In controlled clinical trials, patients predominantly with moderate to severe motor fluctuations while on SINEMET (Carbidopa-Levodopa) were randomized to therapy with either SINEMET or SINEMET CR (Carbidopa-Levodopa) Sustained-Release. The adverse experience frequency profile of SINEMET CR did not differ substantially from that of SINEMET, as shown in Table I.

Abnormal laboratory findings occurring at a frequency of 1% or greater in approximately 443 patients who received SINEMET CR and 475 who received SINEMET (Carbidopa-Levodopa) during controlled clinical trials included: decreased hemoglobin and hematocrit; elevated serum glucose; white blood cells, bacteria and blood in the urine.

The adverse experiences observed in patients in uncontrolled studies were similar to those seen in controlled clinical studies.

Other adverse experiences reported overall in clinical trials in 748 patients treated with SINEMET CR, listed by body system in order of decreasing frequency, include:

Body as a Whole: Asthenia, fatigue, abdominal pain, orthostatic effects.

Cardiovascular: Palpitation, hypertension, hypotension, myocardial infarction.

Gastrointestinal: Gastrointestinal pain, dysphagia, heartburn.

Metabolic: Weight loss.

Musculoskeletal: Leg pain.

Nervous System/Psychiatric: Chorea, somnolence, falling, anxiety, disorientation, decreased mental acuity, gait abnormalities, extrapyramidal disorder, agitation, nervousness, sleep disorders, memory impairment.

Respiratory: Cough, pharyngeal pain, common cold.

Skin: Rash.

Special Senses: Blurred vision.

Urogenital: Urinary incontinence.

Laboratory Tests: Decreased white blood cell count and serum potassium; increased BUN, serum creatinine and serum LDH; protein and glucose in the urine.

The following adverse experiences have been reported in post-marketing experience with SINEMET CR:

Cardiovascular: Cardiac irregularities, syncope.

Gastrointestinal: Taste alterations, dark saliva.

Hypersensitivity: Angioedema, uticaria, pruritus, bullous lesions (including pemphigus-like reactions).

Nervous System/Psychiatric: Neuroleptic malignant syndrome (see WARNINGS), increased tremor, peripheral neuropathy, psychotic episodes including delusions and paranoid ideation, increased libido.

Skin: Alopecia, flushing, dark sweat.

Urogenital: Dark urine.

Other adverse reactions that have been reported with levodopa alone and with various carbidopa-levodopa formulations and may occur with SINEMET CR are:

Cardiovascular: Phlebitis.

Gastrointestinal: Gastrointestinal bleeding, development of duodenal ulcer, sialor-rhea, bruxism, hiccups, flatulence, burning sensation of tongue.

Hematologic: Hemolytic and nonhemolytic anemia, thrombocytopenia, leukope-nia, agranulocytosis.

Hypersensitivity: Henoch-Schonlein purpura.

Metabolic: Weight gain, edema.

Nervous System/Psychiatric: Ataxia, depression with suicidal tendencies, dementia, euphoria, convulsions (however, a causal relationship has not been established); bradykinetic episodes, numbness, muscle twitching, blepharospasm (which may be taken as an early sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, activation of latent Horner's syndrome, nightmares.

Skin: Malignant melanoma (see also CONTRAINDICATIONS), increased sweating.

Special Senses: Oculogyric crises, mydriasis, diplopia.

Urogenital: Urinary retention, priapism.

Miscellaneous: Faintness, hoarseness, malaise, hot flashes, sense of stimulation, bizarre breathing patterns.

Laboratory Tests: Abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), bilirubin, Coombs test, uric acid.

Caution should be exercised when the following drugs are administered concomitantly with SINEMET CR.

Symptomatic postural hypotension has occurred when carbidopa-levodopa preparations were added to the treatment of patients receiving some antihyperten-sive drugs. Therefore, when therapy with SINEMET CR is started, dosage adjustment of the antihypertensive drug may be required.

For patients receiving monoamine oxidase (MAO) inhibitors (Type A or B), see CONTRAINDICATIONS. Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone (see CONTRAINDICATIONS).

There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa preparations.

Dopamine D₂ receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with SINEMET CR should be carefully observed for loss of therapeutic response.

Iron salts may reduce the bioavailability of levodopa and carbidopa. The clinical relevance is unclear.

Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.

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