Prescription Drug Information: Carbidopa

CARBIDOPA- carbidopa tablet
TruPharma, LLC

When carbidopa is to be given to carbidopa-naive patients who are being treated with levodopa, the two drugs should be given at the same time, starting with no more than 20 to 25% of the previous daily dosage of levodopa when given without carbidopa. At least twelve hours should elapse between the last dose of levodopa and initiation of therapy with carbidopa and levodopa. See the WARNINGS and DOSAGE AND ADMINISTRATION sections before initiating therapy.

DESCRIPTION

Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (–)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C10 H14 N2 O4 •H2 O, and its structural formula is:

Chemical Structure
(click image for full-size original)

Carbidopa tablets contain 25 mg of carbidopa. Inactive ingredients are FD&C Yellow 6, magnesium stearate, microcrystalline cellulose, pregelatinized starch and silicon dioxide.

Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.3.

CLINICAL PHARMACOLOGY

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.

Mechanism of Action

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.

The incidence of levodopa-induced nausea and vomiting is less when carbidopa is used with levodopa than when levodopa is used without carbidopa. In many patients this reduction in nausea and vomiting will permit more rapid dosage titration.

Carbidopa inhibits decarboxylation of peripheral levodopa. Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the recommended doses. It does not appear to cross the blood-brain barrier readily and does not affect the metabolism of levodopa within the central nervous system at doses of carbidopa that are recommended for maximum effective inhibition of peripheral decarboxylation of levodopa.

Since its decarboxylase-inhibiting activity is limited primarily to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain. However, since levodopa and carbidopa compete with certain amino acids for transport across the gut wall, the absorption of levodopa and carbidopa may be impaired in some patients on a high protein diet.

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.

In clinical pharmacologic studies, simultaneous administration of separate tablets of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine when compared to the two drugs administered at separate times.

Supplemental pyridoxine (vitamin B6 ) can be given to patients when they are receiving carbidopa and levodopa concomitantly or as SINEMET® CR (carbidopa-levodopa) Sustained-Release or SINEMET® (carbidopa-levodopa). Previous reports in the medical literature cautioned that high doses of vitamin B6 should not be taken by patients on levodopa therapy alone because exogenously administered pyridoxine would enhance the metabolism of levodopa to dopamine. The introduction of carbidopa to levodopa therapy, which inhibits the peripheral decarboxylation of levodopa to dopamine, counteracts the metabolicenhancing effect of pyridoxine.

Carbidopa is combined with levodopa in SINEMET® (carbidopa-levodopa) and SINEMET® CR (carbidopa-levodopa) Sustained-Release tablets. These combination tablets are available in three strengths for SINEMET® ®: SINEMET® 10-100 (carbidopa-levodopa), SINEMET® 25-250 (carbidopa-levodopa) (1:10 ratio of carbidopa to levodopa) and SINEMET® 25-100 (carbidopa-levodopa) (1:4 ratio of carbidopa to levodopa), and in two strengths for SINEMET® CR: SINEMET® CR 50-200 (carbidopa-levodopa) Sustained-Release and SINEMET® CR 25-100 (carbidopa-levodopa) Sustained-Release (1:4 ratio of carbidopa to levodopa). Clinical trials show that these ratios of carbidopa and levodopa provide useful therapeutic effects in most patients.

Carbidopa Indications and Usage

Carbidopa tablets are indicated for use with SINEMET® (carbidopa-levodopa) or with levodopa 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.

Carbidopa tablets are for use with SINEMET® (carbidopa-levodopa) in patients for whom the dosage of SINEMET® (carbidopa-levodopa) provides less than adequate daily dosage (usually 70 mg daily) of carbidopa.

Carbidopa tables are for use with levodopa in the occasional patient whose dosage requirement of carbidopa and levodopa necessitates separate titration of each entity.

Carbidopa tablets are used with SINEMET® (carbidopa-levodopa) or with levodopa to permit the administration of lower doses of levodopa with reduced nausea and vomiting, more rapid dosage titration, and with a somewhat smoother response. However, patients with markedly irregular (“on-off”) responses to levodopa have not been shown to benefit from the addition of carbidopa.

Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, supplemental pyridoxine (vitamin B6 ), can be given to patients when they are receiving carbidopa and levodopa concomitantly or as SINEMET® (carbidopa-levodopa).

Although the administration of carbidopa tablets 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 alone have improved when carbidopa and levodopa were given concurrently. This was most likely due to decreased peripheral decarboxylation of levodopa rather than to a primary effect of carbidopa on the peripheral nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa.

In considering whether to give carbidopa tablets with SINEMET® (carbidopa-levodopa) or with levodopa to patients who have nausea and/or vomiting, the physician should be aware that, while many patients may be expected to improve, some may 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 and levodopa with levodopa alone, about half the patients with nausea and/or vomiting on levodopa alone improved spontaneously despite being retained on the same dose of levodopa during the controlled portion of the trial.

CONTRAINDICATIONS

Carbidopa tablets are contraindicated in patients with known hypersensitivity to any component of this drug.

Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with levodopa or carbidopa-levodopa combination products with or without carbidopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with levodopa. SINEMET® (carbidopa-levodopa), or 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).

Levodopa or carbidopa-levodopa products, with or without carbidopa, are contraindicated in patients with narrow-angle glaucoma.

Because levodopa or carbidopa-levodopa products, with or without carbidopa, may activate a malignant melanoma, they should not be used in patients with suspicious, undiagnosed skin lesions or a history of melanoma.

WARNINGS

Carbidopa has no antiparkinsonian effect when given alone. It is indicated for use with SINEMET® (carbidopa-levodopa) or levodopa. Carbidopa does not decrease adverse reactions due to central effects of levodopa.

When carbidopa is to be given to carbidopa-naive patients who are being treated with levodopa alone, the two drugs should be given at the same time. At least twelve hours should elapse between the last dose of levodopa and initiation of therapy with carbidopa and levodopa in combination. Start with no more than one-fifth (20%) to one-fourth (25%) of the previous daily dosage of levodopa when given without carbidopa. See the DOSAGE AND ADMINISTRATION section before initiating therapy.

As with levodopa, concomitant administration of carbidopa and levodopa may cause involuntary movements and 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. Because carbidopa permits more levodopa to reach the brain and, thus, more dopamine to be formed, dyskinesias may occur at lower levodopa dosages and sooner with concomitant use of carbidopa and levodopa or carbidopa-levodopa combination products than with levodopa alone. The occurrence of dyskinesias may require levodopa dosage reduction.

Levodopa, with or without carbidopa, should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic, or endocrine disease.

Care should be exercised in administering levodopa, with or without carbidopa, 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 alone there is a possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.

Neuroleptic Malignant Syndrome (NMS):

Sporadic cases of a symptom complex resembling NMS have been reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as levodopa, SINEMET® (carbidopa-levodopa), or SINEMET® CR (carbidopa-levodopa) Sustained-Release. Therefore, patients should be observed carefully when the dosage of levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia. Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin, have been reported.

The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has not been demonstrated in controlled studies.

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