carbidopa-levodopa 25-100 tab (generic sinemet)

Cautions

Adverse effects occur in most patients who receive levodopa (with or without carbidopa). Adverse effects of levodopa are numerous and are usually dose dependent and reversible. The incidence of levodopa-induced nausea and vomiting is generally less when carbidopa is used in conjunction with the drug. However, concomitant administration of carbidopa does not decrease adverse reactions resulting from the central effects of levodopa and in fact some CNS effects may occur at lower dosage and more rapidly during therapy with levodopa-carbidopa combinations than with levodopa alone. The adverse effect profile reported with levodopa and carbidopa administered as extended-release tablets is comparable to that with conventional oral preparations.

Whenever the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo) is used, consideration should be given to the possible adverse effects reported with the individual components.

Nervous System and Muscular Effects

The most common serious adverse effects of levodopa are choreiform, dystonic, dyskinetic, and other adventitious movements. Involuntary movements occur in about 50% of patients on long-term therapy and may consist of grimacing, bruxism, gnawing, chewing, twisting and protrusion of the tongue, rhythmic opening and closing of the mouth, bobbing and wave-like motions of the head with or without gesticulation, slow rhythmic movements of the neck, hands or feet, jerky movements of the shoulder or pelvic girdle, and opisthotonos or ballismus. Intermittent myoclonic body jerks during sleep, ataxia, increased hand tremor, and muscle twitching and blepharospasm (which may be an early sign of excessive dosage) may also occur. Involuntary movements are usually dose related and may require reduction of dosage. They do not usually occur in nonparkinsonian patients such as those with chronic manganese intoxication. Because carbidopa allows more levodopa to reach the brain, dyskinesias may occur at lower dosages and more rapidly when levodopa is used in conjunction with carbidopa than when levodopa is used alone. A symptom complex resembling the neuroleptic malignant syndrome also has been reported. (See Cautions: Precautions and Contraindications.)

At least 3 forms of ''bradykinetic episodes'' may occur in some patients on long-term levodopa therapy. In one form, a gradual return of parkinsonian symptoms may occur toward the end of an inter-dose period. This can be minimized by more frequent administration of the drug. In the ''on-off'' phenomenon, a sudden loss of effectiveness with an abrupt onset of akinesia (''off'' effect) which may last from 1 minute to an hour followed by an equally sudden return of effectiveness (''on'' effect) may occur many times daily. This occasionally can be minimized by increasing the number of doses per day. Akinesia paradoxica (''start hesitation''), a sudden hypotonic freezing in which the patient frequently falls because he becomes akinetic just as he starts to walk, may be relieved by reducing the dosage of levodopa. Although the cause of these episodes has not been precisely determined, it appears that they may result from a combination of progression of the disease and excessive levodopa dosage.

Numerous mild to severe CNS and psychiatric disturbances may be produced by levodopa and may include decreased attention span, memory loss, insouciance, nervousness, anxiety, agitation, restlessness, confusion, insomnia, vivid dreams, nightmares, daytime somnolence, euphoria, malaise, fatigue, pathologic gambling, increased libido (including hypersexuality), and symptoms related to impulse control. Serious psychiatric disturbances requiring reduction of dosage or complete withdrawal of the drug have included severe mental depression with or without suicidal tendencies, dementia, toxic delirium, paranoid delusions, hallucinations, and hypomania with inappropriate or excessive sexual behavior. Severe psychotic episodes are most likely to occur in patients with a history of mental disorders. Levodopa promotes release of pituitary growth hormone which may potentiate the cerebral effects of the drug.

GI Effects

Nausea, vomiting, and anorexia (which may be accompanied by weight loss) occur frequently in patients receiving levodopa. Adverse GI effects of levodopa generally occur early in therapy while dosage is being increased and may be relieved by temporary reduction of dosage or administration of the drug with food. Other adverse GI effects which have been reported less frequently include duodenal ulcer, GI bleeding, constipation, diarrhea, epigastric and abdominal distress and pain, flatulence, hiccups, sialorrhea, dry mouth, dysphagia, change in taste sensation (including bitter taste), burning of the tongue, and trismus.

Cardiovascular Effects

Orthostatic hypotension occurs frequently following therapeutic doses of levodopa; however, it is usually asymptomatic and tolerance usually develops within a few months. If orthostatic hypotension causes dizziness or syncope, levodopa dosage should be reduced and the patient should be advised to wear elastic stockings until previous dosage of levodopa is tolerated.

Cardiac irregularities occur infrequently with levodopa and may include palpitation, sinus tachycardia, ventricular tachycardia or extrasystole, atrial flutter or fibrillation, or block of atrioventricular conduction. Cardiac arrhythmias caused by levodopa can be prevented by concomitant administration of a β-adrenergic antagonist such as propranolol. Other reported adverse cardiovascular effects of levodopa include flushing and hypertension.

Other Adverse Effects

Adverse respiratory effects of levodopa include episodic hyperventilation, bizarre breathing patterns, hoarseness, and excessive nasal discharge. Adverse reactions affecting the urinary tract include urinary frequency, retention, incontinence, and dark urine. Adverse ocular effects include blurred vision, diplopia, mydriasis or miosis, widening of the palpebral fissures, activation of latent Horner's syndrome, and oculogyric crises. However, levodopa has been reported to reduce the incidence and severity of oculogyric crises in some patients with postencephalitic parkinsonian syndrome. Rarely, phlebitis, leukopenia, hemolytic or nonhemolytic anemia, thrombocytopenia, agranulocytosis, and decreased hemoglobin and hematocrit have occurred. If leukopenia occurs during levodopa therapy, the drug should be discontinued, at least temporarily.

Other adverse effects reported to occur in patients receiving levodopa include muscle cramps, a sense of stimulation, headache, weakness, numbness, increased sweating, dark sweat or other body fluids (e.g., saliva), pigmentation of the skin and teeth, rash, hot flashes, postmenopausal bleeding, weight gain or loss, priapism, edema, and alopecia. The development or exacerbation of malignant melanoma has been reported rarely in patients receiving levodopa therapy; however, a causal relationship to the drug has not been fully established to date.

Transient elevations in serum alkaline phosphatase, AST (SGOT), ALT (SGPT), LDH, bilirubin, and BUN concentrations may occur in patients receiving levodopa therapy. Serum concentrations of BUN, creatinine, and uric acid may be lower when levodopa is used in conjunction with carbidopa than when levodopa is used alone. Rarely, positive direct antiglobulin (Coombs') test results have been reported during prolonged therapy with levodopa.

Development of a scleroderma-like illness, manifested by proximal muscle weakness, pain and swelling of the hands and feet, a pruritic rash, and weight loss, has been reported in one patient receiving carbidopa and oxitriptan (l-5HTP) for the treatment of intention myoclonus. Although the exact pathogenetic mechanism of this adverse effect has not been determined, it has been suggested that a simultaneous increase in blood serotonin concentration and an enzyme defect producing an increase in serum kynurenine (a metabolite of tryptophan) concentration, which result from the combined use of carbidopa and oxitriptan, are responsible for the occurrence of this scleroderma-like illness.

Precautions and Contraindications

Levodopa should be used with extreme caution, if at all, in patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. When levodopa therapy is initiated in these patients, intensive coronary care facilities should be immediately available. Levodopa should also be used with caution in patients with bronchial asthma or emphysema who may require the use of sympathomimetic drugs. Levodopa should be administered with caution to patients with severe cardiovascular, pulmonary, renal, hepatic, or endocrine disease.

Levodopa should be administered with caution to patients with a history of active peptic ulcer because there is a possibility that levodopa may cause upper GI hemorrhage in such patients.

Since levodopa may cause psychiatric changes, the drug should be used with extreme caution in psychotic patients and all patients should be carefully observed for development of depression and suicidal tendencies. The drug should also be used with caution in patients with a history of seizure disorders.

Patients should be observed closely when levodopa dosage is reduced abruptly or the drug is discontinued, especially in patients receiving an antipsychotic agent concomitantly, since a symptom complex resembling the neuroleptic malignant syndrome has occurred following abrupt withdrawal of antiparkinsonian agents. The symptom complex may include muscular rigidity, elevated body temperature, mental changes, diaphoresis, tachycardia, tachypnea, and/or increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations.

Dopaminergic agents, including levodopa, may be associated with somnolence and, very rarely, with episodes of sudden onset of sleep, which may occur without the patient's awareness or without warning during daily activities. Patients receiving therapy with dopaminergic agents, including levodopa, must be informed of this risk and advised to exercise caution when driving or operating machinery. Patients should be advised that they must refrain from driving or operating machinery if they experience somnolence and/or an episode of sudden sleep onset.

Data from epidemiologic studies indicate that patients with parkinsonian syndrome have a twofold to approximately sixfold greater risk of developing melanoma than the general population. It is unclear whether this increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat the disease). Because of these findings, patients and clinicians should monitor for melanoma on a frequent and regular basis. The manufacturer recommends that dermatologic examinations be performed periodically by qualified clinicians (e.g., dermatologists).

Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges have been reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including levodopa-carbidopa). Although a causal relationship has not been established, these urges stopped in some cases when dosage was reduced or the drug was discontinued. Clinicians should ask patients whether they have developed new or increased gambling urges, sexual urges, or other urges while receiving levodopa-carbidopa and should advise them of the importance of reporting such urges. If a patient develops such urges while receiving levodopa-carbidopa, consideration should be given to reducing the dosage or discontinuing the drug.

Geriatric patients who respond to levodopa should resume normal activity gradually and with caution because increased mobility may lead to fractures, particularly if an underlying condition such as osteoporosis is present. Diabetic patients should be closely monitored during levodopa therapy because the drug may adversely affect control of blood glucose.

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that Parcopa orally disintegrating tablets contain aspartame (NutraSweet), which is metabolized in the GI tract to provide phenylalanine following oral administration.

When the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo) is used, the precautions and contraindications associated with all the drugs in the formulation must be considered.

Periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function should be performed in all patients receiving extended levodopa therapy. Because some patients receiving levodopa have experienced abnormal bleeding episodes following prostatectomy, it has been recommended that hematologic studies be performed during the postoperative evaluation of all patients receiving the drug. Levodopa is contraindicated in patients receiving nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine). (See Drug Interactions: Psychotherapeutic Agents.) Levodopa and carbidopa are contraindicated in patients with known hypersensitivity to the drugs. Levodopa is contraindicated in patients with angle-closure glaucoma. Levodopa may be administered with caution to patients with open-angle glaucoma if intraocular pressure is monitored and remains well controlled. Because levodopa may exacerbate malignant melanoma, the drug should not be used in patients with a history of melanoma or in patients with undiagnosed pigmented lesions.

Pediatric Precautions

Safety and efficacy of levodopa with carbidopa in patients younger than 18 years of age have not been established.

Pregnancy and Lactation

Pregnancy

Safe use of levodopa or carbidopa during pregnancy has not been established. Reproduction studies in rodents using levodopa in daily dosages greater than 200 mg/kg have shown adverse effects on fetal and postnatal growth and viability, and studies in rabbits using the drug alone or in conjunction with carbidopa have shown visceral and skeletal malformations. Levodopa should be administered to pregnant women or women who might become pregnant only when the benefits to the mother outweigh the possible risks to the mother and fetus.

Distribution of levodopa into human milk has been reported in at least one nursing woman. Carbidopa is distributed into milk in rats; it is not known whether carbidopa is distributed into human milk. Levodopa-carbidopa should be used with caution in nursing women.