in geriatric patients ≥65 years of age than in younger adults.126

Pregnancy and Lactation

Pregnancy

There are no adequate and well-controlled studies of levodopa and carbidopa in pregnant women.105,108 Reproduction studies in rodents using levodopa and carbidopa at dosages approximately 5 and 2 times greater than the maximum human dosage, respectively, have shown adverse effects on fetal and postnatal growth and viability,105 and studies in rabbits using the drug alone or in conjunction with carbidopa have shown visceral and skeletal malformations. Levodopa and carbidopa should be administered to pregnant women or women who might become pregnant only when the benefits to the mother outweigh the possible risks to the mother and fetus.105,108

Levodopa is distributed into human milk.105,107 Carbidopa is distributed into milk in rats; it is not known whether carbidopa is distributed into human milk.106 Levodopa-carbidopa should be used with caution in nursing women.105 The known benefits of breast-feeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the infant from the drug or underlying maternal condition.126

Anticholinergic Agents

Anticholinergic agents may act synergistically with levodopa to decrease tremor in the management of parkinsonian syndrome and this interaction is often used to therapeutic advanta however, anticholinergic agents can exacerbate abnormal involuntary movements. In addition, these drugs (particularly in high dosage) may diminish the beneficial effects of levodopa by delaying its absorption thus increasing gastric metabolism of the drug. At least theoretically, this could result in levodopa toxicity when anticholinergic therapy is stopped.

Benzodiazepines

A few levodopa-treated patients have experienced decreased control of parkinsonian symptoms when chlordiazepoxide or diazepam was added to their therapeutic regimen. For this reason, these drugs and probably other benzodiazepines should be administered with caution to patients receiving levodopa.

Dopamine Antagonists

Dopamine antagonists (e.g., phenothiazines, butyrophenones, metoclopramide, risperidone) may reduce the therapeutic effects of levodopa; caution is advised if these drugs are used concomitantly and patients should be monitored for worsening parkinsonian symptoms.107,117

Although metoclopramide-induced increases in gastric emptying may enhance the bioavailability of levodopa, metoclopramide can exacerbate parkinsonian symptoms secondary to its antagonistic effects on dopamine receptors.104,105

Dopamine-depleting Agents

Concomitant use of levodopa and dopamine-depleting agents (reserpine, tetrabenazine) or other drugs known to deplete monoamine stores is not recommended.107

Hypotensive Agents

Because of the risk of symptomatic orthostatic hypotension, levodopa should be used with caution in patients receiving hypotensive agents.107 If used concomitantly, dosage adjustment of the hypotensive agent may be necessary.107 In addition, methyldopa (like carbidopa) is a decarboxylase inhibitor and can cause toxic CNS effects such as psychosis if administered concomitantly with levodopa.

Iron Salts

Iron salts can decrease absorption of levodopa-carbidopa; caution is advised if iron salts are used concomitantly with levodopa-carbidopa and patients should be monitored for worsening parkinsonian symptoms.104,105,106,107,117 Some clinicians recommend that iron supplements be taken at least 2 hours before or after administration of levodopa.157

Isoniazid

Isoniazid may antagonize the therapeutic effects of levodopa and should be used with caution during levodopa therapy; patients should be observed for loss of therapeutic response to levodopa.104,105,106,107

MAO Inhibitors

Concomitant use of nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine) and levodopa-carbidopa is contraindicated because of the risk of hypertensive crises. Therapy with these MAO inhibitors must be discontinued at least 2 weeks prior to initiation of levodopa-carbidopa therapy.

Levodopa may be administered concomitantly with a selective MAO-B inhibitor (e.g., selegiline).107 However, concomitant use of levodopa-carbidopa and selegiline may be associated with severe orthostatic hypotension and patients should be monitored accordingly.107,117

Papaverine

Several patients have experienced decreased therapeutic response to levodopa when papaverine was added to their therapeutic regimen.54 Caution is advised if these drugs are used concomitantly and patients should be observed for loss of therapeutic response.107

Phenytoin

Phenytoin administration has substantially interfered with the therapeutic effects of levodopa in several patients receiving levodopa for the treatment of idiopathic parkinsonian syndrome or chronic manganese intoxication.55 Caution is advised if these drugs are used concomitantly and patients should be observed for loss of therapeutic response.107

Pyridoxine

Administration of 10-25 mg of pyridoxine hydrochloride (vitamin B₆) may cause a rapid reversal of antiparkinsonian effects of levodopa when levodopa is used alone. Concomitant administration of carbidopa with levodopa prevents the reversal of levodopa effects caused by pyridoxine.

Tricyclic Antidepressants

Tricyclic antidepressants should be used with caution in patients receiving levodopa-carbidopa.107 Tricyclic antidepressants can augment postural hypotension and possibly interfere with absorption of levodopa by delaying gastric emptying and retarding delivery of levodopa to intestinal absorption sites. In addition, other adverse reactions, including hypertension and dyskinesia, have been reported rarely when the drugs were used concomitantly.107

Laboratory Test Interferences

Elevated protein-bound iodine concentrations have been reported during levodopa therapy but were apparently caused by an iodine dye used to color the levodopa capsules used in the study. Elevation of serum and urinary uric acid concentrations have been noted during levodopa therapy when colorimetric test methods were used. Levodopa administration does not affect uric acid determinations utilizing uricase.

Levodopa can produce false-positive reactions for urinary glucose in tests based on cupric sulfate reagent (Benedict's reagent or Clinitest^® tablets) and false-negative reactions in tests using glucose oxidase (Clinistix^®, Tes-Tape^®). An accurate measurement of urinary glucose may be obtained if the paper strip is only partially immersed in the urine so that the paper strip can act as an ascending chromatographic system; the top portion of the paper will give a true color change for glucose. False-positive reactions for urine ketones have been reported in patients receiving levodopa when the test was performed with sodium nitroprusside reagent (Acetest^®, Ketostix^®, Labstix^®). In urine screening tests for phenylketonuria, the urine of patients receiving levodopa turned a black-brown color on addition of ferric chloride solution thus interfering with the test.

Patients receiving levodopa have also shown falsely elevated urinary catecholamine concentrations as measured by the Hingerty method. Although levodopa administration results in small increases in urinary VMA excretion, urinary VMA as measured by the Pisano method may be falsely decreased in patients receiving the drug.

Acute Toxicity

Levodopa overdosage should be treated symptomatically. Immediate gastric lavage, maintenance of an adequate airway, and judicious administration of IV fluids is indicated. ECG monitoring and careful observation of the patient for development of cardiac arrhythmias are imperative. Antiarrhythmic therapy should be given if necessary. The value of hemodialysis in the management of levodopa overdosage is not known. Pyridoxine is not effective in reversing the actions of levodopa-carbidopa.

Pharmacology

Levodopa penetrates the CNS and is enzymatically converted to dopamine in the basal ganglia. There is considerable evidence that symptoms of parkinsonian syndrome, regardless of the cause of the syndrome, are related to depletion of dopamine in the corpus striatum, and levodopa is believed to act principally by increasing dopamine concentration in the brain. In addition, other metabolites of levodopa may contribute to the drug's antiparkinsonian activity. Dysregulation of brain serotonin activity may also occur.

Concurrent administration of a decarboxylase inhibitor such as carbidopa inhibits the peripheral decarboxylation of levodopa by aromatic l-amino acid decarboxylase without affecting the metabolism of the drug within the CNS. Thus, more levodopa is available for transport to the brain. Carbidopa, in doses that effectively inhibit peripheral decarboxylation of levodopa, has little effect on the CNS, cardiovascular system, or GI system.

Pharmacokinetics

Absorption

Although substantial amounts of levodopa are metabolized in the lumen of the stomach and intestines, the drug is considered rapidly and well absorbed from the GI tract. GI absorption of levodopa from conventional preparations is slower and peak plasma concentrations are lower when the drug is ingested with food. Absorption of the drug may be particularly impaired in patients receiving a high-protein diet, since levodopa competes with certain amino acids for GI transport mechanisms. In one study in patients with parkinsonian syndrome receiving 3-8 g of levodopa daily as a conventional tablet preparation with food, average plasma concentrations of levodopa were approximately 1 mcg/mL with a range of 0.2-2.8 mcg/mL. However, considerable variation in plasma concentrations has been reported among patients and in the same patient on different occasions. The relationship of plasma levodopa concentrations to clinical effects has not been established.

Conventional (immediate-release) and orally disintegrating tablets of carbidopa-levodopa are formulated to begin releasing the drugs within 30 minutes of administration.104,107,109 Administration of levodopa and carbidopa as orally disintegrating tablets reportedly results in pharmacokinetic values similar to values observed with the conventional tablet preparation.109

Oral bioavailability of levodopa from extended-release carbidopa-levodopa tablets is reduced and peak plasma concentrations are delayed compared with those from conventional tablet preparations; however, there is considerably less fluctuation in plasma levodopa concentrations between doses with the extended-release tablets. Food increases the extent of GI absorption and peak plasma levodopa concentrations by about 50 and 25%, respectively, following a single oral dose as extended-release tablets. In healthy geriatric individuals 56-67 years of age, the mean time to peak plasma levodopa concentration was 2 or 0.5 hours with single doses of extended-release or conventional tablet preparations of the combination, respectively, and the peak concentration achieved with the extended-release tablets was 35% of that achieved with conventional tablet preparations. Bioavailability of levodopa from the extended-release tablets was about 70-75% of that from conventional tablet preparations of the combination in this age group. Oral bioavailability and peak plasma levodopa concentrations are comparable following single doses and thrice-daily doses (at steady state) of extended-release tablets in geriatric individuals. In addition, mean trough plasma concentrations of levodopa at steady state with extended-release tablets were about twice those with conventional oral preparations.

The extended-release capsule formulation of carbidopa-levodopa consists of both immediate-release and extended-release components.117,119 The capsule formulation is designed to provide an initial rapid absorption of levodopa similar to immediate-release carbidopa-levodopa and then subsequently provide stable levodopa concentrations with reduced peak-to-trough fluctuations in plasma concentrations.119 Following oral administration of the extended-release capsules, an initial rapid increase in plasma levodopa concentrations is observed, followed by sustained plasma concentrations for about 4-5 hours; lower peak to trough fluctuation is observed at steady state with the extended-release capsules compared with immediate-release carbidopa-levodopa preparations.117,119 The bioavailability of levodopa from extended-release carbidopa-levodopa capsules is approximately 70% relative to immediate-release preparations.117 Peak levodopa concentrations achieved with the extended-release capsules is 30% of that achieved with immediate-release preparations when given in comparable doses.117

Following oral inhalation of a single dose of levodopa inhalation powder, the median time to peak plasma concentration is about the same as that for immediate-release carbidopa-levodopa tablets (approximately 0.5 hours).126,129 Bioavailability of levodopa from inhaled levodopa is approximately 70% relative to immediate-release oral levodopa tablets.126 Time to peak plasma concentration of the drug following oral inhalation is approximately 15 minutes faster, but peak plasma concentrations and systemic exposure are substantially lower, compared with orally administered immediate-release carbidopa-levodopa.127

Following initiation of the 16-hour infusion of carbidopa-levodopa enteral suspension, peak plasma concentrations of levodopa are obtained in 2.5 hours.118 Bioavailability of the enteral suspension is comparable to that of oral immediate-release carbidopa-levodopa.118 However, variability in plasma concentrations of carbidopa and levodopa is reduced with continuous enteral infusion compared with oral administration.118,133 Absorption of levodopa from the enteral suspension is not influenced by gastric emptying rate.118

Therapeutic response to levodopa usually consists of short-duration improvement (occurring after each dose and disappearing within 5 hours) and long-duration improvement (occurring with prolonged therapy and not subsiding during the 10-hour period following the last dose at night and the first morning dose). The long-duration response usually does not disappear until 3-5 days after levodopa is discontinued.

About 40-70% of a dose of carbidopa is absorbed following oral administration. Although levodopa does not appear to enhance the absorption of carbidopa, carbidopa may enhance the absorption of levodopa by suppressing the metabolism of levodopa in the GI tract. Plasma levodopa concentrations are increased when carbidopa and levodopa are administered concomitantly, principally because of inhibition by carbidopa of the peripheral metabolism of levodopa. (See Elimination under Pharmacokinetics.)

Distribution

Levodopa is widely distributed into most body tissues and the total volume of distribution is about 65% of body weight. There is considerable uptake of levodopa by the pancreas, liver, GI tract, salivary glands, kidneys, and skin. Probably less than 1% of absorbed levodopa penetrates the CNS and only a small amount enters the brain.

Levodopa is approximately 10-30% bound to plasma proteins.106

Carbidopa is also widely distributed into most body tissues; however, it does not cross the blood-brain barrier. Carbidopa crosses the placenta and is distributed into milk.

At a concentration of 1 mcg/mL, about 36% of carbidopa is bound to plasma proteins.

Elimination

The plasma half-life of levodopa is approximately 1 hour. The plasma half-life of carbidopa is 1-2 hours. When levodopa and carbidopa are administered concurrently, the plasma half-life of levodopa is increased to about 1.5-2 hours. When levodopa and carbidopa are administered with entacapone or tolcapone, (catechol- O -methyltransferase COMT inhibitors), the plasma half-life of levodopa is increased to 1.3-2 or 3.5 hours respectively. Because administration as extended-release tablets results in prolonged release and absorption of levodopa from the GI tract, the apparent half-life of levodopa may be prolonged with this formulation compared with conventional tablet formulations.

Substantial amounts of levodopa are metabolized in the lumen of the stomach and intestines and on first pass through the liver. There is some evidence that the metabolism of levodopa is accelerated during prolonged therapy, possibly secondary to enzyme induction. Most absorbed levodopa is decarboxylated to dopamine; more than 95% of the drug is decarboxylated peripherally by aromatic l-amino acid decarboxylase, a widely distributed enzyme. Carbidopa inhibits only the peripheral decarboxylation of levodopa since, like dopamine, carbidopa does not cross the blood-brain barrier. Peripheral aromatic l-amino acid decarboxylase is saturated by daily doses of 70-100 mg of carbidopa. Small amounts of levodopa are metabolized to norepinephrine, epinephrine, and 3-methoxytyramine. A small quantity of levodopa is methylated to 3- O -methyldopa; this metabolite is present in plasma and accumulates in the CNS because of its long half-life. The importance of these minor metabolites has not yet been determined, but 3- O -methyldopa does not appear to relieve parkinsonian symptoms. Dopamine is further metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA) and excreted in urine. HVA, DOPAC, and dopamine are the metabolites of levodopa present in CSF. Carbidopa is not extensively metabolized; about 30% of an oral dose of carbidopa is excreted in urine unchanged within 24 hours.

About 80-85% of a dose of radiolabeled levodopa is excreted in urine within 24 hours. DOPAC and HVA account for about 50% and HVA has been reported to account for 13-42% of an ingested dose. Small amounts of the drug are excreted in urine as vanillylmandelic acid (VMA), 3- O -methyldopa, and norepinephrine. Less than 1% of a dose of levodopa is excreted in urine unchanged. When carbidopa and levodopa are administered concurrently, the urinary excretion of dopamine, DOPAC, and HVA is substantially diminished, and the amount of unchanged levodopa excreted in urine has been reported to be increased to 6%.

Chemistry and Stability

Chemistry

Levodopa

Levodopa is the levorotatory isomer of dihydroxyphenylalanine and the metabolic precursor of dopamine. Levodopa is commercially available in combination with carbidopa. Levodopa also is commercially available as a fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo^®).106 Levodopa occurs as a white to off-white, odorless, crystalline powder and is slightly soluble in water and insoluble in alcohol.

Extended-release tablets of levodopa and carbidopa (Sinemet^® CR) contain the drugs in a polymeric-based delivery system that controls the release of the drugs over an approximately 4- to 6-hour period by slowly eroding in the GI tract.

The extended-release capsule formulation of carbidopa-levodopa (Rytary^®) consists of both immediate-release and extended-release components.117,119

Carbidopa

Carbidopa is a decarboxylase inhibitor that inhibits decarboxylation of levodopa to dopamine. Carbidopa is commercially available in combination with levodopa and is also available as a single entity. Carbidopa occurs as a white to creamy white, odorless or practically odorless powder and is slightly soluble in water and practically insoluble in alcohol. Although carbidopa is commercially available as the monohydrate, potency is described in terms of anhydrous carbidopa.

Stability

Levodopa is rapidly oxidized and darkens in the presence of moisture; the color change indicates loss of potency. Commercially available preparations containing levodopa and carbidopa should be protected from exposure to light, moisture, and excessive heat. Tablets containing levodopa and carbidopa should be stored at a temperature of 25°C but may be exposed briefly to temperatures ranging from 15-30°C. Extended-release capsules of levodopa and carbidopa should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.117

The Inbrija^® inhaler and capsules should be stored in a dry place at 20-25°C, but may be exposed to temperatures of 15-30°C.126 The capsules should be kept in their blister pack until ready to use and should not be stored in inhalers.126

Cassettes containing carbidopa-levodopa enteral suspension should be stored in the freezer at -20°C.118 Prior to dispensing, the cassettes should be thawed in the refrigerator at 2-8°C.118 The cassettes should be protected from light and kept in the carton prior to use.118

Only references cited for selected revisions after 1984 are available electronically.

54. Duvoisin RC. Antagonism of levodopa by papaverine. JAMA . 1975; 231:845-6. [PubMed 1172755]

55. Mendez JS, Cotzias GC, Mena I et al. Diphenylhydantoin. Blocking of levodopa effects. Arch Neurol . 1975; 32:44-6. [PubMed 123156]

101. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology . 2001; 56:S1-S88.

102. Chong BS, Mersfelder TL. Entacapone. Ann Pharmacother . 2000; 34:1056-65. [PubMed 10981253]

104. Mylan Pharmaceuticals. Carbidopa and levodopa orally disintegrating tablets. Morgantown, WV; 2016 Sept.

105. Merck. Sinemet^® CR (carbidopa-levodopa) sustained-release tablets prescribing information. Whitehouse Station, NJ; 2018 Apr.

106. Novartis. Stalevo^® 50, Stalevo^® 75, Stalevo^® 100, Stalevo^® 125, Stalevo^® 150, Stalevo^® 200 (carbidopa, levodopa and entacapone) tablets prescribing information. East Hanover, NJ; 2019 Dec.

107. Merck. Sinemet^® (carbidopa-levodopa) tablets prescribing information. Whitehouse Station, NJ; 2018 Apr.

108. Valeant. Lodosyn^® (carbidopa) tablets prescribing information. Bridgewater, NJ; 2017 Feb.

109. Anon. Parcopa: a rapidly dissolving formulation of carbidopa/levodopa. Med Lett Drugs Ther . 2005; 47:12. [PubMed 15706700]

110. American Medical Association Council on Scientific Affairs. Aspartame: review of safety issues. JAMA . 1985; 254:400 2. [PubMed 2861297]

111. Gossel TA. A review of aspartame: characteristics, safety and uses. US Pharm . 1984; 9:26,28 30.

112. Food and Drug Administration. Aspartame as an inactive ingredient in human drug products; labeling requirements. Proposed rule. [21 CFR Part 201] Fed Regist . 1983; 48:54993 5. (lDIS 178728)

113. Food and Drug Administration. Food additives permitted for direct addition to food for human consumption; aspartame. Final rule. [21 CFR Part 172] Fed Regist . 1983; 48:31376 82. (IDIS 172957)

114. Anon. Aspartame and other sweeteners. Med Lett Drugs Ther . 1982; 24:1 2. [PubMed 7054648]

115. Lewitt PA. Levodopa for the treatment of Parkinson's disease. N Engl J Med . 2008; 359:2468-76. [PubMed 19052127]

116. PD Med Collaborative Group, Gray R, Ives N et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet . 2014; 384:1196-205. [PubMed 24928805]

117. Amneal. Rytary^® (carbidopa-levodopa) extended-release capsules prescribing information. Bridgwater, NJ; 2019 Dec.

118. AbbVie. Duopa^® (carbidopa-levodopa) enteral suspension prescribing information. North Chicago, IL; 2019 Dec.

119. Mittur A, Gupta S, Modi NB. Pharmacokinetics of Rytary®, An Extended-Release Capsule Formulation of Carbidopa-Levodopa. Clin Pharmacokinet . 2017; 56:999-1014. [PubMed 28236251]

120. Fahn S, Oakes D, Shoulson I et al. Levodopa and the progression of Parkinson's disease. N Engl J Med . 2004; 351:2498-508. [PubMed 15590952]

121. Verschuur CVM, Suwijn SR, Boel JA et al. Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease. N Engl J Med . 2019; 380:315-324. [PubMed 30673543]

122. Bressman S, Saunders-Pullman R. When to Start Levodopa Therapy for Parkinson's Disease. N Engl J Med . 2019; 380:389-390. [PubMed 30673551]

123. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA . 2014 Apr 23-30; 311:1670-83. [PubMed 24756517]

124. Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn) . 2013; 19:1189-212. [PubMed 24092286]

125. Patel T, Chang F, Parkinson Society Canada. Parkinson's disease guidelines for pharmacists. Can Pharm J (Ott) . 2014; 147:161-70. [PubMed 24847369]

126. Acorda. Inbrija^® (levodopa) inhalation powder prescribing information. Ardsley, NY; 2018 Dec.

127. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 209184Orig1s000: Summary Review. From FDA website. [Web]

128. LeWitt PA, Hauser RA, Pahwa R et al. Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol . 2019; 18:145-154. [PubMed 30663606]

129. . Inhaled levodopa (Inbrija) for Parkinson's disease. Med Lett Drugs Ther . 2019; 61:73-74. [PubMed 31169799]

130. . Duopa--a carbidopa/levodopa enteral suspension for Parkinson's disease. Med Lett Drugs Ther . 2015; 57:112. [PubMed 26218794]

131. Olanow CW, Kieburtz K, Odin P et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol . 2014; 13:141-9. [PubMed 24361112]

132. Lopiano L, Modugno N, Marano P et al. Motor and non-motor outcomes in patients with advanced Parkinson's disease treated with levodopa/carbidopa intestinal gel: final results of the GREENFIELD observational study. J Neurol . 2019; 266:2164-2176. [PubMed 31134377]

133. Virhammar J, Nyholm D. Levodopa-carbidopa enteral suspension in advanced Parkinson's disease: clinical evidence and experience. Ther Adv Neurol Disord . 2017; 10:171-187. [PubMed 28344656]

134. Fernandez HH, Standaert DG, Hauser RA et al. Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: final 12-month, open-label results. Mov Disord . 2015; 30:500-9. [PubMed 25545465]

135. Antonini A, Poewe W, Chaudhuri KR et al. Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry. Parkinsonism Relat Disord . 2017; 45:13-20. [PubMed 29037498]

136. Burack M, Aldred J, Zadikoff C et al. Implementing Levodopa-Carbidopa Intestinal Gel for Parkinson Disease: Insights from US Practitioners. Mov Disord Clin Pract . 2018 Jul-Aug; 5:383-393. [PubMed 30363427]

157. . Drugs for Parkinson's disease. Med Lett Drugs Ther . 2017; 59:187-194. [PubMed 29136401]