Sinemet CR

Name: Sinemet CR

What is levodopa-carbidopa, and how does it work (mechanism of action)?

Carbidopa-levodopa is a combination of two drugs, levodopa and carbidopa. Carbidopa-levodopa is used in the treatment of Parkinson's disease. Parkinson's disease is believed to be caused by low levels of dopamine in certain parts of the brain. When levodopa is taken orally, it crosses into the brain through the "blood- brain barrier." Once it crosses, it is converted to dopamine. The resulting increase in brain dopamine concentrations is believed to improve nerve conduction and assist the movement disorders in Parkinson disease. Carbidopa does not cross the blood-brain barrier. Carbidopa is added to the levodopa to prevent the breakdown of levodopa before it crosses into the brain. The addition of carbidopa allows lower doses of levodopa to be used. This reduces the risk of side effects from levodopa such as nausea and vomiting. This combination medicine was approved by the FDA in 1988.

Uses of Sinemet CR

Sinemet CR is a prescription medication used to treat symptoms of Parkinson's disease.

It is also used to treat Parkinson's-like symptoms that may develop after encephalitis (swelling of the brain) or injury to the nervous system caused by carbon monoxide poisoning or manganese poisoning.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Other Requirements

  • Store Sinemet CR at room temperature.
  • Keep this and all medications out of the reach of children.

What is the most important information I should know about Sinemet CR (carbidopa and levodopa)?

You should not use carbidopa and levodopa if you have narrow-angle glaucoma.

Do not use carbidopa and levodopa if you have used an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Sinemet CR - 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) immediate release tablets, the conventional formulation. However, Sinemet CR is less systemically bioavailable than SINEMET and may require increased daily doses to achieve the same level of symptomatic relief as provided by SINEMET.

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. However, global ratings of improvement as assessed by both patient and physician were better during therapy with Sinemet CR than with SINEMET. In patients without motor fluctuations, Sinemet CR, under controlled conditions, provided the same therapeutic benefit with less frequent dosing when compared to SINEMET.

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. The maximum concentration of levodopa after a single dose of Sinemet CR was about 35% of the standard SINEMET (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 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 (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. Because the bioavailability of levodopa from Sinemet CR relative to SINEMET 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.

Special Populations

Geriatric

A study in eight young healthy subjects (21-22 yr) and eight elderly healthy subjects (69-76 yr) showed that the absolute bioavailability of levodopa was similar between young and elderly subjects following oral administration of levodopa and carbidopa. However, the systemic exposure (AUC) of levodopa was increased by 55% in elderly subjects compared to young subjects. Based on another study in forty patients with Parkinson's disease, there was a correlation between age of patients and the increase of AUC of levodopa following administration of levodopa and an inhibitor of peripheral dopa decarboxylase. AUC of levodopa was increased by 28% in elderly patients (≥ 65 yr) compared to young patients (< 65 yr). Additionally, mean value of Cmax for levodopa was increased by 24% in elderly patients (≥ 65 yr) compared to young patients (< 65 yr) (see PRECAUTIONS, Geriatric Use).

The AUC of carbidopa was increased in elderly subjects (n=10, 65-76 yr) by 29% compared to young subjects (n=24, 23-64 yr) following IV administration of 50 mg levodopa with carbidopa (50 mg). This increase is not considered a clinically significant impact.

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. See DOSAGE AND ADMINISTRATION section before initiating 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 central nervous system (CNS) effects, e.g., dyskinesias, will occur at lower dosages and sooner during therapy with Sinemet CR than with levodopa alone.

Patients receiving Sinemet CR may develop increased dyskinesias compared to SINEMET. Dyskinesias are a common side effect of carbidopa levodopa treatment. The occurrence of dyskinesias may require dosage reduction.

All patients should be observed carefully for the development of depression with concomitant suicidal tendencies.

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.

Falling Asleep During Activities of Daily Living and Somnolence

Patients taking Sinemet CR alone or with other dopaminergic drugs have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of motor vehicles). Road traffic accidents attributed to sudden sleep onset have been reported. Although many patients reported somnolence while on dopaminergic medications, there have been reports of road traffic accidents attributed to sudden onset of sleep in which the patient did not perceive any warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Sudden onset of sleep has been reported to occur as long as one year after the initiation of treatment.

Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre-existing somnolence, although some patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving or operating machines during treatment with Sinemet CR. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with Sinemet CR.

Before initiating treatment with Sinemet CR, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with Sinemet CR such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing Sinemet CR in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with Sinemet CR continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Hyperpyrexia and Confusion

Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as levodopa, carbidopa levodopa and carbidopa levodopa extended release. Therefore, patients should be observed carefully when the dosage of levodopa 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.

Adverse Reactions

In controlled clinical trials, patients predominantly with moderate to severe motor fluctuations while on SINEMET were randomized to therapy with either SINEMET or Sinemet CR. The adverse experience frequency profile of Sinemet CR did not differ substantially from that of SINEMET, as shown in Table 1.

Table 1: Clinical Adverse Experiences Occurring in 1% or Greater of Patients
Adverse Experience Sinemet CR

n=491
%
SINEMET

n=524
%
Dyskinesia 16.5 12.2
Nausea 5.5 5.7
Hallucinations 3.9 3.2
Confusion 3.7 2.3
Dizziness 2.9 2.3
Depression 2.2 1.3
Urinary tract infection 2.2 2.3
Headache 2.0 1.9
Dream abnormalities 1.8 0.8
Dystonia 1.8 0.8
Vomiting 1.8 1.9
Upper respiratory infection 1.8 1.0
Dyspnea 1.6 0.4
'On-Off' phenomena 1.6 1.1
Back pain 1.6 0.6
Dry mouth 1.4 1.1
Anorexia 1.2 1.1
Diarrhea 1.2 0.6
Insomnia 1.2 1.0
Orthostatic hypotension 1.0 1.1
Shoulder pain 1.0 0.6
Chest pain 1.0 0.8
Muscle cramps 0.8 1.0
Paresthesia 0.8 1.1
Urinary frequency 0.8 1.1
Dyspepsia 0.6 1.1
Constipation 0.2 1.5

Abnormal laboratory findings occurring at a frequency of 1% or greater in approximately 443 patients who received Sinemet CR and 475 who received SINEMET during controlled clinical trials included: decreased hemoglobin and hematocrit; elevated serum glucose; white blood cells, bacteria and blood in the urine.

The adverse experiences observed in patients in uncontrolled studies were similar to those seen in controlled clinical studies.

Other adverse experiences reported overall in clinical trials in 748 patients treated with Sinemet CR, listed by body system in order of decreasing frequency, include:

Body as a Whole

Asthenia, fatigue, abdominal pain, orthostatic effects.

Cardiovascular

Palpitation, hypertension, hypotension, myocardial infarction.

Gastrointestinal

Gastrointestinal pain, dysphagia, heartburn.

Metabolic

Weight loss.

Musculoskeletal

Leg pain.

Nervous System/Psychiatric

Chorea, somnolence, falling, anxiety, disorientation, decreased mental acuity, gait abnormalities, extrapyramidal disorder, agitation, nervousness, sleep disorders, memory impairment.

Respiratory

Cough, pharyngeal pain, common cold.

Skin

Rash.

Special Senses

Blurred vision.

Urogenital

Urinary incontinence.

Laboratory Tests

Decreased white blood cell count and serum potassium; increased BUN, serum creatinine and serum LDH; protein and glucose in the urine.

The following adverse experiences have been reported in postmarketing experience with Sinemet CR:

Cardiovascular

Cardiac irregularities, syncope.

Gastrointestinal

Taste alterations, dark saliva.

Hypersensitivity

Angioedema, urticaria, pruritus, bullous lesions (including pemphigus-like reactions).

Nervous System/Psychiatric

Increased tremor, peripheral neuropathy, psychotic episodes including delusions and paranoid ideation, pathological gambling, increased libido including hypersexuality, impulse control symptoms.

Skin

Alopecia, flushing, dark sweat.

Urogenital

Dark urine.

Other adverse reactions that have been reported with levodopa alone and with various carbidopa levodopa formulations and may occur with Sinemet CR are:

Cardiovascular

Phlebitis.

Gastrointestinal

Gastrointestinal bleeding, development of duodenal ulcer, sialorrhea, bruxism, hiccups, flatulence, burning sensation of tongue.

Hematologic

Hemolytic and non-hemolytic anemia, thrombocytopenia, leukopenia, agranulocytosis.

Hypersensitivity

Henoch-Schönlein purpura.

Metabolic

Weight gain, edema.

Nervous System/Psychiatric

Ataxia, depression with suicidal tendencies, dementia, euphoria, convulsions (however, a causal relationship has not been established); bradykinetic episodes, numbness, muscle twitching, blepharospasm (which may be taken as an early sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, activation of latent Horner's syndrome, nightmares.

Skin

Malignant melanoma (see also CONTRAINDICATIONS), increased sweating.

Special Senses

Oculogyric crises, mydriasis, diplopia.

Urogenital

Urinary retention, priapism.

Miscellaneous

Faintness, hoarseness, malaise, hot flashes, sense of stimulation, bizarre breathing patterns.

Laboratory Tests

Abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), bilirubin, Coombs test, uric acid.

How is Sinemet CR Supplied

No. 3919  Sinemet CR 50-200 (carbidopa levodopa) Sustained-Release Tablets containing 50 mg of carbidopa and 200 mg of levodopa, are dappled-purple in color, oval, compressed tablets, that are coded "521" on one side and plain on the other. They are supplied as follows:

          NDC 0006-3919-68 bottles of 100.

No. 3918  Sinemet CR 25-100 (carbidopa levodopa) Sustained-Release Tablets containing 25 mg of carbidopa and 100 mg of levodopa, are dappled-purple in color, oval, compressed tablets, that are coded "601" on one side and plain on the other. They are supplied as follows:

          NDC 0006-3918-68 bottles of 100.

Storage and Handling

Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Store in a tightly closed container, protected from light and moisture.

Dispense in a tightly closed, light-resistant container.

Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Manufactured by:
Mylan Pharmaceuticals, Inc.
Morgantown, WV 26505, USA

Copyright © 1996-2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.

Revised: 07/2014

uspi-mk0295b-txr-1407r003

Rx Only

For the Consumer

Applies to carbidopa / levodopa: oral capsule extended release, oral tablet, oral tablet disintegrating, oral tablet extended release

Other dosage forms:

  • route not applicable suspension

Along with its needed effects, carbidopa / levodopa may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking carbidopa / levodopa:

More common
  • Twitching, twisting, uncontrolled repetitive movements of the tongue, lips, face, arms, or legs
Less common
  • Bladder pain
  • bloody or cloudy urine
  • chest pain
  • confusion
  • difficult, burning, or painful urination
  • discouragement
  • feeling sad or empty
  • frequent urge to urinate
  • inability to move the eyes
  • increased blinking or spasms of the eyelid
  • irritability
  • lack of appetite
  • loss of interest or pleasure
  • lower back or side pain
  • seeing, hearing, or feeling things that are not there
  • sticking out of tongue
  • tiredness
  • trouble concentrating
  • trouble in breathing, speaking, or swallowing
  • trouble sleeping
  • uncontrolled twisting movements of the neck, trunk, arms, or legs
  • unusual facial expressions
Incidence not known
  • Anxiety
  • black, tarry stools
  • bluish color
  • blurred vision
  • changes in skin color
  • chest discomfort
  • chills
  • convulsions
  • cough or hoarseness
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • dry mouth
  • false beliefs that cannot be changed by facts
  • fast, irregular, pounding, or racing heartbeat or pulse
  • feelings about hurting oneself or others
  • fever with or without chills
  • general feeling of tiredness or weakness
  • high fever
  • hyperventilation
  • increased in sexual ability, desire, drive, or performance
  • increased interest in sexual intercourse
  • increased sweating
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • loss of bladder control
  • lower back or side pain
  • nausea
  • pain
  • pain or discomfort in the arms, jaw, back, or neck
  • restlessness
  • seeing, hearing, or feeling things that are not there
  • severe muscle stiffness
  • shaking
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swelling of the foot or leg
  • swollen glands
  • tenderness
  • tiredness
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • unusually pale skin
  • vomiting

Some side effects of carbidopa / levodopa may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common
  • Acid or sour stomach
  • back or shoulder pain
  • belching
  • body aches or pain
  • burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
  • diarrhea
  • difficulty having a bowel movement (stool)
  • ear congestion
  • headache
  • heartburn
  • indigestion
  • loss of voice
  • muscle cramps
  • nasal congestion
  • runny nose
  • sneezing
  • stomach discomfort, upset, or pain
  • unusual dreams
  • weight loss
Incidence not known
  • Abdominal or stomach distress
  • bad, unusual, or unpleasant (after) taste
  • belching
  • change in taste
  • dark sweat
  • double vision
  • enlarged pupils
  • feeling of warmth
  • hair loss or thinning of the hair
  • lack or loss of strength
  • redness of the face, neck, arms, and occasionally, upper chest
  • seeing double
  • skin rash, hives or welts, itching

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