Description: Levodopa (L-dopa) is an aromatic amine that is metabolized to dopamine. The use of levodopa revolutionized the treatment of Parkinson's disease when it was introduced in the 1960s and it is considered the gold standard therapy for Parkinson's disease. The response to levodopa therapy in Parkinson's disease is seen as a dramatic improvement in function and, usually, quality of life. Symptoms that usually respond to levodopa treatment include rigidity, tremor, bradykinesia, gait, hypomimia, and micrographia. Other symptoms of Parkinson's disease such as imbalance, dysarthria, sexual dysfunction, excessive sweating, sensory problems, and constipation do not always respond well to levodopa therapy. Large doses of levodopa are required for therapeutic effects; large doses are likely to cause nausea and other adverse effects. Most commonly, levodopa is given in combination with a decarboxylase inhibitor such as carbidopa (see Carbidopa monograph and Carbidopa; Levodopa monograph). The FDA approved levodopa in 1970. Mechanism of Action: Levodopa is the metabolic precursor of dopamine. In patients with idopathic Parkinson's disease or parkinsonism, there is a degerneration of the dopaminergic neurons of the substantia nigra, pars compacta and, to a lesser extent, in the ventral temenal area that is associated with a reduction in striatal dopamine content. The severity of the motor deficit is proportional to the dopamine defficiency. Unlike dopamine, levodopa is able to diffuse into the central nervous system, and is then converted to dopamine. The resulting change in dopamine-acetylcholine balance is believed to improve nerve impulse control and to be the basis of the drug's antiparkinsonian activity. Levodopa treatment does not reverse the course or stop the progression of the disease. Patients who experience response fluctations (i.e., dyskinesias, "on-off" effects, etc.) appear to have reduced metabolism of levodopa and storage of dopamine. In these patients, levodopa is metabolized in the extracellular space and dopamine is released directly to the active site. Therefore, the decline in motor function follows the decreases in levodopa concentrations since there is no dopamine storage serving as a buffer. Parkinson's disease patients who do not have response fluctations, exhibit a residual capacity of production and storage of endogenous dopamine and lower doses of levodopa are required. This storage buffer is responsible for the lag time between decline in levodopa concentrations and dopamine-induced motor response. It is not known if response fluctations are also induced by receptor desensitization or inhibition of the active transport of levodopa across the blood-brain barrier by the metabolite of levodopa, 3-O-methyldopa. Pharmacokinetics: Levodopa is given orally. Following oral administration, amino acid transport mechanisms carry levodopa across the membrane of the GI tract, with approximately 30�50% of the drug entering the circulation. It is thought that high concentrations of amino acids in the GI tract (i.e., a high-protein diet) can interfere with absorption of levodopa. However, there is evidence to suggest that amino acid-levodopa transport competition is more likely to occur during levodopa transport across the blood-brain barrier. Any food (i.e., high fat or high protein) or drug that delays gastric emptying may decrease the absorption of levodopa. Approximately 95% of a dose of levodopa is metabolized to dopamine by L-aromatic amino acid decarboxylase in the stomach, intestines, and liver. The plasma half-life of levodopa is about 50 minutes. Less than 1% of the levodopa dose reaches the CNS when given without a decarboxylase inhibitor (e.g., carbidopa). Levodopa is excreted in the urine as metabolites, including dopamine and homovanillic acid (HVA). In 24 hours, 13�42% of the levodopa dose is excreted as HVA. The duration of effect is patient- and disease-dependent; some patients may require every 2-hour dosing of levodopa.

Indications...Dosage For the treatment of idiopathic Parkinson's disease (paralysis agitans), post-encephatlitic parkinsonism, parkinsonism associated with cerebral arteriosclerosis, and symptomatic parkinsonism that may follow injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication: NOTE: The optimal daily dose of levodopa (i.e., the dose producing maximal improvement of symptoms with tolerable side effects) must be determined and carefully titrated for each individual patient. Oral dosage: Adults: Initially, 500 mg to 1 g PO divided into 2 or more doses with food. The total daily dose is then gradually increased in increments <= 750 mg every 3�7 days, as tolerated. The usual optimal therapeutic dosage is <= 8 g/day PO. Rarely a patient may be given more than 8 g/day if carefully titrated. In some patients, a significant therapeutic response may not be obtained until after 6 months of treatment. NOTE: If carbidopa will be added to a patient who has previously been receiving levodopa monotherapy, the initial daily dosage of levodopa should be no greater than 20�25% of the previous daily levodopa amount. Maximum Dosage Limits �Adults: 8 g/day PO in the majority of patients. Rarely, some patients may require higher doses, but this is the exception. �Elderly: 8 g/day PO in the majority of patients. Rarely, some patients may require higher doses, but this is the exception. �Adolescents: Safe and effective use has not been established. �Children: Safe and effective use has not been established. Patients with renal impairment: No dosage adjustment needed. Patients with hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Administration Oral Administration �Administer orally with 6�8 ounces of water at least 30 minutes before eating or 1 hour after meals to maximize absorption. Levodopa may be taken with a small non-protein snack, such as fruit or a cracker, to avoid nausea. Administering with food may decrease absorption. �Store at room temperature between 15� and 30�C (59� and 86�F). Protect from light. Keep container tightly closed. Throw away any unused medicine after the expiration date

Contraindications Levodopa is contraindicated in patients who are allergic to the medication. Avoid abrupt discontinuation of levodopa therapy. Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome have been associated with dose reductions and withdrawal of levodopa. Patients should be closely monitored if abrupt reduction or discontinuation of levodopa therapy is required, especially if they are also receiving neuroleptics. Patients should be observed closely for manifestations of this symptom complex including tachycardia, muscular rigidity, elevation of body temperature, mental status changes, diaphoresis, tachypnea, and increases in serum creatinine levels. Cases of neuroleptic malignant syndrome have been reported post-surgery so close monitoring is warranted; reinstitute levodopa therapy as soon as possible post-surgery. In addition, some patients receiving levodopa have experienced postoperative bleeding episodes, so hematological studies are recommended for all patients who undergo surgery while receiving this drug. Levodopa should be administered with extreme caution to patients with cardiac disease. Levodopa should be used with caution in patients a history of myocardial infarction who have residual cardiac arrhythmias (i.e., atrial, nodal, or ventricular arrhythmias). Cardiac monitoring in a facility with provisions for intensive cardiac care is recommended during initial titration of levodopa in patients with significant cardiac disease. Levodopa should be used with caution in patients with a history of bronchial asthma and emphysema on sympathomimetic therapies; levodopa has additional sympathomimetic effects. Because levodopa may alter breathing patterns or respiratory rates in some patients, it should be used under careful observation in patients with severe pulmonary disease. Levodopa should be administered with caution to patients with renal disease or hepatic disease. Levodopa may increase the risk of upper GI hemorrhage in patients with a history of active peptic ulcer disease, so it should be used with extreme caution in such patients. Levodopa can cause mental status or nervous system changes. The elderly may be more susceptible to the CNS effects of levodopa, especially when initiating therapy or increasing dosages. All patients receiving the drug should be monitored closely for signs of mental disturbances including depression and/or suicidal ideation. Levodopa should be used with caution in patients with a history of a seizure disorder or known psychosis or other psychiatric illness. Concomitant use of non-selective monoamine oxidase inhibitors (MAOIs) with levodopa can result in hypertensive crisis, and simultaneous use of these agents is contraindicated. Non-selective MAOIs should be discontinued 2�4 weeks before initiation of levodopa combination therapy (see Drug Interactions). Patients with diabetes mellitus should be monitored during levodopa therapy. Alterations in blood glucose may occur in some individuals as a result of the sympathomimetic effects of levodopa. Levodopa may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. False-negative tests may result with use of glucose-oxidase methods of testing for glucosuria. Levodopa is contraindicated for use in patients with closed-angle glaucoma. Levodopa may be used in patients with open-angle glaucoma if intraocular pressure is closely monitored and controlled. Levodopa can activate melanoma, so the drug is contraindicated in patients with a history of melanoma, or in patients with suspicious, undiagnosed pigmented lesions. Levodopa is considered a FDA pregnancy risk category C agent. Although animal reproduction studies have shown adverse fetal effects due to levodopa administration, none have been observed in a limited number of human pregnancies. Levodopa does cross the placenta, and there is no information on the effect of chronic in utero exposure to levodopa. Therefore, in making the decision to administer this drug during pregnancy, the potential risks to the fetus must be weighed against the potential benefits to the mother. Levodopa should not be given to lactating women who are breast-feeding their infants. It is not known if levodopa is distributed into breast milk, however, levodopa inhibits lactation by inhibiting prolactin release. The suppression of milk production by levodopa may be partial or complete. The safety and efficacy of levodopa in children have not been established. Rarely, falsely diagnosed pheochromocytoma has been reported in patients receiving levodopa. Caution should be exercised with interpreting the plasma and urine levels of catecholamines and catecholamine metabolites in patients on levodopa.

nteractions Concomitant administration of amantadine, benztropine, bromocriptine, procyclidine, or trihexyphenidyl with levodopa can enhance the therapeutic effects of levodopa. Combining these drugs may be therapeutic in patients with parkinsonism and may allow for reduced dosages of levodopa. If administered before halogenated anesthetics, levodopa without concomitant use of a decarboxylase inhibitor (e.g., carbidopa) has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6�8 hours before administering halogenated inhalational anesthetics. Otherwise, when general anesthetics are required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication. Agents with dopamine antagonist properties may decrease the effectiveness of levodopa in the CNS. These agents can cause abrupt and severe worsening of Parkinson's disease symptoms. The following medications should be avoided, if possible, in patients treated with levodopa: droperidol, haloperidol, loxapine, metoclopramide, molindone, olanzapine, papaverine, phenothiazines, pimozide, quetiapine, risperidone, and thiothixene. Metoclopramide may also increase the absorption of levodopa by increasing gastric emptying. Concomitant use of non-selective monoamine oxidase inhibitors (MAOIs), such as isocarboxazid, phenelzine, or tranylcypromine, or drugs with MAOI-like activity (e.g., furazolidone; isoniazid, INH; linezolid; or procarbazine) with levodopa can result in hypertensive crisis. Simultaneous use of these agents is contraindicated. Non-selective MAOIs should be discontinued 2�4 weeks before initiation of levodopa therapy. Levodopa may be administered concomitantly with the manufacturer's recommended dose of a MAOI with selectivity for MAO type B (i.e., selegiline). However, concurrent therapy with selegiline and levodopa may be associated with severe orthostatic hypotension not attributable to levodopa alone. Dosages of levodopa should be reduced 2�3 days after beginning selegiline therapy. Rarely, the combination of tricyclic antidepressants and levodopa has been associated with adverse reactions including hypertension and dyskinesia. Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. Methyldopa can interfere with the antiparkinsonian actions of levodopa and increase the risk of CNS toxicity including psychosis. Rauwolfia alkaloids, such as reserpine, deplete dopamine stores in the brain, thereby antagonizing the effects of levodopa. Phenytoin can interfere with the effects of levodopa by enhancing the metabolism of the drug. Concomitant use of cocaine with levodopa can result in an increase in the risk of developing cardiac arrhythmias. Levodopa should be used cautiously in patients who are known users of cocaine. Conversely, electrocardiographic monitoring should be considered when using cocaine in patients receiving levodopa. Foods with a high protein content may interfere with the absorption of levodopa. Since amino acid transport mechanisms carry levodopa across the membrane of the GI tract, it is thought that high concentrations of amino acids in the GI tract (i.e., a high-protein diet) can interfere with absorption of levodopa. There is evidence, however, to suggest that the amino acid-levodopa competition is more likely during levodopa transport across the blood-brain barrier, which may result in an erratic response to the drug. This problem may be more common in persons who have severe on/off motor fluctuations. Patients with protein sensitivity may consume the majority of their protein in the evening or eat small amounts throughout the day, avoiding high protein foods near the time of taking levodopa to help to prevent these problems. It has been recommended to take levodopa at least 30 minutes before eating or one hour after meals. Patients with Parkinson's disease should avoid foods high in fat or fiber around the time of taking levodopa. These foods may delay gastric emptying, which can decrease and delay the absorption of levodopa. Patients should avoid eating foods high in vitamin B6 (e.g., cereal grains, legumes, vegetables, liver, meat, and eggs) at or around the times they are taking their levodopa therapy. Vitamin B6 may decrease the effectiveness of levodopa when it is given without a decarboxylase inhibitor. Pyridoxine, vitamin B6, in doses as low as 10 mg/day, can accelerate the rate of aromatic amino acid decarboxylation, thus increasing the peripheral conversion of levodopa to dopamine. This action diminishes levodopa's therapeutic effects by decreasing the amount of levodopa that is available to cross into the CNS. Patients receiving levodopa single-agent therapy (i.e., without a decarboxylase inhibitor like carbidopa) should avoid vitamin B6 supplements. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours. In a small study, Parkinson's disease patients who were stable on carbidopa; levodopa therapy experienced a 47% decrease in peak plasma levels of levodopa and a 30% reduction in AUC when this therapy was given concurrently with ferrous sulfate. Peak carbidopa levels and AUC were also decreased. Some patients experienced a loss of clinical efficacy with concurrent ferrous sulfate ingestion. Levodopa therapy has been reported to cause a decrease in S-adenosyl-L-methionine, SAM-e, concentrations within the CNS. The implications of this pharmacologic activity are not known at this time.[2590] Intracerebral injections of SAM-e have been reported to induce Parkinson's like symptoms in animals.[2608] However, at least one clinical report of the use of SAM-e for the treatment of depression in Parkinson's patients has been published. The authors reported that while significant improvement in the Hamilton rating scale for depression occurred, none of the 21 patients required alterations in their levodopa dosage. The motor component of the disease was not affected.[2609] Until more is known about the CNS effects of SAM-e supplementation, SAM-e should be used cautiously in patients on levodopa therapy. Cabergoline and levodopa both increase dopaminergic function centrally. Cabergoline is used as an adjunct to levodopa/carbidopa therapy in patients with Parkinson's disease experiencing motor fluctuations. Although this combination appears safe and effective overall, additive neurologic effects are possible. Hallucinations have been reported with the concurrent use of cabergoline and levodopa. [ Revised 2/5/01 ]

Levodopa Larodopa� | Larodopa�, Dopar�

2590. Bottigleri T, Hyland K, Reynolds EH. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 1994;48:137�52.

2608. Charlton CG. Depletion of nigrostriatal and forebrain tyrosine hydroxylase by S-adenosylmethionine: a model that may explain the occurrence of depression in Parkinson's disease. Life Sci 1997;61:495�502.

2609. Carrieri PB, Indaco A, Gentile S, et al. S-adenosyl-methionine treatment of depression in patients with Parkinson's disease: a double-blind placebo crossover study versus placebo. Curr Ther Res 1990;48:154�60.