Carbidopa and Levodopa (Page 2 of 6)

Special Populations

Geriatric

A study in eight young healthy subjects (21-22 yr) and eight elderly healthy subjects (69-76 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 (≥ 65 yr) compared to young patients (< 65 yr). Additionally, mean value of Cmax for levodopa was increased by 24% in elderly patients (≥ 65 yr) compared to young patients (< 65 yr) (see PRECAUTIONS: Geriatric Use).

The AUC of carbidopa was increased in elderly subjects (n = 10, 65-76 yr) by 29% compared to young subjects (n = 24, 23-64 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 extended-release tablets are indicated in the treatment of Parkinson’s disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication.

CONTRAINDICATIONS

Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with carbidopa and levodopa extended-release tablets. These inhibitors must be discontinued at least two weeks prior to initiating therapy with carbidopa and levodopa extended-release. Carbidopa and levodopa extended-release 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 extended-release is contraindicated in patients with known hypersensitivity to any component of this drug and in patients with narrow-angle glaucoma.

WARNINGS

When patients are receiving levodopa without a decarboxylase inhibitor, levodopa must be discontinued at least twelve hours before carbidopa and levodopa extended-release is started. In order to reduce adverse reactions, it is necessary to individualize therapy. See DOSAGE AND ADMINISTRATION section before initiating therapy.

Carbidopa and levodopa extended-release should be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage (see DOSAGE AND ADMINISTRATION).

Carbidopa does not decrease adverse reactions due to central effects of levodopa. By permitting more levodopa to reach the brain, particularly when nausea and vomiting is not a dose-limiting factor, certain adverse central nervous system (CNS) effects, e.g., dyskinesias, will occur at lower dosages and sooner during therapy with carbidopa and levodopa extended-release than with levodopa alone.

Patients receiving carbidopa and levodopa extended-release may develop increased dyskinesias compared to carbidopa and levodopa immediate-release. Dyskinesias are a common side effect of carbidopa-levodopa treatment. The occurrence of dyskinesias may require dosage reduction.

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

Carbidopa and levodopa extended-release 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 carbidopa and levodopa extended-release 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 carbidopa and levodopa extended-release may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.

Falling Asleep During Activities of Daily Living and Somnolence

Patients taking carbidopa and levodopa extended-release alone or with other dopaminergic drugs have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of motor vehicles). Road traffic accidents attributed to sudden sleep onset have been reported. Although many patients reported somnolence while on dopaminergic medications, there have been reports of road traffic accidents attributed to sudden onset of sleep in which the patient did not perceive any warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Sudden onset of sleep has been reported to occur as long as one year after the initiation of treatment.

Falling asleep while engaged in activities of daily living usually occurs in patients experiencing preexisting somnolence, although some patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving or operating machines during treatment with carbidopa and levodopa extended-release. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with carbidopa and levodopa extended-release.

Before initiating treatment with carbidopa and levodopa extended-release, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with carbidopa and levodopa extended-release such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing carbidopa and levodopa extended-release in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with carbidopa and levodopa extended-release continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Hyperpyrexia and Confusion

Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as levodopa, carbidopa-levodopa and carbidopa and levodopa extended-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.

PRECAUTIONS

General

As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are recommended during extended therapy.

Patients with chronic wide-angle glaucoma may be treated cautiously with carbidopa and levodopa extended-release provided the intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular pressure during therapy.

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