Carbidopa, Levodopa and Entacapone Tablets

The following adverse reactions described in this section are related to at least one of the components of Carbidopa, Levodopa and Entacapone Tablets (i.e., levodopa, carbidopa, and/or entacapone) based upon the safety experience in clinical trials (especially pivotal trials) or in postmarketing reports.

Falling Asleep During Activities of Daily Living and Somnolence

Patients with Parkinson’s disease treated with Carbidopa, Levodopa and Entacapone Tablets or other carbidopa/levodopa products have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (including the operation of motor vehicles). Some of these episodes resulted in accidents. Although many of these patients reported somnolence while taking entacapone, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported to occur up to one year after initiation of treatment.

Somnolence was reported in 2% of patients taking entacapone and 0% in placebo in controlled trials. It is reported that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although 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 also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with Carbidopa, Levodopa and Entacapone Tablets.

Before initiating treatment with Carbidopa, Levodopa and Entacapone Tablets, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase this risk such as use of concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Carbidopa, Levodopa and Entacapone Tablets  should ordinarily be discontinued [see Dosage and Administration (2.5) and Warnings and Precautions (5.7)]. If the decision is made to continue Carbidopa, Levodopa and Entacapone Tablets, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Hypotension, Orthostatic Hypotension and Syncope

Reports of syncope were generally more frequent in patients in both treatment groups who had had a prior episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement). Hypotension, orthostatic hypotension, and syncope are observed in patients treated with drugs that increase central dopaminergic tone including Carbidopa, Levodopa and Entacapone Tablets.

Dyskinesia

Dyskinesia (involuntary movements) may occur or be exacerbated at lower dosages and sooner with Carbidopa, Levodopa and Entacapone Tablets than with preparations containing only carbidopa and levodopa. The occurrence of dyskinesias may require dosage reduction.

In pivotal trials, the treatment difference incidence of dyskinesia was 10% and for carbidopa-levodopa plus 200 mg entacapone. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The treatment difference incidence of study withdrawal for dyskinesia was 1% for carbidopa-levodopa-entacapone.

Depression and Suicidality

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.

Hallucinations and/or Psychotic-Like Behavior

Dopaminergic therapy in patients with Parkinson’s disease has been associated with hallucinations. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with carbidopa, levodopa, entacapone and carbidopa, levodopa, respectively. Hallucinations led to hospitalization in 1% and 0.3% of patients in the carbidopa, levodopa, entacapone and carbidopa, levodopa, groups, respectively. Agitation occurred in 1% of patients treated with carbidopa, levodopa, entacapone and 0% treated with carbidopa, levodopa.

Impulse Control and/or Compulsive Behaviors

Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications generally used for the treatment of Parkinson’s disease and which increase central dopaminergic tone, including entacapone taken with levodopa and carbidopa. In some cases, although not all, these urges were reported to have stopped when the dose of anti-Parkinson medications was reduced or discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with entacapone. Physicians should consider dose reduction or stopping Carbidopa, Levodopa and Entacapone Tabletsif a patient develops such urges while taking Carbidopa, Levodopa and Entacapone Tablets [seeDosage and Administration (2.5), Warnings and Precautions (5.7)].

Withdrawal-Emergent Hyperpyrexia and Confusion

Cases of hyperpyrexia and confusion resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reduction or withdrawal of therapy with carbidopa, levodopa and entacapone. However, in some cases, hyperpyrexia and confusion were reported after initiation of treatment with entacapone. Hyperpyrexia and confusion are uncommon but they may be life‑threatening with a variety of features, including hyperpyrexia/fever/hyperthermia, muscle rigidity, involuntary movements, altered consciousness/mental status changes, delirium, autonomic dysfunction, tachycardia, tachypnea, sweating, hyper‑ or hypotension, and abnormal laboratory findings (e.g., creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin).

If a patient needs to discontinue or reduce their daily dose of Carbidopa, Levodopa and Entacapone Tablets, the dose should be decreased slowly, with supervision from a health care provider [see Dosage and Administration (2.5)]. Specific methods for tapering entacapone have not been systematically evaluated.

Diarrhea and Colitis

In clinical trials of entacapone, diarrhea developed in 60 of 603 (10%) and 16 of 400 (4%) of patients treated with 200 mg of entacapone or placebo in combination with levodopa and dopa decarboxylase inhibitor, respectively. In patients treated with entacapone, diarrhea was generally mild to moderate in severity (8.6%) but was regarded as severe in 1.3%. Diarrhea resulted in withdrawal in 10 of 603 (1.7%) patients, 7 (1.2%) with mild and moderate diarrhea and 3 (0.5%) with severe diarrhea. Diarrhea generally resolved after discontinuation of entacapone. Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 to 12 weeks after entacapone is started, but it may appear as early as the first week and as late as many months after the initiation of treatment. Diarrhea may be associated with weight loss, dehydration, and hypokalemia.

Postmarketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis. In these cases diarrhea has usually been moderate to severe, watery and non-bloody, at times associated with dehydration, abdominal pain, weight loss, and hypokalemia. In the majority of cases, diarrhea and other colitis-related symptoms resolved or significantly improved when entacapone treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of entacapone but recurred after retreatment with entacapone.

If prolonged diarrhea is suspected to be related to Carbidopa, Levodopa and Entacapone Tablets, the drug should be discontinued and appropriate medical therapy considered. If the cause of prolonged diarrhea remains unclear or continues after stopping entacapone, then further diagnostic investigations including colonoscopy and biopsies should be considered.

Rhabdomyolysis

Cases of severe rhabdomyolysis have been reported with entacapone when used in combination with carbidopa and levodopa. Severe prolonged motor activity including dyskinesia may possibly account for rhabdomyolysis. Most of the cases were manifested by myalgia and increased values of creatine phosphokinase (CPK) and myoglobin. Some of the reactions also included fever and/or alteration of consciousness. It is also possible that rhabdomyolysis may be a result of the syndrome described in Withdrawal-Emergent Hyperpyrexia and Confusion[seeWarnings and Precautions (5.7)].

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 Carbidopa, Levodopa and Entacapone Tablets, for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).  

Interaction with Drugs Metabolized by COMT

Drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha‑methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rate, arrhythmia, and/or increased blood pressure.

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. Although these adverse reactions may be related to the ergoline structure of these compounds, a possible causal role of nonergot derived drugs (e.g., entacapone, levodopa), which increase dopaminergic activity, has also been considered. The expected incidence of fibrotic complications is so low that even if entacapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that it would have been detected in a cohort of the size exposed to entacapone during its clinical development. Four cases of pulmonary fibrosis have been reported during clinical development of entacapone; 3 of these patients were also treated with pergolide and 1 with bromocriptine. The duration of treatment with entacapone ranged from 7 months to 17 months.

Peptic Ulcer Disease

As with levodopa, treatment with Carbidopa, Levodopa and Entacapone Tablets may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.

Hepatic Impairment

Patients with hepatic impairment should be treated with caution [see Clinical Pharmacology (12.3)]. As with levodopa, periodic evaluation of hepatic function is recommended during extended therapy.

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 and Entacapone Tablets than with levodopa.

Carbidopa, Levodopa and Entacapone Tablets 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 carbidopa/levodopa therapy.

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. In animals, administration of carbidopa-levodopa or entacapone during pregnancy was associated with developmental toxicity, including increased incidences of fetal malformations. Carbidopa, Levodopa and Entacapone Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In nonclinical studies in which carbidopa-levodopa was administered to pregnant animals, increased incidences of visceral and skeletal malformations were observed in rabbits at all doses and ratios of carbidopa-levodopa tested, which ranged from 10 times (carbidopa)-5 times (levodopa) to 20 times (carbidopa)-10 times (levodopa) the maximum recommended human dose (MRHD) of 1,600 mg/day. In rats, there was a decrease in the number of live pups delivered by dams receiving approximately two times (carbidopa)-five times (levodopa) the MRHD throughout organogenesis. No effects on malformation frequencies were observed in mice receiving up to 20 times the MRHD of carbidopa-levodopa.

In embryo-fetal development studies of entacapone, pregnant animals received doses of up to 1,000 mg/kg/day (rats) or 300 mg/kg/day (rabbits) throughout organogenesis. Increased incidences of fetal variations were evident in litters from rats treated with the highest dose, in the absence of overt signs of maternal toxicity. The maternal plasma entacapone exposure (AUC) associated with this dose was approximately 34 times that in humans at the MRHD. Increased frequencies of abortions and late/total resorptions and decreased fetal weights were observed in the litters of rabbits treated with maternally toxic doses of 100 mg/kg/day (plasma AUCs les than that in humans at the MRHD) or greater. There were no increases in malformation rates in these studies.

When entacapone was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies (macrophthalmia, microphthalmia, anophthalmia) was observed in the litters of dams treated with doses of 160 mg/kg/day (plasma AUCs seven times that in humans at the MRHD) or greater, in the absence of maternal toxicity. Administration of up to 700 mg/kg/day (plasma AUCs 28 times that in humans at the MRHD) to rats during the latter part of gestation and throughout lactation produced no evidence of developmental impairment in the offspring.

Nursing Mothers

Carbidopa and entacapone are excreted in rat milk. It is not known whether entacapone, carbidopa, or levodopa is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Carbidopa, Levodopa and Entacapone Tablets are administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of Carbidopa, Levodopa and Entacapone Tablets, 43.8% were 65 years old and over, while 7.2% were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients; however, greater sensitivity of some older individuals cannot be excluded.

Carbidopa, Levodopa and Entacapone Tablets have not been studied in Parkinson’s disease patients or in healthy volunteers older than 75 years [see Clinical Pharmacology (12.3)].

Renal Impairment

Renal impairment does not affect pharmacokinetics of entacapone. There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment [see Clinical Pharmacology (12.3)].

Hepatic Impairment or Biliary Obstruction

There are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment. Carbidopa, Levodopa and Entacapone Tablets should be administered cautiously to patients with biliary obstruction or hepatic disease since biliary excretion appears to be the major route of excretion of entacapone and hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone [see Clinical Pharmacology (12.3)].

Mechanism of Action

Levodopa

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 because it does not cross the blood‑brain barrier. However, levodopa the metabolic precursor of dopamine, does cross the blood‑brain barrier, and is presumably converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves the symptoms of Parkinson’s disease.

Carbidopa

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. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain.

Entacapone

Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).

COMT catalyzes the transfer of the methyl group of S‑adenosyl‑L‑methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include DOPA, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. When decarboxylation of levodopa is prevented by carbidopa, COMT becomes the major metabolizing enzyme for levodopa, catalyzing its metabolism to 3‑methoxy‑4‑hydroxy‑L‑phenylalanine (3‑OMD).

Pharmacokinetics

The pharmacokinetics of Carbidopa, Levodopa and Entacapone Tablets has been studied in healthy subjects (age 45 years to 75 years). Overall, following administration of corresponding doses of levodopa, carbidopa and entacapone as Carbidopa, Levodopa and Entacapone Tablets or as carbidopa and levodopa product plus entacapone tablets, the mean plasma concentrations of levodopa, carbidopa, and entacapone are comparable.

Absorption and Distribution
Both levodopa and entacapone are rapidly absorbed and eliminated, and their distribution volume is moderately small. Carbidopa is absorbed and eliminated slightly more slowly compared with levodopa and entacapone. There are substantial inter- and intra-individual variations in the absorption of levodopa, carbidopa and entacapone, particularly concerning its Cmax.

The food-effect on the Carbidopa, Levodopa and Entacapone Tablets has not been evaluated. Because levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients after eating a high protein meal. Meals rich in large neutral amino acids may delay and reduce the absorption of levodopa [see Patient Counseling Information (17)].

Levodopa
The pharmacokinetic properties of levodopa following the administration of single-dose Carbidopa, Levodopa and Entacapone Tablets are summarized in Table 3.

Levodopa is bound to plasma protein only to a minor extent (about 10% to 30%).

Carbidopa

Following administration of carbidopa, levodopa and entacapone tablet as a single dose to healthy male and female subjects, the peak concentration of carbidopa was reached within 2.5 hours to 3.4 hours on average. The mean Cmax ranged from about 40 nanogram per mL to 225 nanogram per mL and the mean AUC from 170 nanogram•h per mL to 1,200 nanogram•h per mL, with different Carbidopa, Levodopa and Entacapone Tablets strengths providing 25 mg, or 37.5 mg of carbidopa.

Carbidopa is approximately 36% bound to plasma protein.

Entacapone

Following administration of carbidopa, levodopa and entacapone tablet as a single dose to healthy male and female subjects, the peak concentration of entacapone in plasma was reached within 0.8 hour to 1.2 hours on average. The mean Cmax of entacapone was about 1,200 nanogram per mL to 1,500 nanogram per mL and the AUC 1,250 nanogram•h per mL to 1,750 nanagram•h per mL after administration of different carbidopa, levodopa and entacapone tablet strengths all providing 200 mg of entacapone.

The plasma protein binding of entacapone is 98% over the concentration range of 0.4 mcg per mL to 50 mcg per mL. Entacapone binds mainly to serum albumin.

Metabolism and Elimination

Levodopa

The elimination half-life of levodopa, the active moiety of antiparkinsonian activity, was 1.7 hours (range 1.1 hours to 3.2 hours).

Levodopa is extensively metabolized to various metabolites. Two major pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by COMT.

Carbidopa

The elimination half‑life of carbidopa was on average 1.6 hours to 2 hours (range 0.7 hour to 4 hours).

Carbidopa is metabolized to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α‑methyl‑3,4-dihydroxyphenylpropionic acid). These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion.

Entacapone

The elimination half‑life of entacapone was on average 0.8 hour to 1 hour (0.3 hour to 4.5 hours).

Entacapone is almost completely metabolized prior to excretion with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis-isomer, the only active metabolite. Entacapone and the cis-isomer are eliminated in the urine as glucuronide conjugates. The glucuronides account for 95% of all urinary metabolites (70% as parent and 25% as cis-isomer glucuronides). The glucuronide conjugate of the cis-isomer is inactive. After oral administration of a 14C-labeled dose of entacapone, 10% of labeled parent and metabolite is excreted in urine and 90% in feces.

Due to short elimination half‑lives, no true accumulation of levodopa or entacapone occurs when they are administered repeatedly.

Renal Impairment

Entacapone

The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose in subjects with normal, moderate, and severely impaired renal functions, without levodopa and dopa decarboxylase inhibitor coadministration. No significant effects of renal function on the pharmacokinetics of entacapone were found.

Levodopa and carbidopa

No studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment.

Hepatic Impairment

Entacapone

Hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone. A single 200 mg dose of entacapone, without levodopa and dopa decarboxylase inhibitor coadministration, showed approximately 2‑fold higher AUC and Cmax values in patients with a history of alcoholism and hepatic impairment (n=10) compared to normal subjects (n=10). All patients had biopsy‑proven liver cirrhosis caused by alcohol. According to Child‑Pugh grading 7 patients with liver disease had mild hepatic impairment and 3 patients had moderate hepatic impairment. As only about 10% of the entacapone dose is excreted in urine, as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug. Carbidopa, Levodopa and Entacapone Tablets should be administered with care to patients with biliary obstruction or hepatic disease.

Levodopa and carbidopa

There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with hepatic impairment.

Geriatric Use

In the pharmacokinetics studies conducted in healthy volunteers following a single dose of carbidopa-, levodopa- and entacapone (as Carbidopa, Levodopa and Entacapone Tablets or as separate carbidopa/levodopa and entacapone tablets):

Levodopa

The AUC of levodopa is significantly (on average 10% to 20%) higher in elderly (60 years to 75 years) than younger subjects (45 years to 60 years). There is no significant difference in the Cmax of levodopa between younger (45 years to 60 years) and elderly subjects (60 years to 75 years).

Carbidopa

There is no significant difference in the Cmax and AUC of carbidopa, between younger (45 years to 60 years) and elderly subjects (60 years to 75 years).

Entacapone

The AUC of entacapone is significantly (on average, 15%) higher in elderly (60 years to 75 years) than younger subjects (45 years to 60 years). There is no significant difference in the Cmax of entacapone between younger (45 years to 60 years) and elderly subjects (60 years to 75 years).

Gender

Pharmacokinetics following a single dose of carbidopa, levodopa and entacapone together, either as Carbidopa, Levodopa and Entacapone Tablets or as separate carbidopa/levodopa and entacapone tablets in healthy volunteers (age range 45 years to 74 years):

Levodopa

The plasma exposure (AUC and Cmax) of levodopa is significantly higher in females than males (on average, 40% for AUC and 30% for Cmax). These differences are primarily explained by body weight. Other published literature showed significant gender effect (higher concentrations in females) even after correction for body weight.

Carbidopa

There is no gender difference in the pharmacokinetics of carbidopa.

Entacapone

There is no gender difference in the pharmacokinetics of entacapone.

Drug Metabolized by COMT

When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa and dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively.

Drugs known to be metabolized by COMT should be administered with caution in patients receiving entacapone regardless of the route of administration [seeDrug Interactions (7.2)].

Drugs Metabolized via CYP2C9

Due to its affinity to CYP2C9 invitro, entacapone may potentially interfere with medicinal products with metabolism dependent on this isoenzyme. In an interaction study in healthy volunteers, entacapone increased the AUC of R-warfarin on average by 18%, and the INR values increased on average by 13% [seeDrug Interactions (7.11)].

Hormone Levels

Of the ingredients in Carbidopa, Levodopa and Entacapone Tablets, levodopa is known to depress prolactin secretion and increase growth hormone levels.

The effectiveness of entacapone as an adjunct to levodopa in the treatment of Parkinson’s disease was established in three 24-week multicenter, randomized, double‑blind, placebo‑controlled studies in patients with Parkinson’s disease. In 2 of these studies (Studies 1 and 2), the patients’ disease was “fluctuating”, i.e., was characterized by documented periods of “On” (periods of relatively good functioning) and “Off” (periods of relatively poor functioning), despite optimum levodopa therapy. There was also a withdrawal period following 6 months of treatment. In the third trial patients were not required to have been experiencing fluctuations. Prior to the controlled part of these studies, patients were stabilized on levodopa for 2 weeks to 4 weeks.

There is limited experience using entacapone in patients who do not experience fluctuations.

In Studies 1 and 2, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of carbidopa/levodopa (up to 10 times daily, but patients averaged 4 doses to 6 doses per day). The double‑blind portion of both studies was 6 months long. Patients periodically recorded the time spent in the “On” and “Off” states in home diaries throughout the duration of the trial. In one study, conducted in the Nordic countries, the primary outcome measure was the total mean time spent in the “On” state during an 18 hour diary recorded day (6 a.m. to midnight). In the other study, the primary outcome measure was the proportion of awake time spent over 24 hours in the “On” state.

In addition to the primary outcome measure, the amount of time spent in the “Off” state was evaluated, and patients were also evaluated by subparts of the Unified Parkinson’s Disease Rating Scale (UPDRS), a frequently used multi‑item rating scale intended to assess mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Part V and VI); an investigator’s and patient’s global assessment of clinical condition, a 7‑point subjective scale designed to assess global functioning in Parkinson’s disease; and the change in daily carbidopa/levodopa dose.

In Study 1, 171 patients were randomized in 16 centers in Finland, Norway, Sweden, and Denmark (Study 1), all of whom received concomitant levodopa plus dopa decarboxylase inhibitor (either carbidopa/levodopa or benserazide/levodopa). In Study 2, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant carbidopa/levodopa.

The following tables (Table 4 and Table 5) display the results of these two studies:

Effects on “On” time did not differ by age, sex, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline.

Withdrawal of entacapone:

In Study 2, abrupt withdrawal of entacapone, without alteration of the dose of carbidopa/levodopa, resulted in a significant worsening of fluctuations, compared to placebo. In some cases, symptoms were slightly worse than at baseline, but returned to approximately baseline severity within 2 weeks following levodopa dose increase on average by 80 mg. In Study 1, similarly, a significant worsening of parkinsonian symptoms was observed after entacapone withdrawal, as assessed 2 weeks after drug withdrawal. At this phase, the symptoms were approximately at baseline severity following levodopa dose increase by about 50 mg.

In the third placebo‑controlled trial (Study 3), a total of 301 patients were randomized in 32 centers in Germany and Austria. In this trial, as in the other 2 studies, entacapone 200 mg was administered with each dose of levodopa and dopa decarboxylase inhibitor (up to 10 times daily) and UPDRS Parts II and III and total daily “On” time were the primary measures of effectiveness. Results for the primary measures, as well as for some secondary measures are presented in Table 6.

Carbidopa, Levodopa and Entacapone Tablets are supplied as film-coated tablets for oral administration in the following two strengths:

Carbidopa, Levodopa and Entacapone Tablets 25 mg/100 mg/200 mg containing 25 mg of carbidopa USP (anhydrous equivalent), 100 mg of levodopa USP and 200 mg of entacapone. The oval shaped tablets are brownish red, biconvex with “100” debossed on one side and “S” debossed on other side.

Bottles of 30’s with Child Resistant Cap………………NDC 47335-909-83

Bottles of 100’s with Child Resistant Cap……………..NDC 47335-909-88

Bottles of 100’s with Non Child Resistant Cap………..NDC 47335-909-08

Bottles of 1000’s with Non Child Resistant Cap………NDC 47335-909-18

Carbidopa, Levodopa and Entacapone Tablets 37.5 mg/150 mg/200 mg containing 37.5 mg of carbidopa USP (anhydrous equivalent), 150 mg of levodopa USP and 200 mg of entacapone. The oval shaped tablets are brownish red, biconvex with “150” debossed on one side and “S” debossed on other side.

Bottles of 30’s with Child Resistant Cap………………NDC 47335-910-83

Bottles of 100’s with Child Resistant Cap……………..NDC 47335-910-88

Bottles of 100’s with Non Child Resistant Cap………..NDC 47335-910-08

Bottles of 1000’s with Non Child Resistant Cap………NDC 47335-910-18

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Dispense in a tight container as defined in the USP.

NDC 47335-909-83
Carbidopa, Levodopa, and Entacapone Tablets
Each film‑coated tablet contains:
Carbidopa, USP ...............25 mg
Levodopa, USP ................100 mg
and
Entacapone .....................200 mg
Rx only
30 Tablets
SUN PHARMA