Tasmar

• Tasmar^®

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 100fold 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. 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)

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.

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.

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 μg/mL (compared to 3 μg/mL and 6 μg/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 μg/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.

Your pharmacist can provide more information about tolcapone.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Because of the risk of potentially fatal, acute fulminant liver failure, Tasmar 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.

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.

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 (eg, 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 judgement. If the dose is increased to 200 mg tid, 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).

Tolcapone is used together with other medicines (carbidopa and levodopa) to treat symptoms of Parkinson's disease, such as stiffness, tremors, muscle spasms, and poor muscle control. Tolcapone increases levels of levodopa in the body.

Tolcapone is usually given to people who are already taking carbidopa and levodopa but have not had successful treatment of symptoms.

Tolcapone may also be used for other purposes not listed in this medication guide.

You should not use this medicine if you have liver disease, if you have ever had liver problems caused by tolcapone, or if you have ever had muscle damage or fever and confusion caused by using any medication.

Do not use tolcapone if you have taken an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, phenelzine, rasagiline, selegiline, and tranylcypromine.

Tolcapone can cause liver failure. Your doctor will perform blood tests to make sure you do not have conditions that would prevent you from safely using tolcapone.

Call your doctor at once if you have nausea, upper stomach pain, feeling tired, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Your liver function will need to be checked often: Every 2 to 4 weeks for the first 6 months of treatment, and then as often as your doctor recommends.

In rare cases, tolcapone can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

Parkinsonian Syndrome

Adjunct to levodopa/carbidopa therapy for the symptomatic treatment of parkinsonian syndrome; concomitant administration of tolcapone with levodopa and a decarboxylase inhibitor results in more sustained plasma levodopa concentrations compared with administration of levodopa and a decarboxylase inhibitor.1 2 3 4 5 6 7 8 9 10 12 13 14 15 16 17 18 19 23 26 28

Generally reserve therapy for patients with parkinsonian syndrome receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to or are not candidates for other adjunctive therapies (e.g., ergot- and nonergot-derivative dopamine receptor agonists, selegiline).1 31 32 (See Boxed Warning.)

Absorption

Bioavailability

Absolute bioavailability following oral administration is about 65–68%.1 27

Rapidly absorbed following oral administration, with peak plasma concentrations generally attained within 2 hours.1 2 3 4 5 8 14 27 28

Onset

Maximum inhibition of erythrocyte COMT activity is achieved within 1 hour and exceeds 80% following a single oral 200-mg dose in healthy individuals;1 2 4 5 8 maximum inhibition is about 80% following administration of 200 mg 3 times daily for 7 days.1 8

Duration

COMT inhibitory activity persists for 16–24 hours following a single oral 200-mg dose in healthy individuals;1 2 4 5 8 inhibition at trough tolcapone concentrations is 30–45% following administration of 200 mg 3 times daily for 7 days.1 8

Food

Administration within 1 hour before or 2 hours after a meal reduces bioavailability by 10–20% compared with administration in the fasting state.1

Distribution

Extent

Distribution into body tissues and fluids is not fully characterized;1 33 however, the drug is not widely distributed.1 2 13

Distributes into brain tissue.1 2 13

Distributes into milk in rats; not known whether tolcapone distributes into human milk.1

Plasma Protein Binding

>99.9% (principally albumin).1 27

Special Populations

In patients with moderate cirrhotic liver disease (Child-Pugh class B), volume of distribution of unbound tolcapone is reduced almost 50%.1 27

Elimination

Metabolism

Extensively metabolized by a variety of mechanisms:1 27 28 glucuronidation (principal metabolic pathway),1 27 28 metabolism by COMT to catechol-3-O-methyltolcapone,1 2 27 28 hydroxylation followed by oxidation to a carboxylic acid derivative,1 28 and reduction followed by N-acetylation.1 In vitro data indicate that CYP3A4 and CYP2A6 catalyze the oxidation reaction.1 28

Elimination Route

Excreted in urine (60%) and feces (40%);1 minimally excreted in urine as unchanged drug (<0.5%).1 27

Half-life

Terminal elimination half-life of tolcapone: 2–3 hours.2 3 4 5 8 27 28

Terminal elimination half-life of catechol-3-O-methyltolcapone: 30–60 hours (but does not appear to accumulate with multiple dosing because tolcapone inhibits COMT).2 3 4 5 8 27

Special Populations

In patients with moderate cirrhotic liver disease (Child-Pugh class B), clearance of unbound tolcapone reduced almost 50%.1 27

In patients with Clcr of 30–130 mL/minute, pharmacokinetics not altered.1

No evidence of gender-, age-, or weight-related pharmacokinetic differences.1 4 5

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies on this medicine have been done only in adult patients. There is no identified potential use of tolcapone in children.

Geriatric

The risk of hallucinations (seeing, hearing, or feeling things that are not there) may be increased in patients older than 75 years of age.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Iproniazid
• Isocarboxazid
• Linezolid
• Nialamide
• Pargyline
• Phenelzine
• Procarbazine
• Tranylcypromine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Hallucinations (seeing, hearing, or feeling things that are not there)—Condition may become worse.

• High fever and confusion or
• Muscle injury, aches, cramps—You should not take tolcapone.

• Kidney problems, severe—Elimination of tolcapone may be decreased, which increases the risk of unwanted effects.

• Liver problems or
• Liver tests higher than normal—This medicine can increase chances of serious liver problems. You should not start taking this medicine if you have these problems.

• Low blood pressure or
• Orthostatic or postural low blood pressure (dizziness or lightheadedness when getting up suddenly from a sitting or lying position)—Condition may become worse.

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).

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).

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 ug∙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).

NDC 0187-0938-01
Rx Only

Tasmar ®
(tolcapone)

100 mg

Each tablet
contains
100 mg tolcapone

90 Tablets