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Uses

Parkinsonian Syndrome

Levodopa is used in the symptomatic treatment of idiopathic Parkinson's disease (paralysis agitans), parkinsonian syndrome (postencephalitic parkinsonism), and symptomatic parkinsonism resulting from carbon monoxide intoxication and/or manganese intoxication. Levodopa is currently the most effective drug for relieving the symptoms of parkinsonian syndrome and is considered by many clinicians to be the drug of choice in the management of idiopathic parkinsonian syndrome. Most clinicians delay introduction of symptomatic therapy until the patient begins to experience functional limitation. Although levodopa traditionally has been considered the drug of choice for the initial symptomatic management of idiopathic parkinsonian syndrome, long-term administration of levodopa is associated with motor complications (dyskinesia and motor fluctuations). One strategy to reduce the risk of motor complications associated with long-term levodopa therapy is to initiate levodopa therapy in combination with a catechol-O-methyltransferase (COMT) inhibitor (entacapone, tolcapone). Another strategy to reduce the risk of motor complications and to improve long-term outcome is to initiate symptomatic therapy with a dopamine receptor agonist (bromocriptine mesylate, pramipexole dihydrochloride, pergolide mesylate, ropinirole hydrochloride) and to add levodopa as supplemental therapy when dopamine receptor agonist monotherapy no longer provides adequate symptom control. However, clinical studies evaluating this strategy are limited both in number and duration, and it remains to be determined whether initiating therapy with a dopamine receptor agonist rather than levodopa results in a more favorable long-term outcome. Factors to consider when choosing an agent for the initial symptomatic management of idiopathic parkinsonian syndrome include patient age, cognitive status, disease severity, and cost. Most clinicians would use levodopa for initial therapy in individuals older than 70 years of age (since these individuals are less likely than younger individuals to develop levodopa-related motor complications and because of concerns about cognitive dysfunction), in patients with cognitive impairment, and in those with severe disease. A dopamine receptor agonist may be preferred for initial therapy in patients 70 years of age or younger.

The effectiveness of levodopa reportedly decreases substantially after the third year of treatment and symptoms of the disease may return to pretreatment levels after 6-7 years of levodopa therapy. Concurrent administration of selegiline hydrochloride, a selective monoamine oxidase (MAO)-B inhibitor, may improve therapeutic response in patients who exhibit a deteriorating response to levodopa-carbidopa therapy. Selegiline therapy appears to be most beneficial when used during the early stages of the '' wearing off'' effect; patients with advanced parkinsonian syndrome and those exhibiting severe ''on-off'' phenomena during levodopa therapy are less likely to benefit from selegiline therapy.

Concomitant administration of levodopa and a decarboxylase inhibitor such as carbidopa generally decreases levodopa dosage requirements by 70-80%, reduces the incidence of levodopa-induced nausea and vomiting, allows a more rapid dosage titration, and may provide a smoother response to levodopa. Therefore, most clinicians currently state that carbidopa used in conjunction with levodopa is the treatment of choice for patients with parkinsonian syndrome who require levodopa. Certain patients who responded poorly to levodopa alone (no longer commercially available in the US as a single-entity preparation) have improved when carbidopa and levodopa were administered concomitantly; however, patients with markedly irregular ''on-off'' responses to levodopa (see Cautions: Nervous System and Muscular Effects) usually have not benefited from combination therapy. Carbidopa has no therapeutic effect when given alone to patients with parkinsonian syndrome and should be used only in conjunction with levodopa. Combination preparations containing levodopa in fixed combinations with carbidopa are commercially available. Carbidopa is also available alone from the manufacturer for use in conjunction with the combination preparations in patients who do not have adequate reduction in nausea and vomiting with the fixed-dosage preparations.

Levodopa completely or partially relieves akinesia, rigidity, and tremor in about 80% of patients treated. Levodopa may be useful in the management of other symptoms of parkinsonian syndrome including dysphagia, sialorrhea, and seborrhea. Levodopa improves functional ability and other secondary motor manifestations such as gait, postural stability, facial expression, swallowing, speech, and handwriting. Levodopa therapy often produces a general alerting response, increased vigor, and a sense of well-being.

In the treatment of parkinsonian syndrome, levodopa-carbidopa may be used in conjunction with amantadine; ergot- and nonergot-derivative dopamine receptor agonists such as apomorphine hydrochloride, bromocriptine, pramipexole dihydrochloride, or ropinirole hydrochloride; antihistamines such as diphenhydramine; or anticholinergic antiparkinsonian agents such as benztropine mesylate, trihexyphenidyl hydrochloride, or procyclidine hydrochloride. When levodopa is administered with an anticholinergic agent, the dosage of each drug may need to be reduced. (See Drug Interactions: Anticholinergic Agents.) Combined therapy with amantadine and levodopa has been reported to be more effective than levodopa alone in some patients who cannot tolerate large dosages of levodopa; however, the addition of amantadine does not usually provide substantial additional benefit when patients are already receiving full therapeutic dosages of levodopa.

Levodopa-carbidopa may be used in conjunction with a COMT inhibitor (i.e., entacapone, tolcapone) for the symptomatic treatment of idiopathic parkinsonian syndrome. Concomitant administration of entacapone or tolcapone with levodopa-carbidopa enhances the efficacy of levodopa in patients with motor fluctuations and in those with stable responses to levodopa. However, tolcapone therapy has been associated with severe hepatocellular injury in some patients. Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone generally should be reserved for patients receiving levodopa who are experiencing symptom fluctuations and are not responding adequately to other adjunctive therapies. Some clinicians consider entacapone the COMT inhibitor of choice. For additional information on such combined therapy, .

Levodopa may be useful in the management of reserpine-induced parkinsonian symptoms; however, levodopa is not effective in controlling extrapyramidal effects induced by antipsychotic agents such as phenothiazines or butyrophenones.

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 mental disorders.

Dosage and Administration

Administration

Levodopa and carbidopa are administered orally.

Levodopa and carbidopa are commercially available as fixed-combination conventional tablets, orally disintegrating tablets, and extended-release tablets. Levodopa-carbidopa conventional tablets and orally disintegrating tablets contain a 1:4 or 1:10 ratio of carbidopa to levodopa. Levodopa-carbidopa extended-release tablets contain a 1:4 ratio of carbidopa to levodopa. Levodopa and carbidopa also are commercially available in fixed combination with entacapone (Stalevo) in a preparation containing a 1:4 ratio of carbidopa to levodopa combined with 200 mg of entacapone. Carbidopa also is commercially available as single-entity conventional tablets; levodopa no longer is commercially available in the US as a single-entity preparation.

In patients with moderate to severe motor fluctuations, better global improvement may be achieved in some patients when extended-release rather than conventional preparations of levodopa-carbidopa are used. However, in clinical studies, such patients receiving the extended-release preparation did not experience quantitatively significant reductions in ''off'' time compared with conventional preparations. In patients without motor fluctuations, the preparations were comparably effective but less frequent dosing was required with the extended-release preparation.

Extended-release tablets of levodopa-carbidopa can be administered as whole or halved tablets, but these should be swallowed intact and not chewed or crushed. 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. 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.

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

The fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo) generally is used in patients receiving stable dosages of levodopa, carbidopa, and entacapone equivalent to those in the combination preparation. The fixed-combination preparation containing levodopa, carbidopa, and entacapone also may be used in certain patients receiving stable dosages of levodopa and carbidopa equivalent to those in the fixed-combination preparation when a decision has been made to add entacapone to the regimen.(See Levodopa, Carbidopa, and Entacapone Fixed Combination, under Dosage: Parkinsonian Syndrome, in Dosage and Administration.) Tablets containing levodopa, carbidopa, and entacapone in fixed combination (Stalevo) should not be divided, and only one tablet should be administered per dosing interval.

Patients should be cautioned not to alter the prescribed dosage regimen and not to add any additional antiparkinsonian therapy, including other levodopa and/or carbidopa preparations, without first consulting their clinician.

Dosage

Parkinsonian Syndrome

Dosage of levodopa-carbidopa must be carefully adjusted according to individual requirements, response, and tolerance. 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.

Because parkinsonian syndrome is progressive, the patient's clinical condition should be evaluated periodically and therapy adjusted as necessary.

Because of the risk of precipitating a symptom complex resembling neuroleptic malignant syndrome, patients should be observed closely if levodopa dosage is reduced abruptly or the drug is discontinued. (See Cautions: Precautions and Contraindications.)

Immediate-release Levodopa-Carbidopa Preparations

When levodopa-carbidopa therapy is initiated using an immediate-release combination preparation (i.e., conventional tablets, orally disintegrating tablets), therapy usually is initiated with a preparation containing 100 mg of levodopa and 25 mg of carbidopa. When a preparation containing 100 mg of levodopa and 25 mg of carbidopa is used, the usual initial dosage is 1 tablet 3 times daily and dosage may be increased by 1 tablet every 1 or 2 days until a maximum dosage of 8 tablets daily (800 mg of levodopa and 200 mg of carbidopa) is reached or adverse effects prevent further increases or necessitate discontinuance of the drugs. If an immediate-release combination preparation containing 100 mg of levodopa with 10 mg of carbidopa 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. Dosage may be increased by 1 tablet every 1 or 2 days until a maximum dosage of 8 tablets daily (800 mg of levodopa and 80 mg of carbidopa) is reached or adverse effects prevent further increases or necessitate discontinuance of the drugs. If the patient requires a higher dosage of levodopa, an immediate-release combination preparation containing 250 mg of levodopa with 25 mg of carbidopa should be used and 1 tablet given 3 or 4 times daily and dosage increased by one-half or 1 tablet every 1 or 2 days until a maximum dosage of 8 tablets daily (2 g of levodopa and 200 mg of carbidopa) is reached.

Maintenance levodopa-carbidopa therapy should be individualized and adjusted according to the desired therapeutic response. Patients receiving maintenance therapy with levodopa-carbidopa should receive at least 70-100 mg of carbidopa daily, 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. Patients who require a low dosage of levodopa (e.g., less than 700 mg daily) will receive doses of carbidopa that will not saturate peripheral aromatic l-amino acid decarboxylase when the combination preparation containing a 1:10 ratio of carbidopa to levodopa is used. Therefore, if nausea and vomiting occur in patients receiving an immediate-release combination preparation containing 100 mg of levodopa with 10 mg of carbidopa, one tablet of an immediate-release preparation containing 100 mg of levodopa with 25 mg of carbidopa may be substituted for one tablet of the preparation containing 100 mg of levodopa with 10 mg of carbidopa. If additional carbidopa is still required, carbidopa dosage may be supplemented by giving a 25-mg dose of carbidopa to these patients with each first daily dose of levodopa-carbidopa and 12. 5-mg or 25-mg doses of carbidopa with each subsequent dose of levodopa-carbidopa. If patients require higher dosages of levodopa while receiving an immediate-release combination preparation containing 100 mg of levodopa with 10 or 25 mg of carbidopa, a combination preparation containing 250 mg of levodopa with 25 mg of carbidopa should be used. Patients receiving an immediate-release combination preparation containing 250 mg of levodopa with 25 mg of carbidopa who require additional carbidopa may receive 25-mg doses of carbidopa with any dose of levodopa-carbidopa as required for optimum therapeutic response. Because experience with carbidopa daily dosages greater than 200 mg is limited, dosage of carbidopa should not exceed 200 mg daily.

Extended-release Levodopa-Carbidopa Preparations

If extended-release tablets of levodopa-carbidopa are used, it should be recognized that this formulation is less bioavailable than immediate-release preparations (i.e., conventional tablets, orally disintegrating tablets) and that increased daily dosage may be required to achieve the same level of symptomatic relief provided by immediate-release preparations. Dosage should be individualized based on patient tolerance and clinical response.

Patients being transferred from an immediate-release levodopa-carbidopa 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. In some patients, up to 30% more levodopa daily may be required initially depending on clinical response.

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

Following initiation of therapy with the extended-release levodopa-carbidopa tablets, doses and/or dosing intervals can be increased or decreased carefully according to patient tolerance and clinical response. Most patients are treated adequately with levodopa 400 mg to 1.6 g daily and carbidopa 100-400 mg daily as extended-release tablets, administered in divided doses at intervals ranging from 4-8 hours while awake. Higher dosages (levodopa 2.4 g and carbidopa 600 mg) and shorter intervals (less than 4 hours) have been used with the extended-release tablets but usually are not recommended. 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. Dosage of the extended-release tablets generally should be adjusted no more frequently than at 3-day intervals. Some patients with advanced disease may benefit from the addition of doses of a conventional preparation of levodopa-carbidopa during brief periods of the day when additional levodopa is needed for symptomatic control.

Levodopa, Carbidopa, and Entacapone Fixed Combination

For patients transferring from therapy with levodopa-carbidopa to the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo), recommendations are available for transferring patients currently receiving levodopa-carbidopa preparations containing a 1:4 ratio of carbidopa to levodopa. Patients receiving entacapone 200 mg with each dose of levodopa-carbidopa (e.g., conventional preparation containing 100 mg of levodopa and 25 mg of carbidopa) can be switched to the corresponding strength of the fixed-combination preparation containing levodopa, carbidopa, and entacapone. The manufacturer states that there is no experience to date in transferring patients currently receiving entacapone together with extended-release preparations of levodopa-carbidopa or levodopa-carbidopa preparations containing a 1:10 ratio of carbidopa to levodopa to the fixed-combination preparation Stalevo.

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. Patients treated with levodopa-carbidopa 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. In such patients, dosage should first be adjusted by administering levodopa-carbidopa (1:4 ratio) and entacapone as separate preparations. 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 levodopa, carbidopa, and entacapone (Stalevo) may be used. 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 levodopa, carbidopa, and entacapone. The initial dosage of the fixed-combination preparation of levodopa, carbidopa, and entacapone should provide the same dosage of levodopa and carbidopa that the patient currently is taking. However, a reduction in the dosage of levodopa-carbidopa or entacapone may be necessary. Because dosage of levodopa, carbidopa, or entacapone cannot be adjusted individually using the fixed-combination preparation, administration of levodopa-carbidopa and entacapone as separate preparations may be necessary.

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

Cautions

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 and in fact some CNS effects may occur at lower dosage and more rapidly during therapy with levodopa-carbidopa combinations than with levodopa alone. The adverse effect profile reported with levodopa and carbidopa administered as extended-release tablets is comparable to that with conventional oral preparations.

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

Nervous System and Muscular Effects

The most common serious adverse effects of levodopa are choreiform, dystonic, dyskinetic, and other adventitious 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. Involuntary movements are usually 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. A symptom complex resembling the neuroleptic malignant syndrome also has been reported. (See Cautions: Precautions and Contraindications.)

At least 3 forms of ''bradykinetic episodes'' may occur in some patients on 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. Serious psychiatric disturbances requiring reduction of dosage or complete withdrawal of the drug have included severe mental depression with or without suicidal tendencies, dementia, toxic delirium, paranoid delusions, hallucinations, and hypomania with inappropriate or excessive sexual behavior. Severe psychotic episodes are most likely to occur in patients with a history of mental disorders. Levodopa promotes release of pituitary growth hormone which may potentiate the cerebral effects of the drug.

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. If orthostatic hypotension causes dizziness or syncope, levodopa dosage should be reduced and the patient should be advised to wear elastic stockings until previous dosage of levodopa is tolerated.

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. Cardiac arrhythmias caused by levodopa can be prevented by concomitant administration of a β-adrenergic antagonist such as propranolol. Other reported adverse cardiovascular effects of levodopa include flushing and hypertension.

Other Adverse Effects

Adverse respiratory effects of levodopa include episodic hyperventilation, bizarre breathing patterns, hoarseness, and excessive nasal discharge. 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 (SGOT), ALT (SGPT), LDH, bilirubin, and BUN concentrations may occur in patients receiving levodopa therapy. Serum concentrations of BUN, creatinine, and uric acid may be lower when levodopa is used in conjunction with carbidopa than when levodopa is used alone. Rarely, positive direct antiglobulin (Coombs') test results have been reported during prolonged therapy with levodopa.

Development of a scleroderma-like illness, manifested by proximal muscle weakness, pain and swelling of the hands and feet, a pruritic rash, and weight loss, has been reported in one patient receiving carbidopa and oxitriptan (l-5HTP) for the treatment of intention myoclonus. Although the exact pathogenetic mechanism of this adverse effect has not been determined, it has been suggested that a simultaneous increase in blood serotonin concentration and an enzyme defect producing an increase in serum kynurenine (a metabolite of tryptophan) concentration, which result from the combined use of carbidopa and oxitriptan, are responsible for the occurrence of this scleroderma-like illness.

Precautions and Contraindications

Levodopa should be used with extreme caution, if at all, in patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. When levodopa therapy is initiated in these patients, intensive coronary care facilities should be immediately available. Levodopa should also be used with caution in patients with bronchial asthma or emphysema who may require the use of sympathomimetic drugs. Levodopa should be administered with caution to patients with severe cardiovascular, pulmonary, renal, hepatic, or endocrine disease.

Levodopa should be administered with caution to patients with a history of active peptic ulcer because there is a possibility that levodopa may cause upper GI hemorrhage in such patients.

Since levodopa may cause psychiatric changes, the drug should be used with extreme caution in psychotic patients and all patients should be carefully observed for development of depression and suicidal tendencies. The drug should also be used with caution in patients with a history of seizure disorders.

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 the neuroleptic malignant syndrome has occurred following abrupt withdrawal of antiparkinsonian agents. The symptom complex may include muscular rigidity, elevated body temperature, mental changes, diaphoresis, tachycardia, tachypnea, and/or increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations.

Dopaminergic agents, including levodopa, may be associated with somnolence and, very rarely, with episodes of sudden onset of sleep, which may occur without the patient's awareness or without warning during daily activities. Patients receiving therapy with dopaminergic agents, including levodopa, must be informed of this risk and advised to exercise caution when driving or operating machinery. Patients should be advised that they must refrain from driving or operating machinery if they experience somnolence and/or an episode of sudden sleep onset.

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. It is unclear whether this increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat the disease). Because of these findings, patients and clinicians should monitor for melanoma on a frequent and regular basis. The manufacturer recommends that dermatologic examinations be performed periodically by qualified clinicians (e.g., dermatologists).

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). Although a causal relationship has not been established, these urges stopped in some cases when dosage was reduced or the drug was discontinued. 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. If a patient develops such urges while receiving levodopa-carbidopa, consideration should be given to reducing the dosage or discontinuing the drug.

Geriatric patients who respond to levodopa should resume normal activity gradually and with caution because increased mobility may lead to fractures, particularly if an underlying condition such as osteoporosis is present. Diabetic patients should be closely monitored during levodopa therapy because the drug may adversely affect control of blood glucose.

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 Parcopa orally disintegrating tablets contain aspartame (NutraSweet), which is metabolized in the GI tract to provide phenylalanine following oral administration.

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.

Periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function should be performed in all patients receiving extended levodopa therapy. 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 is contraindicated in patients receiving nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine). (See Drug Interactions: Psychotherapeutic Agents.) Levodopa and carbidopa are contraindicated in patients with known hypersensitivity to the drugs. Levodopa is contraindicated in patients with angle-closure glaucoma. Levodopa may be administered with caution to patients with open-angle glaucoma if intraocular pressure is monitored and remains well controlled. Because levodopa may exacerbate malignant melanoma, the drug should not be used in patients with a history of melanoma or in patients with undiagnosed pigmented lesions.

Pediatric Precautions

Safety and efficacy of levodopa with carbidopa in patients younger than 18 years of age have not been established.

Pregnancy and Lactation

Pregnancy

Safe use of levodopa or carbidopa during pregnancy has not been established. Reproduction studies in rodents using levodopa in daily dosages greater than 200 mg/kg have shown adverse effects on fetal and postnatal growth and viability, and studies in rabbits using the drug alone or in conjunction with carbidopa have shown visceral and skeletal malformations. Levodopa 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.

Distribution of levodopa into human milk has been reported in at least one nursing woman. Carbidopa is distributed into milk in rats; it is not known whether carbidopa is distributed into human milk. Levodopa-carbidopa should be used with caution in nursing women.

Drug Interactions

Psychotherapeutic Agents

Nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine) should not be administered concomitantly with levodopa because hypertensive crises may result. Therapy with monoamine oxidase inhibitors must be discontinued at least 2 weeks prior to initiation of levodopa therapy. Levodopa may be administered concomitantly with a selective inhibitor of MAO-B (e.g., selegiline). However, concomitant use of levodopa-carbidopa and selegiline may be associated with severe orthostatic hypotension not attributable to levodopa-carbidopa alone.

Tricyclic antidepressants may be administered to patients receiving levodopa; however, 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. Although the clinical importance of these interactions has not been established, the possibility that they may occur should be considered.

Phenothiazines, butyrophenones, and possibly thioxanthenes and other antipsychotic agents antagonize the therapeutic effects of levodopa and these drugs should be administered with caution, if at all, during levodopa or levodopa-carbidopa therapy. A few levodopa-treated patients have experienced decreased control of parkinsonian symptoms when chlordiazepoxide hydrochloride 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.

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.

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 advantage; 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.

Hypotensive Agents

Levodopa should be used with caution in patients receiving hypotensive agents. If used concomitantly, the hypotensive effect of levodopa may necessitate dosage reduction of these drugs. In addition, methyldopa (like carbidopa) is a decarboxylase inhibitor and can cause toxic CNS effects such as psychosis if administered concomitantly with levodopa.

Concomitant administration of reserpine with levodopa has been reported to diminish the patient's response to levodopa. Pending further documentation of this interaction, reserpine should probably be avoided in patients receiving levodopa.

General Anesthetics

Concurrent administration of levodopa and cyclopropane or halogenated hydrocarbon general anesthetics may result in cardiac arrhythmias. It has been suggested that other anesthetic agents be utilized whenever a surgical procedure is required in a patient receiving levodopa. Whenever a general anesthetic is required, levodopa may be continued as long as the patient is able to take fluids and medication orally. If therapy is interrupted, the patient should be observed for neuroleptic malignant syndrome and the usual daily dose given as soon as the patient can take oral medication.

Other Drugs

Several patients have experienced decreased therapeutic response to levodopa when papaverine was added to their therapeutic regimen of levodopa-carbidopa. It has been suggested that papaverine should not be administered to patients receiving levodopa.

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. It has been suggested that it is inadvisable to add phenytoin to therapeutic regimens containing levodopa.

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.

Iron salts have been reported to decrease the bioavailability of levodopa and carbidopa; however, the clinical importance of this interaction has not been established.

Isoniazid may antagonize the therapeutic effects of levodopa and should be used with caution during levodopa therapy; patient should be observed for loss of therapeutic response to levodopa.

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 from conventional tablet preparations 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 and orally disintegrating tablets of levodopa-carbidopa are formulated to begin releasing the drugs within 30 minutes of administration. Administration of levodopa and carbidopa as orally disintegrating tablets reportedly results in pharmacokinetic values similar to values observed with the conventional tablet preparation.

Oral bioavailability of levodopa from extended-release tablets of the combination 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 concentration achieved 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 oral extended-release tablets was about 70-75% of that from conventional tablet preparations of the combination or IV levodopa in this age group. However, in young adults, the bioavailability from oral extended-release tablets of the combination was 44% of that of IV levodopa. 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.

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 Pharmacokinetics: Elimination.)

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.

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%.