The P-I-E-N-O Parkinsn's List Drug Database
carbidopa/levodopa / SinemetTM , Sinemet CRTM , AtametTM , MedoparTM , MadoparTM
ANTIPARKINSON:
Description: SinemetTM is a combination drug containing levodopa and carbidopa. SinemetTM is used in the treatment of parkinsonism. Carbidopa is added to levodopa to inhibit the peripheral destruction of levodopa. SinemetTM is marketed in several strengths containing carbidopa and levodopa in ratios of either 1:10 or 1:4. This combination agent was approved by the FDA in 1988.
Mechanism of Action: Parkinsonism is believed to be related to reduced levels of dopamine in the corpus striatum. Levodopa is the metabolic precursor of dopamine. Levodopa diffuses into the central nervous system where it is converted to dopamine. The resulting change in dopamine-acetylcholine balance is believed to improve nerve impulse control and to be the basis of the drug's antiparkinsonian activity. Carbidopa is a noncompetitive decarboxylase inhibitor that, when administered with levodopa, inhibits the peripheral conversion of levodopa to dopamine, thereby increasing the CNS bioavailability of dopamine. Carbidopa does not cross the blood- brain barrier. The addition of carbidopa allows lower doses of levodopa to be used, minimizing adverse reactions from levodopa such as nausea and vomiting. The carbidopa-levodopa combination also allows for a more rapid, even titration of effect.
Pharmacokinetics: SinemetTM is administered orally. Following oral administration, amino acid transport mechanisms carry levodopa across the membrane of the GI tract, with approximately 30-50% of the drug entering the circulation. As a result, high concentrations of amino acids in the GI tract (i.e., a high- protein diet) can interfere with absorption of levodopa. Bioavailability of controlled-release preparations of levodopa- carbidopa is approximately 71% compared with 99% for regular- release preparations.
Levodopa-carbidopa distributes throughout the body, but due to peripheral metabolism, less than 1% of levodopa reaches the CNS; carbidopa does not penetrate the CNS. Approximately 95% of a dose of levodopa is metabolized to dopamine by L-aromatic amino acid decarboxylase in the stomach, intestines, and liver. Carbidopa is not appreciably metabolized. The onset of action of levodopa-carbidopa can be observed 2-3 weeks after therapy is initiated, but some patients require up to 6 months of therapy before beneficial effects are seen. The plasma half-life of both levodopa and carbidopa is roughly 1-2 hours, and the duration of action of a dose is 5 hours. Levodopa-carbidopa is eliminated renally as dopamine metabolites and small amounts as unchanged drug.
CONTRAINDICATIONS/PRECAUTIONS: Levodopa-carbidopa should be used with caution in patients with cardiac arrhythmias, especially if associated with a history of myocardial infarction. Levodopa-carbidopa should be administered with extreme caution to patients with cardiac disease.
Levodopa-carbidopa should be administered with caution to patients with pulmonary disease, renal disease, or hepatic disease.
Levodopa-carbidopa can cause upper GI hemorrhage in patients with a history of active peptic ulcer disease, so it should be used with extreme caution in such patients.
Levodopa-carbidopa can cause mental status changes and should be used with caution in patients with a history of psychosis. All patients receiving the drug should be monitored closely for signs of mental disturbances including depression and/or suicidal thoughts.
A neuroleptic malignant syndrome-like symptom complex can develop following discontinuation of levodopa, especially in patients receiving antipsychotic agents concomitantly. Patients should be observed closely for manifestations of this symptom complex including tachycardia, muscular rigidity, elevation of body temperature, mental status changes, diaphoresis, tachypnea, and increases in serum creatinine levels.
Patients with diabetes mellitus should be monitored closely during levodopa-carbidopa therapy because the drug can alter blood glucose levels.
Some preparations of levodopa that do not contain carbidopa contain tartrazine, which can cause allergic reactions in susceptible individuals.
Some patients receiving levodopa have experienced postoperative bleeding episodes, so hematological studies are recommended for all patients who undergo surgery while receiving this drug.
Levodopa is contraindicated for use in patients with closed-angle glaucoma. The drug may be used in patients with open-angle glaucoma if intraocular pressure is closely monitored and controlled.
Levodopa can worsen malignant melanoma, so the drug is contraindicated in patients with a history of melanoma or in patients with undiagnosed pigmented lesions.
Concomitant use of monoamine oxidase inhibitors (MAOIs) with levodopa-carbidopa can result in hypertensive crisis, and simultaneous use of these agents is contraindicated. MAOIs should be discontinued 2-4 weeks before initiation of levodopa- carbidopa combination therapy (see Drug Interactions).
Levodopa-carbidopa is classified as pregnancy risk category C. Although no adequate human studies have examined the effects of this drug on the fetus, animal reproduction studies have shown adverse fetal effects. Therefore, in making the decision to administer this drug during pregnancy, the potential risks to the fetus must be weighed against the potential benefits to the mother.
DRUG INTERACTIONS: Concomitant administration of amantadine, benztropine, procyclidine, or trihexyphenidyl with levodopa-carbidopa can enhance the therapeutic effects of levodopa but should not be used in patients with a history of psychosis.
Carbidopa-levodopa can cause cardiac arrhythmias if administered before inhalation of hydrocarbon general anesthetics. This interaction is presumably due to the levodopa-induced increases in dopamine. Levodopa-carbidopa should be discontinued 6-8 hours before the administration of general anesthetics.
Droperidol; haloperidol; loxapine; phenothiazines; thioxanthenes (thiothixene and chlorprothixene); and possibly papaverine inhibit dopamine receptors in the brain, exacerbating parkinsonism and antagonizing the therapeutic effects of levodopa. Molindone can block dopamine receptors in the brain, interfering with the antiparkinsonian effects of levodopa and levodopa can antagonize the antipsychotic effects of molindone.
Rauwolfia alkaloids, such as reserpine, deplete dopamine stores in the brain, thereby antagonizing the effects of levodopa.
Phenytoin can interfere with the effects of levodopa-carbidopa by enhancing the metabolism of the drug.
The concomitant administration of bromocriptine with levodopa-carbidopa can result in additive effects that can be used to therapeutic advantage and allow for reduced dosages of levodopa-carbidopa.
Concomitant use of cocaine with levodopa-carbidopa can result in an increase in the risk of developing cardiac arrhythmias. Levodopa-carbidopa should be used cautiously in patients who are known users of cocaine. Conversely, electrocardiographic monitoring should be considered when using cocaine in patients receiving levodopa-carbidopa.
High-protein diets can interfere with the absorption of levodopa from the GI tract, thereby delaying its effects. Amino acids can compete with levodopa for transport into the brain, producing an erratic response to the drug.
Concomitant use of antihypertensive agents with levodopa-carbidopa can result in additive hypotensive effects.
Methyldopa can interfere with the antiparkinsonian actions of levodopa-carbidopa and increase the risk of CNS toxicity including psychosis.
Concomitant use of monoamine oxidase inhibitors (MAOIs) with levodopa-carbidopa can result in hypertensive crisis. Simultaneous use of these agents is contraindicated. MAOIs should be discontinued 2-4 weeks before initiation of levodopa- carbidopa therapy.
The adverse effects associated with levodopa, including orthostatic hypotension, confusion, dyskinesias, nausea, and hallucinations, can be exacerbated by concomitant administration of selegiline. Dosages of levodopa should be reduced within 2-3 days after beginning selegiline therapy.
ADVERSE REACTIONS: Nearly all patients receiving levodopa-carbidopa experience some sort of adverse effect. These effects are usually dose-related and reversible. The levodopa-carbidopa combination preparation generally causes fewer GI effects than does levodopa alone. However, adverse CNS effects can occur more quickly and at lower doses with the combination preparations than with levodopa alone.
Sporadic movements are the most common of the serious effects of levodopa-carbidopa therapy and include choreiform, dystonia, and dyskinetic movements. Involuntary movements, including chewing, bruxism, gnawing, twisting, protrusion of the tongue, opening and closing the mouth, bobbing of the head, rhythmic movements of the feet or hands, quick movements of the shoulder, and ballismus, have been reported and may necessitate dosage reduction. Blepharospasm (which may indicate toxicity), muscle twitching, ataxia, myoclonic mucle jerks during sleep, and hand tremor also have been reported.
Neuroleptic malignant syndrome can develop following discontinuance of levodopa, especially in patients receiving antipsychotic agents concomitantly. Patients should be observed closely for manifestations of this symptom complex, which includes tachycardia, muscular rigidity, elevation of body temperature, mental changes, diaphoresis, tachypnea, and increases in serum creatinine levels.
"Bradykinetic episodes," including akinesia, sudden return of effectiveness, and akinesia paradoxica, can occur during levodopa therapy and is likely due to both disease progression and excessive levodopa dosage. The akinesia episode, a sudden lack of effectiveness with concomitant akinesia, can last from 1 minute to an hour. This may be followed by a sudden return of effectiveness, and the cycle can occur many times a day. This effect can be minimized by increasing the frequency of administered doses per day. Akinesia paradoxica, an abrupt hypotonic reaction in which the patient usually falls because of akinesia occurring as he/she begins to walk, may be alleviated by dosage reduction.
Psychiatric disturbances can occur with the administration of levodopa-carbidopa including memory loss, anxiety, nervousness, agitation, restlessness, confusion, insomnia, nightmares, daytime somnolence, euphoria, malaise, and fatigue. Severe mental depression also has been reported, as well as suicidal tendencies, dementia, toxic delirium, hallucinations, paranoid delusion, psychosis, and hypomania.
Adverse GI effects are common in patients receiving levodopa- carbidopa and include nausea/vomiting, anorexia, and weight loss. Although levodopa-carbidopa can be administered with food to offset nausea, it should be noted that high-protein foods can interfere with levodopa oral absorption.
Orthostatic hypotension is a frequent adverse effect of levodopa therapy and occurs even with therapeutic dosages. Tolerance usually develops within a few months. Cardiac arrhythmias also can occur during levodopa-carbidopa therapy but are relatively infrequent. Flushing and hypertension have also been reported.
Other adverse effects associated with levodopa-carbidopa include episodic hyperventilation, bizarre breathing patterns, hoarseness, and increased nasal secretions. Urinary retention, polyuria, and urinary incontinence also have been reported. Leukopenia, although infrequent, can occur during levodopa- carbidopa therapy and warrants temporary discontinuance of the drug.
Levodopa can worsen malignant melanoma, so the drug is contraindicated for use in patients with a history of melanoma or in patients with undiagnosed pigmented lesions.
PATIENT INFORMATION:
What do levodopa-carbidopa tablets do?
Levodopa-carbidopa (SinemetTM ) is a combination of two medicines. Levodopa can help correct an imbalance of chemicals in the brain thought to be responsible for Parkinson's disease. Levodopa will not cure Parkinson's disease, but will help to control the symptoms and slow down the progression of the disease. Levodopa will work alone. Using a combination with carbidopa means smaller doses of levodopa are needed, and this reduces some unwanted side effects. Generic levodopa-carbidopa tablets are not yet available.
What should my doctor, dentist, or pharmacist know before I take levodopa- carbidopa?
They need to know if you have any of these conditions:
How should I take this medicine?
Take levodopa-carbidopa tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. It is best to take levodopa-carbidopa on an empty stomach. If the medicine upsets your stomach you can take food 15 to 30 minutes after your dose. Take your doses at regular intervals. Do not take your medicine more often than directed.
Special precautions for use in children:
This medicine is not for children under 18 years old.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is less than 2 hours to your next dose, take only that dose. Do not take double or extra doses. Try not to miss a dose.
What other medicines can interact with levodopa-carbidopa?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking levodopa-carbidopa?
Serious side effects with levodopa-carbidopa include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with levodopa-carbidopa include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take levodopa-carbidopa?
Visit your doctor for regular checks on your progress. It may be several weeks or months before you feel the full effect of levodopa-carbidopa. Continue to take your medicine on a regular schedule and do not stop taking except on your doctor's advice.
A high-protein diet can slow or prevent absorption of levodopa. Pyridoxine (vitamin B) can also reduce the effects of levodopa. Avoid vitamins and foods containing large amounts of pyridoxine (e.g., avocados, bacon, beans, beef liver, dry skim milk, oatmeal, peas, pork, sweet potatoes, tuna). Discuss your diet with your doctor or nutritionist.
You may get dizzy or have difficulty controlling your movements. Until you know how levodopa; carbidopa affects you, do not drive, use machinery, or do anything that needs mental alertness. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can increase possible dizziness; avoid alcoholic drinks.
If you are going to have surgery, tell your doctor or dentist that you are taking levodopa-carbidopa.
If you are diabetic you may get false results for sugar or ketones in your blood or urine. Check with your doctor before changing the dose of your diabetic medicine.
Levodopa-carbidopa sometimes makes urine and sweat darken; this is of no cause for concern.
If you have been taking levodopa-carbidopa for a year or longer, you may get an "on-off" effect. The medicine apparently stops working for anything from a minute to several hours, then suddenly starts working again. If you get an "off" period, you may fall as you start walking. Tell your doctor if you fall, he/she may need to adjust your dosage.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Protect from light. Keep container tightly closed. Throw away any unused medicine after the expiration date.
Parkinsn's Archive Treasures Page
John Cottingham is the webmaster of this site.
