Sinemet CR

Although specific interaction studies were not performed with other concomitant drugs, in clinical trials of SINEMET CR patients were allowed to receive tricyclic antidepressants, benzodiazepines, propranolol, thiazides, angiotensin converting enzyme inhibitors, calcium channel blockers, digoxin, H₂ antagonists, salicylates and other nonsteroidal anti-inflammatory drugs. SINEMET CR was also used with other antiparkinson agents (see Dosage and Administration).

Dopamine D₂ receptor antagonists (e.g., phenothiazines, butyrophenones, and risperidone) may reduce the therapeutic effects of levodopa. 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 observed carefully for loss of therapeutic response.

Concomitant therapy with selegiline and levodopa-carbidopa preparations may be associated with severe orthostatic hypotension not attributable to levodopa-carbidopa 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. (For patients receiving monoamine oxidase inhibitors, see Contraindications.)

Since levodopa competes with certain amino acids, the absorption of levodopa may be impaired in some patients on a high protein diet.

Symptomatic postural hypotension has occurred when levodopa/decarboxylase inhibitor combinations were added to the treatment of patients receiving antihypertensive drugs. Therefore, when therapy with SINEMET CR is started, dosage adjustment of the antihypertensive drug may be required.

SINEMET CR may cause a false-positive reaction for urinary ketone bodies when a tape test 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 with levodopa-carbidopa 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 levodopa-carbidopa therapy.

When general anesthesia is required, SINEMET CR should be discontinued the night before. Therapy with SINEMET CR may be continued as soon as the patient is able to take medication by mouth.

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

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.

Isoniazid may reduce the therapeutic effects of levodopa.

Studies have demonstrated that ferrous sulphate decreases the bioavailability of carbidopa and/or levodopa. Because this interaction may be due to the formation of drug-iron complexes, other iron supplement formulations and iron-containing multivitamins may have similar effects.

Patients should be observed carefully if abrupt reduction or discontinuation of SINEMET CR is required, especially if the patient is receiving neuroleptics (see Warnings and Precautions).

If general anesthesia is required, SINEMET CR may be continued as long as the patient is permitted to take oral medication. If therapy is interrupted temporarily, the usual dosage should be administered as soon as the patient is able to take oral medication.

Doses and dosing intervals must be adjusted on an individual basis, depending upon therapeutic response. An interval of at least 3 days between dosage adjustments is recommended. Most patients have been adequately treated with 2 to 8 tablets of SINEMET CR 200/50 per day, administered as divided doses at intervals ranging from 4 to 12 hours during the waking day.

If the divided doses of SINEMET CR 200/50 are not equal, it is recommended that the smaller doses be given at the end of the day.

Anticholinergic agents, dopamine agonists, amantadine and lower doses of selective MAO-B inhibitors can be given with SINEMET CR. When combining therapies, dosage adjustments may be necessary.

SINEMET CR 100/25 is available to facilitate titration when 100 mg steps are required and as an alternative to the half tablet of SINEMET CR 200/50.

If a tablet is missed, it should be taken as soon as possible. If it is almost time to take the next tablet, the missed tablet should not be taken, and the normal schedule should be resumed.

Levodopa or SINEMET (levodopa and carbidopa) must be discontinued at least eight hours before therapy with SINEMET CR 200/50 is started. SINEMET CR should be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage. In patients with mild to moderate disease, the initial dose is usually 1 tablet of SINEMET CR 200/50 two times daily.

SINEMET CR (levodopa and carbidopa) tablets contain a 4:1 ratio of levodopa to carbidopa. SINEMET CR 200/50 contains levodopa 200 mg/carbidopa 50 mg (anhydrous equivalent) per tablet. SINEMET CR 100/25 contains levodopa 100 mg/carbidopa 25 mg (anhydrous equivalent) per tablet. The daily dosage of SINEMET CR must be determined by careful titration. Patients should be monitored closely during the dose adjustment period, particularly with regard to appearance or worsening of nausea or abnormal involuntary movements, including dyskinesias, chorea and dystonia.

SINEMET CR 200/50 may be administered as whole or as half tablets. SINEMET CR 100/25 should only be administered as whole tablets. To maintain the controlled release properties of the product, tablets should not be chewed or crushed.

Standard antiparkinson drugs, other than levodopa alone, may be continued while SINEMET CR is being administered, although their dosage may have to be adjusted. The delayed onset of action with SINEMET CR may require the supplemental use of conventional SINEMET tablets for optimal control in the mornings.

SINEMET CR 100/25 may be used in early stage patients who have not had prior levodopa therapy or to facilitate titration when necessary in patients receiving SINEMET CR 200/50. The initial recommended dose is 1 tablet of SINEMET CR 100/25 twice daily. For patients who require more levodopa, a daily dose of 1 to 4 tablets of SINEMET CR 100/25 twice a day is generally well-tolerated.

When appropriate, levodopa therapy may also be initiated with SINEMET CR 200/50. The initial recommended dose in patients with mild to moderate disease is 1 tablet of SINEMET CR 200/50 two times daily. Initial dosages should not exceed 600 mg per day of levodopa or be given at intervals of less than 6 hours.

Because Parkinson's disease is progressive, periodic clinical evaluations are recommended and adjustment of the dosage regimen of SINEMET CR may be required.

ataxia, numbness, increased hand tremor, muscle twitching, blepharospasm (which may be taken as an early sign of excess dosage, consideration of dosage reduction may be needed at this time), trismus, activation of latent Horner's syndrome, euphoria and dementia, depression with suicidal tendencies, bradykinetic episodes.

urinary retention, hematuria, and priapism.

sialorrhea, bruxism, hiccups, gastrointestinal bleeding, flatulence, burning sensation of tongue, development of duodenal ulcer.

Laboratory tests which have been reported to be abnormal are creatinine, uric acid, alkaline phosphatase, AST, ALT, lactic dehydrogenase, bilirubin, and blood urea nitrogen, and Coomb’s test.

Decreased hemoglobin, hematocrit, white blood cell count and serum potassium have been reported as well as bacteria, blood, protein and glucose in the urine.

Abnormalities in various laboratory tests have occurred with SINEMET and may also occur with SINEMET CR.

Henoch-Schoenlein purpura.

leukopenia, hemolytic and non-hemolytic anemia, thrombocytopenia, agranulocytosis.

Other adverse reactions that have been reported with levodopa or SINEMET and may be potential side effects with SINEMET CR are listed below.

Pathological (compulsive) gambling has been reported in post-market data, including those in the literature, for antiparkinson drugs. Sporadic cases of pathological (compulsive) gambling have been reported in patients treated with dopaminergic agents, including levodopa. Dosage adjustment should be considered in the management of this behaviour.

In controlled clinical trials involving 748 patients with moderate to severe motor fluctuations, SINEMET CR (levodopa and carbidopa) did not produce side effects which were unique to the controlled release formulation.

The adverse reaction reported most frequently was dyskinesia (12.8%). Occasionally, prolonged, and at times, severe afternoon dyskinesias have occurred in some patients.

Other adverse reactions that were reported frequently were: nausea (5.5%), hallucinations (5.3%), confusion (4.9%), dizziness (3.5%), headache (2.5%), depression (2.5%), chorea (2.5%), dry mouth (2.3%), somnolence (2.1%), including very rarely excessive daytime somnolence and sudden sleep onset episodes, dream abnormalities (2.1%), dystonia (2.0%) and asthenia (2.0%).

Adverse reactions occurring less frequently (less than 2%) were:

Other adverse reactions reported in clinical trials or in post-marketing experience include: orthostatic effects, hypertension, myocardial infarction, cardiac irregularities, syncope, hypotensive episodes, dysphagia, heartburn, taste alterations, dark saliva, leg pain, shoulder pain, back pain, angioedema, urticaria, pruritus, bullous lesions (including pemphigus-like reactions), nervousness, sleep disorders, neuroleptic malignant syndrome (see Warnings and Precautions), increased tremor, peripheral neuropathy, increased libido including hypersexuality, psychotic episodes including delusions and paranoid ideation, cough, pharyngeal pain, common cold, upper respiratory infection, blurred vision, flushing, alopecia, rash, dark sweat, dark urine, urinary incontinence, urinary frequency, urinary tract infection, malignant melanoma (see Contraindications and Warnings and Precautions, Skin).

diplopia, dilated pupils, oculogyric crises.

weight gain, edema, faintness, hoarseness, malaise, hot flashes, sense of stimulation, bizarre breathing patterns.

Convulsions have occurred; however, a causal relationship with levodopa or levodopa/carbidopa combinations has not been established.

increased sweating.

arrhythmias, non-specific ECG changes, phlebitis.

The safety and effectiveness of SINEMET CR in patients under 18 years of age has not been established.

Each pink-colored, oval-shaped, biconvex, compressed tablet, engraved 601 with bar on one side and SINEMET CR on the other, contains: levodopa 100 mg and carbidopa 25 mg (anhydrous equivalent). Nonmedicinal ingredients: hydroxypropyl cellulose, magnesium stearate, polyvinyl acetate-crotonic acid copolymer and red ferric oxide. Bottles of 100.

Each peach-colored, oval-shaped, biconvex, scored compressed tablet, engraved 521 on one side and SINEMET CR on the other, contains: levodopa 200 mg and carbidopa 50 mg (anhydrous equivalent). Nonmedicinal ingredients: D&C yellow No. 10 Aluminum Lake, hydroxypropyl cellulose, magnesium stearate, polyvinyl acetate-crotonic acid copolymer and red ferric oxide. Bottles of 100, 250 and 500.

SINEMET CR is a controlled-release formulation of levodopa and carbidopa, in a ratio of 4:1. The tablet contains a polymer-based drug delivery system which controls the release of levodopa and carbidopa as it slowly erodes.

SINEMET CR should be administered cautiously to patients with a history of peptic ulcer disease due to the possibility of upper gastrointestinal hemorrhage.

If general anesthesia is required, SINEMET CR may be continued as long as the patient is permitted to take oral medication. If therapy is interrupted temporarily, the usual dosage should be administered as soon as the patient is able to take oral medication (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Interruption of Therapy).

Patients with chronic wide angle glaucoma may be treated cautiously with SINEMET CR (levodopa and carbidopa), provided the intraocular pressure is well controlled and the patient monitored carefully for changes in intraocular pressure during therapy.

Although the effects of SINEMET CR on human pregnancy and lactation are unknown, both levodopa and combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits. Therefore, use of SINEMET CR in women of child-bearing potential requires that the anticipated benefits of the drug be weighed against possible hazards to the mother and to the fetus.

Pathological (compulsive) gambling, hypersexuality, and increased libido have been reported in patients treated with dopaminergic agents including SINEMET CR (see Adverse Reactions). Dose reduction/taper discontinuation should be considered.

Patients who improve while on therapy with SINEMET CR should increase physical activities gradually, with caution, consistent with other medical considerations such as the presence of osteoporosis or phlebothrombosis.

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.

Certain side effects that have been reported with SINEMET CR may affect some patients’ ability to drive or operate machinery.

Given the reported cases of somnolence and sudden onset of sleep (not necessarily preceded by somnolence), physicians should caution patients about the risk of operating hazardous machinery, including driving motor vehicles, while taking SINEMET CR. If drowsiness or sudden onset of sleep should occur, patients should be informed to refrain from driving or operating machines and to immediately contact their physician (see Warnings and Precautions, Boxed Serious Warnings and Precautions, Sudden Onset of Sleep).

Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. For the reasons stated above, patients and healthcare providers are advised to monitor for melanomas frequently and on a regular basis when using SINEMET CR for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

When patients are receiving levodopa monotherapy or SINEMET (levodopa and carbidopa), this medication must be discontinued at least 8 hours before therapy with SINEMET CR is started. (For appropriate dosage substitutions, see Dosage and Administration.)

Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function are recommended during extended therapy (see Adverse Reactions).

As with levodopa or SINEMET, SINEMET CR may cause involuntary movements and mental disturbances. These reactions are thought to be due to increased brain dopamine following administration of levodopa. These adverse reactions may be more prolonged with SINEMET CR than with SINEMET.

SINEMET CR should be used cautiously in patients who have a history of seizures or have conditions associated with seizure or have a lowered seizure threshold.

A symptom complex resembling the neuroleptic malignant syndrome including muscular rigidity, elevated body temperature, altered consciousness, mental changes, autonomic instability and increased serum creatine phosphokinase has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy. Therefore, patients should be observed carefully when the dosage of SINEMET CR is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function are recommended during extended therapy (see Adverse Reactions).

SINEMET CR may cause a false-positive reaction for urinary ketone bodies when a tape test is used for determination of ketonuria. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on levodopa or levodopa-carbidopa therapy. (See Drug Interactions, Drug-Laboratory Test Interactions.)

Safety of SINEMET CR in patients under 18 years of age has not been established.

Hallucinations and confusion are known side effects of treatment with dopaminergic agents, including levodopa. Patients should be aware of the fact that hallucinations (mostly visual) can occur.

It is not known whether carbidopa is excreted in human milk. In a study of one nursing mother with Parkinson’s disease, excretion of levodopa in breast milk was reported. SINEMET CR should not be given to nursing mothers unless the anticipated benefits to the mother outweigh the potential hazards to the infant.

Care should be exercised in administering SINEMET CR to patients with a history of recent 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 administration and titration, in a facility with provisions for intensive cardiac care.

SINEMET CR (levodopa and carbidopa), a combination of levodopa, the metabolic precursor of dopamine, and carbidopa, an aromatic amino acid decarboxylase inhibitor, is available in a polymer-based controlled-release tablet formulation. SINEMET CR can be useful in reducing “off” time in patients treated previously with a conventional levodopa/decarboxylase inhibitor combination who have had predictable peak dose dyskinesias and unpredictable motor fluctuations.

The symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. While the administration of dopamine is ineffective in the treatment of Parkinson's disease because it does not cross the blood-brain barrier, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier and is converted to dopamine in the basal ganglia. This is thought to be the mechanism whereby levodopa relieves the symptoms of Parkinson's disease.

Levodopa is rapidly decarboxylated to dopamine in peripheral 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 attended by nausea and other adverse reactions, some of which are attributable to dopamine formed in peripheral tissues.

Carbidopa, a decarboxylase inhibitor, does not cross the blood-brain barrier and does not affect the metabolism of levodopa within the central nervous system. Since its decarboxylase inhibiting activity is limited to peripheral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain. Combined therapy with levodopa and carbidopa reduces the amount of levodopa required for optimum therapeutic benefit by about 75-80%, permits an earlier response to therapy, and also reduces the incidence of nausea, vomiting and cardiac arrhythmias. Combined therapy, however, does not decrease adverse reactions due to central effects of levodopa.

Following years of treatment with preparations containing levodopa, an increasing number of parkinsonian patients develop fluctuations in motor performance and dyskinesias. The advanced form of motor fluctuations (“on-off” phenomenon) is characterized by unpredictable swings from mobility to immobility. Although the causes of the motor fluctuations are not completely understood, it has been demonstrated that they can be attenuated by treatment regimens that produce steady plasma levels of levodopa.

In clinical trials, patients with motor fluctuations experienced reduced “off” time with SINEMET CR when compared with SINEMET. Global ratings of improvement and activities of daily living in the “on” and “off” states, as assessed by both patient and physician, were slightly better in some patients during therapy with SINEMET CR than with SINEMET. In patients without motor fluctuations, SINEMET CR provided therapeutic benefit similar to SINEMET but with less frequent dosing.

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.

In general, peak levodopa plasma levels are lower, bioavailability is less and time to reach peak levels is delayed when using SINEMET CR. Levodopa plasma levels following a single dose are essentially identical to those following repeated administration. However, with SINEMET CR, levodopa plasma concentrations fluctuate less, namely peak plasma levels are lower and end of dose levels (trough concentrations) higher than after conventional therapy.

The bioavailability of 2 half tablets of SINEMET CR 200/50 is approximately 20% greater than that of one intact tablet. The bioavailability of SINEMET CR is somewhat increased in the presence of food. Dose-proportionality has been demonstrated over the dose range of one and two SINEMET CR 200/50 Tablets.

The pharmacokinetics of levodopa following administration of SINEMET CR 100/25 were studied in patients with Parkinson's disease. Chronic three month, open-label, twice daily dosing with SINEMET CR 100/25 (range: 200 mg levodopa, 50 mg carbidopa up to 600 mg levodopa, 150 mg carbidopa per day) did not result in accumulation of plasma levodopa. The dose-adjusted bioavailability for one SINEMET CR 100/25 tablet was equivalent to that for one SINEMET CR 200/50 tablet. The mean peak concentration of levodopa following the administration of one SINEMET CR 100/25 tablet was greater than 50% of that following one SINEMET CR 200/50 tablet. Mean time-to-peak plasma levels may be slightly less for SINEMET CR 100/25 than for SINEMET CR 200/50.

Elimination half-life of levodopa in the presence of carbidopa is about 1.5 hours. Following SINEMET CR, the apparent half-life of levodopa may be prolonged because of continuous absorption.