A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Comtan Side Effects, and Drug Interactions - Entacapone
Comtan Side Effects, and Drug Interactions - Entacapone
SIDE EFFECTS
During the pre-marketing development
of entacapone, 1450 patients with Parkinson’s Disease were treated
with entacapone. Included were patients with fluctuating symptoms,
as well as those with stable
responses to levodopa therapy. All patients received concomitant
treatment with levodopa
preparations, however, and were similar in other clinical
aspects.
The most commonly observed adverse events (>5%) in the double-blind,
placebo-controlled trials (N=1003) associated with the use of C.M.A.
and not seen at an equivalent
frequency among the
placebo-treated patients were: dyskinesia/hyperkinesia, nausea,
urine discoloration, diarrhea,
and abdominal pain.
Approximately 14% of the 603 patients given entacapone in the double-blind,
placebo-controlled trials discontinued treatment
due to adverse events compared to 9 % of the 400 patients who received
placebo. The most frequent causes of discontinuation in decreasing
order are: psychiatric
reasons (2% vs. 1%), diarrhea
(2% vs. 0%), dyskinesia/hyperkinesia (2% vs. 1%), nausea (2% vs.
1%), abdominal pain
(1% vs. 0%), and aggravation of Parkinson’s Disease symptoms (1%
vs. 1%).
Adverse Event Incidence in Controlled Clinical Studies
Table 4 lists treatment
emergent adverse events
that occurred in at least 1% of patients treated with entacapone
participating in the double-blind, placebo-controlled studies and
that were numerically more common in the entacapone group, compared
to placebo. In these studies,
either entacapone or placebo
was added to levodopa/carbidopa (or levodopa/benserazide).
Table 4.
Summary of Patients with Adverse Events after Start of Trial
Drug Administration At
least 1 % in C.M.A.
group and > Placebo
|
SYSTEM ORGAN CLASS
|
COMTAN
|
Placebo
|
|
|
(n = 603)
% of patients
|
(n = 400)
% of patients
|
|
SKIN AND APPENDAGES DISORDERS
|
|
|
2
|
1
|
|
MUSCULO- SKELETAL SYSTEM DISORDERS
|
|
Back pain
|
2
|
1
|
|
CENTRAL & PERIPHERAL NERVOUS SYSTEM
DISORDERS
|
|
Dyskinesia
|
25
|
15
|
|
Hyperkinesia
|
10
|
5
|
|
Hypokinesia
|
9
|
8
|
|
Dizziness
|
8
|
6
|
|
SPECIAL SENSES OTHER, DISORDERS
|
|
Taste perversion
|
1
|
0
|
|
PSYCHIATRIC DISORDERS
|
|
Anxiety
|
2
|
1
|
|
Somnolence
|
2
|
0
|
|
Agitation
|
1
|
0
|
|
GASTRO- INTESTINAL SYSTEM DISORDERS
|
|
Nausea
|
14
|
8
|
|
Diarrhea
|
10
|
4
|
|
Abdominal pain
|
8
|
4
|
|
Constipation
|
6
|
4
|
|
Vomiting
|
4
|
1
|
|
Mouth dry
|
3
|
0
|
|
Dyspepsia
|
2
|
1
|
|
Flatulence
|
2
|
0
|
|
Gastritis
|
1
|
0
|
|
Gastro-intestinal disorders nos
|
1
|
0
|
|
RESPIRATORY SYSTEM DISORDERS
|
|
Dyspnea
|
3
|
1
|
|
PLATELET, BLEEDING & CLOTTING DISORDERS
|
|
Purpura
|
2
|
1
|
|
URINARY SYSTEM DISORDERS
|
|
Urine discoloration
|
10
|
0
|
|
BODY AS
A WHOLE – GENERAL DISORDERS
|
|
Back pain
|
4
|
2
|
|
Fatigue
|
6
|
4
|
|
Asthenia
|
2
|
1
|
|
RESISTANCE MECHANISM DISORDERS
|
|
Infection bacterial
|
1
|
0
|
The prescriber should be aware that these figures cannot be used
to predict the incidence
of adverse events in the course of usual medical practice where
patient characteristics
and other factors differ from those that prevailed in the clinical
studies. Similarly, the cited frequencies cannot be compared with
figures obtained from other clinical
investigations involving different treatments, uses, and investigators.
The cited figures do, however, provide the prescriber with some
basis for estimating the
relative contribution of drug
and nondrug factors to the adverse events observed in the population
studied.
Effects of gender
and age on adverse reactions:
No differences were noted
in the rate of adverse
events attributable to entacapone by age or gender.
DRUG ABUSE AND DEPENDENCE
Entacapone is not a controlled substance. Animal studies to evaluate
the drug abuse
and potential dependence
have not been conducted. Although clinical trials have not revealed
any evidence of the
potential for abuse,
tolerance or physical
dependence, systematic
studies in humans designed to evaluate these effects have not been
performed.
DRUG INTERACTIONS
In vitro studies of human
CYP enzymes showed that entacapone inhibited the CYP enzymes 1A2,
2A6, 2C9, 2C19, 2D6, 2E1 and 3A only at very high concentrations
(IC50 from 200 to over 1000 µM; an oral 200 mg
dose achieves a highest
level of approximately 5 µM in people); these enzymes would
therefore not be expected to be inhibited in clinical use.
Protein Binding: Entacapone is highly protein
bound (98%). In vitro
studies have shown no binding
displacement between
entacapone and other highly bound
drugs, such as warfarin,
salicylic acid, phenylbutazone,
and diazepam.
Drugs Metabolized by Catechol-O-methyltransferase (COMT):
(See WARNINGS)
Hormone levels: Levodopa is known to depress prolactin
secretion and increase growth
hormone levels. Treatment
with entacapone coadministered with levodopa/dopa decarboxylase
inhibitor does not
change these effects.
Effect of Entacapone on the Metabolism of Other Drugs:
See WARNINGS regarding concomitant
use of C.M.A. and non-selective
MAO inhibitors.
No interaction was noted with the MAO-B inhibitor
selegiline in two multiple-dose interaction studies when entacapone
was coadministered with a levodopa/dopa decarboxylase
inhibitor (n=29).
More than 600 Parkinson’s disease patients in clinical
trials have used selegiline in combination with entacapone and levodopa/dopa
decarboxylase
inhibitor.
As most entacapone excretion
is via the bile, caution
should be exercised when drugs known to interfere with biliary
excretion, glucuronidation,
and intestinal beta-glucuronidase
are given concurrently with entacapone. These include probenecid,
cholestyramine, and some antibiotics (e.g. erythromycin, rifamipicin,
ampicillin and chloramphenicol).
No interaction with the tricyclic antidepressant
imipramine was shown in a single-dose study with entacapone without
coadministered levodopa/dopa-decarboxylase inhibitor.
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