levodopa-carbidopa
Sinemet 10-100, Sinemet 25-100, Sinemet 25-250, Sinemet CR 25-100, Sinemet CR 50-200

Available forms
Available by prescription only
Tablets: 10 mg carbidopa with 100 mg levodopa (Sinemet 10-100), 25 mg carbidopa with 100 mg levodopa (Sinemet 25-100), 25 mg carbidopa with 250 mg levodopa (Sinemet 25-250)
Tablets (sustained-release): 25 mg carbidopa with 100 mg levodopa (Sinemet CR 25-100), 50 mg carbidopa with 200 mg levodopa (Sinemet CR 50-200)

Indications and dosages
 Parkinsonism. Adults: Most patients respond to a 25 mg/100 mg combination (1 tablet P.O. t.i.d.). Dose may be increased q 1 or 2 days to maximum of 8 tablets or 1 tablet of 10 mg/100 mg t.i.d. or q.i.d. up to 2 tablets q.i.d.; or 1 sustained-release tablet b.i.d. at intervals at least 6 hours apart. Intervals may be adjusted based on patient response. Usual dose is 2 to 8 tablets daily in divided doses every 4 to 8 hours while awake.
 Carefully adjust maintenance therapy based on patient tolerance and desired therapeutic response. Usual maintenance dosage is 3 to 6 tablets of 25 mg carbidopa/250 mg levodopa P.O. daily in divided doses. Don’t exceed 8 tablets of 25 mg carbidopa/250 mg levodopa daily. Optimum daily dose must be determined by careful adjustment for each patient.
 Daily dose of carbidopa should be 70 to 100 mg or more to suppress the peripheral metabolism of levodopa.

Pharmacodynamics
Decarboxylase-inhibiting action: Carbidopa inhibits the peripheral decarboxylation of levodopa, thus slowing its conversion to dopamine in extracerebral tissues. This results in an increased availability of levodopa for transport to the brain, where it undergoes decarboxylation to dopamine.

Pharmacokinetics
Absorption: 40% to 70% of dose is absorbed after oral administration. Plasma levodopa levels increase when carbidopa and levodopa are administered together because carbidopa inhibits the peripheral metabolism of levodopa.
Distribution: Carbidopa is distributed widely in body tissues except the CNS. Levodopa is also distributed into breast milk.
Metabolism: Carbidopa isn’t metabolized extensively. It inhibits metabolism of levodopa in the GI tract, thus increasing its absorption from the GI tract and its level in plasma.
Excretion: 30% of the dose is excreted unchanged in urine within 24 hours. When given with carbidopa, the amount of levodopa excreted unchanged in urine increases by about 6%. Half-life is 1 to 2 hours.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug; in those with acute angle-closure glaucoma, melanoma, or undiagnosed skin lesions; and within 14 days of MAO inhibitor therapy.
  Use cautiously in patients with severe CV, endocrine, pulmonary, renal, or hepatic disorders; peptic ulcer; psychiatric illness; MI with residual arrhythmias; bronchial asthma; emphysema; and well-controlled, chronic open-angle glaucoma.

Interactions
Drug-drug. Amantadine, benztropine, procyclidine, trihexyphenidyl: May increase efficacy of levodopa. May be used for therapeutic benefit.
Anesthetics, hydrocarbon inhalation: May cause arrhythmias because of increased endogenous dopamine concentration. Discontinue levodopa 6 to 8 hours before giving anesthetics such as halothane.
Antacids that contain calcium, magnesium, or sodium bicarbonate: May increase levodopa absorption. Give antacids 1 hour after levodopa.
Anticonvulsants (such as hydantoins, phenytoin), benzodiazepines, haloperidol, papaverine, phenothiazines, rauwolfia alkaloids, thioxanthenes: May decrease therapeutic effects of levodopa. Monitor patient for decreased effectiveness.
Antihypertensives: Increases hypotensive effect. Monitor blood pressure.
Bromocriptine: May produce additive effects. Reduce levodopa dosage if necessary.
MAO inhibitors: May cause hypertensive crisis. Discontinue MAO inhibitors for 2 to 4 weeks before starting levodopa.
Methyldopa: May alter antiparkinsonian effects of levodopa and produce additive toxic CNS effects. Avoid use together.
Molindone: May inhibit antiparkinsonian effect of levodopa by blocking dopamine receptors in the brain. Avoid use together.
Sympathomimetics: May increase risk of arrhythmias. Dosage reduction of the sympathomimetic is recommended; the administration of carbidopa with levodopa reduces the tendency of sympathomimetics to cause dopamine-induced arrhythmias. Reduce levodopa dose.

Adverse reactions
CNS: choreiform, dystonic, and dyskinetic movements; involuntary grimacing, head movements, myoclonic body jerks, ataxia, tremor, and muscle twitching; bradykinetic episodes; psychiatric disturbances; anxiety; disturbing dreams; euphoria; malaise; fatigue; severe depression; neuroleptic malignant syndrome; suicidal tendencies; dementia; delirium; hallucinations (may necessitate reduction or withdrawal of drug); confusion; insomnia; agitation.
CV: orthostatic hypotension, cardiac irregularities, phlebitis.
EENT: blepharospasm, blurred vision, diplopia, mydriasis or miosis, oculogyric crises, excessive salivation.
GI: dry mouth, bitter taste, nausea, vomiting, anorexia, constipation, flatulence, diarrhea, abdominal pain.
GU: urinary frequency, urine retention, urinary incontinence, darkened urine, priapism.
Hematologic: hemolytic anemia, thrombocytopenia, leukopenia, agranulocytosis.
Hepatic: hepatotoxicity.
Metabolic: weight loss at start of therapy.
Respiratory: hyperventilation, hiccups.
Skin: dark perspiration.

Effects on lab test results
• May increase uric acid, BUN, ALT, AST, alkaline phosphatase, LDH, and bilirubin levels.
• May decrease hemoglobin and WBC, granulocyte, and platelet counts.

Overdose and treatment
There have been no reports of overdose with carbidopa. Signs and symptoms of levodopa overdose are irregular heartbeat and palpitations, severe continuous nausea and vomiting, spasm or closing of eyelids.
 Treatment of overdose includes immediate gastric lavage and an antiarrhythmic, if needed. Pyridoxine isn’t effective in reversing the actions of carbidopa and levodopa combinations.

Special considerations
• Twitching of muscles and eyelids may be an early sign of overdose.
• If patient is being treated with levodopa, discontinue at least 8 hours before starting levodopa-carbidopa. Initial combination therapy should provide no more than 20% to 25% of previous levodopa dosage.
• The combination drug usually reduces the amount of levodopa needed by 75%, thereby reducing the risk of adverse reactions.
• Sustained-release tablets may be split but never crushed or chewed.
• For patients being transferred from conventional levodopa-carbidopa preparation to an extended-release preparation, the extended-release tablet should provide 10% to 30% more levodopa daily.
• Pyridoxine (vitamin B₆) doesn’t reverse beneficial effects of levodopa-carbidopa. Multivitamins can be taken without fear of losing control of symptoms.
• Dosage adjustment is based on patient’s response and tolerance to drug. Therapeutic and adverse reactions occur more rapidly with levodopa-carbidopa combination than with levodopa alone. Observe and monitor vital signs, especially while dosage is being adjusted.
• Test patients on long-term therapy regularly for diabetes and acromegaly; periodically repeat blood test and liver and kidney function studies.
• If therapy is interrupted temporarily, usual daily dosage may be given as soon as patient resumes oral medications.
• Maximum effectiveness of drug may not occur for several weeks or months.
• Antiglobulin determinations (Coombs’ test) are occasionally positive after long-term use. Thyroid function determinations may inhibit thyroid-stimulating hormone response to protirelin.
• Serum and urine uric acid determinations may show false elevations. Urine glucose determinations using copper reduction method may show false-positive results; with the glucose oxidase method, false-negative results. Urine ketone determination using dip-stick method, urine norepinephrine determinations, and urine protein determinations using Lowery test may show false-positive results.
Breast-feeding patients
• Because levodopa may inhibit lactation, don’t use drug in breast-feeding women.
Pediatric patients
• Safety of drug in children younger than age 18 hasn’t been established.
Geriatric patients
• Smaller doses may be required in elderly patients because of their reduced tolerance to the effects of levodopa-carbidopa.
• These patients, especially those with osteoporosis, should resume normal activity gradually because increased mobility may increase the risk of fractures.
• Elderly patients are especially vulnerable to adverse CNS effects, such as anxiety, confusion, or nervousness; those with heart disease are more susceptible to cardiac effects.

Patient education
• Instruct patient to report adverse reactions and therapeutic effects.
• Warn patient of possible dizziness or orthostatic hypotension, especially at start of therapy. Tell patient to change position slowly and dangle legs before getting out of bed. Elastic stockings may be helpful in some patients.
• Tell patient to eat shortly after taking drug to relieve gastric irritation.
• Inform patient that drug may cause urine or sweat to darken.
• Tell patient to take a missed dose as soon as possible, to skip a missed dose if next scheduled dose is within 2 hours, and never to double the dose.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use