PARCOPA- carbidopa and levodopa tablet, orally disintegrating
PARCOPA® (carbidopa-levodopa orally disintegrating tablets) is a combination of carbidopa and levodopa for the treatment of Parkinson’s disease and syndrome. PARCOPA® is an orally administered formulation of carbidopa-levodopa which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.24. It is designated chemically as (–)-L-α-hydrazino-α-methyl-ß-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C10 H14 N2 O4• H2 O, and its structural formula is:
Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.23.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (–)-L-α-amino-ß-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C9 H11 NO4, and its structural formula is:
PARCOPA® is supplied as tablets in three strengths:
PARCOPA® 25/100, containing 25 mg of carbidopa and 100 mg of levodopa.
PARCOPA® 10/100, containing 10 mg of carbidopa and 100 mg of levodopa.
PARCOPA® 25/250, containing 25 mg of carbidopa and 250 mg of levodopa.
Inactive ingredients are aspartame, citric acid, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial mint flavor and sodium bicarbonate. PARCOPA® 10/100 and 25/250 also contain FD&C blue #2 HT aluminum lake. PARCOPA® 25/100 also contains yellow 10 iron oxide.
Parkinson’s disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system affecting the mobility and control of the skeletal muscular system. Its characteristic features include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility.
Current evidence indicates that symptoms of Parkinson’s disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson’s disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson’s disease.
When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. For this reason, large doses of levodopa are required for adequate therapeutic effect and these may often be accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues.
Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients on a high protein diet.
Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier and does not affect the metabolism of levodopa within the central nervous system.
The incidence of levodopa-induced nausea and vomiting is less with carbidopa-levodopa than with levodopa. In many patients, this reduction in nausea and vomiting will permit more rapid dosage titration.
Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain.
Carbidopa reduces the amount of levodopa required to produce a given response by about
75 percent and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid.
The plasma half-life of levodopa is about 50 minutes, without carbidopa. When carbidopa and levodopa are administered together, the half-life of levodopa is increased to about 1.5 hours. At steady state, the bioavailability of carbidopa from carbidopa-levodopa tablets is approximately 99% relative to the concomitant administration of carbidopa and levodopa.
In clinical pharmacologic studies, simultaneous administration of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine than administration of the two drugs at separate times.
Pyridoxine hydrochloride (vitamin B6 ), in oral doses of 10 mg to 25 mg, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine; therefore, PARCOPA® can be given to patients receiving supplemental pyridoxine (vitamin B6 ).
PARCOPA® is indicated in the treatment of the symptoms of idiopathic Parkinson’s disease (paralysis agitans), postencephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication. PARCOPA® is indicated in these conditions to permit the administration of lower doses of levodopa with reduced nausea and vomiting, with more rapid dosage titration, with a somewhat smoother response, and with supplemental pyridoxine (vitamin B6 ).
In some patients, a somewhat smoother antiparkinsonian effect results from therapy with carbidopa-levodopa than with levodopa. However, patients with markedly irregular (“on-off”) responses to levodopa have not been shown to benefit from carbidopa-levodopa therapy.
Although the administration of carbidopa permits control of parkinsonism and Parkinson’s disease with much lower doses of levodopa, there is no conclusive evidence at present that this is beneficial other than in reducing nausea and vomiting, permitting more rapid titration, and providing a somewhat smoother response to levodopa.
Certain patients who responded poorly to levodopa have improved when carbidopa-levodopa was substituted. This is most likely due to decreased peripheral decarboxylation of levodopa which results from administration of carbidopa rather than to a primary effect of carbidopa on the nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa in parkinsonian syndromes.
In considering whether to give PARCOPA® to patients already on levodopa who have nausea and/or vomiting, the practitioner should be aware that, while many patients may be expected to improve, some do not. Since one cannot predict which patients are likely to improve, this can only be determined by a trial of therapy. It should be further noted that in controlled trials comparing carbidopa-levodopa with levodopa, about half of the patients with nausea and/or vomiting on levodopa improved spontaneously despite being retained on the same dose of levodopa during the controlled portion of the trial.
Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with PARCOPA®. These inhibitors must be discontinued at least two weeks prior to initiating therapy with PARCOPA®. PARCOPA® may be administered concomitantly with the manufacturer’s recommended dose of an MAO inhibitor with selectivity for MAO type B
(e.g., selegiline HCl) (See Precautions, Drug interactions).
PARCOPA® is contraindicated in patients with known hypersensitivity to any component of this drug, and in patients with narrow-angle glaucoma.
Because levodopa may activate a malignant melanoma, PARCOPA® should not be used in patients with suspicious, undiagnosed skin lesions or a history of melanoma.
When PARCOPA® (carbidopa-levodopa orally disintegrating tablets) is to be given to patients who are being treated with levodopa, levodopa must be discontinued at least twelve hours before therapy with PARCOPA® (carbidopa-levodopa orally disintegrating tablets) is started. In order to reduce adverse reactions, it is necessary to individualize therapy. See Dosage and Administration section before initiating therapy.
The addition of carbidopa with levodopa in the form of PARCOPA® reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa. Because carbidopa permits more levodopa to reach the brain and more dopamine to be formed, certain adverse CNS effects, e.g., dyskinesias (involuntary movements), may occur at lower dosages and sooner with PARCOPA® than with levodopa alone.
Levodopa alone, as well as PARCOPA® , is associated with dyskinesias. The occurrence of dyskinesias may require dosage reduction.
As with levodopa, PARCOPA® may cause mental disturbances. These reactions are thought to be due to increased brain dopamine following administration of levodopa. All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Patients with past or current psychoses should be treated with caution.
PARCOPA® should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease.
As with levodopa, care should be exercised in administering PARCOPA® to patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. In such patients, cardiac function should be monitored with particular care during the period of initial dosage adjustment, in a facility with provisions for intensive cardiac care.
As with levodopa, treatment with PARCOPA® may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.
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