When patients are receiving levodopa without a decarboxylase inhibitor, levodopa must be discontinued at least twelve hours before SINEMET CR is started. In order to reduce adverse reactions, it is necessary to individualize therapy. SINEMET CR should be substituted at a dosage that will provide approximately 25 percent of the previous levodopa dosage (see DOSAGE AND ADMINISTRATION).

Patients receiving SINEMET CR may develop increased dyskinesias compared to SINEMET (Carbidopa-Levodopa). Dyskinesias are a common side effect of carbidopa-levodopa treatment. The occurrence of dyskinesias may require dosage reduction.

As with levodopa, SINEMET CR may cause mental disturbances. These reactions are thought to be due to increased brain dopamine following administration of lev-odopa. 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.

SINEMET CR 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 SINEMET CR 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 SINEMET CR may increase the 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 SINEMET and SINEMET CR.

Therefore, patients should be observed carefully when the dosage of SINEMET CR 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, myo-globinuria, 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 anti-cholinergic 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 bromocrip-tine, and muscle relaxants, such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has not been demonstrated in controlled studies.

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 SINEMET CR provided the intraocular pressure is well controlled and the patient is monitored carefully for changes in intraocular pressure during therapy.

The patient should be informed that SINEMET CR is a sustained-release formulation of carbidopa-levodopa which releases these ingredients over a 4- to 6-hour period. It is important that SINEMET CR be taken at regular intervals according to the schedule outlined by the physician. The patient should be cautioned not to change the prescribed dosage regimen and not to add any additional antiparkinson medications, including other carbidopa-levodopa preparations, without first consulting the physician.

If abnormal involuntary movements appear or get worse during treatment with SINEMET CR, the physician should be notified, as dosage adjustment may be necessary.

Patients should be advised that sometimes the onset of effect of the first morning dose of SINEMET CR may be delayed for up to 1 hour compared with the response usually obtained from the first morning dose of SINEMET. The physician should be notified if such delayed responses pose a problem in treatment.

Patients should be advised that, occasionally, dark color (red, brown, or black) may appear in saliva, urine, or sweat after ingestion of SINEMET CR. Although the color appears to be clinically insignificant, garments may become discolored.

The patient should be informed that a change in diet to foods that are high in protein may delay the absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also delays stomach emptying, thus delaying the absorption of levodopa. Iron salts (such as in multi-vitamin tablets) may also reduce the amount of levodopa available to the body. The above factors may reduce the clinical effectiveness of the levodopa or carbidopa-levodopa therapy.

Patients must be advised that the whole or half tablet should be swallowed without chewing or crushing.

NOTE : The suggested advice to patients being treated with SINEMET CR is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of carbidopa-levodopa preparations than with levodopa.

Carbidopa-levodopa preparations, such as SINEMET (Carbidopa-Levodopa) and SINEMET CR (Carbidopa-Levodopa) Sustained-Release, may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria.

Cases of falsely diagnosed pheochromocytoma in patients on carbidopa-levodopa therapy have been reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on levodopa or carbidopa-levodopa therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year bioassay of SINEMET, no evidence of carcinogenicity was found in rats receiving doses of approximately two times the maximum daily human dose of car-bidopa and four times the maximum daily human dose of levodopa (equivalent to 8 SINEMET CR tablets).

In reproduction studies with SINEMET, no effects on fertility were found in rats receiving doses of approximately two times the maximum daily human dose of car-bidopa and four times the maximum daily human dose of levodopa (equivalent to 8 SINEMET CR tablets).

Pregnancy Category C. No teratogenic effects were observed in a study in mice receiving up to 20 times the maximum recommended human dose of SINEMET. There was a decrease in the number of live pups delivered by rats receiving approximately two times the maximum recommended human dose of carbidopa and approximately five times the maximum recommended human dose of levodopa during organogenesis. SINEMET caused both visceral and skeletal malformations in rabbits at all doses and ratios of carbidopa/levodopa tested, which ranged from 10 times/5 times the maximum recommended human dose of carbidopa-levodopa to 20 times/10 times the maximum recommended human dose of carbidopa-levodopa.

There are no adequate or well-controlled studies in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in fetal tissue appeared to be minimal. Use of SINEMET CR in women of childbearing potential requires that the anticipated benefits of the drug be weighed against possible hazards to mother and child.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SINEMET CR is administered to a nursing woman.

Safety and effectiveness in pediatric patients have not been established. Use of the drug in patients below the age of 18 is not recommended.

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