SIDE EFFECTS

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. All 3 cases were reported within the first six months of initiation of treatment with TASMAR (tolcapone) . Analysis of the laboratory monitoring data in over 3,400 TASMAR (tolcapone) 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 (tolcapone) .

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 (tolcapone) . The incidence of idiopathic potentially fatal fulminant hepatic failure (ie, 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 (tolcapone) users is uncertain. TASMAR (tolcapone) 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 events are, therefore, shown for these two populations combined.

The most commonly observed adverse events ( > 5%) in the double-blind, placebo-controlled trials (N=892) associated with the use of TASMAR (tolcapone) not seen at an equivalent frequency among the placebotreated patients were dyskinesia, nausea, sleep disorder, dystonia, dreaming excessive, anorexia, cramps muscle, orthostatic complaints, somnolence, diarrhea, confusion, dizziness, headache, hallucination, vomiting, constipation, fatigue, upper respiratory tract infection, falling, sweating increased, urinary tract infection, xerostomia, abdominal pain, urine discoloration.

Approximately 16% of the 592 patients who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse events 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 Event Incidence in Controlled Clinical Studies

Table 4 lists treatment emergent adverse events 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 were added to levodopa/carbidopa (or benserazide).

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse events incidence rate in the population studied.

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

Other events reported by 1% or more of patients treated with TASMAR (tolcapone) but that were equally or more frequent in the placebo group were arthralgia, pain limbs, anxiety, micturition frequency, fractures, vision blurred, pneumonia, paresis, lethargy, asthenia, edema peripheral, gait abnormal, taste alteration, weight decrease and sinusitis.

Effects of Gender and Age on Adverse Reactions

Experience in clinical trials have suggested that 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. Females may be more likely to develop somnolence than males.

Other Adverse Events Observed During All Trials in Patients With Parkinson's Disease

TASMAR (tolcapone) has been administered in 1536 patients with Parkinson's disease in clinical trials. 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 (tolcapone) .

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.

Postmarketing Reports

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure.

Psychiatric Disorders

impulse control symptoms, pathological gambling, increased libido including hypersexuality.

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.

Read the entire FDA prescribing information for Tasmar (Tolcapone) »