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TASMAR

 * Generic Name: tolcapone
 * Brand Name: Tasmar
 * Drug Class: Antiparkinson Agents, COMT Inhibitors

Medical Editor: John P. Cunha, DO, FACOEP Last updated on RxList: 7/6/2023

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 * Tasmar User Reviews


DRUG SUMMARY

WHAT ARE SIDE EFFECTS OF TASMAR?

Tasmar (tolcapone) is an inhibitor of catechol-O-methyltransferase (COMT) used
together with carbidopa and levodopa to treat symptoms of Parkinson's disease,
such as stiffness, tremors, muscle spasms, and poor muscle control. Tasmar is
usually reserved for use only in people who have used carbidopa and levodopa
without success in treating their Parkinson's disease. When used with carbidopa
and levodopa, Tasmar increases levels of levodopa in the body.

WHAT ARE SIDE EFFECTS OF TASMAR?

Tasmar may cause serious side effects including:

 * hives,
 * difficulty breathing,
 * swelling of your face, lips, tongue, or throat,
 * lightheadedness,
 * severe or ongoing diarrhea,
 * confusion,
 * hallucinations,
 * unusual thoughts or behavior,
 * worsening tremors,
 * stiffness,
 * muscle spasms,
 * nausea,
 * loss of appetite,
 * right-sided upper stomach pain,
 * tiredness,
 * dark urine,
 * clay-colored stools,
 * yellowing of the skin or eyes (jaundice), and
 * increased urges to gamble or sexual urges

Get medical help right away, if you have any of the symptoms listed above.

Common side effects of Tasmar include nausea, vomiting, unwanted/uncontrolled
movements, diarrhea, constipation, headache, drowsiness, trouble sleeping
(insomnia), increased number of dreams, increased sweating, dry mouth, gas,
abdominal pain, muscle cramps, tiredness, unusual skin changes, dizziness,
lightheadedness on standing, cold symptoms (stuffy nose, sneezing, sore throat),
confusion, weight loss, agitation, or anxiety.

Seek medical care or call 911 at once if you have the following serious side
effects:

 * Serious eye symptoms such as sudden vision loss, blurred vision, tunnel
   vision, eye pain or swelling, or seeing halos around lights;
 * Serious heart symptoms such as fast, irregular, or pounding heartbeats;
   fluttering in your chest; shortness of breath; and sudden dizziness,
   lightheadedness, or passing out;
 * Severe headache, confusion, slurred speech, arm or leg weakness, trouble
   walking, loss of coordination, feeling unsteady, very stiff muscles, high
   fever, profuse sweating, or tremors.

This document does not contain all possible side effects and others may occur.
Check with your physician for additional information about side effects.

DOSAGE FOR TASMAR

Treatment with Tasmar should always be initiated at a dose of 100 mg three times
daily, always as an adjunct to levodopa/carbidopa therapy.

WHAT DRUGS, SUBSTANCES, OR SUPPLEMENTS INTERACT WITH TASMAR?

Tasmar may interact with cold or allergy medicine, narcotics, sleeping pills,
muscle relaxers, medicine for seizures, depression or anxiety, other Parkinson's
medications, apomorphine, blood thinners, desipramine, dobutamine, epinephrine,
isoproterenol, or methyldopa. Tell your doctor all medications and supplements
you use.

TASMAR DURING PREGNANCY OR BREASTFEEDING

During pregnancy, Tasmar should be used only when prescribed. It is unknown if
this medication passes into breast milk. Consult your doctor before
breastfeeding.

ADDITIONAL INFORMATION

Our Tasmar (tolcapone) Side Effects Drug Center provides a comprehensive view of
available drug information on the potential side effects when taking this
medication.


FDA DRUG INFORMATION

 * Drug Description
 * Indications
 * Dosage
 * Side Effects
 * Drug Interactions
 * Warnings
 * Precautions
 * Overdose & Contraindications
 * Clinical Pharmacology
 * Medication Guide

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 show
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.

Cases of severe hepatocellular injury, including fulminant liver failure
resulting in death, have been reported in postmarketing use. As of May 2005, 3
cases of fatal fulminant hepatic failure have been reported from more than
40,000 patient years of worldwide use. This incidence may be 10- to 100-fold
higher than the background incidence in the general population. Underreporting
of cases may lead to significant underestimation of the increased risk
associated with the use of TASMAR. All 3 cases were reported within the first
six months of initiation of treatment with TASMAR. Analysis of the laboratory
monitoring data in over 3,400 TASMAR-treated patients participating in clinical
trials indicated that increases in SGPT/ALT or SGOT/AST, when present, generally
occurred within the first 6 months of treatment with TASMAR.

A prescriber who elects to use TASMAR in face of the increased risk of liver
injury is strongly advised to monitor patients for evidence of emergent liver
injury. Patients should be advised of the need for self-monitoring for both the
classical signs of liver disease (e.g., clay colored stools, jaundice) and the
nonspecific ones (eg, fatigue, loss of appetite, lethargy).

Although a program of periodic laboratory monitoring for evidence of
hepatocellular injury is recommended, it is not clear that 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. 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 periodically (i.e. every 2 to 4
weeks) for the first 6 months of therapy. After the first six months, periodic
monitoring is recommended at intervals deemed clinically relevant. Although more
frequent monitoring increases the chances of early detection, the precise
schedule for monitoring is a matter of clinical judgment. If the dose is
increased to 200 mg tid (see DOSAGE AND ADMINISTRATION section), liver enzyme
monitoring should take place before increasing the dose and then be conducted
every 2 to 4 weeks for the following 6 months of therapy. After six months,
periodic monitoring is recommended at intervals deemed clinically relevant.

TASMAR should be discontinued if SGPT/ALT or SGOT/AST levels exceed 2 times the
upper limit of normal or if clinical signs and symptoms suggest the onset of
hepatic dysfunction (persistent nausea, fatigue, lethargy, anorexia, jaundice,
dark urine, pruritus, and right upper quadrant tenderness).


DESCRIPTION FOR TASMAR

TASMAR® is available as tablets containing 100 mg tolcapone.

Tolcapone, an inhibitor of catechol-O-methyltransferase (COMT), is used in the
treatment of Parkinson's disease as an adjunct to levodopa/carbidopa therapy. It
is a yellow, odorless, non-hygroscopic, crystalline compound with a relative
molecular mass of 273.25. The chemical name of tolcapone is
3,4-dihydroxy-4'-methyl-5nitrobenzophenone. Its empirical formula is C14H11NO5
and its structural formula is:







Inactive ingredients: Core: lactose monohydrate, microcrystalline cellulose,
dibasic calcium phosphate anhydrous, povidone K-30, sodium starch glycolate,
talc and magnesium stearate. Film coating: hydroxypropyl methylcellulose,
titanium dioxide, talc, ethylcellulose, triacetin and sodium lauryl sulfate,
with the following dye system: yellow and red iron oxide.




USES FOR TASMAR

TASMAR is indicated as an adjunct to levodopa and carbidopa for the treatment of
the signs and symptoms of idiopathic Parkinson's disease. 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. Because of the
risk of liver injury and because TASMAR, when it is effective, provides an
observable symptomatic benefit, the patient who fails to show substantial
clinical benefit within 3 weeks of initiation of treatment, should be withdrawn
from TASMAR.

The effectiveness of TASMAR was demonstrated in randomized controlled trials in
patients receiving concomitant levodopa therapy with carbidopa or another
aromatic amino acid decarboxylase inhibitor who experienced end of dose
wearing-off phenomena as well as in patients who did not experience such
phenomena (see CLINICAL PHARMACOLOGY: Clinical Studies).


DOSAGE FOR TASMAR

Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR
(tolcapone) should ordinarily be used in patients with Parkinson's disease on
ldopa/ 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 SHOW
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. These patients should not ordinarily be considered
for retreatment with TASMAR.

Only prescribe TASMAR for patients taking concomitant carbidopa levodopa
therapy. The initial dose of TASMAR is always 100 mg three times per day. The
recommended daily dose of TASMAR is also 100 mg tid. In clinical trials,
elevations in ALT occurred more frequently at the dose of 200 mg tid. While it
is unknown whether the risk of acute fulminant liver failure is increased at the
200-mg dose, it would be prudent to use 200 mg only if the anticipated
incremental clinical benefit is justified (see BOXED WARNING, WARNINGS, and
PRECAUTIONS: Laboratory Tests). If a patient fails to show the expected
incremental benefit on the 200-mg dose after a total of 3 weeks of treatment
(regardless of dose), TASMAR should be discontinued.

In clinical trials, the first dose of the day of TASMAR was always taken
together with the first dose of the day of levodopa/carbidopa, and the
subsequent doses of TASMAR were given approximately 6 and 12 hours later.

In clinical trials, the majority of patients required a decrease in their daily
levodopa dose if their daily dose of levodopa was >600 mg or if patients had
moderate or severe dyskinesias before beginning treatment.

To optimize an individual patient's response, reductions in daily levodopa dose
may be necessary. In clinical trials, the average reduction in daily levodopa
dose was about 30% in those patients requiring a levodopa dose reduction.
(Greater than 70% of patients with levodopa doses above 600 mg daily required
such a reduction.)

TASMAR can be combined with both the immediate and sustained release
formulations of levodopa/carbidopa.

TASMAR may be taken with or without food (see CLINICAL PHARMACOLOGY).

PATIENTS WITH IMPAIRED HEPATIC FUNCTION

TASMAR therapy should not be initiated in any patient with liver disease or two
SGPT/ALT or SGOT/AST values greater than the upper limit of normal. (see BOXED
WARNING, WARNINGS, and CLINICAL PHARMACOLOGY)

PATIENTS WITH IMPAIRED RENAL FUNCTION

No dose adjustment of TASMAR is recommended for patients with mild to moderate
renal impairment. However, patients with severe renal impairment should be
treated with caution. The safety of tolcapone has not been examined in subjects
who had creatinine clearance less than 25 mL/min (see CLINICAL PHARMACOLOGY).

WITHDRAWING PATIENTS FROM TASMAR

As with any dopaminergic drug, withdrawal or abrupt reduction in the TASMAR dose
may lead to emergence of signs and symptoms of Parkinson's disease or
Hyperpyrexia and Confusion, a syndrome complex resembling the neuroleptic
malignant syndrome (see PRECAUTIONS: Events Reported With Dopaminergic Therapy).
If a decision is made to discontinue treatment with TASMAR, then it is
recommended to closely monitor the patient and adjust 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
TASMAR has not been systematically evaluated. As the duration of COMT inhibition
with TASMAR is generally 5 to 6 hours on average, decreasing the frequency of
dosage to twice or once a day may not in itself prevent withdrawal effects.


HOW SUPPLIED

TASMAR is supplied as film-coated tablets containing 100 mg tolcapone. The 100
mg beige to yellowish beige tablet is hexagonal and biconvex. Debossed on one
side of the 100 mg tablet is TASMAR and the tablet strength (100), on the other
side is a V.

TASMAR 100 mg Tablets: bottles of 90 (NDC 0187-0938-01).

STORAGE

Store in tight containers at 20° to 25°C (68° to 77°F); excursions permitted to
15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Manufactured by: Bausch Health Companies Inc. Steinbach, MB R5G 1Z7, Canada.
Revised Oct 2020.




SIDE EFFECTS FOR TASMAR

Cases of severe hepatocellular injury, including fulminant liver failure
resulting in death, have been reported in postmarketing use. As of May 2005,
three cases of fatal fulminant hepatic failure have been reported from more than
40,000 patient years of worldwide use. This incidence may be 10- to 100-fold
higher than the background incidence in the general population. All three cases
were reported within the first six months of initiation of treatment with
TASMAR. Analysis of the laboratory monitoring data in over 3,400 TASMAR-treated
patients participating in clinical trials indicated that increases in SGPT/ALT
or SGOT/AST, when present, generally occurred within the first 6 months of
treatment with TASMAR.

The imprecision of the estimated increase is due to uncertainties about the base
rate and the actual number of cases occurring in association with TASMAR. The
incidence of idiopathic potentially fatal fulminant hepatic failure (i.e., not
due to viral hepatitis or alcohol) is low. One estimate, based upon transplant
registry data, is approximately 3/1,000,000 patients per year in the United
States. Whether this estimate is an appropriate basis for estimating the
increased risk of liver failure among TASMAR users is uncertain. TASMAR users,
for example, differ in age and general health status from candidates for liver
transplantation. Similarly, underreporting of cases may lead to significant
underestimation of the increased risk associated with the use of TASMAR.

During the premarketing development of tolcapone, two distinct patient
populations were studied, patients with end-of-dose wearing-off phenomena and
patients with stable responses to levodopa therapy. All patients received
concomitant treatment with levodopa preparations, however, and were similar in
other clinical aspects. Adverse reactions are shown for these two populations
combined.

The most commonly observed adverse reactions in the double-blind,
placebo-controlled trials (N=892), with a difference in incidence (TASMAR minus
Placebo) of at least 5% or greater in the 100 mg or 200 mg TASMAR-treated groups
compared to placebo, were dyskinesia, nausea, diarrhea, anorexia, sleep
disorder, vomiting, urine discoloration, somnolence, hallucination, dystonia,
and sweating.

Approximately 16% of the 592 patients who participated in the double-blind,
placebo-controlled trials discontinued treatment due to adverse reactions
compared to 10% of the 298 patients who received placebo. Diarrhea was by far
the most frequent cause of discontinuation (approximately 6% in tolcapone
patients vs. 1% on placebo).

ADVERSE REACTION INCIDENCE IN CONTROLLED CLINICAL STUDIES

Table 4 lists treatment emergent adverse reactions that occurred in at least 1%
of patients treated with tolcapone participating in the double-blind,
placebo-controlled studies and were numerically more common in at least one of
the tolcapone groups. In these studies, either tolcapone or placebo was added to
levodopa/carbidopa (or benserazide).

The prescriber should be aware that these figures cannot be used to predict the
incidence of adverse reactions 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. However, the cited figures do provide the
prescriber with some basis for estimating the relative contribution of drug and
nondrug factors to the adverse reactions incidence rate in the population
studied.

Table 4. Summary of Patients With Adverse Reactions After Start of Trial Drug
Administration (At Least 1% in TASMAR Group and at Least One TASMAR Dose Group
Greater Than Placebo)

Placebo Tolcapone tid N = 298 100 mg
N = 296 200 mg
N = 298 Adverse Reactions (%) (%) (%) Dyskinesia 20 42 51 Nausea 18 30 35 Sleep
Disorder 18 24 25 Dystonia 17 19 22 Dreaming Excessive 17 21 16 Anorexia 13 19
23 Cramps Muscle 17 17 18 Orthostatic Complaints 14 17 17 Somnolence 14 18 14
Diarrhea 8 16 18 Confusion 9 11 10 Dizziness 10 13 6 Headache 7 10 11
Hallucination 5 8 10 Vomiting 4 8 10 Constipation 5 6 8 Fatigue 6 7 3 Upper
Respiratory Tract Infection 3 5 7 Falling 4 4 6 Sweating Increased 2 4 7 Urinary
Tract Infection 4 5 5 Xerostomia 2 5 6 Abdominal Pain 3 5 6 Syncope 3 4 5 Urine
Discoloration 1 2 7 Dyspepsia 2 4 3 Influenza 2 3 4 Dyspnea 2 3 3 Balance Loss 2
3 2 Flatulence 2 2 4 Hyperkinesia 1 3 2 Chest Pain 1 3 1 Hypotension 1 2 2
Paresthesia 2 3 1 Stiffness 1 2 2 Arthritis 1 2 1 Chest Discomfort 1 1 2
Hypokinesia 1 1 3 Micturition Disorder 1 2 1 Pain Neck 1 2 2 Burning 0 2 1 Sinus
Congestion 0 2 1 Agitation 0 1 1 Bleeding Dermal 0 1 1 Irritability 0 1 1 Mental
Deficiency 0 1 1 Hyperactivity 0 1 1 Malaise 0 1 0 Panic Reaction 0 1 0 Tumor
Skin 0 1 0 Cataract 0 1 0 Euphoria 0 1 0 Fever 0 0 1 Alopecia 0 1 0 Eye Inflamed
0 1 0 Hypertonia 0 0 1 Tumor Uterus 0 1 0



EFFECTS OF GENDER ON ADVERSE REACTIONS

Female patients may be more likely to develop somnolence than males.

OTHER ADVERSE EVENTS OBSERVED DURING ALL TRIALS IN PATIENTS WITH PARKINSON'S
DISEASE

During these trials, all adverse events were recorded by the clinical
investigators using terminology of their own choosing. To provide a meaningful
estimate of the proportion of individuals having adverse events, similar types
of adverse events were grouped into a smaller number of standardized categories
using COSTART dictionary terminology. These categories are used in the listing
below.

All reported events that occurred at least twice (or once for serious or
potentially serious events), except those already listed above, trivial events
and terms too vague to be meaningful are included, without regard to
determination of a causal relationship to TASMAR.

Events are further classified within body system categories and enumerated in
order of decreasing frequency using the following definitions: frequent adverse
events are defined as those occurring in at least 1/100 patients; infrequent
adverse events are defined as those occurring in between 1/100 and 1/1000
patients; and rare adverse events are defined as those occurring in fewer than
1/1000 patients.

Nervous System - frequent: depression, hypesthesia, tremor, speech disorder,
vertigo, emotional lability; infrequent: neuralgia, amnesia, extrapyramidal
syndrome, hostility, libido increased, manic reaction, nervousness, paranoid
reaction, cerebral ischemia, cerebrovascular accident, delusions, libido
decreased, neuropathy, apathy, choreoathetosis, myoclonus, psychosis, thinking
abnormal, twitching; rare: antisocial reaction, delirium, encephalopathy,
hemiplegia, meningitis.

Digestive System - frequent: tooth disorder; infrequent: dysphagia,
gastrointestinal hemorrhage, gastroenteritis, mouth ulceration, increased
salivation, abnormal stools, esophagitis, cholelithiasis, colitis, tongue
disorder, rectal disorder; rare: cholecystitis, duodenal ulcer, gastrointestinal
carcinoma, stomach atony.

Body as a Whole - frequent: flank pain, accidental injury, abdominal pain,
infection; infrequent: hernia, pain, allergic reaction, cellulitis, infection
fungal, viral infection, carcinoma, chills, infection bacterial, neoplasm,
abscess, face edema; rare: death.

Cardiovascular System - frequent: palpitation; infrequent: hypertension,
vasodilation, angina pectoris, heart failure, atrial fibrillation, tachycardia,
migraine, aortic stenosis, arrhythmia, arteriospasm, bradycardia, cerebral
hemorrhage, coronary artery disorder, heart arrest, myocardial infarct,
myocardial ischemia, pulmonary embolus; rare: arteriosclerosis, cardiovascular
disorder, pericardial effusion, thrombosis.

Musculoskeletal System - frequent: myalgia; infrequent: tenosynovitis,
arthrosis, joint disorder.

Urogenital System - frequent: urinary incontinence, impotence; infrequent:
prostatic disorder, dysuria, nocturia, polyuria, urinary retention, urinary
tract disorder, hematuria, kidney calculus, prostatic carcinoma, breast
neoplasm, oliguria, uterine atony, uterine disorder, vaginitis; rare: bladder
calculus, ovarian carcinoma, uterine hemorrhage.

Respiratory System - frequent: bronchitis, pharyngitis; infrequent: cough
increased, rhinitis, asthma, epistaxis, hyperventilation, laryngitis, hiccup;
rare: apnea, hypoxia, lung edema.

Skin and Appendages - frequent: rash; infrequent: herpes zoster, pruritus,
seborrhea, skin discoloration, eczema, erythema multiforme, skin disorder,
furunculosis, herpes simplex, urticaria.

Special Senses - frequent: tinnitus; infrequent: diplopia, ear pain, eye
hemorrhage, eye pain, lacrimation disorder, otitis media, parosmia; rare:
glaucoma. Metabolic and Nutritional - infrequent: edema, hypercholesteremia,
thirst, dehydration.

Hemic and Lymphatic System - infrequent: anemia; rare: leukemia,
thrombocytopenia.

Endocrine System - infrequent: diabetes mellitus.

Unclassified - infrequent: surgical procedure.

To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at
1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


DRUG INTERACTIONS FOR TASMAR

PROTEIN BINDING

Although tolcapone is highly protein bound, in vitro studies have shown that
tolcapone at a concentration of 50 mcg/mL did not displace other highly
protein-bound drugs from their binding sites at therapeutic concentrations. The
experiments included warfarin (0.5 to 7.2 mcg/mL), phenytoin (4.0 to 38.7
mcg/mL), tolbutamide (24.5 to 96.1 mcg/mL) and digitoxin (9.0 to 27.0 mcg/mL).

DRUGS METABOLIZED BY CATECHOL-O-METHYLTRANSFERASE (COMT)

Tolcapone may influence the pharmacokinetics of drugs metabolized by COMT.
However, no effects were seen on the pharmacokinetics of the COMT substrate
carbidopa. The effect of tolcapone on the pharmacokinetics of other drugs of
this class such as α-methyldopa, dobutamine, apomorphine, and isoproterenol has
not been evaluated. A dose reduction of such compounds should be considered when
they are co-administered with tolcapone.

EFFECT OF TOLCAPONE ON THE METABOLISM OF OTHER DRUGS

In vitro experiments have been performed to assess the potential of tolcapone to
interact with isoenzymes of cytochrome P450 (CYP). No relevant interactions with
substrates for CYP 2A6 (warfarin), CYP 1A2 (caffeine), CYP 3A4 (midazolam,
terfenadine, cyclosporine), CYP 2C19 (S-mephenytoin) and CYP 2D6 (desipramine)
were observed in vitro. The absence of an interaction with desipramine, a drug
metabolized by cytochrome P450 2D6, was also confirmed in an in vivo study where
tolcapone did not change the pharmacokinetics of desipramine.

Due to its affinity to cytochrome P450 2C9 in vitro, tolcapone may interfere
with drugs, whose clearance is dependent on this metabolic pathway, such as
tolbutamide and warfarin. However, in an in vivo interaction study, tolcapone
did not change the pharmacokinetics of tolbutamide. Therefore, clinically
relevant interactions involving cytochrome P450 2C9 appear unlikely. Similarly,
tolcapone did not affect the pharmacokinetics of desipramine, a drug metabolized
by cytochrome P450 2D6, indicating that interactions with drugs metabolized by
that enzyme are unlikely. Since clinical information is limited regarding the
combination of warfarin and tolcapone, coagulation parameters should be
monitored when these two drugs are co-administered.

DRUGS THAT INCREASE CATECHOLAMINES

Tolcapone did not influence the effect of ephedrine, an indirect
sympathomimetic, on hemodynamic parameters or plasma catecholamine levels,
either at rest or during exercise. Since tolcapone did not alter the
tolerability of ephedrine, these drugs can be co-administered.

When TASMAR was given together with levodopa/carbidopa and desipramine, there
was no significant change in blood pressure, pulse rate and plasma
concentrations of desipramine. Overall, the frequency of adverse events
increased slightly. These adverse events were predictable based on the known
adverse reactions to each of the three drugs individually. Therefore, caution
should be exercised when desipramine is administered to Parkinson's disease
patients being treated with TASMAR and levodopa/carbidopa.

In clinical trials, patients receiving TASMAR/levodopa preparations reported a
similar adverse event profile independent of whether or not they were also
concomitantly administered selegiline (a selective MAO-B inhibitor).

DRUG ABUSE AND DEPENDENCE

Tolcapone is not a controlled substance.

Studies conducted in rats and monkeys did not reveal any potential for physical
or psychological dependence. 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.




WARNINGS FOR TASMAR

(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 show
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 tid and
3% of patients at 200 mg tid. 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 tid and 0.7%
at 200 mg tid. Elevated enzymes led to discontinuation in 0.3% and 1.7% of
patients treated with 100 mg tid and 200 mg tid, 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., phenelzine
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-selective
MAO inhibitor.

Tolcapone can be taken concomitantly with a selective MAO-B inhibitor (e.g.,
selegiline).

FALLING ASLEEP DURING ACTIVITIES OF DAILY LIVING AND SOMNOLENCE

Tolcapone (TASMAR) increases plasma levels of levodopa in patients taking
concomitant carbidopa levodopa products (see DOSAGE AND ADMINISTRATION).
Patients taking carbidopa levodopa products alone or with other dopaminergic
medications have reported suddenly falling asleep without prior warning of
sleepiness while engaged in activities of daily living (includes the operation
of motor vehicles). Some of these episodes resulted in automobile accidents.
Although many of these patients reported somnolence while on TASMAR, some did
perceive that they had no warning signs, such as excessive drowsiness, and
believed that they were alert immediately prior to the event. Some patients
reported these events one year after the initiation of treatment.

The risk for somnolence was increased with TASMAR treatment (TASMAR 100 mg-18%,
200 mg-14%, vs placebo-13%) compared to placebo treatment. In clinical trials,
discontinuation due to somnolence occurred in 1% of patients treated with 200 mg
TASMAR and 0% of patients treated with 100 mg TASMAR or placebo. Falling asleep
while engaged in activities of daily living usually occurs in patients
experiencing pre-existing somnolence, although some patients may not give such a
history. For this reason, prescribers should continually reassess patients for
drowsiness or sleepiness especially since some of the events occur well after
the start of treatment. Prescribers should 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 or an episode of sudden sleep onset should not participate in these
activities during treatment with TASMAR.

Before initiating treatment with TASMAR, advise patients about the potential to
develop drowsiness and ask specifically about factors that may increase the risk
for somnolence with TASMAR such as the use of concomitant sedating medications
and the presence of sleep disorders. Consider discontinuing TASMAR in patients
who report significant daytime sleepiness or episodes of falling asleep during
activities that require active participation (e.g., conversations, eating,
etc.). If treatment with TASMAR continues, patients should be advised not to
drive and to avoid other potentially dangerous activities that might result in
harm if patients become somnolent. There is insufficient information to
establish that dose reduction will eliminate episodes of falling asleep while
engaged in activities of daily living.


PRECAUTIONS FOR TASMAR

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 tid,
respectively. A total of 2%, 5% and 4% of the patients treated with placebo, 100
mg and 200 mg TASMAR tid, 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
tid, 100 mg tid 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 tid, 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 tid, 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%, 0.7% and
1.7% of patients in the placebo, 100 mg and 200 mg TASMAR tid 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/PSYCHOTIC-LIKE BEHAVIOR

In clinical trials, hallucinations developed in approximately 5% of patients
treated with placebo, compared to 8% and 10% of patients treated with 100 mg or
200 mg three times per day, respectively. Hallucinations led to drug
discontinuation and premature withdrawal from clinical trials in 0.3% of
patients treated with placebo, compared to 1.4% and 1.0% of patients treated
with TASMAR 100 mg or 200 mg TASMAR three times per day, respectively.
Hallucinations led to hospitalization in 0.0% of patients in the placebo group,
compared to 1.7% and 0.0% of patients treated with 100 mg or 200 mg TASMAR three
times per day, 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. The incidence of
hallucination may be increased in elderly patients over 75 years treated with
TASMAR (see Geriatric Use).

Postmarketing reports indicate that patients may experience new or worsening
mental status and behavioral changes, which may be severe, including
psychotic-like behavior during TASMAR treatment or after starting or increasing
the dose of TASMAR. Other drugs prescribed to improve the symptoms of
Parkinson’s disease may have similar effects on thinking and behavior. This
abnormal thinking and behavior may present with one or more symptoms, including
paranoid ideation, delusions, hallucinations, confusion, psychotic-like
behavior, disorientation, aggressive behavior, agitation, and delirium.

Ordinarily, patients with a major psychotic disorder should not be treated with
TASMAR 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 TASMAR.

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 their dose
of levodopa. Dyskinesia was the most common adverse reaction observed in
controlled trials and developed in approximately 20% of patients treated with
placebo, compared to 42% and 51% of patients treated with TASMAR 100 mg or 200
mg three times daily, respectively. The rates of withdrawal for dyskinesia were
0.0% in the placebo group, compared to 0.3% and 1.0% in the groups receiving
TASMAR 100 mg or 200 mg three times a day, respectively.

IMPULSE CONTROL/COMPULSIVE BEHAVIORS

Reports suggest that patients may experience an intense urge to gamble,
increased sexual urges, intense urges to spend money, binge eating, and/or other
intense urges, and the inability to control these urges. These reports are
associated with patients taking TASMAR in conjunction with carbidopa/levodopa,
as well as other medications that increase central dopaminergic tone and that
are used to treat patients with Parkinson’s disease. In some cases, although not
all, these urges were reported to have stopped when the dose was reduced or the
medication was 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
TASMAR. Physicians should consider dose reduction or stopping the medication if
a patient develops such urges while taking TASMAR (see PATIENTS INFORMATION).

RHABDOMYOLYSIS

Cases of severe rhabdomyolysis, with one case of multi-organ 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 PRECAUTIONS: Events Reported With Dopaminergic Therapy).

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 that would confirm the 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 tid, respectively. The etiology of
the increase with TASMAR has not always been explained (for example, by urinary
tract infection or warfarin 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 tid, 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 three of these cases, CPK was elevated as well. One patient died,
and the other three patients recovered over periods of approximately 2, 4 and 6
weeks. Rare cases of this symptom complex have been reported during marketed
use. It is difficult to determine if TASMAR played a role in the pathogenesis of
these events because these patients received several concomitant medications
affecting the central nervous system such as monoaminergic (i.e., MAO-I,
tricyclic and selective serotonin reuptake inhibitors) and anticholinergic
agents.

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).

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 TASMAR for
any indication. Ideally, periodic skin examination should be performed by
appropriately qualified individuals (e.g., dermatologists).

LABORATORY TESTS

Although a program of frequent laboratory monitoring for evidence of
hepatocellular injury is deemed essential, it is not clear that 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. 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 periodically (i.e. every 2 to 4
weeks) for the first 6 months of therapy. After the first six months, periodic
monitoring is recommended at intervals deemed clinically relevant. Although more
frequent monitoring increases the chances of early detection, the precise
schedule for monitoring is a matter of clinical judgment.

If the dose is increased to 200 mg tid (see DOSAGE AND ADMINISTRATION), liver
enzyme monitoring should take place before increasing the dose and then be
conducted every 2 to 4 weeks for the following 6 months of therapy. After six
months, periodic monitoring is recommended at intervals deemed clinically
relevant.

Discontinue TASMAR if SGPT/ALT or SGOT/AST levels exceed 2 times the upper limit
of normal or if clinical signs and symptoms suggest the onset of hepatic
dysfunction (e.g., 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 PRECAUTIONS: Rhabdomyolysis). Patients with severe
renal impairment should be treated with caution (see INDICATIONS, DOSAGE AND
ADMINISTRATION, BOXED WARNING and WARNINGS).

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 to 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 1.7
(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

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 (5.7
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 part 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.

GERIATRIC USE

Parkinson’s disease is primarily an affliction of the elderly. Consequently, the
mean age of patients in tolcapone clinical trials was 60 to 65 years. To
investigate safety as it relates to advancing age, three subgroups were
identified: less than 65 years, 65 to 75 years, and greater than 75 years. There
were generally no consistent agerelated trends in safety parameters. However,
patients greater than 75 years of age may be more likely to develop
hallucinations than patients less than 75 years of age, while patients over 75
may be less likely to develop dystonia (see PRECAUTIONS:
Hallucinations/Psychotic-Like Behavior). In tolcapone clinical trials, measures
of therapeutic efficacy (effects on “Off” time, levodopa dose, and effects on
Activities of Daily Living) were not affected by age (see CLINICAL PHARMACOLOGY:
Clinical Studies). Tolcapone pharmacokinetics have not been found to be affected
by age (see CLINICAL PHARMACOLOGY: Special Populations).


OVERDOSE INFORMATION FOR TASMAR

The highest dose of tolcapone administered to humans was 800 mg tid, with and
without levodopa/carbidopa co-administration. This was in a 1-week study in
elderly, healthy volunteers. The peak plasma concentrations of tolcapone at this
dose were on average 30 mcg/mL (compared to 3 mcg/mL and 6 mcg/mL with 100 mg
and 200 mg tolcapone, respectively). Nausea, vomiting and dizziness were
observed, particularly in combination with levodopa/carbidopa.

The threshold for the lethal plasma concentration for tolcapone based on animal
data is >100 mcg/mL. Respiratory difficulties were observed in rats at high oral
(gavage) and intravenous doses and in dogs with rapidly injected intravenous
doses.

MANAGEMENT OF OVERDOSE

Hospitalization is advised. General supportive care is indicated. Based on the
physicochemical properties of the compound, hemodialysis is unlikely to be of
benefit.


CONTRAINDICATIONS FOR TASMAR

TASMAR tablets are contraindicated in patients with liver disease, in patients
who were withdrawn from TASMAR because of evidence of TASMAR-induced
hepatocellular injury or who have demonstrated hypersensitivity to the drug or
its ingredients.

TASMAR is also contraindicated in patients with a history of nontraumatic
rhabdomyolysis or hyperpyrexia and confusion possibly related to medication (see
PRECAUTIONS: Events Reported With Dopaminergic Therapy).


CLINICAL PHARMACOLOGY FOR TASMAR

MECHANISM OF ACTION

Tolcapone is a selective and reversible inhibitor of
catechol-O-methyltransferase (COMT).

In mammals, COMT is distributed throughout various organs. The highest
activities are in the liver and kidney. COMT also occurs in the heart, lung,
smooth and skeletal muscles, intestinal tract, reproductive organs, various
glands, adipose tissue, skin, blood cells and neuronal tissues, especially in
glial cells. COMT catalyzes the transfer of the methyl group of
S-adenosyl-L-methionine to the phenolic group of substrates that contain a
catechol structure. Physiological substrates of COMT include dopa,
catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated
metabolites. The function of COMT is the elimination of biologically active
catechols and some other hydroxylated metabolites. In the presence of a
decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa
catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the
brain and periphery.

The precise mechanism of action of tolcapone is unknown, but it is believed to
be related to its ability to inhibit COMT and alter the plasma pharmacokinetics
of levodopa. When tolcapone is given in conjunction with levodopa and an
aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of
levodopa are more sustained than after administration of levodopa and an
aromatic amino acid decarboxylase inhibitor alone. It is believed that these
sustained plasma levels of levodopa result in more constant dopaminergic
stimulation in the brain, leading to greater effects on the signs and symptoms
of Parkinson's disease in patients as well as increased levodopa adverse
effects, sometimes requiring a decrease in the dose of levodopa. Tolcapone
enters the CNS to a minimal extent, but has been shown to inhibit central COMT
activity in animals.

PHARMACODYNAMICS

COMT ACTIVITY IN ERYTHROCYTES

Studies in healthy volunteers have shown that tolcapone reversibly inhibits
human erythrocyte catechol-O-methyltransferase (COMT) activity after oral
administration. The inhibition is closely related to plasma tolcapone
concentrations. With a 200-mg single dose of tolcapone, maximum inhibition of
erythrocyte COMT activity is on average greater than 80%. During multiple dosing
with tolcapone (200 mg tid), erythrocyte COMT inhibition at trough tolcapone
blood concentrations is 30% to 45%.

EFFECT ON THE PHARMACOKINETICS OF LEVODOPA AND ITS METABOLITES

When tolcapone is administered together with levodopa/carbidopa, it increases
the relative bioavailability (AUC) of levodopa by approximately twofold. This is
due to a decrease in levodopa clearance resulting in a prolongation of the
terminal elimination half-life of levodopa (from approximately 2 hours to 3.5
hours). In general, the average peak levodopa plasma concentration (Cmax) and
the time of its occurrence (Tmax) are unaffected. The onset of effect occurs
after the first administration and is maintained during long-term treatment.
Studies in healthy volunteers and Parkinson's disease patients have confirmed
that the maximal effect occurs with 100 mg to 200 mg tolcapone. Plasma levels of
3-OMD are markedly and dose-dependently decreased by tolcapone when given with
levodopa/carbidopa.

Population pharmacokinetic analyses in patients with Parkinson's disease have
shown the same effects of tolcapone on levodopa plasma concentrations that occur
in healthy volunteers.

PHARMACOKINETICS OF TOLCAPONE

Tolcapone pharmacokinetics are linear over the dose range of 50 mg to 400 mg,
independent of levodopa/carbidopa co-administration. The elimination half-life
of tolcapone is 2 to 3 hours and there is no significant accumulation. With tid
dosing of 100 mg or 200 mg, Cmax is approximately 3 mcg/mL and 6 mcg/mL,
respectively.

ABSORPTION

Tolcapone is rapidly absorbed, with a Tmax of approximately 2 hours. The
absolute bioavailability following oral administration is about 65%. Food given
within 1 hour before and 2 hours after dosing of tolcapone decreases the
relative bioavailability by 10% to 20% (see DOSAGE AND ADMINISTRATION).

DISTRIBUTION

The steady-state volume of distribution of tolcapone is small (9 L). Tolcapone
does not distribute widely into tissues due to its high plasma protein binding.
The plasma protein binding of tolcapone is >99.9% over the concentration range
of 0.32 to 210 mcg/mL. In vitro experiments have shown that tolcapone binds
mainly to serum albumin.

METABOLISM AND ELIMINATION

Tolcapone is almost completely metabolized prior to excretion, with only a very
small amount (0.5% of dose) found unchanged in urine. The main metabolic pathway
of tolcapone is glucuronidation; the glucuronide conjugate is inactive. In
addition, the compound is methylated by COMT to 3-O-methyl-tolcapone. Tolcapone
is metabolized to a primary alcohol (hydroxylation of the methyl group), which
is subsequently oxidized to the carboxylic acid. In vitro experiments suggest
that the oxidation may be catalyzed by cytochrome P450 3A4 and P450 2A6. The
reduction to an amine and subsequent N-acetylation occur to a minor extent.
After oral administration of a 14C-labeled dose of tolcapone, 60% of labeled
material is excreted in urine and 40% in feces. Tolcapone is a
low-extraction-ratio drug (extraction ratio = 0.15) with a moderate systemic
clearance of about 7 L/h.

SPECIAL POPULATIONS

Tolcapone pharmacokinetics are independent of sex, age, body weight, and race
(Japanese, Black and Caucasian). Polymorphic metabolism is unlikely based on the
metabolic pathways involved.

HEPATIC IMPAIRMENT

A study in patients with hepatic impairment has shown that moderate
non-cirrhotic liver disease had no impact on the pharmacokinetics of tolcapone.
In patients with moderate cirrhotic liver disease (Child-Pugh Class B), however,
clearance and volume of distribution of unbound tolcapone was reduced by almost
50%. This reduction may increase the average concentration of unbound drug by
twofold (see DOSAGE AND ADMINISTRATION). 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 (see BOXED
WARNING).

RENAL IMPAIRMENT

The pharmacokinetics of tolcapone have not been investigated in a specific renal
impairment study. However, the relationship of renal function and tolcapone
pharmacokinetics has been investigated using population pharmacokinetics during
clinical trials. The data of more than 400 patients have confirmed that over a
wide range of creatinine clearance values (30 mL/min to 130 mL/min) the
pharmacokinetics of tolcapone are unaffected by renal function. This could be
explained by the fact that only a negligible amount of unchanged tolcapone
(0.5%) is excreted in the urine. The glucuronide conjugate of tolcapone is
mainly excreted in the urine but is also excreted in the bile. Accumulation of
this stable and inactive metabolite should not present a risk in renally
impaired patients with creatinine clearance above 25 mL/min (see DOSAGE AND
ADMINISTRATION). Given the very high protein binding of tolcapone, no
significant removal of the drug by hemodialysis would be expected.

DRUG INTERACTIONS

See DRUG INTERACTIONS.

CLINICAL STUDIES

The effectiveness of TASMAR as an adjunct to levodopa in the treatment of
Parkinson's disease was established in three multicenter randomized controlled
trials of 13 to 26 weeks' duration, supported by four 6-week trials whose
results were consistent with those of the longer trials. In two of the longer
trials, tolcapone was evaluated in patients whose Parkinson's disease was
characterized by deterioration in their response to levodopa at the end of a
dosing interval (so-called fluctuating patients with wearing-off phenomena). In
the remaining trial, tolcapone was evaluated in patients whose response to
levodopa was relatively stable (so-called non-fluctuators).

FLUCTUATING PATIENTS

In two 3-month trials, patients with documented episodes of wearing-off
phenomena, despite optimum levodopa therapy, were randomized to receive placebo,
tolcapone 100 mg tid or 200 mg tid. The formal double-blind portion of the trial
was 3 months long, and the primary outcome was a comparison between treatments
in the change from baseline in the amount of time spent "On" (a period of
relatively good functioning) and "Off" (a period of relatively poor
functioning). Patients recorded periodically, throughout the duration of the
trial, the time spent in each of these states.

In addition to the primary outcome, patients were also assessed using sub-parts
of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used
multi-item rating scale intended to evaluate mentation (Part I), activities of
daily living (Part II), motor function (Part III), complications of therapy
(Part IV), and disease staging (Parts V and VI); an Investigator's Global
Assessment of Change (IGA), a subjective scale designed to assess global
functioning in 5 areas of Parkinson's disease; the Sickness Impact Profile
(SIP), a multi-item scale in 12 domains designed to assess the patient's
functioning in multiple areas; and the change in daily levodopa/carbidopa dose.

In one of the studies, 202 patients were randomized in 11 centers in the United
States and Canada. In this trial, all patients were receiving concomitant
levodopa and carbidopa. In the second trial, 177 patients were randomized in 24
centers in Europe. In this trial, all patients were receiving concomitant
levodopa and benserazide.

The following tables display the results of these 2 trials:

Table 1. U.S./Canadian Fluctuator Study

Primary Measure Baseline
(hrs) Change from Baseline
at Month 3
(hrs) p-value* Hours of Wake Time "Off"†   Placebo 6.2 -1.2 -   100 mg tid 6.4
-2.0 0.169   200 mg tid 5.9 -3.0 <0.001 Hours of Wake Time "On"†   Placebo 8.7
1.4 -   100 mg tid 8.1 2.0 0.267   200 mg tid 9.1 2.9 0.008 Secondary Measures
Baseline Change from Baseline at Month 3 p-value* Levodopa Total Daily Dose (mg)
  Placebo 948 16 -   100 mg tid 788 -166 <0.001   200 mg tid 865 -207 <0.001
Global (overall) % Improved   Placebo - 42 -   100 mg tid - 71 <0.001   200 mg
tid - 91 <0.001 UPDRS Motor   Placebo 19.5 -0.4 -   100 mg tid 17.6 -1.9 0.217
  200 mg tid 20.6 -2.0 0.210 UPDRS ADL   Placebo 7.5 -0.3 -   100 mg tid 7.7
-0.8 0.487   200 mg tid 8.3 0.2 0.412 SIP (total)   Placebo 14.7 -2.2 -   100 mg
tid 14.9 -0.4 0.210   200 mg tid 17.6 -0.3 0.216 *Compared to placebo. Nominal p
values are not adjusted for multiple comparisons.
†"Off" or "On" are based on the percent of waking day "Off" or "On", assuming a
16-hour waking day.



Table 2. European Fluctuator Study

Primary Measure Baseline
(hrs) Change from Baseline
at Month 3
(hrs) p-value* Hours of Wake Time "Off"†   Placebo 6.1 -0.7 -   100 mg tid 6.5
-2.0 0.008   200 mg tid 6.0 -1.6 0.081 Hours of Wake Time "On"†   Placebo 8.5
-0.1 -   100 mg tid 8.1 1.7 0.003   200 mg tid 8.4 1.7 0.003 Secondary Measures
Baseline Change from Baseline
at Month 3 p-value* Levodopa Total Daily Dose (mg)   Placebo 660 -29 -   100 mg
tid 667 -109 0.025   200 mg tid 675 -122 0.010 Global (overall) % Improved
  Placebo - 37 -   100 mg tid - 70 0.003   200 mg tid - 78 <0.001 UPDRS Motor
  Placebo 24.0 -2.1 -   100 mg tid 22.4 -4.2 0.163   200 mg tid 22.4 -6.5 0.004
UPDRS ADL   Placebo 7.9 -0.5 -   100 mg tid 7.5 -0.9 0.408   200 mg tid 7.7 -1.3
0.097 SIP (total)   Placebo 21.6 -0.9 -   100 mg tid 16.6 -1.9 0.419   200 mg
tid 18.4 -4.2 0.011 *Compared to placebo. Nominal p values are not adjusted for
multiple comparisons.
†"Off" or "On" are based on the percent of waking day "Off" or "On", assuming a
16-hour waking day.



Effects on “Off” time and levodopa dose did not differ by age or sex.

NON-FLUCTUATING PATIENTS

In this study, 298 patients with idiopathic Parkinson's disease on stable doses
of levodopa/carbidopa who were not experiencing wearing-off phenomena were
randomized to placebo, tolcapone 100 mg tid, or tolcapone 200 mg tid for 6
months at 20 centers in the United States and Canada. The primary measure of
effectiveness was the Activities of Daily Living portion (Subscale II) of the
UPDRS. In addition, the change in daily levodopa dose, other subscales of the
UPDRS, and the SIP were assessed as secondary measures. The results are
displayed in the following table:

Table 3. U.S./Canadian Non-fluctuator Study

Primary Measure Baseline Change from Baseline
at Month 6 p-value* UPDRS ADL   Placebo 8.5 0.1 -   100 mg tid 7.5 -1.4 <0.001
  200 mg tid 7.9 -1.6 <0.001 Secondary Measures Baseline Change from Baseline
at Month 6 p-value* Levodopa Total Daily Dose (mg)   Placebo 364 47 -  100 mg
tid 370 -21 <0.001   200 mg tid 381 -32 <0.001 UPDRS Motor   Placebo 19.7 0.1 -
  100 mg tid 17.3 -2.0 0.018   200 mg tid 16.0 -2.3 0.008 SIP (total)   Placebo
6.9 0.4 -   100 mg tid 7.3 -0.9 0.044   200 mg tid 7.3 -0.7 0.078 Percent of
Patients who Developed Fluctuations   Placebo - 26 -   100 mg tid - 19 0.297
  200 mg tid - 14 0.047 *Compared to placebo. Nominal p values are not adjusted
for multiple comparisons.



Effects on Activities of Daily Living did not differ by age or sex.


PATIENT INFORMATION FOR TASMAR

Patients should be instructed to take TASMAR only as prescribed.

TASMAR should not be used by patients until there has been a complete discussion
of the risks and the patient has provided written acknowledgement that the risks
have been explained (see PATIENT ACKNOWLEDGEMENT OF RISKS section).

Inform patients about clinical signs and symptoms that suggest the onset of
hepatic injury (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark
urine, pruritus, and right upper quadrant tenderness) (see WARNINGS). If
symptoms of hepatic failure occur, patients should be advised to contact their
physician immediately. Inform patients of the need to have regular blood tests
to monitor liver enzymes.

Advise patients that sleepiness or drowsiness may occur and that they should not
drive a car or operate other complex machinery until they have gained sufficient
experience on TASMAR to gauge whether or not it adversely affects their mental
and/or motor performance. Advise patients to exercise caution while driving,
operating machines, or working at heights during treatment with TASMAR. Because
of the possible additive sedative effects, caution should also be used when
patients are taking other CNS depressants in combination with TASMAR. Inform
patients that nausea may occur, especially at the initiation of treatment with
TASMAR.

Inform patients that hallucinations and other psychotic-like behavior may occur.

Advise patients about the possibility of developing or worsening of existing
dyskinesia and/or dystonia after starting TASMAR.

Advise patients that they may develop postural (orthostatic) hypotension with or
without symptoms such as dizziness, nausea, syncope, and sometimes sweating.
Advise patients to rise slowly, especially after long periods of sitting or
lying down. Hypotension may be more likely when patients first start treatment
with TASMAR.

Instruct patients and caregivers to report intense urges to gamble, increased
sexual urges, increase in spending money, binge eating, and other intense urges
as well as the inability to control these urges to the prescriber while taking
TASMAR.

Although TASMAR has not been shown to be teratogenic in animals, it is always
given in conjunction with levodopa/carbidopa, which is known to cause visceral
and skeletal malformations in the rabbit. Accordingly, patients should be
advised to notify their physicians if they become pregnant or intend to become
pregnant during therapy (see PRECAUTIONS: Pregnancy).

Tolcapone is excreted into maternal milk in rats. Because of the possibility
that tolcapone may be excreted into human milk, advise patients to notify their
physicians if they intend to breastfeed or are breastfeeding an infant.


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