July 26, 2016
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Stalevo

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Stalevo




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

The following adverse reactions described in this section are related to at least one of the components of Stalevo (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 Stalevo 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 pre-existing 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 Stalevo.

Before initiating treatment with Stalevo, 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.), Stalevo should ordinarily be discontinued [see DOSAGE AND ADMINISTRATION and Withdrawal-Emergent Hyperpyrexia and Confusion]. If the decision is made to continue Stalevo, 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 Stalevo.

Dyskinesia

Dyskinesia (involuntary movements) may occur or be exacerbated at lower dosages and sooner with Stalevo 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 1.0% 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 Stalevo if a patient develops such urges while taking Stalevo [see DOSAGE AND ADMINISTRATION, Withdrawal-Emergent Hyperpyrexia and Confusion].

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 Stalevo, the dose should be decreased slowly, with supervision from a health care provider [see DOSAGE AND ADMINISTRATION]. Specific methods for tapering entacapone have not been systematically evaluated.

Diarrhea And Colitis

In clinical trials of entacapone, diarrhea developed in 60 of 603 (10.0%) and 16 of 400 (4.0%) 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 Stalevo, 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 [see Withdrawal-Emergent Hyperpyrexia and Confusion].

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 Stalevo, 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 Stalevo 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]. 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 Stalevo than with levodopa.

Stalevo 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In rats, oral administration of carbidopa-levodopa for 2 years resulted in no evidence of carcinogenicity at doses of approximately 2 times (carbidopa)-4 times (levodopa) the maximum recommended human dose (MRHD).

Two-year carcinogenicity studies of entacapone were conducted in mice and rats. Mice were treated once daily by oral gavage with doses of 20, 100, or 600 mg/kg/day (0.05, 0.3, or 2 times the MRHD on a mg/m² basis). Because of a high incidence of premature mortality in mice receiving the highest dose of entacapone, the mouse study is not an adequate assessment of carcinogenicity. Rats were treated with entacapone at oral doses of 20, 90, or 400 mg/kg/day. An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with the highest dose of entacapone. Plasma exposures (AUC) associated with the highest dose not associated with increased renal tumors were approximately 5 times that in humans at the MRHD of entacapone.

The carcinogenic potential of entacapone administered in combination with carbidopa-levodopa has not been evaluated.

Mutagenesis

Carbidopa was mutagenic in the in vitro bacterial reverse mutation (Ames) assay in the presence and absence of metabolic activation, and in the in vitro mouse lymphoma thymidine kinase (tk) assay in the absence of metabolic activation. Carbidopa was negative in the in vivo mouse micronucleus assay.

Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. Entacapone, either alone or in combination with carbidopa-levodopa, was negative in the in vivo mouse micronucleus and in the Ames assays.

Impairment of Fertility

In reproduction studies, no effects on fertility were found in rats receiving carbidopa-levodopa at doses of approximately 2 times (carbidopa)-4 times (levodopa) the MRHD.

In rats treated orally with entacapone (up to 700 mg/kg/day), no effects on fertility or general reproductive performance were observed. Plasma exposures (AUC) at the highest dose tested were approximately 30 times that in humans at the MRHD of entacapone. Delayed mating was evident in females at the highest dose tested.

Use In Specific Populations

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. Stalevo 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 Stalevo is 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 Stalevo, 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.

Stalevo tablets have not been studied in Parkinson's disease patients or in healthy volunteers older than 75 years [see CLINICAL PHARMACOLOGY].

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].

Hepatic Impairment Or Biliary Obstruction

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

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 2/10/2016

Warnings
Precautions

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