Carbidopa and Levodopa

CARBIDOPA AND LEVODOPA- carbidopa and levodopa tablet
McKesson Corporation dba SKY Packaging

Rx Only

DESCRIPTION

Carbidopa and levodopa is a combination product for the treatment of Parkinson’s disease and syndrome. Carbidopa, USP an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water. It is designated chemically as (-)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its molecular formula is C10 H14 N2 O4 ∙H2 O, and has the following structural formula:

Chemical Structure
(click image for full-size original)

C10 H14 N2 O4 ∙H2 O M.W. 244.24

Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.23.

Levodopa, USP an aromatic amino acid, is a white, crystalline compound, slightly soluble in water. It is designated chemically as (-)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its molecular formula is C9 H11 NO4 , and has the following structural formula:

Chemical Structure

C9 H11 NO4 M.W. 197.19

Carbidopa and levodopa tablets, USP for oral administration, are supplied in three strengths:

10 mg/100 mg, containing 10 mg of carbidopa and 100 mg of levodopa.

25 mg/100 mg, containing 25 mg of carbidopa and 100 mg of levodopa.

25 mg/250 mg, containing 25 mg of carbidopa and 250 mg of levodopa.

In addition, each tablet contains the following inactive ingredients:

10 mg/100 mg — Corn starch, FD&C blue #2 aluminum lake, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (maize).
25 mg/100 mg — Corn starch, D&C yellow #10 aluminum lake, FD&C yellow #6 aluminum lake (sunset yellow lake), magnesium stearate, microcrystalline cellulose, and pregelatinized starch (maize).
25 mg/250 mg — Corn starch, FD&C blue #2 aluminum lake, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (maize).

CLINICAL PHARMACOLOGY

Mechanism of Action

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.

Pharmacodynamics

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 the combination product 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.

Pharmacokinetics

Carbidopa reduces the amount of levodopa required to produce a given response by about 75% 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 and 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, carbidopa and levodopa can be given to patients receiving supplemental pyridoxine (vitamin B6 ).

Special Populations

Geriatric

A study in eight young healthy subjects (21 to 22 yr) and eight elderly healthy subjects (69 to 76 yr) showed that the absolute bioavailability of levodopa was similar between young and elderly subjects following oral administration of levodopa and carbidopa. However, the systemic exposure (AUC) of levodopa was increased by 55% in elderly subjects compared to young subjects. Based on another study in forty patients with Parkinson’s disease, there was a correlation between age of patients and the increase of AUC of levodopa following administration of levodopa and an inhibitor of peripheral dopa decarboxylase. AUC of levodopa was increased by 28% in elderly patients (greater than or equal to 65 yr) compared to young patients (less than 65 yr). Additionally, mean value of Cmax for levodopa was increased by 24% in elderly patients (greater than or equal to 65 yr) compared to young patients (less than 65 yr) (see PRECAUTIONS, Geriatric Use).

The AUC of carbidopa was increased in elderly subjects (n=10, 65 to 76 yr) by 29% compared to young subjects (n=24, 23 to 64 yr) following IV administration of 50 mg levodopa with carbidopa (50 mg). This increase is not considered a clinically significant impact.

INDICATIONS AND USAGE

Carbidopa and levodopa tablets, USP are indicated in the treatment of Parkinson’s disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication.

Carbidopa allows patients treated for Parkinson’s disease to use much lower doses of levodopa. Some patients who responded poorly to levodopa have improved on carbidopa and levodopa. This is most likely due to decreased peripheral decarboxylation of levodopa caused by administration of carbidopa rather than by a primary effect of carbidopa on the nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa.

Carbidopa may also reduce nausea and vomiting and permit more rapid titration of levodopa.

CONTRAINDICATIONS

Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with carbidopa and levodopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with this combination product. Carbidopa and levodopa 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).

Carbidopa and levodopa is contraindicated in patients with known hypersensitivity to any component of this drug, and in patients with narrow-angle glaucoma.

WARNINGS

When carbidopa and levodopa tablets are to be given to patients who are being treated with levodopa, levodopa must be discontinued at least twelve hours before therapy with the combination product 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 this combination product 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 central nervous system (CNS) effects, e.g., dyskinesias (involuntary movements), may occur at lower dosages and sooner with carbidopa and levodopa than with levodopa alone.

All patients should be observed carefully for the development of depression with concomitant suicidal tendencies.

Carbidopa and levodopa 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 the combination product, 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 the combination product may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.

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