Package Insert and Label Information: SINEMET CR
SINEMET CR- carbidopa and levodopa tablet, extended release
Bristol-Myers Squibb Pharma Company
DESCRIPTION
SINEMET* CR (Carbidopa-Levodopa) is a sustained-release combination of carbidopa and levodopa for the treatment of Parkinson’s disease and syndrome.
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*Registered
trademark of MERCK & CO., INC.
COPYRIGHT
© MERCK & CO., INC., 1996 All rights
reserved
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 C10 H14 N2 O4 •H2 O 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 C9 H11 NO4 and its structural formula is:
SINEMET CR is supplied as sustained-release tablets containing either 50 mg of carbidopa and 200 mg of levodopa, or 25 mg of carbidopa and 100 mg of levodopa. Inactive ingredients: hydroxypropyl cellulose, polyvinylacetate-crotonic acid copolymer, magnesium stearate and red ferric oxide. SINEMET CR 50-200 also contains D&C Yellow 10.
The 50-200 tablet is supplied as an oval, scored, biconvex, compressed tablet that is peach colored. The 25-100 tablet is supplied as an oval, biconvex, compressed tablet that is pink colored. The SINEMET CR tablet is a polymeric-based drug delivery system that controls the release of carbidopa and levodopa as it slowly erodes. SINEMET CR 25-100 is available to facilitate titration and as an alternative to the half-tablet of SINEMET CR 50-200.
CLINICAL PHARMACOLOGY
Mechanism of Action
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.
Current evidence indicates that 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 apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson’s disease.
Pharmacodynamics
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.
Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain.
Patients treated with levodopa therapy for Parkinson’s disease may develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia, and akinesia. The advanced form of motor fluctuations (‘on-off’ phenomenon) is characterized by unpredictable swings from mobility to immobility. Although the causes of the motor fluctuations are not completely understood, in some patients they may be attenuated by treatment regimens that produce steady plasma levels of levodopa.
SINEMET CR contains either 50 mg of carbidopa and 200 mg of levodopa, or 25 mg of carbidopa and 100 mg of levodopa in a sustained-release dosage form designed to release these ingredients over a 4- to 6-hour period. With SINEMET CR there is less variation in plasma levodopa levels than with SINEMET* (Carbidopa-Levodopa), the conventional formulation. However, SINEMET CR (Carbidopa-Levodopa) Sustained-Release is less systemically bioavailable than SINEMET (Carbidopa-Levodopa) and may require increased daily doses to achieve the same level of symptomatic relief as provided by SINEMET (Carbidopa-Levodopa).
In clinical trials, patients with moderate to severe motor fluctuations who received SINEMET CR did not experience quantitatively significant reductions in ‘off’ time when compared to SINEMET (Carbidopa-Levodopa). However, global ratings of improvement as assessed by both patient and physician were better during therapy with SINEMET CR than with SINEMET (Carbidopa-Levodopa). In patients without motor fluctuations, SINEMET CR, under controlled conditions, provided the same therapeutic benefit with less frequent dosing when compared to SINEMET (Carbidopa-Levodopa).
Pharmacokinetics
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.
Elimination half-life of levodopa in the presence of carbidopa is about 1.5 hours. Following SINEMET CR, the apparent half-life of levodopa may be prolonged because of continuous absorption.
In healthy elderly subjects (56-67 years old) the mean time-to-peak concentration of levodopa after a single dose of SINEMET CR 50-200 was about 2 hours as compared to 0.5 hours after standard SINEMET (Carbidopa-Levodopa). The maximum concentration of levodopa after a single dose of SINEMET CR was about 35% of the standard SINEMET (Carbidopa-Levodopa) (1151 vs. 3256 ng/mL). The extent of availability of levodopa from SINEMET CR was about 70-75% relative to intravenous levodopa or standard SINEMET (Carbidopa-Levodopa) in the elderly. The absolute bioavailability of levodopa from SINEMET CR (relative to I.V.) in young subjects was shown to be only about 44%. The extent of availability and the peak concentrations of levodopa were comparable in the elderly after a single dose and at steady state after t.i.d. administration of SINEMET CR 50-200. In elderly subjects, the average trough levels of levodopa at steady state after the CR tablet were about 2 fold higher than after the standard SINEMET (Carbidopa-Levodopa) (163 vs. 74 ng/mL).
In these studies, using similar total daily doses of levodopa, plasma levodopa concentrations with SINEMET CR fluctuated in a narrower range than with SINEMET (Carbidopa-Levodopa). Because the bioavailability of levodopa from SINEMET CR relative to SINEMET (Carbidopa-Levodopa) is approximately 70-75%, the daily dosage of levodopa necessary to produce a given clinical response with the sustained-release formulation will usually be higher.
The extent of availability and peak concentrations of levodopa after a single dose of SINEMET CR 50-200 increased by about 50% and 25%, respectively, when administered with food.
At steady state, the bioavailability of carbidopa from SINEMET Tablets is approximately 99% relative to the concomitant administration of carbidopa and levodopa. At steady state, carbidopa bioavailability from SINEMET CR 50-200 is approximately 58% relative to that from SINEMET.
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.
INDICATIONS AND USAGE
SINEMET CR is indicated in the treatment of the symptoms of idiopathic Parkinson’s disease (paralysis agitans), postencephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication.
CONTRAINDICATIONS
Nonselective MAO inhibitors are contraindicated for use with SINEMET CR. These inhibitors must be discontinued at least two weeks prior to initiating therapy with SINEMET CR. SINEMET CR 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 PRECAUTIONS: Drug Interactions).
SINEMET CR 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 CR should not be used in patients with suspicious, undiagnosed skin lesions or a history of melanoma.
WARNINGS
When patients are receiving levodopa without a decarboxylase inhibitor, levodopa must be discontinued at least twelve hours before SINEMET CR is started. In order to reduce adverse reactions, it is necessary to individualize therapy. SINEMET CR should be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage (see DOSAGE AND ADMINISTRATION).
Carbidopa does not decrease adverse reactions due to central effects of levodopa. By permitting more levodopa to reach the brain, particularly when nausea and vomiting is not a dose-limiting factor, certain adverse CNS effects, e.g., dyskinesias, will occur at lower dosages and sooner during therapy with SINEMET CR (Carbidopa-Levodopa) Sustained-Release than with levodopa alone.
Patients receiving SINEMET CR may develop increased dyskinesias compared to SINEMET (Carbidopa-Levodopa). Dyskinesias are a common side effect of carbidopa-levodopa treatment. The occurrence of dyskinesias may require dosage reduction.
As with levodopa, SINEMET CR 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 CR 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 CR 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 CR may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.
Neuroleptic Malignant Syndrome (NMS)
Sporadic cases of a symptom complex resembling NMS have been reported in association with dose reductions or withdrawal of SINEMET and SINEMET CR.
Therefore, patients should be observed carefully when the dosage of SINEMET CR is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia. Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin have been reported.
The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has not been demonstrated in controlled studies.
PRECAUTIONS
General
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 CR 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 Information for Patients).
Melanoma
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 providers are advised to monitor for melanomas frequently and on a regular basis when using SINEMET CR for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
Information for Patients
The patient should be informed that SINEMET CR is a sustained-release formulation of carbidopa-levodopa which releases these ingredients over a 4- to 6-hour period. It is important that SINEMET CR 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.
If abnormal involuntary movements appear or get worse during treatment with SINEMET CR, the physician should be notified, as dosage adjustment may be necessary.
Patients should be advised that sometimes the onset of effect of the first morning dose of SINEMET CR may be delayed for up to 1 hour compared with the response usually obtained from the first morning dose of SINEMET (Carbidopa-Levodopa). The physician should be notified if such delayed responses pose a problem in treatment.
Patients should be advised that, occasionally, dark color (red, brown, or black) may appear in saliva, urine, or sweat after ingestion of SINEMET CR. Although the color appears to be clinically insignificant, garments may become discolored.
The patient should be informed 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 must be advised that the whole or half tablet should be swallowed without chewing or crushing.
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 PRECAUTIONS: General.)
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 CR. 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 CR. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges, or other intense urges while taking SINEMET CR. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking SINEMET CR.
NOTE: The suggested advice to patients being treated with SINEMET CR 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.
Laboratory Tests
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 carbidopa-levodopa preparations than with levodopa.
Carbidopa-levodopa preparations, such as SINEMET (Carbidopa-Levodopa) and SINEMET CR, 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.
