Tasmar (Tolcapone)

TASMAR™

Roche

Tolcapone

Antiparkinsonian – COMT-inhibitor

Action And Clinical Pharmacology: Tolcapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).

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 enzyme which is responsible for the metabolism of levodopa to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD).

The mechanism of action of tolcapone is believed to be related to its ability to inhibit COMT and thereby alter the plasma pharmacokinetics of levodopa. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor (AADC-I), such as carbidopa or benserazide, plasma levels of levodopa are more sustained than after the administration of levodopa and an AADC-I alone. The 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 as well as increased levodopa adverse effects, requiring a decrease in the daily dose of levodopa.

There is some evidence that high levels of plasma 3-OMD are associated with poor response to levodopa in patients with Parkinson’s disease. Tolcapone markedly reduces the plasma levels of 3-OMD.

Pharmacodynamics: Effect of Tolcapone on Erythrocyte COMT Activity: Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte COMT activity after oral administration. The inhibition is dose-related and tolerance does not develop to this effect. With a 200 mg single dose of tolcapone, maximum inhibition of erythrocyte COMT activity was approximately 80%. During repeated dosing with tolcapone (200 mg t.i.d.), erythrocyte COMT inhibition was 30 to 45% at trough tolcapone plasma concentrations.

Effect of Tolcapone on the Pharmacokinetics of Levodopa and 3-OMD: When tolcapone is administered together with levodopa/AADC-I (carbidopa or benserazide), it increases the relative bioavailability (AUC) of levodopa by approximately 2-fold. This is due to a decrease in levodopa clearance resulting in a prolongation of its terminal elimination half-life (t1/2 ¡). In healthy, elderly volunteers (n=36, age: 55 to 75 years), the terminal elimination half-life of levodopa increased from 1.9 hours in placebo-treated subjects to 3.2 hours in subjects treated with tolcapone, 200 mg t.i.d. Average peak levodopa plasma concentration (Cmax) and the time of its occurrence (tmax) were unaffected. The onset of effect of tolcapone occurred after its first administration.

Population pharmacokinetic analyses in patients with Parkinson’s disease have corroborated the effects of tolcapone on the pharmacokinetics of levodopa shown in healthy volunteers. During long-term clinical trials, tolcapone increased the relative bioavailability of levodopa, prolonged its elimination half-life, and thus, reduced the fluctuations in levodopa plasma concentrations (Cmax-Cmin).

Studies in healthy volunteers and in patients with Parkinson’s disease have confirmed that (a) maximal effects occur with the 100 and 200 mg doses of tolcapone, given t.i.d., and (b) tolcapone given in combination with levodopa/AADC-I, decreases markedly and dose-dependently the plasma levels of 3-OMD.

The effect of tolcapone, on the pharmacokinetics of levodopa, was similar with all pharmaceutical formulations of levodopa/carbidopa and levodopa/benserazide, and was independent of the dose of levodopa.

Pharmacokinetics: Volunteers: The pharmacokinetics of tolcapone were linear in young volunteers over the single dose range of 50 to 400 mg and in elderly volunteers at the therapeutic doses (100 and 200 mg t.i.d.), and were independent of levodopa/AADC-I (carbidopa or benserazide) coadministration. The elimination half-life was 2 to 3 hours. Accumulation was not seen during t.i.d. dosing.

Patients With Parkinson’s Disease: Population pharmacokinetic analyses indicated that the pharmacokinetics of tolcapone in patients with Parkinson’s disease were in agreement with those observed in healthy volunteers. In a dose range of 50 to 400 mg t.i.d., the exposure to tolcapone was dose proportional. The mean Cmax and AUC values at the 200 mg t.i.d. dose were 6 µg/mL and 25.1 µg•h/mL, respectively. The pharmacokinetic behavior of tolcapone was stable during long-term treatment. AUC values were similar in fluctuating and nonfluctuating patients. The elimination half-life of tolcapone was somewhat longer in patients than in volunteers, i.e., approximately 4 to 8 hours. Gender and age did not seem to affect the pharmacokinetics of tolcapone.

Absorption: Tolcapone is rapidly absorbed with a tmax of approximately 2 hours. The absolute bioavailability following oral administration is about 65%. In clinical trials, there were no restrictions as to how the drug was taken in relation to meals. Population pharmacokinetic studies indicated that while food delayed the absorption of tolcapone, its relative bioavailability was still 80 to 90% when the drug was taken within 1 hour before and 2 hours after meals.

Distribution and Protein Binding: The volume of distribution (Vss) of tolcapone in healthy volunteers after i.v. administration was small (9 L). In patients, a higher volume of distribution (15 to 35 L) was estimated after oral dosing. 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 30 µg/mL. At clinical doses, mean Cmax values were <10 µg/mL at the 200 mg dose. In vitro experiments have shown that tolcapone binds mainly to serum albumin.

Metabolism/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 conjugation to its inactive glucuronide. In addition, the compound is methylated by COMT to 3-O-methyl-tolcapone and metabolized by cytochromes P450 3A4 and P450 2A6 to a primary alcohol (hydroxylation of the 4′ methyl group), which is subsequently oxidized to the carboxylic acid. Reduction to a putative amine, as well as the subsequent N-acetylation, occur to a minor extent. After oral administration of 4-labeled tolcapone, 60% of the labeled material is excreted in urine, and 40% in feces. More than 50% of the labeled dose of tolcapone is identified as 8 metabolites. Numerous additional metabolites account for the rest, none of them exceeding 5% of dose.

Tolcapone is a low-extraction-ratio drug (extraction ratio = 0.15), with a moderate systemic clearance of about 7 L/hour.

Hepatic Impairment: A study in patients with hepatic impairment has shown that moderate noncirrhotic liver disease did not affect the pharmacokinetics of tolcapone. However, in patients with moderate cirrhotic liver disease, clearance and volume of distribution of unbound tolcapone were reduced by 44% and 35%, respectively, when compared to values seen in demographically matched healthy volunteers. Since the reduction in clearance may increase the average concentration of unbound tolcapone approximately 2-fold, special dosing recommendations are given for patients with moderate cirrhotic liver disease (see Dosage).

In patients with moderate liver cirrhosis, the Cmax and AUC of tolcapone glucuronide increased substantially (AUC values were 7.4 g•h/mL in healthy volunteers, 20 gh/mL in subjects with noncirrhotic liver disease, and 52 g•h/mL in subjects with cirrhotic liver disease). However, since tolcapone glucuronide is inactive and since this metabolic pathway is irreversible, it is unlikely that the changes will be clinically significant.

Renal Impairment: A specific study to evaluate the pharmacokinetics of tolcapone in patients with renal impairment has not been carried out. However, population pharmacokinetic analysis has shown in more than 400 patients that the clearance of tolcapone was not affected in a clinically meaningful way when creatinine clearance was > 30 mL/min. This could be explained by the fact that only a negligible amount of unchanged tolcapone is excreted in the urine, and the main metabolite, tolcapone-glucuronide, is excreted both in urine and bile (feces).

Drug Interactions : Studies Assessing Potential Drug Interactions : Effect of Tolcapone on the Pharmacokinetics of Other Drugs: Protein Binding: Although tolcapone is highly protein-bound, in vitro studies have shown that tolcapone, at 50 g/mL (approximately 5-fold higher than therapeutic concentrations) did not displace other highly protein-bound drugs at therapeutic concentrations, like warfarin (0.5 to 7.2 g/mL), phenytoin (7.9 to 38.7 g/mL), tolbutamide (24.5 to 96.1 g/mL), or digitoxin (9.0 to 27.0 g/mL) from their binding sites.

Cytochrome P450 Metabolism: The effect of tolcapone on the metabolism of various drugs has been investigated utilizing human liver microsome preparations. Although tolcapone is not metabolized via CYP2C9, its affinity for the enzyme was greater than those of tolbutamide and diclofenac; consequently, tolcapone decreased the formation of their hydroxy metabolites in vitro. However, in a clinical study in healthy volunteers tolcapone did not affect either the pharmacokinetics or the hypoglycemic effect of tolbutamide. In vitro interaction between tolcapone and warfarin, a substrate of CYP2C9 was not evaluated. Since clinical information is limited regarding a potential interaction between these two drugs, coagulation parameters should be monitored when they are given concomitantly (see Precautions).

No relevant interactions were observed in vitro between tolcapone and substrates of CYP2A6 (coumarin), CYP1A2 (caffeine), CYP3A4 (midazolam, terfenadine, cyclosporin), CYP2C19 (S-mephenytoin) and CYP2D6 (desipramine).

Effect of Drugs on the Metabolism of Tolcapone: Glucuronidation: The major route of elimination of tolcapone is by glucuronidation. In vitro studies with desipramine and naproxen, drugs which are highly protein-bound and are metabolized via glucuronidation, did not indicate interference with tolcapone glucuronidation.

Cytochrome P450 Metabolism: Although under in vitro conditions midazolam, which is metabolized by CYP3A4, competed with the formation of the hydroxy metabolite of tolcapone, the fraction of tolcapone, which is metabolized by this isozyme, represents a minor metabolic pathway and no significant interactions are expected under clinical conditions.

Clinical Trials: Up to April 1, 1996, 1 685 patients have been exposed to tolcapone, with 647 patients being exposed for over a year and 117 patients being exposed for over 2 years.

The effectiveness of tolcapone, as an adjunct to levodopa/AADC-I (carbidopa or benserazide) therapy in the treatment of Parkinson’s disease, was demonstrated in randomized placebo-controlled trials in patients who experienced end of dose wearing off phenomena (fluctuating patients) and in patients whose response to levodopa was relatively stable (nonfluctuating patients). The majority of the patients in the clinical trials were at stages 1.5 to 2.5 on the Hoehn and Yahr scale and only limited experience is available in patients who were at stage 4 on the Hoehn and Yahr scale.

Adjunct Therapy in Fluctuating Patients: In three phase III multicentre placebo-controlled studies, patients with documented episodes of wearing off phenomena, despite optimal levodopa therapy, were randomized to receive placebo (n=196) or tolcapone at doses of 100 mg t.i.d. (n=198) or 200 mg t.i.d. (n=200). The primary outcome measure was a comparison between treatments in the change from baseline in the amount of time spent off/on (based upon patient diaries recording time “on” and “off”). The formal double-blind portion of the trial was 3 months (2 of the studies) or 6 weeks (1 study). Based on a 16-hour waking day, the decreases in off time versus baseline ranged between 0.3 to 1.2, 1.9 to 2.1 and 1.6 to 2.9 hours in the placebo, 100 mg t.i.d. and 200 mg t.i.d. groups, respectively. Expressed as percentages, the decreases in off time ranged between 5 to 19%, 29 to 34% and 27 to 49% in the placebo, 100 mg t.i.d. and 200 mg t.i.d. groups, respectively. The difference between the placebo and Tasmar groups was significant. The Investigator’s Global Assessment of Change also showed a statistically significant improvement in tolcapone-treated patients. In addition, the total daily dose of levodopa was significantly reduced in the tolcapone groups.

The improvement in off time, due to tolcapone treatment, was independent of the concomitant use of selegiline or dopamine agonist, the amount of slow-release-levodopa as a proportion of the total daily dose of levodopa, and the duration of levodopa therapy. There were no gender or age-related differences in effectiveness.

Adjunct Therapy in Nonfluctuating Patients: In a phase III multicentre study, 298 patients with Parkinson’s disease on stable doses of levodopa/carbidopa, who were not experiencing wearing off phenomena, were randomized to placebo, tolcapone 100 mg t.i.d., or tolcapone 200 mg t.i.d. for 6 months. The primary measure of efficacy was the Activities of Daily Living (ADL) subscale of the UPDRS (Unified Parkinson’s Disease Rating Scale). Mean ADL scores did not change in the placebo group while they decreased by 18 and 21% in patients treated with 100 mg t.i.d. or 200 mg t.i.d. of tolcapone, respectively. The differences between the placebo and tolcapone groups were significant. In nonfluctuating patients, the mean daily doses of levodopa at baseline were relatively low, namely 364 mg, 370 mg, and 382 mg in the placebo, 100 mg t.i.d. and 200 mg t.i.d. tolcapone groups, respectively. At 6 months, the mean daily dose of levodopa increased by 46.6 mg in the placebo group while it decreased in the tolcapone groups (100 mg t.i.d.: -20.8 mg; 200 mg t.i.d.: -32.3 mg). The difference between the placebo and tolcapone groups was significant. In tolcapone-treated patients the total scores and motor scores (subscale III) of the UPDRS decreased by 11 to 13%, while decreases in the placebo-treated patients ranged between one to two percent. The difference was statistically significant.

The improvement in ADL, due to tolcapone treatment, was independent of concomitant use of selegiline and duration of levodopa therapy. There were no gender or age-related differences in effectiveness.

Indications And Clinical Uses: As an adjunct to levodopa/carbidopa and levodopa/benserazide for the treatment of the signs and symptoms of idiopathic Parkinson’s disease. Since tolcapone should be used in combination with levodopa, the prescribing information for levodopa/carbidopa and levodopa/benserazide are also applicable when tolcapone is added to the treatment regimen.

Contra-Indications: Patients with known hypersensitivity to tolcapone or the excipients of the drug product.

Tolcapone should not be given in conjunction with nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine and tranylcypromine). The combination of MAO-A and MAO-B inhibitors is equivalent to nonselective MAO inhibition; therefore, they should not both be given concomitantly with tolcapone and levodopa preparations. Selective MAO-B inhibitors should not be used at higher than recommended doses (e.g., selegiline 10 mg/day) when coadministered with tolcapone.

Precautions: Orthostatic Hypotension: The incidence of orthostatic hypotension was slightly higher in the tolcapone treatment groups than in the placebo group. Orthostatic hypotension at baseline was a predisposing factor; however, this was true for tolcapone and placebo-treated patients alike. Concomitant treatment with a dopamine agonist increased slightly the incidence of orthostatic hypotension in the 200 mg t.i.d. tolcapone group (17% versus 11% in the presence and absence of a dopamine agonist, respectively). Syncope and falling occurred with a higher incidence in patients who had orthostatic hypotension (at the 200 mg t.i.d. dose, syncope was 10.3% versus 4.2%, falling was 10.3% versus 5.4% in patients with or without orthostatic hypotension, respectively). Gender and age had no apparent effect on the rates of orthostatic hypotension.

Dyskinesia: In patients treated with tolcapone, dyskinesia was the most common adverse event. Dyskinesia was dose-related and much more prevalent in fluctuating than nonfluctuating patients (see Adverse Effects). Concomitant treatment with selegiline, dopamine agonists and controlled-release levodopa (>70% of the daily dose) increased the incidence of dyskinesia. Although decreasing the dose of levodopa may ameliorate this adverse event, many patients in the controlled clinical trials continued to experience dyskinesia.

Hallucinations: The incidence of hallucinations was higher in the tolcapone groups than in the placebo group, it occurred in a dose-related manner and was more prevalent in the fluctuating than nonfluctuating patients (see Adverse Effects). Patients who had this adverse event prior to initiating tolcapone treatment and those with a pretreatment levodopa dose of >750 mg/day, had a higher rate of hallucinations. Hallucinations were commonly accompanied by confusion.

Diarrhea: Diarrhea was the most common nondopaminergic adverse reaction associated with tolcapone treatment. In the clinical trials, diarrhea developed in 16% and 18% of patients receiving tolcapone, at 100 and 200 mg t.i.d. doses, respectively, compared to 8% of patients receiving placebo. In some of the patients diarrhea was persistent and severe. Diarrhea was also the adverse reaction which most commonly led to discontinuation of treatment with 1.0, 5.4 and 6% of patients treated with placebo, 100 mg and 200 mg tolcapone t.i.d., respectively, withdrawing from the trials prematurely. Diarrhea usually started during the second, third or fourth month of treatment but may appear as early as 2 weeks and as late as many months after the initiation of treatment. Tolcapone-induced diarrhea was generally described as watery. The mechanism underlying the diarrhea has not yet been elucidated. In the clinical trials, diarrhea observed during tolcapone treatment was sometimes associated with anorexia (decreased appetite).

Elevated Liver Transaminases: An increase of liver transaminases (ALT and/or AST) to more than 3 times the upper limit of normal (ULN) occurred in 1.7 and 3.1% of patients receiving tolcapone at 100 mg and 200 mg t.i.d. doses, respectively. Increases to more than 8 times the ULN occurred in 0.3 and 0.7% of patients at the 100 mg and 200 mg t.i.d. doses, respectively. The incidence of elevated liver transaminases was higher in females than males (4.8% versus 1.5%). Approximately one third of patients with elevated enzymes had diarrhea. Elevated liver enzymes led to discontinuation of treatment in 0.3 and 1.7% of patients treated with tolcapone, 100 mg and 200 mg t.i.d., respectively. The majority of cases of elevated liver transaminases occurred 1 to 6 months after starting treatment, although elevated levels were seen at earlier times as well. In about half of the cases, transaminase levels returned to pretreatment levels within 1 to 3 months while patients continued treatment with tolcapone. In patients who discontinued treatment, transaminase levels generally declined within 2 to 3 weeks but it may take as long as 1 to 2 months to return to normal.

Liver transaminase levels should be determined prior to initiating treatment with tolcapone and monitored approximately every 6 weeks for the first 6 months. If elevations occur during this period, and the decision is made to continue treatment, monitoring of liver enzymes is recommended at approximately 2-week intervals. If transaminase levels keep on increasing or if clinical jaundice develops, treatment should be discontinued.

Neuroleptic Malignant Syndrome (NMS): This rare and potentially life-threatening syndrome is characterized by muscular rigidity, elevated temperature and altered consciousness associated with elevated serum creatine phosphokinase (CPK). The syndrome has been reported in association with rapid dose reduction, withdrawal of, or changes in treatment with dopaminergic antiparkinson therapy.

There have been 4 cases of NMS during tolcapone treatment. Three of the cases involved females (aged 74, 65 and 54 years), all these patients were Japanese. The fourth case involved a Caucasian male, aged 64 years. All patients were receiving levodopa/AADC-I and dopamine agonist treatment. The time of NMS, with respect to treatment with tolcapone, varied greatly, namely it occurred after 153, 99, 15 and 362 days. In all cases, CPK levels and WBC counts were markedly elevated, mild to moderate fever was also present. Two of the 4 patients had muscle rigidity. One of the female patients died due to respiratory failure, the other patients recovered. The investigators considered all cases to be probably related to tolcapone treatment.

If tolcapone is discontinued, physicians should consider increasing the patient’s daily levodopa dose (see Dosage).

Urine Discoloration: Tolcapone and its metabolites are yellow and can cause a harmless intensification in the color of the patient’s urine.

Special Populations: Renal/Hepatic Impairment: No information is available on the tolerability of tolcapone in patients with severe renal impairment (creatinine clearance <30 mL/min) (see Pharmacology, Pharmacokinetics and Metabolism). These patients should be treated with caution.

In patients with moderate cirrhotic liver disease, the clearance of unbound tolcapone is substantially reduced and the concentration of unbound drug increased approximately 2-fold (see Pharmacology, Pharmacokinetics and Metabolism). These patients should receive only the lower recommended dose of tolcapone (see Dosage).

Women: During tolcapone treatment, some adverse events occurred with a higher incidence in women than men. They included nausea, anorexia, diarrhea and elevated liver transaminases.

Geriatrics: During tolcapone treatment, some adverse events occurred with a higher incidence in patients over 75 years of age (n=95) compared to younger patients. They included diarrhea and hallucinations.

Carcinogenesis: Carcinogenicity studies, in which tolcapone was administered in the diet for 104 weeks, were conducted in rats. The doses were approximately 50, 250 and 450 mg/kg/day. In male rats, tolcapone exposures (in terms of AUC) were 1, 6.3 and 13 times the maximal human exposure; in female rats, tolcapone exposures (in terms of AUC) were 1.7, 11.8 and 26.4 times the maximal human exposure. There was evidence of renal tubular injury and renal tubular tumor formation. Minimal to marked damage to renal tubules, consisting of proximal tubule cell degeneration, single cell necrosis, hyperplasia and karyocytomegaly, occurred at the doses that were associated with renal tumors. A low incidence of renal tubular cell adenomas occurred in middle-and high-dose females and in high-dose males. The incidence of uterine adenocarcinomas was increased in high-dose female rats. In a 1-year toxicity study in rats, administered tolcapone at 150 and 450 mg/kg/day doses, renal tubule damage, characterized by proximal tubule cell degeneration and the presence of atypical nuclei, were observed. One adenocarcinoma in a high-dose male rat was also seen.

The carcinogenic potential of tolcapone in combination with levodopa/AADC-I has not been examined.

Pregnancy: The use of tolcapone during pregnancy is not recommended.

Tolcapone will always be given concomitantly with levodopa/AADC-I preparations which are known to cause visceral and skeletal malformations in the rabbit. 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.

Tolcapone, when administered alone during organogenesis, was not teratogenic in rats at doses up to 300 mg/kg/day (5.7 times the recommended daily clinical dose of 600 mg on a mg/mbasis) or in rabbits at doses up to 400 mg/kg/day (15 times the recommended daily clinical dose of 600 mg on a mg/mbasis).

Lactation: In animal studies, tolcapone was excreted in maternal milk. It is not known whether tolcapone is excreted in human milk. Since the safety of tolcapone in infants is unknown, women should not breast-feed during treatment with tolcapone.

Children: Safety and efficacy of tolcapone have not been established in the pediatric population and use in patients below the age of 18 is not recommended.

Drug Interactions : Protein Binding: Although tolcapone is highly protein bound, in vitro studies have shown that at 50 µg/mL (approximately 5-fold higher than therapeutic concentrations), it did not displace warfarin, tolbutamide, digitoxin and phenytoin from their binding sites (see Pharmacology, Drug Interactions).

Drugs Metabolized by Catechol-O-methyltransferase (COMT): Tolcapone may influence the pharmacokinetics of drugs metabolized by COMT. No effects were seen on the pharmacokinetics of the COMT substrate carbidopa. However, an interaction was observed with benserazide, which may lead to increased levels of benserazide and its active metabolite. The magnitude of the effect depended upon the dose of benserazide. Plasma concentrations of benserazide, observed after co-administration of tolcapone and levodopa/benserazide, 100/ 25 mg, were still within the range of values observed with levodopa/benserazide alone. However, after the coadministration of tolcapone and levodopa/benserazide, 200/50 mg, benserazide plasma concentrations could be increased above the levels usually observed with levodopa/benserazide alone. The most prominent sign of benserazide toxicity is fatty liver degeneration in dogs. However, pharmacokinetic data indicate that the median AUC values of benserazide in dogs, at subtoxic doses, were considerably higher than AUC values seen in humans. A subanalysis of tolcapone safety in patients, receiving 25 mg versus 50 mg doses of benserazide, did not indicate different rates of occurrence of liver transaminase elevations.

The effect of tolcapone on the pharmacokinetics of other drugs metabolized by COMT, such as a-methyldopa, dobutamine, apomorphine, epinephrine and isoproterenol has not been evaluated. A dose reduction of such compounds should be considered when they are coadministered with tolcapone.

Effect of Tolcapone on the Metabolism of Other Drugs: Due to its in vitro affinity for cytochrome P450 2C9, tolcapone may interfere with drugs whose clearance is dependent on this metabolic pathway, such as tolbutamide and warfarin. In an interaction study (n=12 male volunteers, aged 21 to 39 years), tolcapone did not affect either the pharmacokinetics or the hypoglycemic effect of tolbutamide.

During clinical trials, 23 patients received a combination of warfarin and tolcapone and no particular pattern of adverse events was observed. However, since clinical experience is limited, coagulation parameters should be monitored when these drugs are coadministered.

Drugs that Increase Catecholamines: Tolcapone, in combination with Sinemet (n=12 male and female volunteers, aged 19 to 39 years), did not affect the pharmacokinetics of desipramine, a drug metabolized by cytochrome P450 2D6. While there were no significant changes in blood pressure or pulse rate, the frequency of adverse events, particularly dizziness, nausea and vomiting, increased. Therefore, caution should be exercised when potent norepinephrine reuptake inhibitors, such as desipramine, maprotiline or venlafaxine are administered to patients with Parkinson’s disease who are being treated with tolcapone and levodopa preparations.

Tolcapone in combination with Sinemet (n=12 male and female volunteers, aged 21 to 30 years) had no effect on the hemodynamic parameters of ephedrine, an indirect acting sympathomimetic drug, either at rest or during exercise. Plasma levels of epinephrine and norepinephrine remained unchanged. Since tolcapone did not affect the tolerability of ephedrine, these drugs may be given concomitantly.

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

Adverse Reactions: Of the 1 685 patients, who received tolcapone during the premarketing clinical trials, 18.8% discontinued treatment due to adverse events. At the clinically recommended doses of tolcapone, in the placebo-controlled, phase III trials, 16.2% (48/296) and 15.4% (46/298) of patients discontinued treatment at the 100 and 200 mg t.i.d. doses, respectively, compared to 10.1% (30/298) of patients receiving placebo. The most common reason for withdrawal in the tolcapone groups was diarrhea, with 5% and 6% of patients withdrawing at the 100 and 200 mg t.i.d. doses, respectively, compared to 1% of patients receiving placebo.

Other adverse events which led to discontinuation of treatment in ³1% of patients (placebo, 100 and 200 mg t.i.d., respectively) included nausea (2%, 1.7%, 2%), elevated liver transaminases (0%, 0.3%, 1.7%), hallucinations (0.3%, 1.4%, 1%), dyskinesia (0%, 0.3%, 1%), confusion (1%, 1.4%, 0.7%) and muscle cramps (1%, 1.4%, 0.3%).

The most commonly reported serious adverse events, defined as those requiring hospitalization (placebo, 100 and 200 mg t.i.d., respectively), included diarrhea (0.3%, 0.7%, 1.7%), dyskinesia (0.3%, 0.3%, 1.3%), and hallucinations (0%, 1.7%, 0%).

Of the 1 685 patients who received tolcapone, 4 patients experienced symptoms suggestive of Neuroleptic Malignant Syndrome (see Precautions and Dosage).

Incidence of Adverse Events in Placebo Controlled Trials: The most frequently observed adverse events, associated with the use of tolcapone were dyskinesia, nausea, sleep disorders, anorexia, dystonia and diarrhea. Incidences were somewhat higher at the 200 mg t.i.d. dose. The incidence of dyskinesia, hallucination and confusion was considerably higher in fluctuating patients, while the incidence of nausea, vomiting and anorexia was higher in nonfluctuating patients. Orthostatic complaints and diarrhea occurred with similar frequencies in fluctuating and nonfluctuating patients.

Some of the most frequently reported adverse events (e.g., dyskinesia, nausea, orthostatic complaints, hallucinations, vomiting), which are considered levodopa-related, become enhanced in the presence of tolcapone. The highest risk of experiencing these dopaminergic adverse events occurred when tolcapone was first added to levodopa/AADC-I therapy, i.e., during the first few weeks of treatment. The prevalence rates tended to drop during the first 2 months, probably reflecting re-optimization of levodopa therapy. Therefore, a reduction in the dosage of levodopa may be necessary when initiating tolcapone treatment (see Dosage).

Laboratory Tests: Liver transaminases, ALT and AST, increased in a dose-dependent manner in tolcapone treated patients (see Precautions). The increases were observed within the first 6 months of treatment. In clinical trials, 0.3% and 1.7% of patients receiving tolcapone, at 100 and 200 mg t.i.d. doses, respectively, withdrew due to elevated liver transaminases. Slight increases in alkaline phosphatase or total bilirubin occurred in 20% and 10% of patients, respectively.

Liver transaminase levels should be monitored approximately every 6 weeks for the first 6 months of treatment with tolcapone. If elevations occur during this period, and the decision is made to continue treatment, monitoring of liver enzymes is recommended at approximately 2-week intervals. If transaminase levels keep on increasing or if clinical jaundice develops, treatment should be discontinued (see Precautions).

ECGs: In the course of the clinical trials, ventricular premature contractions were recorded in tolcapone treated patients but not in placebo treated patients. The incidence of ventricular premature contractions was 0.3 and 1.7% in patients treated with the 100 mg and 200 mg t.i.d. doses, respectively.

Adverse events reported by ³1% of patients treated with tolcapone: Body as a Whole: fatigue, lethargy, peripheral edema, malaise, weight decrease, trauma, fever.

Nervous System: falling, tremor, loss of balance, hypoesthesia, hyperkinesia, paresthesia, paresis, speech disorder, burning, gait abnormal, vertigo, hyperactivity.

Psychiatric: depression, agitation, asthenia, emotional lability, anxiety, impotence, irritability, mental deficiency, panic reaction, hypertonia, euphoria.

Gastrointestinal: flatulence, abdominal discomfort.

Cardiovascular: hypotension, chest discomfort, palpitation.

Musculoskeletal: muscle cramps, back pain, arthralgia, pain in limbs, stiffness, neck pain, myalgia, arthritis.

Urogenital: urinary tract infection, micturition disorder, micturition frequency, urinary incontinence.

Skin and Appendages: rash, alopecia.

Respiratory: pneumonia, dyspnea, bronchitis, pharyngitis, sinusitis, sinus congestion.

Special Senses: tinnitus, taste alteration, cataract, vision blurred, eye inflamed.

Miscellaneous: tooth disorder, dermal bleeding, fractures, skin tumor, tumor of the uterus.

Additional adverse events are listed below. They include all adverse events that were reported in the overall clinical program for tolcapone. The events are enumerated using the following criteria: Infrequent: adverse events occur in less than 1% but at least 1/1 000 patients; Rare: adverse events occur in less than 1/1 000 patients.

Body as a Whole: Infrequent: hernia, pain, allergic reaction, cellulitis, fungal infection, viral infection, carcinoma, chills, abscess, face edema, joint edema.

Nervous System: Infrequent: neuralgia, memory disturbance, aggravated parkinsonism, sensory disturbance, migraine, neuropathy, cerebral ischemia, stroke. Rare: dementia, spasms.

Psychiatric: Infrequent: asthenia, aggressive reaction, paranoid reaction, delusion, nervousness. Rare: behavioral disturbances, libido disorder, compulsive reaction, personality disorder.

Gastrointestinal: Infrequent: dysphagia, gastrointestinal hemorrhage, gastrointestinal inflammation, oral canker sores, hernia inguinal, frequent bowel movements, esophagitis, hernia hiatal, tongue discoloration. Rare: appetite disturbances, tongue dryness.

Cardiovascular: Infrequent: hypertension, vasodilation, angina pectoris, heart failure, atrial fibrillation, tachycardia, aortic stenosis, arrythmia, arteriospasm, bradycardia, cerebral hemorrhage, coronary artery disorder, heart arrest, myocardial infarct, myocardial ischemia, pulmonary embolus. Rare: arteriosclerosis, cardiovascular disorder, pericardial effusion, thrombosis.

Musculoskeletal: Infrequent: sprains and strains, carpal tunnel syndrome, intervertebral disc disorder, bone spur, tendinitis. Rare: pathological fracture, leg discomfort, muscle disorder.

Urogenital: Infrequent: prostatic disorder, hematuria, urinary retention, urinary tract bleeding, dysuria, nocturia, polyuria, kidney calculus, vaginitis, enlarged prostate, bladder disorder. Rare: bladder calculus, ovarian carcinoma, uterine hemorrhage, kidney failure, abnormal renal function.

Skin and Appendages: Infrequent: herpes zoster, skin disorder, herpes simplex, erythema multiforme, pruritus, skin discoloration, cellulitis, seborrhea, eczema, furunculosis, urticaria.

Respiratory: Infrequent: increased cough, asthma, epistaxis, hyperventilation, rhinitis, laryngitis, dryness of pharynx, hiccup. Rare: lung edema, apnea, wheezing, hypoxia.

Special Senses: Infrequent: diplopia, ear pain, eye hemorrhage, eye pain, lacrimation disorder, otitis media, parosmia. Rare: glaucoma.

Metabolic and Nutritional: Infrequent: edema, hypercholesteremia, thirst, dehydration.

Miscellaneous: Infrequent: anemia, surgical procedure.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The highest dose of tolcapone administered to humans was 800 mg t.i.d., with and without levodopa coadministration. 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 and 6 µg/mL with the 100 mg and 200 mg t.i.d. doses of tolcapone, respectively). Nausea, vomiting and dizziness were observed, particularly in combination with levodopa.

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 i.v. doses and in dogs with rapidly injected i.v. 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.

Dosage And Administration: Tolcapone is administered orally 3 times a day, as an adjunct to levodopa/AADC-I (carbidopa or benserazide) therapy. The first dose of the day should be taken together with the first dose of the day of a levodopa/AADC-I preparation, and the subsequent doses should be given approximately 6 and 12 hours later.

Tolcapone may be taken with or without food (see Pharmacology, Pharmacokinetics and Metabolism).

Tolcapone can be combined with all pharmaceutical formulations of levodopa/carbidopa and levodopa/benserazide.

Therapy with tolcapone should be initiated with 100 mg t.i.d. In clinical trials, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa was >600 mg or if patients had moderate or severe dyskinesias.

After adjustment of levodopa dose, an increase to 200 mg tolcapone t.i.d. is recommended, if in the opinion of the physician further benefit may be expected without excessive dopaminergic adverse reactions. After increasing the dose of tolcapone to 200 mg t.i.d., a further readjustment of the dose of levodopa may be needed. In clinical trials, the average reduction in daily levodopa dose was about 30% in those patients who required a levodopa dose reduction. (Greater than 70% of patients with levodopa doses above 600 mg daily required such a reduction.)

The maximum therapeutic dose of 200 mg t.i.d. (600 mg/day) should not be exceeded since the safety and efficacy of higher doses have not been evaluated systematically and there is no evidence that higher doses provide any additional benefit.

Patients with Impaired Hepatic or Renal Function (see Pharmacology and Precautions): In patients with moderate to severe cirrhosis, the dose of tolcapone should be kept at 100 mg t.i.d. and not escalated to 200 mg t.i.d.

No dose adjustment of tolcapone is recommended for patients with mild to moderate renal impairment (creatinine clearance ³30 mL/min). The safety of tolcapone has not been evaluated in patients whose creatinine clearance was <30 mL/min.

Discontinuation of Tolcapone: Due to the possibility for the occurrence of Neuroleptic Malignant Syndrome (NMS) upon a sudden decrease in the dose of dopaminergic drugs, including tolcapone (see Precautions), physicians should consider increasing the patient’s levodopa dose if tolcapone is discontinued.

Availability And Storage: 100 mg: Each pale to light yellow, hexagonal, biconvex, film-coated tablet, with “ROCHE” and “100” engraved on one side, contains: tolcapone 100 mg. Nonmedicinal ingredients: calcium hydrogen phosphate, ethylcellulose, hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, microcrystalline cellulose, povidone K30, sodium lauryl sulfate, sodium starch glycolate, talc, titanium dioxide and triacetin. Blisters of 30 and 60. Glass bottles of 100.

200 mg: Each brown to orange yellow, hexagonal, biconvex, film-coated tablet, with “ROCHE” and “200” engraved on one side, contains: tolcapone 200 mg. Nonmedicinal ingredients: calcium hydrogen phosphate, ethylcellulose, hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, microcrystalline cellulose, povidone K30, sodium lauryl sulfate, sodium starch glycolate, talc, titanium dioxide and triacetin. Blisters of 30 and 60. Glass bottles of 100.

Store at room temperature (15 to 30°C).

TASMAR™ Roche Tolcapone Antiparkinsonian – COMT-inhibitor

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