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
Tasmar Warnings, Precautions, Pregnancy, Nursing, Abuse - Tolcapone
Tasmar Warnings, Precautions, Pregnancy, Nursing, Abuse - Tolcapone
WARNINGS
(SEE BOXED WARNING) Because of the risk
of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone)
should ordinarily be used in patients with Parkinson’s disease on l-dopa/carbidopa
who are experiencing symptom fluctuations and are not responding satisfactorily
to or are not appropriate candidates for other adjunctive therapies (see
INDICATIONS and DOSAGE
AND ADMINISTRATION sections).
Because of the risk of liver injury and because TASMAR, when it is effective,
provides an observable symptomatic benefit, the patient who fails to wshow
substantial clinical benefit within 3 weeks of initiation of treatment,
should be withdrawn from TASMAR.
TASMAR therapy should not be initiated if the patient exhibits clinical
evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than
the upper limit of normal. Patients with severe dyskinesia or dystonia
should be treated with caution (see
PRECAUTIONS
:
Rhabdomyolysis).
Patients who develop evidence of hepatocellular injury while on TASMAR
and are withdrawn from the drug for any reason may be at increased risk
for liver injury if TASMAR is reintroduced. Accordingly, such patients
should not ordinarily be considered for retreatment.
In controlled Phase 3 trials, increases to more than 3 times the upper
limit of normal in ALT or AST occurred in approximately 1% of patients
at 100 mg t.i.d. and 3% of patients at 200 mg t.i.d. Females were more
likely than males to have an increase in liver enzymes (approximately
5% vs 2%). Approximately one third of patients with elevated enzymes had
diarrhea. Increases to more than 8 times the upper limit of normal in
liver enzymes occurred in 0.3% at 100 mg t.i.d. and 0.7% at 200 mg t.i.d.
Elevated enzymes led to discontinuation in 0.3% and 1.7% of patients treated
with 100 mg t.i.d. and 200 mg t.i.d., respectively. Elevations usually
occurred within 6 weeks to 6 months of starting treatment. In about half
the cases with elevated liver enzymes, enzyme levels returned to baseline
values within 1 to 3 months while patients continued TASMAR treatment.
When treatment was discontinued, enzymes generally declined within 2 to
3 weeks but in some cases took as long as 1 to 2 months to return to normal.
Monoamine oxidase (MAO) and COMT are the two major enzyme systems
involved in the metabolism of catecholamines. It is theoretically possible,
therefore, that the combination of TASMAR and a non-selective MAO inhibitor
(e.g., pheneizine and tranylcypromine) would result in inhibition of the
majority of the pathways responsible for normal catecholamine metabolism.
For this reason, patients should ordinarily not be treated concomitantly
with TASMAR and a non-elective MAO inhibitor.
Tolcapone can be taken concomitantly with a selective MAO-B inhibitor
(e.g., selegiline).
PRECAUTIONS
Hypotension/Syncope
Dopaminergic therapy in Parkinson’s disease patients has been associated
with orthostatic hypotension. Tolcapone enhances levodopa bioavailability
and, therefore, may increase the occurrence of orthostatic hypotension.
In TASMAR clinical trials, orthostatic hypotension was documented at least
once in 8%, 14% and 13% of the patients treated with placebo, 100 mg and
200 mg TASMAR t.i.d., respectively. A total of 2%, 5% and 4% of the patients
treated with placebo, 100 mg and 200 mg TASMAR t.i.d., respectively, reported
orthostatic symptoms at some time during their treatment and also had
at least one episode of orthostatic hypotension documented (however, the
episode of orthostatic symptoms itself was invariably not accompanied
by vital sign measurements). Patients with orthostasis at baseline were
more likely than patients without symptoms to have orthostatic hypotension
during the study, irrespective of treatment group. In addition, the effect
was greater in tolcapone-treated patients than in placebo-treated patients.
Baseline treatment with dopamine agonists or selegiline did not appear
to increase the likelihood of experiencing orthostatic hypotension when
treated with TASMAR. Approximately 0.7% of the patients treated with TASMAR
(5% of patients who were documented to have had at least one episode of
orthostatic hypotension) eventually withdrew from treatment due to adverse
events presumably related to hypotension.
In controlled Phase 3 trials, approximately 5%, 4% and 3% of tolcapone
200 mg t.i.d., 100 mg t.i.d. and placebo patients, respectively, reported
at least one episode of syncope. Reports of syncope were generally more
frequent in patients in all three treatment groups who had an episode
of documented hypotension (although the episodes of syncope, obtained
by history, were themselves not documented with vital sign measurement)
compared to patients who did not have any episodes of documented hypotension.
Diarrhea
In clinical trials, diarrhea developed in approximately 8%, 16% and 18%
of patients treated with placebo, 100 mg and 200 mg TASMAR t.i.d., respectively.
While diarrhea was generally regarded as mild to moderate in severity,
approximately 3% to 4% of patients on tolcapone had diarrhea which was
regarded as severe. Diarrhea was the adverse event which most commonly
led to discontinuation, with approximately 1%, 5% and 6% of patients treated
with placebo, 100 mg and 200 mg TASMAR t.i.d., respectively, withdrawing
from the trials prematurely. Discontinuing TASMAR for diarrhea was related
to the severity of the symptom. Diarrhea resulted in withdrawal in approximately
8%, 40% and 70% of patients with mild, moderate and severe diarrhea, respectively.
Although diarrhea generally resolved after discontinuation of TASMAR,
it led to hospitalization in 0.3%, 07% and 1.7% of patients in the placebo,
100 mg and 200 mg TASMAR t.i.d. groups.
Typically, diarrhea presents 6 to 12 weeks after tolcapone is started,
but it may appear as early as 2 weeks and as late as many months after
the initiation of treatment. Clinical trial data suggested that diarrhea
associated with tolcapone use may sometimes be associated with anorexia
(decreased appetite).
No consistent description of tolcapone-induced diarrhea has been derived
from clinical trial data, and the mechanism of action is currently unknown.
It is recommended that all cases of persistent diarrhea should be followed
up with an appropriate work-up (including occult blood samples).
Hallucinations
In clinical trials, hallucinations developed in approximately 5%, 8%
and 10% of patients treated with placebo, 100 mg and 200 mg TASMAR t.i.d.,
respectively. Hallucinations led to drug discontinuation and premature
withdrawal from clinical trials in 0.3%, 1.4% and 1.0% of patients treated
with placebo, 100 mg and 200 mg TASMAR t.i.d., respectively. Hallucinations
led to hospitalization in 0.0%, 1.7% and 0.0% of patients in the placebo,
100 mg and 200 mg TASMAR t.i.d. groups, respectively.
In general, hallucinations present shortly after the initiation of therapy
with tolcapone (typically within the first 2 weeks). Clinical trial data
suggest that hallucinations associated with tolcapone use may be responsive
to levodopa dose reduction. Patients whose hallucinations resolved had
a mean levodopa dose reduction of 175 mg to 200 mg (20% to 25%) after
the onset of the hallucinations. Hallucinations were commonly accompanied
by confusion and to a lesser extent sleep disorder (insomnia) and excessive
dreaming.
Dyskinesia
TASMAR may potentiate the dopaminergic side effects of levodopa and may
cause and/or exacerbate preexisting dyskinesia. 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 mean dose of levodopa. The rates of withdrawal for dyskinesia were
0.0%, 0.3% and 1.0% for placebo, 100 mg and 200 mg TASMAR t.i.d., respectively.
Rhabdomyolysis
Cases of severe rhabdomyolysis, with one case of multiorgan system failure
rapidly progressing to death, have been reported. The complicated nature
of these cases makes it impossible to determine what role, if any, TASMAR
played in their pathogenesis. Severe prolonged motor activity including
dyskinesia may account for rhabdomyolysis. Some cases, however, included
fever, alteration of consciousness and muscular rigidity. It is possible,
therefore, that the rhabdomyolysis may be a result of the syndrome described
in Hyperpyrexia and Confusion (see Events Reported
With Dopaminergic Therapy below).
Renal Impairment
No dosage adjustment is needed in patients with mild to moderate renal
impairment, however, patients with severe renal impairment should be treated
with caution (see CLINICAL PHARMACOLOGY:
Pharmacokinetics of Tolcapone and DOSAGE
AND ADMINISTRATION).
Renal Toxicity: When rats were dosed daily for 1 or 2 years
(exposures 6 times the human exposure or greater) there was a high incidence
of proximal tubule cell damage consisting of degeneration, single cell
necrosis, hyperplasia, karyocytomegaly and atypical nuclei. 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 it has been speculated that these
toxicities may occur as the result of a species-specific mechanism, experiments
which would confirm that theory have not been conducted.
Hepatic Impairment
Because of the risk of liver injury, TASMAR therapy should not be initiated
in any patient with liver disease. For similar reasons, treatment should
not be initiated in patients who have two SGPT/ALT or SGOT/AST values
greater than the upper limit of normal (see BOXED
WARNING) or any other evidence of hepatocellular dysfunction.
Hematuria: The rates of hematuria in placebo-controlled
trials were approximately 2%, 4% and 5% in placebo, 100 mg and 200 mg
TASMAR t.i.d., respectively. The etiology of the increase with TASMAR
has not always been explained (for example, by urinary tract infection
or coumadin therapy). In placebo-controlled trials in the United States
(N= 593) rates of microscopically confirmed hematuria were approximately
3%, 2% and 2% in placebo, 100 mg and 200 mg TASMAR t.i.d., respectively.
Events Reported With Dopaminergic Therapy
The events listed below are known to be associated with the use of drugs
that increase dopaminergic activity, although they are most often associated
with the use of direct dopamine agonists. While cases of Hyperpyrexia
and Confusion have been reported in association with tolcapone withdrawal
(see paragraph below), the expected incidence of fibrotic complications
is so low that even if tolcapone caused these complications at rates similar
to those attributable to other dopaminergic therapies, it is unlikely
that even a single example would have been detected in a cohort of the
size exposed to tolcapone.
Hyperpyrexia and Confusion
In clinical trials, four cases of a symptom complex resembling the neuroleptic
malignant syndrome(characterized by elevated temperature, muscular rigidity,
and altered consciousness), similar to that reported in association with
the rapid dose reduction or withdrawal of other dopaminergic drugs, have
been reported in association with the abrupt withdrawal or lowering of
the dose of tolcapone. In 3 of these cases, CPK was elevated as well.
One patient died, and the other 3 patients recovered over periods of approximately
2, 4 and 6 weeks. Rare cases of this symptom complex have been reported
during marketed use. These cases are of a complicated nature including
the concomitant administration of several medications affect log brain
monoaminergic (i.e, MAO-I, tricyclic and selective serotonin reuptake
inhibitors) and anticholinergic systems. It is difficult, therefore, to
determine what role, if any, TASMAR played in the pathogenesis. It may,
therefore, be prudent to be particularly cautious if several concomitant
medications of these types are used.
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. While these complications may resolve
when the drug is discontinued, 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,
tolcapone) that increase dopaminergic activity can cause them is unknown.
Three cases of pleural effusion, one with pulmonary fibrosis, occurred
during clinical trials. These patients were also on concomitant dopamine
agonists (pergolide or bromocriptine) and had a prior history of cardiac
disease or pulmonary pathology (nonmalignant lung lesion).
Information for Patients
See PATIENT INFORMATION section.
Laboratory Tests
Although a program of frequent laboratory monitoring for evidence
of hepatocellular injury is deemed essential, it is not clear that baseline
and periodic monitoring of liver enzymes will prevent the occurrence of
fulminant liver failure. However, it is generally believed that early
detection of drug-induced hepatic injury along with immediate withdrawal
of the suspect drug enhances the likelihood for recovery. It is also widely
held, without a robust body of evidence, that patients with preexisting
hepatic disease are more vulnerable to hepatotoxins. Accordingly, the
following liver monitoring program is recommended.
Before starting treatment with TASMAR, the physician should conduct appropriate
tests to exclude the presence of liver disease. In patients determined
to be appropriate candidates for treatment with TASMAR, serum glutamic-pyruvic
transaminase (SGPT/ALT) and serum glutamic-oxaloacetic transaminase (SGOT/AST)
levels should be determined at baseline and then every 2 weeks for the
first year of therapy, every 4 weeks for the next 6 months and then every
8 weeks thereafter.
If the dose is increased to 200 mg t.i.d. (see DOSAGE
AND ADMINISTRATION section), liver enzyme monitoring should take
place before increasing the dose and then be reinitiated at the frequency
above.
TASMAR should be discontinued if SGPT/ALT or SGOT/AST exceeds the upper
limit of normal or if clinical signs and symptoms suggest the onset of
hepatic failure (persistent nausea, fatigue, lethargy, anorexia, jaundice,
dark urine, pruritus, and right upper quadrant tenderness).
Special Populations
TASMAR therapy should not be initiated if the patient exhibits clinical
evidence of active liver disease or two SGPT/ALT or SGOT/AST values greater
than the upper limit of normal. Patients with severe dyskinesia or dystonia
should be treated with caution (see Rhabdomyolysis above
). Patients with severe renal impairment should be treated with
caution (see INDICATIONS, DOSAGE
AND ADMINISTRATION, BOXED WARNING
and WARNINGS
).
Drug Interactions
See DRUG INTERACTIONS section.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenesis: Carcinogenicity studies in which tolcapone
was administered in the diet were conducted in mice and rats. Mice were
treated for 80 (female) or 95 (male) weeks with doses of 100, 300 and
800 mg/kg/day, equivalent in 0.8, 1.6 and 4 times human exposure (AUC=80
mcg• hr/mL) at the recommended daily clinical
dose of 600 mg. Rats were treated for 104 weeks with doses of 50, 250
and 450 mg/kg/day. Tolcapone exposures were 1, 6.3 and 13 times the human
exposure in male rats and 1.7, 11.8 and 26.4 times the human exposure
in female rats. There was an increased incidence of uterine adenocarcinomas
in female rats at exposure equivalent to 26.4 times the human exposure.
There was evidence of renal tubular injury and renal tubular tumor formation
in rats. A low incidence of renal tubular cell adenomas occurred in middle-and
high-dose female rats; tubular cell carcinomas occurred in middle-and
high-dose male and high-dose female rats, with a statistically significant
increase in high-dose males. Exposures were equivalent to 6.3 (males)
or 11.8 (females) times the human exposure or greater; no renal tumors
were observed at exposures of 1 (males) or 17 (females) times the human
exposure. Minimal-to-marked damage to the renal tubules, consisting of
proximal tubule cell degeneration, single cell necrosis, hyperplasia and
karyocytomegaly, occurred at the doses associated with renal tumors. Renal
tubule damage, characterized by proximal tubule cell degeneration and
the presence of atypical nuclei, as well as one adenocarcinoma in a high-dose
male, were observed in a 1-year study in rats receiving doses of tolcapone
of 150 and 450 mg/kg/day. These histopathological changes suggest the
possibility that renal tumor formation might be secondary to chronic cell
damage and sustained repair, but this relationship has not been established,
and the relevance of these findings to humans is not known. There was
no evidence of carcinogenic effects in the long-term mouse study. The
carcinogenic potential of tolcapone in combination with levodopa/carbidopa
has not been examined.
Mutagenesis: Tolcapone was clastogenic in the in
vitro mouse lymphoma/thymidine kinase assay in the presence of metabolic
activation. Tolcapone was not mutagenic in the Ames test, the in vitro
V79/HPRT gene mutation assay, or the unscheduled DNA synthesis assay.
It was not clastogenic in an in vitro chromosomal aberration assay in
cultured human lymphocytes, or in an in vivo micronucleus assay in mice.
Impairment of Fertility: Tolcapone did not affect fertility
and general reproductive performance in rats at doses up to 300 mg/kg/day
(5.7 times the human dose on a mg/m2 basis).
Pregnancy
Pregnancy Category C. Tolcapone, when administered alone
during organogenesis, was not teratogenic at doses of up to 300 mg/kg/day
in rats or up to 400 mg/kg/day in rabbits (57 times and 15 times the recommended
daily clinical dose of 600 mg, on a mg/m2 basis, respectively).
In rabbits, however, an increased rate of abortion occurred at a dose
of 100 mg/kg/day (3.7 times the daily clinical dose on a mg/m2
basis) or greater evidence of maternal toxicity (decreased weight gain,
death) was observed at 300 mg/kg in rats and 400 mg/kg in rabbits. When
tolcapone was administered to female rats during the last party of gestation
and throughout lactation, decreased litter size and impaired growth and
learning performance in female pups were observed at a dose of 250/150
mg/kg/day (dose reduced from 250 to 150 mg/kg/day during late gestation
due to high rate of maternal mortality; equivalent to 4.8/2.9 times the
clinical dose on a mg/m2 basis).
Tolcapone is always given concomitantly with levodopa/carbidopa, which
is known to cause visceral and skeletal malformations in rabbits. The
combination of tolcapone (100 mg/kg/day) with levodopa/carbidopa (80/20
mg/kg/day) produced an increased incidence of fetal malformations (primarily
external and skeletal digit defects) compared to levodopa/carbidopa alone
when pregnant rabbits were treated throughout organogenesis. Plasma exposures
to tolcapone (based on AUC) were 0.5 times the expected human exposure,
and plasma exposures to levodopa were 6 times higher than those in humans
under therapeutic conditions. In a combination embryo-fetal development
study in rats, fetal body weights were reduced by the combination of tolcapone
(10, 30 and 50 mg/kg/day) and levodopa/carbidopa (120/30 mg/kg/day) and
by levodopa/carbidopa alone. Tolcapone exposures were 0.5 times expected
human exposure or greater: levodopa exposures were 21 times the expected
human exposure or greater. The high dose of 50 mg/kg/day of tolcapone
given alone was not associated with reduced fetal body weight (plasma
exposures of 1.4 times the expected human exposure).
There is no experience from clinical studies regarding the use of TASMAR
in pregnant women. Therefore, TASMAR should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Nursing Women
In animal studies, tolcapone was excreted into maternal rat milk. It
is not known whether tolcapone is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when tolcapone
is administered to a nursing woman.
Pediatric Use
There is no identified potential use of tolcapone in pediatric patients.
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