Tolcapone (Systemic)


VA CLASSIFICATION
Primary: CN500

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidyskinetic (COMT inhibitor){01}

Indications

General considerations
Potentially life-threatening cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in association with use of tolcapone {03}. Patients should be monitored for evidence of emergent liver injury {03}, and should be advised to self-monitor for signs of liver disease (such as light-colored stools, jaundice, persistent nausea, fatigue, anorexia, lethargy, dark urine, pruritus, and upper right quadrant tenderness) {03} {04}. Tolcapone should be discontinued if liver enzyme values exceed the upper limit of normal or if clinical signs suggest the onset of hepatic failure {03}. Frequent laboratory monitoring to detect evidence of hepatocellular injury is considered essential; however, it is not clear that baseline and periodic monitoring of liver enzymes will prevent the occurrence of fulminant liver failure {03}. Patients who develop evidence of hepatocellular injury and are withdrawn from tolcapone may be at increased risk for liver injury if the medication is reintroduced {03}. Physicians are advised to obtain written informed consent from the patient after a complete discussion of the risk-benefit profile of tolcapone {03} {04}.

Accepted

Parkinson"s disease (treatment adjunct) {01}—Tolcapone is used as an adjunct to levodopa and carbidopa for the treatment of the symptoms of idiopathic Parkinson"s disease {01} in patients who are experiencing symptom fluctuations and who have not responded to, or are unable to tolerate, alternative medications. {03} If the patient fails to show substantial clinical benefit within 3 weeks of initiation of treatment, tolcapone should be withdrawn {03} {04}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    273.25 {01}

Mechanism of action/Effect:

Tolcapone is a selective and reversible inhibitor of catechol- O-methyltransferase (COMT) {01}. COMT catalyzes the transfer of the methyl group of S-adenosyl- L-methionine to the phenolic group of substrates that contains a catechol structure {01}. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites {01}. The function of COMT is to eliminate biologically active catechols and some other hydroxylated metabolites {01}. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme (for levodopa) that catalyzes the metabolism to 3-methoxy-4-hydroxy- L-phenylalanine (3-OMD) in the brain and peripheral tissues {01}. Although the precise mechanism of action of tolcapone is not known, it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa {01}. Administration of tolcapone in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, produces more sustained plasma levels of levodopa than administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone {01}. These sustained plasma levels of levodopa may result in more constant dopaminergic stimulation in the brain, leading to increased therapeutic effects on the symptoms of Parkinson's disease, as well as increased adverse effects; a decrease in the levodopa dosage may be required {01}.

Pharmacodynamics

Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte catechol- O-methytransferase (COMT) activity after oral administration, and that this inhibition is closely related to plasma tolcapone concentrations {01}. Maximum inhibition of erythrocyte COMT activity averages > 80% following a single 200-mg dose of tolcapone {01}. Following multiple doses of tolcapone (200 mg three times a day), erythrocyte COMT inhibition at trough tolcapone blood concentrations is 30 to 45% {01}.

Pharmacokinetics

Tolcapone pharmacokinetics are linear over the dose range of 50 to 400 mg, independent of levodopa/carbidopa coadministration {01}.

Absorption:

Tolcapone is rapidly absorbed {01}. Absolute bioavailability following oral administration is about 65% {01}. Food given within 1 hour before or 2 hours after dosing of tolcapone decreases the relative bioavailability by 10 to 20% {01}.

Distribution:

Steady-state volume of distribution (Vol D) is small, about 9 liters {01}. Tolcapone is not widely distributed into tissues due to its high degree of plasma protein binding {01}.

Protein binding:

Very high (> 99.9%) {01}. In vitro studies have shown that tolcapone binds primarily to serum albumin {01}.

Biotransformation:

Tolcapone is almost completely metabolized {01}. The primary metabolic pathway is glucuronidation to an inactive metabolite {01}. Tolcapone is also methylated by COMT to 3- O-methyl-tolcapone {01}. Hydroxylation of the methyl group on tolcapone results in a primary alcohol, which is subsequently oxidized to carboxylic acid {01}. In vitro experiments have suggested that the oxidation may be catalyzed by cytochrome P450 3A4 and P450 2A6 {01}. Further reduction of the oxidized product to an amine and subsequent N-acetylation occur to a minor extent {01}.

Polymorphic metabolism is not likely to occur, based on the metabolic pathways involved {01}.

In patients with moderate cirrhotic liver disease (Child-Pugh Class B), clearance and Vol D of unbound tolcapone may be reduced by almost 50%, resulting in a twofold increase in the average concentration of unbound drug {01}.

Half-life:


Elimination:

2 to 3 hours {01}. No significant accumulation occurs {01}.


Time to peak concentration:

Approximately 2 hours {01}.

Peak plasma concentration

Peak plasma concentrations (C max) were reported to be 3 micrograms per milliliter (mcg/mL) following tolcapone dosing of 100 mg three times a day, and 6 mcg/mL following tolcapone dosing of 200 mg three times a day {01}.

Elimination:
    Renal {01}. Following administration of an oral dose of radiolabeled tolcapone, 60% is excreted in urine {01}. Only a very small amount (approximately 0.5% of a dose) is found unchanged in the urine.
    Fecal {01}. Following administration of an oral dose of radiolabeled tolcapone, 40% is excreted in feces {01}.


In dialysis—
        Because of the very high degree of protein binding of tolcapone, no significant removal by hemodialysis is expected {01}.


Effect of tolcapone on the pharmacokinetics of levodopa and its metabolites

When administered together with levodopa/carbidopa, tolcapone increases the relative bioavailability (area under the plasma concentration–time curve [AUC]) of levodopa by approximately twofold {01}. This increase in bioavailability is due to a decrease in levodopa clearance that prolongs the terminal elimination half-life of levodopa from approximately 2 hours to 3.5 hours {01}. The average peak levodopa plasma concentration (C max) and the time of its occurrence (T max) generally are not affected {01}. The onset of effect occurs after the first administration and is maintained during long-term treatment {01}. The maximum effect occurs with 100 to 200 mg of tolcapone {01}. When given with levodopa/carbidopa, tolcapone markedly decreases plasma levels of 3-methoxy-4-hydroxy- L-phenylalanine (3-OMD) in a dose-dependent manner {01}.

Population pharmacokinetic analyses in patients with Parkinson's disease have shown the same effects of tolcapone on levodopa plasma concentrations as those that occur in healthy volunteers {01}.


Precautions to Consider

Carcinogenicity/Tumorigenicity

Carcinogenicity studies were conducted in rats that received tolcapone for 104 weeks at doses of 50, 250, and 450 milligrams per kilogram of body weight (mg/kg) per 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, respectively {01}. There was an increased incidence of uterine adenocarcinomas in female rats at 26.4 times the human exposure {01}. Evidence of renal tubular injury and renal tubular tumor formation in rats also was reported {01}. A low incidence of renal tubular cell adenomas occurred in middle- and high-dose male and high-dose female rats, with a statistically significant increase in high-dose males {01}. No renal tumors were observed at exposures of 1 (males) or 1.7 (females) times the human exposure {01}. 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 {01}. Renal tubule damage, characterized by proximal tubule cell degeneration and the presence of atypical nuclei, as well as one instance of adenocarcinoma in a high-dose male, were observed in a year-long study in rats receiving tolcapone doses of 150 and 450 mg/kg per day {01}. These histopathologic 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 {01}.

Carcinogenicity studies in mice that received tolcapone in the diet at doses of 100, 300, and 800 mg/kg per day for 80 weeks (female) or 95 weeks (male) showed no evidence of carcinogenic effects {01}.

The carcinogenic potential of tolcapone in combination with levodopa/carbidopa has not been studied {01}.

Mutagenicity

Tolcapone was clastogenic in the in vitro mouse lymphoma/thymidine kinase assay in the presence of metabolic activation {01}. Tolcapone was not mutagenic in the Ames test, the in vitro V79/HPRT gene mutation assay, or the unscheduled DNA synthesis assay {01}. It was not clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes, or in an in vivo micronucleus assay in mice {01}.

Pregnancy/Reproduction
Fertility—
Tolcapone did not affect fertility and general reproductive performance in rats receiving up to 300 mg/kg per day (5.7 times the human dose on a mg-per-square-meter of body surface area [mg/m 2] basis) {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

In rabbits receiving tolcapone doses ³ 100 mg/kg per day (3.7 times the recommended daily clinical dose on a mg/m 2 basis), increased incidences of abortion occurred {01}. Evidence of maternal toxicity (decreased weight gain and death) occurred at tolcapone doses of 300 mg/kg in rats (5.7 times the recommended daily clinical dose on a mg/m 2 basis) and 400 mg/kg in rabbits (15 times the recommended daily clinical dose on a mg/m 2 basis) {01}. Tolcapone was administered to female rats during the last part of gestation and throughout lactation at a dose that was decreased from 250 mg/kg (4.8 times the recommended clinical dose on a mg/m 2 basis) per day to 150 mg/kg (2.9 times the recommended clinical dose on a mg/m 2 basis) per day due to a high rate of maternal mortality; this resulted in decreased litter size, and impaired growth and learning performance in female pups {01}.

Tolcapone is always given concomitantly with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in rabbits {01}. When pregnant rabbits were treated concomitantly with tolcapone (100 mg/kg per day) and levodopa/carbidopa (80/20 mg/kg per day) throughout organogenesis, an increased incidence of fetal malformations (primarily external and skeletal digit defects) occurred as compared to the incidence seen when levodopa/carbidopa was administered without tolcapone. Plasma exposures to tolcapone (based on area under the plasma concentration–time curve [AUC]) were 0.5 times the expected human exposure, and plasma exposures to levodopa were six times higher than those in humans under therapeutic conditions {01}. In a combined embryo-fetal development study conducted in rats, fetal body weights were reduced by the combination of tolcapone (10, 30, and 50 mg/kg per day) and levodopa/carbidopa (120/30 mg/kg per day) and by levodopa/carbidopa administered alone {01}. Tolcapone exposures were 0.5 times the expected human exposure or greater; levodopa exposures were 21 times the expected human exposure or greater {01}. Tolcapone administered without levodopa/carbidopa at a dose of 50 mg/kg per day (plasma exposures of 1.4 times the expected human exposure) did not result in reduced fetal body weight {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether tolcapone is distributed into breast milk {01}. In animal studies, tolcapone was shown to appear in maternal rat milk {01}. Risk-benefit must be considered before administering tolcapone to a woman who is breast-feeding.

Pediatrics

There is no identified potential use of tolcapone in pediatric patients {01}.


Geriatrics


The relative risk of hallucinations may be increased in patients older than 75 years of age {01}.


Pharmacogenetics

The pharmacokinetics of tolcapone are independent of sex, age, body weight, and race (Japanese, black, and white) {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: In vitro studies have shown that highly protein-bound tolcapone, at a concentration of 50 mcg per mL, did not displace other highly protein-bound agents (including warfarin, phenytoin, tolbutamide, and digitoxin) from their binding sites at therapeutic concentrations {01}.
Tolcapone may influence the pharmacokinetics of agents metabolized by catechol- O-methyltransferase (COMT) {01}. However, no effects were seen on the COMT substrate carbidopa.
The potential of tolcapone to interact with the isoenzymes of cytochrome P450 (CYP) was assessed in in vitro experiments {01}. 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 {01}. Due to its affinity to cytochrome P450 2C9 in vitro , tolcapone potentially may interfere with agents whose clearance is dependent on this pathway, such as tolbutamide and warfarin {01}. In an in vivo interaction study, however, tolcapone did not change the pharmacokinetics of tolbutamide; clinically relevant interactions involving cytochrome P450 2C9, therefore, appear unlikely {01}.
Tolcapone did not alter the effects of ephedrine, an indirect sympathomimetic, on hemodynamic parameters or on plasma catecholamine levels, either at rest or during exercise {01}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Desipramine{01}    (when tolcapone was administered concomitantly with levodopa/carbidopa and desipramine, the frequency of adverse effects increased slightly; caution should be exercised when desipramine is administered to Parkinson's disease patients receiving this combination of medications {01})


Medications metabolized by catechol- O-methyltransferase [COMT]{01} , such as:
Apomorphine{01}
Dobutamine{01}
Isoproterenol{01}
Methyldopa{01}    (although the effect of tolcapone on these agents has not been evaluated, dose reductions of these medications may be needed when they are coadministered with tolcapone {01})


Monoamine oxidase inhibitors, nonselective, including phenelzine and tranylcypromine{01}    (because monoamine oxidase [MAO] and catechol- O-methyltransferase [COMT] are the two major enzyme systems involved in the metabolism of catecholamines, it is theoretically possible that concurrent administration of tolcapone with these medications would result in inhibition of the majority of pathways needed for normal catecholamine metabolism; tolcapone may be taken concomitantly with a selective MAO-B inhibitor such as selegiline {01})


Warfarin{01}    (clinical information is limited regarding concomitant use of warfarin and tolcapone; coagulation parameters should be monitored {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medicine should not be used when the following medical problem exists:
» Hepatic function impairment{03}    (increased risk of liver injury, including potentially fatal fulminant liver failure)


Risk-benefit should be considered when the following medical problems exist
» Dyskinesia, severe{03} or
» Dystonia{03}    (condition may be exacerbated; condition may contribute to development of rhabdomyolysis)


» Hallucinations{01}
» Hypotension{01} or
» Orthostatic hypotension{01}    (condition may be exacerbated)


» Renal function impairment, severe{01}    (elimination may be impaired; caution should be exercised)


Sensitivity to tolcapone{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Alanine aminotransferase (ALT [SGPT]){01} or
» Aspartate aminotransferase (AST [SGOT]){01}    (because of the risk of potentially fatal fulminant liver failure, baseline testing should be conducted to exclude the presence of liver disease; after initiation of tolcapone therapy, transaminase values should be monitored every 2 weeks for the first year of treatment; values should be monitored every 4 weeks for the next 6 months, and then every 8 weeks thereafter; if a dosage increase is anticipated, liver enzymes should be monitored before the dose is increased, and then the above monitoring schedule should be reinstated [i.e., monitoring every 2 weeks for the first year, etc.]; if transaminase values exceed the upper limit of normal or if clinical signs suggest the onset of hepatic failure, tolcapone should be discontinued; it is not clear that baseline and periodic monitoring of liver enzymes will prevent the occurrence of fulminant liver failure)




Side/Adverse Effects

Note: Cases of severe hepatocellular injury, including idiopathic fulminant liver failure resulting in death, have been reported in the postmarketing use of tolcapone {03} {04}. In addition to cooperating with laboratory monitoring, patients should be advised to self-monitor for signs of liver disease, including anorexia, dark urine, fatigue, jaundice, lethargy, light-colored stools, persistent nausea, pruritus, and upper right quadrant tenderness {03} {04}. Patients who develop evidence of hepatocellular injury and are withdrawn from tolcapone may be at increased risk of liver injury if the medication is reintroduced {03}.
Patients with Parkinson's disease who are receiving dopaminergic therapy may experience orthostatic hypotension {01}. Because tolcapone enhances levodopa bioavailability, it may increase the occurrence of orthostatic hypotension {01}. In clinical trials, patients with orthostasis at baseline were more likely than patients without symptoms to experience orthostatic hypotension during the study {01}. In addition, the effect was greater in tolcapone-treated patients than in placebo-treated patients {01}. Baseline treatment with dopamine agonists or selegiline did not appear to increase the likelihood of orthostatic hypotension for patients treated with tolcapone {01}. Syncope also was reported and generally occurred more frequently in patients who had a documented episode of hypotension {01}.
Tolcapone may cause or exacerbate pre-existing dyskinesia {01}. It may also potentiate the dopaminergic side effects of levodopa {01}. Dyskinesia may be ameliorated by reducing the concomitant levodopa dose {01}.
Four cases of a symptom complex characterized by elevated temperature, muscular rigidity, and altered consciousness, and resembling the neuroleptic malignant syndrome, have been reported in association with the abrupt withdrawal or lowering of the dose of tolcapone; similar symptoms have been reported in association with the rapid dose reduction or withdrawal of other dopaminergic medications {01}. Three of these four patients also had elevated creatine kinase (CK) {01}. One patient died, and the other three patients recovered over periods ranging from 2 to 6 weeks {01}. The role of tolcapone in the pathogenesis of this symptom complex has not been established {03}.
Cases of severe rhabdomyolysis, including one case of multiorgan system failure rapidly progressing to death, have been reported {03}. The role of tolcapone in the pathogenesis of these cases is unclear {03}. Severe prolonged motor activity, including dyskinesia, may be a contributing factor, or rhabdomyolysis may be a result of the symptom complex described above {03}.
Fibrotic complications, including retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening, have been reported in some patients treated with ergot-derived dopaminergic agents {01}. These complications may resolve upon discontinuation of the medication, but complete resolution does not always occur {01}. Although these fibrotic effects are believed to be associated with the ergoline structure of these compounds, it is not known if non–ergot-derived medications that increase dopaminergic activity, such as tolcapone, may produce similar adverse effects {01}. During clinical trials with tolcapone, three cases of pleural effusion, including one with pulmonary fibrosis, were reported {01}. These patients also were taking concomitant dopamine agonists (pergolide or bromocriptine) and had a prior history of cardiac disease or pulmonary pathology (nonmalignant lung lesion) {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Abdominal pain{01}
    
anorexia{01} (loss of appetite)
    
diarrhea{01}
    
dizziness{01}
    
dyskinesia{01} (twitching, twisting, or other unusual body movements)
    
dystonia{01} (twisting or other unusual body movements)
    
hallucinations{01} (seeing, feeling, or hearing things that are not there)
    
headache{01}
    
insomnia{01} (trouble in sleeping)
    
nausea{01}
    
orthostatic complaints{01} (dizziness or lightheadedness when getting up from a lying or sitting position)
    
somnolence{01} (drowsiness)
    
syncope{01} (fainting)
    
upper respiratory tract infection{01} (cough; fever; nasal congestion; runny nose; sneezing; sore throat)
    
vomiting{01}

Note: Diarrhea is usually of mild to moderate severity, but approximately 3 to 4% of patients in clinical trials had severe diarrhea {01}. Typically, diarrhea presents 6 to 12 weeks after initiation of tolcapone therapy, but it may start as early as 2 weeks or as late as many months after tolcapone treatment is started {01}. Anorexia may be associated with the diarrhea {01}. No mechanism underlying these symptoms is known, and no consistent description of tolcapone-induced diarrhea has emerged from clinical trials of the medication {01}. It is recommended that all cases of persistent diarrhea be evaluated with an appropriate medical work-up that includes checking for occult blood {01}. A 55-year-old female patient who received tolcapone in doses of 200 mg three times a day for 53 days developed diarrhea followed 4 days later by yellowing of the skin and eyes; she died 7 days after the onset of diarrhea {01}. No liver function tests were performed in this patient after the onset of symptoms {01}.
Hallucinations may be more likely to develop in patients older than 75 years of age {01}. In general, hallucinations present shortly after the initiation of tolcapone therapy, typically within the first 2 weeks {01}. Hallucinations are commonly accompanied by confusion and, less commonly, by insomnia and excessive dreaming {01}. Decreasing the concomitant dose of levodopa may help alleviate hallucinations {01}.
Dystonia is more likely to develop in patients younger than 75 years of age {01}. Somnolence is more likely to occur in female patients than in male patients {01}.


Incidence less frequent
    
Chest pain{01}
    
confusion{01}
    
dyspnea{01} (troubled breathing)
    
fatigue{01} (unusual tiredness or weakness)
    
falling{01}
    
hematuria{01} (blood in urine)
    
hyperkinesia{01} (hyperactivity)
    
influenza-like symptoms{01} (chills; fever; general feeling of discomfort or illness; headache; muscle pain)
    
loss of balance control{01}

Incidence rare
    
Agitation{01}
    
arthritis{01} (joint pain, redness, or swelling)
    
burning of feet{02}
    
chest discomfort{01}
    
dark urine
    
fatigue (unusual tiredness or weakness)
    
hyperactivity{01}
    
hypotension{01} (low blood pressure)
    
irritability{01}
    
jaundice (yellow eyes or skin)
    
lethargy (unusual drowsiness, dullness, or feeling of sluggishness)
    
light-colored stools
    
mental deficiency{01} (difficulty in thinking or concentrating)
    
muscle cramps{01}
    
neck pain{01}
    
paresthesia{01} (burning, prickling, or tingling sensations)
    
persistent nausea
    
pruritus (itching)
    
right upper quadrant tenderness (tenderness in upper right part of abdomen)
    
sinus congestion{01} (headache; stuffy nose)
    
stiffness{01}
    
urinary tract infection{01} (bloody or cloudy urine; difficult or painful urination; frequent urge to urinate)

Note: Patients should be advised to report any signs of liver disease to their physician immediately. Signs may include anorexia, dark urine, fatigue, jaundice, lethargy, light-colored stools, persistent nausea, pruritus, and right upper quadrant tenderness.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Constipation{01}
    
excessive dreaming{01}
    
increased sweating{01}
    
xerostomia{01} (dryness of mouth)

Incidence less frequent
    
Dyspepsia{01} (heartburn)
    
flatulence{01} (gas)



Those not indicating need for medical attention
Incidence more frequent
    
Discoloration of urine to bright yellow{02}



Those indicating the need for medical attention if they occur together after medication is discontinued
    
Confusion
    
fever
    
muscle rigidity




Overdose
For information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The highest dose of tolcapone administered to humans was in a study in healthy elderly volunteers who received 800 mg of tolcapone three times a day (with or without concomitant levodopa/carbidopa administration) for 1 week {01}. Nausea, vomiting, and dizziness were observed, particularly in combination with levodopa/carbidopa {01}.

Treatment of overdose
To enhance elimination—Due to the very high degree of protein binding of tolcapone, hemodialysis is not likely to be beneficial {01}.

Supportive care—Hospitalization is advised {01}. General supportive care is indicated {01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tolcapone (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to tolcapone

Pregnancy—Risk-benefit must be considered





Breast-feeding—Risk-benefit must be considered





Use in children—There is no identified potential use of tolcapone in the pediatric age group






Use in the elderly—Hallucinations are more likely to occur in patients older than 75 years of age
Other medical problems, especially hepatic function impairment, severe dyskinesia, dystonia, hallucinations, hypotension, orthostatic hypotension, or severe renal function impairment

Proper use of this medication
» Compliance with therapy; not taking more or less medicine than prescribed

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician and regular liver function tests

» Importance of self-monitoring for signs of liver dysfunction and informing physician of such signs

» Checking with physician before discontinuing medication; gradual dosage reduction may be needed

» Possible drowsiness, dizziness, lightheadedness, weakness, trouble in thinking or concentrating; caution when driving or doing jobs requiring alertness and coordination

» Caution when getting up suddenly from lying or sitting position

» Possible hallucinations, especially in older patients

» Medication causes urine to turn bright yellow


Side/adverse effects
Signs of potential side effects, especially abdominal pain, anorexia, diarrhea, dizziness, dyskinesia, dystonia, hallucinations, headache, insomnia, nausea, orthostatic complaints, somnolence, syncope, upper respiratory tract infection, vomiting, chest pain, confusion, dyspnea, fatigue, falling, hematuria, hyperkinesia, influenza-like symptoms, loss of balance control, agitation, arthritis, burning of feet, chest discomfort, dark urine, fatigue, hyperactivity, hypotension, irritability, jaundice, lethargy, light-colored stools, mental deficiency, muscle cramps, neck pain, paresthesia, persistent nausea, pruritus, right upper quadrant tenderness, sinus congestion, stiffness, and urinary tract infection


General Dosing Information
Tolcapone should not be initiated in patients with clinical evidence of liver disease or with liver enzyme values greater than the upper limit of normal. Because of the risk of potentially fatal liver injury, tolcapone should be discontinued if the patient fails to show substantial clinical benefit within 3 weeks of initiation of treatment {03}.

Patients with severe dyskinesia or dystonia should receive tolcapone with caution, since these conditions may contribute to rhabdomyolysis {03}.

Tolcapone may be administered with either the immediate-release or the sustained-release formulation of levodopa/carbidopa {01}.

In premarketing clinical trials, patients who were taking a daily dose of levodopa in excess of 600 mg, or who had moderate to severe dyskinesia before beginning treatment, were the most likely to require a decrease in their daily levodopa dose after tolcapone therapy was initiated {01}. The average reduction of the daily levodopa dose needed was about 30% {01}. More than 70% of patients with levodopa doses above 600 mg a day required such a reduction {01}.

Rapid dose reduction or abrupt withdrawal of tolcapone may cause withdrawal-emergent hyperpyrexia and confusion {01}.

Diet/Nutrition
Tolcapone may be taken with or without food {01}.


Oral Dosage Forms

TOLCAPONE TABLETS

Usual adult dose
Parkinson's disease
Oral, initially 100 mg three times a day, always in conjunction with levodopa/carbidopa therapy {01}. Since it is not known whether the risk of fulminant liver failure is increased when the dose is increased to 200 mg three times a day, this dosage should be used only if the anticipated incremental clinical benefit is justified. If incremental benefit is not demonstrated after a total of three weeks of treatment, regardless of dose, tolcapone therapy should be discontinued {03}.

Note: Tolcapone should not be initiated in patients with clinical evidence of liver disease or with liver enzyme values greater than the upper limit of normal.
In clinical trials, more than seventy percent of patients taking levodopa doses greater than 600 mg a day required decreases in the levodopa dose after tolcapone therapy was initiated {01}. The average levodopa dose reduction needed in these patients was about thirty percent {01}.
Tolcapone has not been evaluated in patients with a creatinine clearance of less than 25 mL per minute (mL/min) {01}.



Usual adult prescribing limits
600 mg a day {01}.

Usual pediatric dose
There is no identified potential use of tolcapone in the pediatric age group {01}.

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


100 mg (Rx) [Tasmar (film coated) (dibasic calcium phosphate anhydrous) (lactose monohydrate) (magnesium stearate) (microcrystalline cellulose) (povidone K-30) (sodium starch glycolate) (talc)]


200 mg (Rx) [Tasmar (film coated) (dibasic calcium phosphate anhydrous) (lactose monohydrate) (magnesium stearate) (microcrystalline cellulose) (povidone K-30) (sodium starch glycolate) (talc)]

Packaging and storage:
Store between 20 and 25 ºC (68 and 77 ºF) in a tight container, unless otherwise specified by manufacturer {01}.

Auxiliary labeling:
   • May cause drowsiness.
   • May cause dizziness.

Additional information:
Supplies of written informed consent forms for the patient are available from the manufacturer, or may be reproduced from the sample form that appears in the official labeling. {03}



Revised: 12/21/1998



References
  1. Tasmar package insert (Roche—US), Rev 1/98, Rec 2/98.
  1. Personal communication, Roche (US) medical information, 3/16/98.
  1. Tasmar package insert (Roche—US), Rev 11/98, Rec 11/19/98.
  1. FDA Talk Paper: New warnings for parkinson's drug, Tasmar. November 16, 1998.
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