INDICATIONS: 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the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR.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 ).

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the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR.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Patients who develop evidence of hepatocellular injury while on TASMAR and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR is reintroduced.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.

ADVERSE REACTIONS: 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 100 mg 200 mg N = 298 N = 296 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 13 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.