Hypotension, Orthostatic Hypotension, And Syncope
Dopaminergic therapy in Parkinson's disease patients has
been associated with orthostatic hypotension. Entacapone enhances levodopa
bioavailability and, therefore, might be expected to increase the occurrence of
orthostatic hypotension. In controlled studies, approximately 1.2% and 0.8% of
200 mg entacapone and placebo patients, respectively, reported at least one
episode of syncope. Reports of syncope were generally more frequent in patients
in both treatment groups who had an episode of documented hypotension.
Hallucinations And Psychotic-Like Behavior
Dopaminergic therapy in patients with Parkinson's disease
has been associated with hallucinations. In clinical studies, hallucinations
led to drug discontinuation and premature withdrawal in 0.8% and 0% of patients
treated with 200 mg Comtan and placebo, respectively. Hallucinations led to
hospitalization in 1.0% and 0.3% of patients in the 200 mg Comtan and placebo
groups, respectively. Agitation occurred in 1% of patients treated with COMTAN
and 0% treated with placebo.
Postmarketing reports indicate that patients may
experience new or worsening mental status and behavioral changes, which may be
severe, including psychotic-like behavior during Comtan treatment or after
starting or increasing the dose of Comtan. Other drugs prescribed to improve
the symptoms of Parkinson's disease can have similar effects on thinking and
behavior. Abnormal thinking and behavior can cause paranoid ideation,
delusions, hallucinations, confusion, disorientation, aggressive behavior,
agitation, and delirium. Psychotic-like behaviors were also observed during the
clinical development of Comtan.
Patients with a major psychotic disorder should
ordinarily not be treated with Comtan because of the risk of exacerbating
psychosis. In addition, certain medications used to treat psychosis may
exacerbate the symptoms of Parkinson's disease and may decrease the
effectiveness of Comtan.
Impulse Control And 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 that are used for the treatment of Parkinson's disease and
that increase central dopaminergic tone, including Comtan 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 Comtan if a patient
develops such urges while taking Comtan.
Diarrhea And Colitis
In clinical studies, diarrhea developed in 60 of 603
(10%) and 16 of 400 (4%) of patients treated with 200 mg Comtan and placebo,
respectively. In patients treated with Comtan, 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 Comtan. Two patients with diarrhea were
hospitalized. Typically, diarrhea presents within 4 weeks 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 Comtan treatment was stopped.
In some patients with biopsy confirmed colitis, diarrhea had resolved or
significantly improved after discontinuation of Comtan but recurred after
retreatment with Comtan.
If prolonged diarrhea is suspected to be related to
Comtan, 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.
Comtan may potentiate the dopaminergic side effects of
levodopa and may cause or exacerbate preexisting dyskinesia. Although
decreasing the dose of levodopa may ameliorate this side effect, many patients
in controlled studies continued to experience frequent dyskinesia despite a
reduction in their dose of levodopa. The incidence of dyskinesia was 25% for
treatment with Comtan and 15% for placebo. The incidence of study withdrawal
for dyskinesia was 1.5% for 200 mg Comtan and 0.8% for placebo.
Other Events Reported With Dopaminergic Therapy
The events listed below are events associated with the
use of drugs that increase dopaminergic activity.
Cases of severe rhabdomyolysis have been reported
following the approval of Comtan. Although the reactions typically occurred
while patients were treated with Comtan, the complicated nature of these cases
makes it difficult to determine what role, if any, Comtan played in their
pathogenesis. Severe prolonged motor activity including dyskinesia may account
for rhabdomyolysis. Signs and symptoms include fever, alteration of
consciousness, myalgia, increased values of creatine phosphokinase (CPK) and
myoglobin (see PRECAUTIONS, Other Events Reported With Dopaminergic
Hyperpyrexia and Confusion
Cases of a symptom complex resembling neuroleptic
malignant syndrome (NMS) characterized by elevated temperature, muscular
rigidity, altered consciousness, and elevated CPK have been reported in
association with the rapid dose reduction or withdrawal of other dopaminergic
drugs. In most of these cases, symptoms began after abrupt discontinuation of
treatment with entacapone or reduction of its dose, or after the initiation of
treatment with entacapone. The complicated nature of these cases makes it
difficult to determine what role, if any, Comtan may have played in their
pathogenesis. No cases have been reported following the abrupt withdrawal or
dose reduction of entacapone treatment during clinical studies.
Prescribers should exercise caution when discontinuing
entacapone treatment. When considered necessary, withdrawal should proceed
slowly. If the decision is made to discontinue treatment with Comtan,
recommendations include monitoring the patient closely and adjusting other
dopaminergic treatments as needed. This syndrome should be considered in the
differential diagnosis for any patient who develops a high fever or severe
rigidity. Tapering Comtan has not been systematically evaluated.
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 events are believed to be related to the ergoline
structure of these compounds, whether other, nonergot derived drugs (e.g.,
entacapone) that increase dopaminergic activity can cause them is unknown. It
should be noted that 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. Four cases of
pulmonary fibrosis were reported during clinical development of entacapone;
three of these patients were also treated with pergolide and one with
bromocriptine. The duration of treatment with entacapone ranged from 7 months
to 17 months.
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
Comtan for any indication. Ideally, periodic skin examinations should be
performed by appropriately qualified individuals (e.g., dermatologists).
In a 1-year toxicity study, entacapone (plasma exposure
20 times that in humans receiving the maximum recommended daily dose of 1,600
mg) caused an increased incidence of nephrotoxicity in male rats that was
characterized by regenerative tubules, thickening of basement membranes,
infiltration of mononuclear cells, and tubular protein casts. These effects
were not associated with changes in clinical chemistry parameters, and there is
no established method for monitoring for the possible occurrence of these
lesions in humans. Although this toxicity could represent a species-specific
effect, there is not yet evidence that this is so.
Patients with hepatic impairment should be treated with
caution. The AUC and Cmax of entacapone approximately doubled in patients with
documented liver disease compared to controls (see CLINICAL PHARMACOLOGY,
Pharmacokinetics of Entacapone and DOSAGE AND ADMINISTRATION).
Comtan is a chelator of iron. The impact of entacapone on
the body's iron stores is unknown; however, a tendency towards decreasing serum
iron concentrations was noted in clinical studies. In a controlled clinical
study serum ferritin levels (as marker of iron deficiency and subclinical
anemia) were not changed with entacapone compared to placebo after one year of
treatment and there was no difference in rates of anemia or decreased
Patients with hepatic impairment should be treated with
caution (see INDICATIONS, DOSAGE AND ADMINISTRATION).
Two-year carcinogenicity studies of entacapone were
conducted in mice and rats. Rats were treated once-daily by oral gavage with
entacapone doses of 20, 90, or 400 mg/kg. 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 this dose were
approximately 20 times higher than estimated plasma exposures of humans
receiving the maximum recommended daily dose (MRDD) of entacapone (1,600 mg).
Mice were treated once daily by oral gavage with doses of 20, 100, or 600 mg/kg
of entacapone (0.05, 0.3, and 2 times the MRDD for humans 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. Although no treatment related tumors were observed in animals
receiving the lower doses, the carcinogenic potential of entacapone has not
been fully evaluated. The carcinogenic potential of entacapone administered in
combination with levodopa and carbidopa has not been evaluated.
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 levodopa and
carbidopa, was not clastogenic in the in vivo mouse micronucleus test or
mutagenic in the bacterial reverse mutation assay (Ames test).
Impairment Of Fertility
Entacapone did not impair fertility or general
reproductive performance in rats treated with up to 700 mg/kg/day (plasma AUCs
28 times those in humans receiving the MRDD of 1,600 mg). Delayed mating, but
no fertility impairment, was evident in female rats treated with 700 mg/kg/day
Pregnancy Category C
In embryofetal development studies, entacapone was
administered to pregnant animals throughout organogenesis at doses of up to
1,000 mg/kg/day in rats and 300 mg/kg/day in rabbits. 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
drug exposure (AUC) associated with this dose was approximately 34 times the
estimated plasma exposure in humans receiving the maximum recommended daily
dose (MRDD) of 1,600 mg. Increased frequencies of abortions, late and 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 0.4
times those in humans receiving the MRDD) or greater. There was no evidence of
teratogenicity in these studies.
However, 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 7 times those
in humans receiving the MRDD) or greater, in the absence of maternal toxicity.
Administration of up to 700 mg/kg/day (plasma AUCs 28 times those in humans
receiving the MRDD) to female rats during the latter part of gestation and
throughout lactation produced no evidence of developmental impairment in the
Entacapone is always given concomitantly with levodopa
and carbidopa, which is known to cause visceral and skeletal malformations in
rabbits. The teratogenic potential of entacapone in combination with levodopa
and carbidopa was not assessed in animals.
There is no experience from clinical studies regarding
the use of Comtan in pregnant women. Therefore, Comtan should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
In animal studies, entacapone was excreted into maternal
It is not known whether entacapone is excreted in human
milk. Because many drugs are excreted in human milk, caution should be
exercised when entacapone is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not