Sinemet Information
Sinemet () Description
Sinemet () * (Carbidopa-Levodopa) is a combination of carbidopa and levodopa for the treatment of Parkinson's disease and syndrome.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (—)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is CHNO•HO, and its structural formula is:
Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.3.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (—)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is CHNO, and its structural formula is:
Sinemet () is supplied as tablets in three strengths:
Sinemet () 25-100, containing 25 mg of carbidopa and 100 mg of levodopa.
Sinemet () 10-100, containing 10 mg of carbidopa and 100 mg of levodopa.
Sinemet () 25-250, containing 25 mg of carbidopa and 250 mg of levodopa.
Inactive ingredients are cellulose, magnesium stearate, and starch. Sinemet () 10-100 and 25-250 Tablets also contain FD&C Blue 2. Sinemet () 25-100 Tablets also contain D&C Yellow 10 and FD&C Yellow 6.
Sinemet () Clinical Pharmacology
Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system affecting the mobility and control of the skeletal muscular system. Its characteristic features include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility.
When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral 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 accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues.
Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients on a high protein diet.
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.
The incidence of levodopa-induced nausea and vomiting is less with Sinemet () than with levodopa. In many patients, this reduction in nausea and vomiting will permit more rapid dosage titration.
Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain.
Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid.
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. At steady state, the bioavailability of carbidopa from Sinemet () tablets is approximately 99% relative to the concomitant administration of carbidopa and levodopa.
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 B), 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; therefore, Sinemet () can be given to patients receiving supplemental pyridoxine (vitamin B).
Sinemet () Indications And Usage
Sinemet () is indicated in the treatment of the symptoms of idiopathic Parkinson's disease (paralysis agitans), post-encephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication. Sinemet () is indicated in these conditions to permit the administration of lower doses of levodopa with reduced nausea and vomiting, with more rapid dosage titration, with a somewhat smoother response, and with supplemental pyridoxine (vitamin B).
In some patients a somewhat smoother antiparkinsonian effect results from therapy with Sinemet () than with levodopa. However, patients with markedly irregular ("on-off") responses to levodopa have not been shown to benefit from Sinemet () .
Although the administration of carbidopa permits control of parkinsonism and Parkinson's disease with much lower doses of levodopa, there is no conclusive evidence at present that this is beneficial other than in reducing nausea and vomiting, permitting more rapid titration, and providing a somewhat smoother response to levodopa.
Certain patients who responded poorly to levodopa have improved when Sinemet () was substituted. This is most likely due to decreased peripheral decarboxylation of levodopa which results from administration of carbidopa rather than to a primary effect of carbidopa on the nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa in parkinsonian syndromes.
In considering whether to give Sinemet () to patients already on levodopa who have nausea and/or vomiting, the practitioner should be aware that, while many patients may be expected to improve, some do not. Since one cannot predict which patients are likely to improve, this can only be determined by a trial of therapy. It should be further noted that in controlled trials comparing Sinemet () with levodopa, about half of the patients with nausea and/or vomiting on levodopa improved spontaneously despite being retained on the same dose of levodopa during the controlled portion of the trial.
Sinemet () Contraindications
Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with Sinemet () . These inhibitors must be discontinued at least two weeks prior to initiating therapy with Sinemet () . Sinemet () may be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl) (see ).
Sinemet () is contraindicated in patients with known hypersensitivity to any component of this drug, and in patients with narrow-angle glaucoma.
Because levodopa may activate a malignant melanoma, Sinemet () should not be used in patients with suspicious, undiagnosed skin lesions or a history of melanoma.
Sinemet () Warnings
The addition of carbidopa with levodopa in the form of Sinemet () reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa. Because carbidopa permits more levodopa to reach the brain and more dopamine to be formed, certain adverse CNS effects, e.g., dyskinesias (involuntary movements), may occur at lower dosages and sooner with Sinemet () than with levodopa alone.
Levodopa alone, as well as Sinemet () , is associated with dyskinesias. The occurrence of dyskinesias may require dosage reduction.
As with levodopa, Sinemet () may cause mental disturbances. These reactions are thought to be due to increased brain dopamine following administration of levodopa. 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.
Sinemet () should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease.
As with levodopa, care should be exercised in administering Sinemet () to patients with a history of 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 adjustment, in a facility with provisions for intensive cardiac care.
As with levodopa, treatment with Sinemet () may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.
Sinemet () Precautions
As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are recommended during extended therapy.
Patients with chronic wide-angle glaucoma may be treated cautiously with Sinemet () provided the intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular pressure during therapy.
Dopaminergic agents, including levodopa, may be associated with somnolence and very rarely episodes of sudden onset of sleep. In some cases, these episodes may occur without awareness or warning during daily activities. Patients must be informed of this and advised to exercise caution while driving or operating machines while being treated with dopaminergic agents, including levodopa. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines (see ).
The patient should be informed that Sinemet () is an immediate-release formulation of carbidopa-levodopa that is designed to begin release of ingredients within 30 minutes. It is important that Sinemet () be taken at regular intervals according to the schedule outlined by the physician. The patient should be cautioned not to change the prescribed dosage regimen and not to add any additional antiparkinson medications, including other carbidopa-levodopa preparations, without first consulting the physician.
Patients should be advised that sometimes a ‘wearing-off’ effect may occur at the end of the dosing interval. The physician should be notified if such response poses a problem to lifestyle.
Patients should be advised that occasionally, dark color (red, brown, or black) may appear in saliva, urine, or sweat after ingestion of Sinemet () . Although the color appears to be clinically insignificant, garments may become discolored.
The patient should be advised that a change in diet to foods that are high in protein may delay the absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also delays stomach emptying, thus delaying the absorption of levodopa. Iron salts (such as in multivitamin tablets) may also reduce the amount of levodopa available to the body. The above factors may reduce the clinical effectiveness of the levodopa or carbidopa-levodopa therapy.
Patients should be alerted to the possibility of sudden onset of sleep during daily activities, in some cases without awareness or warning signs, when they are taking dopaminergic agents, including levodopa. Patients should be advised to exercise caution while driving or operating machinery and that if they have experienced somnolence and/or sudden sleep onset, they must refrain from these activities. (See .)
There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease, including Sinemet () . Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Sinemet () . Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges, or other intense urges while taking Sinemet () . Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Sinemet () .
NOTE: The suggested advice to patients being treated with Sinemet () is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of Sinemet () than with levodopa.
Sinemet () may cause a false-positive reaction for urinary ketone bodies when a test tape 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 on carbidopa-levodopa 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 carbidopa-levodopa therapy.
Caution should be exercised when the following drugs are administered concomitantly with
Symptomatic postural hypotension occurred when Sinemet () was 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.
For patients receiving MAO inhibitors (Type A or B), see . Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone (see ).
There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and Sinemet () .
Dopamine D receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa. In addition, 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 therapeutic response.
Iron salts may reduce the bioavailability of levodopa and carbidopa. The clinical relevance is unclear.
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.
In a two-year bioassay of Sinemet () , no evidence of carcinogenicity was found in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa.
In reproduction studies with Sinemet () , no effects on fertility were found in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa.
Sinemet () Adverse Reactions
The most common adverse reactions reported with Sinemet () have included dyskinesias, such as choreiform, dystonic, and other involuntary movements and nausea.
The following other adverse reactions have been reported with Sinemet () :
Other adverse reactions that have been reported with levodopa alone and with various carbidopa-levodopa formulations, and may occur with Sinemet () are:
Sinemet () Overdosage
Management of acute overdosage with Sinemet () is the same as management of acute overdosage with levodopa. Pyridoxine is not effective in reversing the actions of Sinemet () .
General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as Sinemet () should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a significant proportion of mice are expected to die to 3360 mg/kg.
Sinemet () Dosage And Administration
The optimum daily dosage of Sinemet () must be determined by careful titration in each patient. Sinemet () tablets are available in a 1:4 ratio of carbidopa to levodopa (Sinemet () 25-100) as well as 1:10 ratio (Sinemet () 25-250 and Sinemet () 10-100). Tablets of the two ratios may be given separately or combined as needed to provide the optimum dosage.
Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 to 100 mg a day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.
Sinemet () How Supplied
Sinemet () 25-100 Tablets are yellow, oval, uncoated tablets, that are scored and coded “650” on one side and “Sinemet () ” on the other side. They are supplied as follows:
0056-0650-68 bottles of 100
Sinemet () 10-100 Tablets are dark dapple-blue, oval, uncoated tablets, that are scored and coded “647” on one side and “Sinemet () ” on the other side. They are supplied as follows:
0056-0647-68 bottles of 100
Sinemet () 25-250 Tablets are light dapple-blue, oval, uncoated tablets, that are scored and coded “654” on one side and “Sinemet () ” on the other side. They are supplied as follows:
0056-0654-68 bottles of 100
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