Sinemet

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 should be carefully observed for loss of antiparkinsonian effect.

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 SINEMET. 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 can occur when SINEMET is added to the treatment of a patient receiving antihypertensive drugs. Therefore, when therapy with SINEMET is started, dosage adjustment of the antihypertensive drug may be required.

SINEMET 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 should be discontinued the night before. Therapy with SINEMET 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:

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.

Levodopa must be discontinued at least twelve hours or more before SINEMET is started. A dosage of SINEMET should be used that will provide approximately 20% of the previous levodopa daily dosage; this can be started in the morning after the day in which the treatment with levodopa has been stopped. For example, if a patient is receiving 4000 mg of levodopa per day, the dosage of SINEMET should not provide more than 750 mg of levodopa per day divided into four to six doses.

Tablets of SINEMET 100/25 should be used to start medication for patients requiring lower dosages of levodopa.

In order to reduce the incidence of adverse reactions and achieve maximal benefit, therapy with SINEMET (levodopa and carbidopa) must be individualized and drug administration must be continuously matched to the needs and tolerance of the patient. It should be borne in mind that the therapeutic range of SINEMET is narrower than that of levodopa alone because of its greater milligram potency. Therefore, titration and adjustment of dosage should be made in small steps and the dosage ranges recommended should usually not be exceeded. The appearance of involuntary movements should be regarded as a sign of levodopa toxicity and as an indication of overdosage, requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinesias.

If a patient being treated with levodopa is switched to therapy with SINEMET, levodopa must be discontinued at least twelve hours or more before therapy with SINEMET is initiated.

SINEMET tablets are available in a 4:1 ratio (SINEMET 100/25) and in a 10:1 ratio of levodopa to carbidopa (SINEMET 100/10 and SINEMET 250/25). Tablets of the two ratios may be given separately or combined as needed to provide the optimal dosage.

Studies have shown that peripheral dopa decarboxylase is saturated by carbidopa at doses between 70 to 150 mg per day. Patients receiving less than 70 mg per day of carbidopa are more likely to experience nausea and vomiting. Experience with total daily dosages of carbidopa greater than 200 mg is limited.

For patients who require only low doses of levodopa, e.g., less than 700 mg, SINEMET 100/25 may be helpful.

Dosage is best initiated with one tablet of SINEMET 100/25 three times a day. This dosage schedule provides 75 mg of carbidopa per day. Dosage may be carefully increased by one tablet every three days until the optimal dosage has been reached which does not produce dyskinesias.

While increasing the dosage during the induction period, the doses should be divided, aiming at a frequency of dosing of at least four times a day. If further titration is necessary after a daily dosage level of six tablets of SINEMET 100/25 has been reached, tablets of SINEMET 100/10 or SINEMET 250/25 may be used as needed to provide the optimal dosage.

Usually no patient should receive more than 1500 mg of levodopa a day. Some patients, including those with postencephalitic parkinsonism, are more sensitive to levodopa and require specially careful dosage adjustment.

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.

Therapy should be individualized and adjusted according to the desired therapeutic response. At least 70 to 100 mg of carbidopa per day should be provided. When a greater proportion of carbidopa is required, one tablet of SINEMET 100/25 may be substituted for each tablet of SINEMET 100/10. When more levodopa is required, SINEMET 250/25 should be substituted for SINEMET 100/25 or 100/10. If necessary, the dosage of SINEMET 250/25 may be increased by one-half or one tablet every day or every other day to a maximum of eight tablets a day. Experience with total daily dosages of carbidopa greater than 200 mg is limited.

Because both therapeutic and adverse responses occur more rapidly with SINEMET than with levodopa alone, patients should be monitored closely during the dose adjustment period. Specifically, involuntary movements will occur more rapidly with SINEMET than with levodopa. The occurrence of involuntary movements may require dosage reduction. Blepharospasm may be a useful early sign of excess dosage in some patients.

Current evidence indicates that other standard antiparkinsonian drugs may be continued while SINEMET is being administered although their dosage may have to be adjusted.

If general anesthesia is required, therapy with SINEMET may be continued as long as the patient is permitted to take fluids and medication by mouth. If therapy is interrupted temporarily, the usual daily dosage may be administered as soon as the patient is able to take oral medication.

sialorrhea, dysphagia, bruxism, hiccups, abdominal pain and distress, flatulence, burning sensation of tongue, gastrointestinal pain, heart burn.

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

Decreased hemoglobin, hematocrit, elevated serum glucose, and white blood cells, bacteria and blood in the urine have been reported.

Decreased white blood cell count and serum potassium; protein and glucose in urine have been reported with levodopa alone and with various levodopa-carbidopa formulations, and may occur with SINEMET.

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.

diplopia, blurred vision, dilated pupils, and oculogyric crises.

The most common serious adverse reactions occurring with SINEMET (levodopa and carbidopa) are dyskinesias, including choreiform, dystonic and other involuntary movements, and nausea. Other serious adverse reactions are mental changes including paranoid ideation and psychotic episodes, depression with or without development of suicidal tendencies, and dementia. Convulsions also have occurred; however, a causal relationship with SINEMET has not been established.

Other adverse reactions reported in clinical trials or in post-marketing experience include:

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

fatigue.

pharyngeal pain, cough.

weight gain or loss, edema.

decreased mental acuity, disorientation, 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 made at this time), trismus, activation of latent Horner’s syndrome, anxiety, euphoria, falling and gait abnormalities, extrapyramidal disorder, nervousness, memory impairment, peripheral neuropathy.

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

angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions (including pemphigus-like reactions).

leg pain.

urinary retention, urinary incontinence, priapism.

flushing.

myocardial infarction.

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

Each dark dapple-blue, oval, scored, uncoated tablet, engraved “647” on one side and “SINEMET” on the other, contains: levodopa 100 mg and carbidopa 10 mg expressed as anhydrous carbidopa. Nonmedicinal ingredients: cornstarch, FD&C Blue #2, magnesium stearate, microcrystalline cellulose and pregelatinized starch. Bottles of 100.

Each yellow, oval, scored, uncoated tablet, engraved “SINEMET” on one side and “650” on the other, contains: levodopa 100 mg and carbidopa 25 mg expressed as anhydrous carbidopa. Nonmedicinal ingredients: cornstarch, D&C Yellow #10, FD&C Yellow #6, magnesium stearate, microcrystalline cellulose and pregelatinized starch. Bottles of 100 and 500.

Each light dapple-blue, oval, scored, uncoated tablet, engraved “SINEMET” on one side, and "654” on the other, contains: levodopa 250 mg and carbidopa 25 mg expressed as anhydrous carbidopa. Nonmedicinal ingredients: cornstarch, FD&C Blue #2, magnesium stearate, microcrystalline cellulose and pregelatinized starch. Bottles of 100.

SINEMET 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, therapy with SINEMET may be continued as long as the patient is permitted to take fluids and medication by mouth. If therapy is interrupted temporarily, the usual daily dosage may be administered as soon as the patient is able to take oral medication (see Dosage and Administration, Adjustment and Maintenance of Therapy).

Although the effects of SINEMET 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 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 (see Adverse Reactions). Dose reduction/taper discontinuation should be considered.

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

Patients should be monitored carefully for the development of depression with suicidal tendencies. Patients with past or current psychoses should be treated with caution.

Certain side effects that have been reported with SINEMET 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. 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 for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

When patients already receiving levodopa are switched to SINEMET, levodopa must be discontinued for at least 12 hours or more before SINEMET is started. SINEMET should be substituted at a dosage that will provide approximately 20% of the previous levodopa dosage (see Dosage and Administration).

Patients who are taking SINEMET should be instructed not to take additional levodopa unless it is prescribed by the physician.

Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function are recommended during extended therapy with SINEMET (levodopa and carbidopa).

The levodopa induced involuntary movements and “on and off” phenomenon may appear earlier with combination therapy.

As with levodopa, SINEMET may cause involuntary movements and mental disturbances. These reactions are thought to be due to increased brain dopamine following administration of levodopa. Because carbidopa permits more levodopa to reach the brain and thus, more dopamine to be formed, dyskinesias may occur at lower dosages and sooner with SINEMET than with levodopa. The occurrence of dyskinesias may require dosage reduction.

SINEMET 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 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 with SINEMET (levodopa and carbidopa).

SINEMET 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).

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

Pupillary dilatation and activation of latent Horner's syndrome have been reported during levodopa treatment. Patients with chronic wide angle glaucoma should therefore be treated cautiously with SINEMET. The intraocular pressure should be well controlled and the patient monitored carefully for changes in intraocular pressure during therapy.

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 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 to patients with a history of myocardial infarction or who have 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.

At steady state, the bioavailability of carbidopa from SINEMET tablets is approximately 99% relative to the concomitant administration of carbidopa and levodopa. Since levodopa competes with certain aminoacids, the absorption of levodopa may be impaired in some patients on a high protein diet.

Following simultaneous administration of carbidopa and levodopa in man, both plasma levels and plasma half-life of levodopa are markedly increased over those found when the same dosage of levodopa is given alone, while plasma levels of dopamine and homovanillic acid are reduced or do not change. Nevertheless, the plasma levels vary greatly between patients.

The plasma half-life of levodopa is about 50 minutes, without carbidopa. When carbidopa and levodopa are administered together, the half-life of levodopa is increased to about 1.5 hours.

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

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.

The 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 because it does not cross the blood-brain barrier. However, 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.

When levodopa is administered orally it is rapidly converted to dopamine by decarboxylation 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 inhibits decarboxylation of peripheral levodopa. It 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.