Included as part of the "PRECAUTIONS" Section
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
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
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%
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
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.
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].
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
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.
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.
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. Falsenegative
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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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
Two-year carcinogenicity studies of entacapone were conducted in mice and rats. In mice, no increase
in tumors was observed at oral doses of 100, 200 and 400 mg/kg/day. At the highest dose tested, plasma
exposures (AUC) were 4 times higher than that in humans at the maximum recommended daily dose
(MRDD) of 1,600 mg. In rats administered oral doses of 20, 90, or 400 mg/kg/day, an increased
incidence of renal tubular adenomas and carcinomas was observed in males at the highest dose tested.
Plasma AUCs at the higher dose not associated with increased renal tumors (90 mg/kg/day) were
approximately 5 times that in humans at the MRDD of entacapone.
The carcinogenic potential of entacapone administered in combination with carbidopa-levodopa has not
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 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 carbidopalevodopa.
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.
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.
Safety and effectiveness in pediatric patients have not been established.
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 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].