Tolcapone

Tolcapone is used in combination with levodopa and carbidopa to treat the signs and symptoms of Parkinson's disease.

This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information.

Pregnancy Category: C

Lactation: not known if secreted in breast milk, use caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

Reversible catechol-O-methyltransferase (COMT) inhibitor that prolongs the half-life of levodopa

Pharmacokinetics

Peak Plasma Time: 2 hr

Concentration (100/200 mg q8hr for7 days): 3.5/6.4 mcg/mL

Excretion: Urine (60%); feces (40%)

Bioavailability: 65-85%

Protein Bound: >99.9%

Half-life elimination: 2-3hr

Vd: 9 L

Metabolism: Liver glucuronidation

Total body clearance: 7 L/hr

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• nausea, upper stomach pain, feeling tired, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• confusion, hallucinations, unusual thoughts or behavior;
• severe or ongoing diarrhea;
• worsening tremors, stiffness, or muscle spasms; or
• a light-headed feeling, like you might pass out.

Common side effects may include:

• drowsiness;
• mild diarrhea;
• sleep problems; or
• increased sweating.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Mechanism of Action

Tolcapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).

In mammals, COMT is distributed throughout various organs. The highest activities are in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. 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 metabolizing enzyme for levodopa catalyzing the metabolism to 3-methoxy-4hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.

The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these 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 in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. Tolcapone enters the CNS to a minimal extent, but has been shown to inhibit central COMT activity in animals.

Pharmacodynamics

Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte catechol-O-methyltransferase  (COMT) activity after oral administration. The inhibition is closely related to plasma tolcapone concentrations. With a 200-mg single dose of tolcapone, maximum inhibition of erythrocyte COMT activity is on average greater than 80%. During multiple dosing with tolcapone (200 mg tid), erythrocyte COMT inhibition at trough tolcapone blood concentrations is 30% to 45%.

Effect on the Pharmacokinetics of Levodopa and its Metabolites

When tolcapone is administered together with levodopa/carbidopa, it increases the relative bioavailability (AUC) of levodopa by approximately twofold. This is due to a decrease in levodopa clearance resulting in a prolongation of the terminal elimination half-life of levodopa (from approximately 2 hours to 3.5 hours). In general, the average peak levodopa plasma concentration (Cmax) and the time of its occurrence (Tmax) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in healthy volunteers and Parkinson's disease patients have confirmed that the maximal effect occurs with 100 mg to 200 mg tolcapone. Plasma levels of 3-OMD are markedly and dose-dependently decreased by tolcapone when given with levodopa/carbidopa.

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

Pharmacokinetics of Tolcapone

Tolcapone pharmacokinetics are linear over the dose range of 50 mg to 400 mg, independent of levodopa/carbidopa co-administration. The elimination half-life of tolcapone is 2 to 3 hours and there is no significant accumulation. With tid dosing of 100 mg or 200 mg, Cmax is approximately 3 μg/mL and 6 μg/mL, respectively.

Tolcapone is rapidly absorbed, with a Tmax of approximately 2 hours. The absolute bioavailability following oral administration is about 65%. Food given within 1 hour before and 2 hours after dosing of tolcapone decreases the relative bioavailability by 10% to 20% (see DOSAGE AND ADMINISTRATION).

The steady-state volume of distribution of tolcapone is small (9 L). 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 210 μg/mL. In vitro experiments have shown that tolcapone binds mainly to serum albumin.

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 glucuronidation; the glucuronide conjugate is inactive. In addition, the compound is methylated by COMT to 3-O-methyl-tolcapone. Tolcapone is metabolized to a primary alcohol (hydroxylation of the methyl group), which is subsequently oxidized to the carboxylic acid. In vitro experiments suggest that the oxidation may be catalyzed by cytochrome P450 3A4 and P450 2A6. The reduction to an amine and subsequent N-acetylation occur to a minor extent. After oral administration of a 14C-labeled dose of tolcapone, 60% of labeled material is excreted in urine and 40% in feces. Tolcapone is a low-extraction-ratio drug (extraction ratio = 0.15) with a moderate systemic clearance of about 7 L/h.

Special Populations

Tolcapone pharmacokinetics are independent of sex, age, body weight, and race (Japanese, Black and Caucasian). Polymorphic metabolism is unlikely based on the metabolic pathways involved.

A study in patients with hepatic impairment has shown that moderate non-cirrhotic liver disease had no impact on the pharmacokinetics of tolcapone. In patients with moderate cirrhotic liver disease (Child-Pugh Class B), however, clearance and volume of distribution of unbound tolcapone was reduced by almost 50%. This reduction may increase the average concentration of unbound drug by twofold (see DOSAGE AND ADMINISTRATION). TASMAR therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (see BOXED WARNING).

The pharmacokinetics of tolcapone have not been investigated in a specific renal impairment study. However, the relationship of renal function and tolcapone pharmacokinetics has been investigated using population pharmacokinetics during clinical trials. The data of more than 400 patients have confirmed that over a wide range of creatinine clearance values (30 mL/min to 130 mL/min) the pharmacokinetics of tolcapone are unaffected by renal function. This could be explained by the fact that only a negligible amount of unchanged tolcapone (0.5%) is excreted in the urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile. Accumulation of this stable and inactive metabolite should not present a risk in renally impaired patients with creatinine clearance above 25 mL/min (see DOSAGE AND ADMINISTRATION). Given the very high protein binding of tolcapone, no significant removal of the drug by hemodialysis would be expected.

Drug Interactions

See PRECAUTIONS: DRUG INTERACTIONS.

Clinical Studies

The effectiveness of TASMAR as an adjunct to levodopa in the treatment of Parkinson's disease was established in three multicenter randomized controlled trials of 13 to 26 weeks' duration, supported by four 6-week trials whose results were consistent with those of the longer trials. In two of the longer trials, tolcapone was evaluated in patients whose Parkinson's disease was characterized by deterioration in their response to levodopa at the end of a dosing interval (so-called fluctuating patients with wearing-off phenomena). In the remaining trial, tolcapone was evaluated in patients whose response to levodopa was relatively stable (so-called nonfluctuators).

In two 3-month trials, patients with documented episodes of wearing-off phenomena, despite optimum levodopa therapy, were randomized to receive placebo, tolcapone 100 mg tid or 200 mg tid. The formal double-blind portion of the trial was 3 months long, and the primary outcome was a comparison between treatments in the change from baseline in the amount of time spent “On” (a period of relatively good functioning) and “Off” (a period of relatively poor functioning). Patients recorded periodically, throughout the duration of the trial, the time spent in each of these states.

In addition to the primary outcome, patients were also assessed using sub-parts of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Parts V and VI); an Investigator's Global Assessment of Change (IGA), a subjective scale designed to assess global functioning in 5 areas of Parkinson's disease; the Sickness Impact Profile (SIP), a multi-item scale in 12 domains designed to assess the patient's functioning in multiple areas; and the change in daily levodopa/carbidopa dose.

In one of the studies, 202 patients were randomized in 11 centers in the United States and Canada. In this trial, all patients were receiving concomitant levodopa and carbidopa. In the second trial, 177 patients were randomized in 24 centers in Europe. In this trial, all patients were receiving concomitant levodopa and benserazide.

The following tables display the results of these 2 trials:

Table 1: US/Canadian Fluctuator Study

Table 2: European Fluctuator Study

Effects on “Off” time and levodopa dose did not differ by age or sex.

In this study, 298 patients with idiopathic Parkinson's disease on stable doses of levodopa/carbidopa who were not experiencing wearing-off phenomena were randomized to placebo, tolcapone 100 mg tid, or tolcapone 200 mg tid for 6 months at 20 centers in the United States and Canada. The primary measure of effectiveness was the Activities of Daily Living portion (Subscale II) of the UPDRS. In addition, the change in daily levodopa dose, other subscales of the UPDRS, and the SIP were assessed as secondary measures. The results are displayed in the following table:

Table 3: US/Canadian Non-fluctuator Study

Effects on Activities of Daily Living did not differ by age or sex.

General

• Symptomatic improvement generally is evident within 3 weeks following initiation of tolcapone.1 7 Discontinue tolcapone if the patient fails to show symptomatic improvement within 3 weeks of initiating therapy.1 (See Boxed Warning.)

Concomitant Levodopa/Carbidopa Therapy

• Administer in conjunction with levodopa/carbidopa (conventional or extended-release preparations).1 9

• To optimize patient response, reductions in the daily levodopa/carbidopa dosage may be necessary.1 6 7 9 16 28 In clinical trials, most patients receiving levodopa dosages >600 mg daily or with moderate to severe dyskinesia prior to initiation of tolcapone required reduction of levodopa dosage (average reduction: about 30%).1 6 7 9 16 23

Discontinuance of Tolcapone

• Discontinuance or abrupt dosage reduction may lead to reemergence of signs and symptoms of parkinsonian syndrome or a symptom complex resembling neuroleptic malignant syndrome (e.g., hyperpyrexia, confusion).1

• If tolcapone is discontinued, monitor the patient closely and adjust the dosage of dopaminergic therapy, if needed.1

• If hyperpyrexia or severe rigidity occurs following drug discontinuance, the differential diagnosis should include the possibility of a symptom complex resembling neuroleptic malignant syndrome.1

• Tapering the dosage of tolcapone has not been systematically evaluated;1 however, reducing the frequency to twice or once daily prior to discontinuance may not prevent these events, since the duration of COMT inhibition associated with tolcapone therapy is 5–6 hours or longer.1 2 4 5 8

Administration

Oral Administration

Administer orally in 3 equally divided doses daily1 6 7 9 16 23 28 without regard to meals.1

In clinical studies, the first dose of the day was administered together with the first dose of the day of levodopa/carbidopa; subsequent doses of tolcapone are administered 6 and 12 hours later.1 6 7 9 28

Dosage

Adults

Usual dosage: 100 mg 3 times daily.1 28

Reserve higher dosage (200 mg 3 times daily) for situations when the anticipated incremental benefit is justified.1 If the patient fails to show the expected clinical benefit while receiving 200 mg 3 times daily for 3 weeks, discontinue the drug.1 (See Hepatic Effects under Cautions.)

Special Populations

Renal Impairment

Dosage adjustment not required in patients with mild to moderate renal impairment (Clcr >30 mL/minute).1 Safety not evaluated in patients with Clcr <25 mL/minute.1

Metabolized in part by COMT1 2 27 28 and by CYP3A4 and CYP2A6.1 28

Inhibits COMT; has affinity for CYP2C9 in vitro.1 20

Drugs Metabolized by Hepatic Microsomal Enzymes

Clinically important interactions with drugs metabolized by CYP2C9 and CYP2D6 are not expected to occur.1 In vitro studies did not reveal important interactions with substrates for CYP isoenzymes 2A6, 1A2, 3A4, 2C19, or 2D6.1

Drugs Metabolized by COMT

Tolcapone may alter the metabolism of drugs metabolized by COMT.1

Drugs Affecting CNS Monoaminergic or Cholinergic System

Symptom complex resembling neuroleptic malignant syndrome reported in patients receiving tolcapone in combination with other drugs that affect brain monoaminergic or anticholinergic systems; caution is advised if such combinations are used.1

Specific Drugs

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Feeling confused.
• Very loose stools (diarrhea).
• Loose stools (diarrhea) that will not go away.
• Blood in the urine.
• Fever.
• Very bad dizziness or passing out.
• Chest pain or pressure.
• Shortness of breath.
• Change in how you act.
• Hallucinations (seeing or hearing things that are not there).
• Mood changes.
• Muscle pain.
• Muscle stiffness.
• Dark urine.
• Strong urges that are hard to control (such as eating, gambling, sex, or spending money).
• A skin lump or growth.
• Change in color or size of a mole.
• Trouble controlling body movements that is new or worse.
• Bad dreams.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness.
• Feeling sleepy.
• Headache.
• Sweating a lot.
• Not able to sleep.
• Not hungry.
• Upset stomach or throwing up.
• Loose stools (diarrhea).
• Hard stools (constipation).
• Feeling tired or weak.
• Change in urine color.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Patients should be instructed to take Tolcapone tablets only as prescribed.

Tolcapone tablets should not be used by patients until there has been a complete discussion of the risks and the patient has provided written acknowledgement that the risks have been explained (see PATIENT ACKNOWLEDGEMENT OF RISKS section).

Inform patients about clinical signs and symptoms that suggest the onset of hepatic injury (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness) (see WARNINGS). If symptoms of hepatic failure occur, patients should be advised to contact their physician immediately.

Inform patients of the need to have regular blood tests to monitor liver enzymes.

Advise patients that sleepiness or drowsiness may occur and that they should not drive a car or operate other complex machinery until they have gained sufficient experience on Tolcapone tablets to gauge whether or not it adversely affects their mental and/or motor performance. Advise patients to exercise caution while driving, operating machines, or working at heights during treatment with Tolcapone tablets. Because of the possible additive sedative effects, caution should also be used when patients are taking other CNS depressants in combination with Tolcapone tablets. Inform patients that nausea may occur, especially at the initiation of treatment with Tolcapone tablets.

Inform patients that hallucinations and other psychotic-like behavior may occur.

Advise patients about the possibility of developing or worsening of existing dyskinesia and/or dystonia after starting Tolcapone tablets.

Advise patients that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Advise patients to rise slowly, especially after long periods of sitting or lying down. Hypotension may be more likely when patients first start treatment with Tolcapone tablets.

Instruct patients and caregivers to report intense urges to gamble, increased sexual urges, increase in spending money, binge eating, and other intense urges as well as the inability to control these urges to the prescriber while taking Tolcapone tablets.

Although Tolcapone tablets has not been shown to be teratogenic in animals, it is always given in conjunction with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in the rabbit. Accordingly, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS: Pregnancy).

Tolcapone is excreted into maternal milk in rats. Because of the possibility that Tolcapone may be excreted into human milk, advise patients to notify their physicians if they intend to breastfeed or are breastfeeding an infant.

Protein Binding

Although Tolcapone is highly protein bound, in vitro studies have shown that Tolcapone at a concentration of 50 µg/mL did not displace other highly protein-bound drugs from their binding sites at therapeutic concentrations. The experiments included warfarin (0.5 to 7.2 µg/mL), phenytoin (4.0 to 38.7 µg/mL), tolbutamide (24.5 to 96.1 µg/mL) and digitoxin (9.0 to 27.0 µg/mL).

Drugs Metabolized by Catechol-O-Methyltransferase (COMT)

Tolcapone may influence the pharmacokinetics of drugs metabolized by COMT. However, no effects were seen on the pharmacokinetics of the COMT substrate carbidopa. The effect of Tolcapone on the pharmacokinetics of other drugs of this class such as α-methyldopa, dobutamine, apomorphine, and isoproterenol has not been evaluated. A dose reduction of such compounds should be considered when they are co-administered with Tolcapone.

Effect of Tolcapone on the Metabolism of Other Drugs

In vitro experiments have been performed to assess the potential of Tolcapone to interact with isoenzymes of cytochrome P450 (CYP). 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 in vitro. The absence of an interaction with desipramine, a drug metabolized by cytochrome P450 2D6, was also confirmed in an in vivo study where Tolcapone did not change the pharmacokinetics of desipramine.

Due to its affinity to cytochrome P450 2C9 in vitro, Tolcapone may interfere with drugs, whose clearance is dependent on this metabolic pathway, such as tolbutamide and warfarin. However, in an in vivo interaction study, Tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions involving cytochrome P450 2C9 appear unlikely. Similarly, Tolcapone did not affect the pharmacokinetics of desipramine, a drug metabolized by cytochrome P450 2D6, indicating that interactions with drugs metabolized by that enzyme are unlikely. Since clinical information is limited regarding the combination of warfarin and Tolcapone, coagulation parameters should be monitored when these two drugs are co-administered.

Drugs That Increase Catecholamines

Tolcapone did not influence the effect of ephedrine, an indirect sympathomimetic, on hemodynamic parameters or plasma catecholamine levels, either at rest or during exercise. Since Tolcapone did not alter the tolerability of ephedrine, these drugs can be co-administered.

When Tolcapone tablets was given together with levodopa/carbidopa and desipramine, there was no significant change in blood pressure, pulse rate and plasma concentrations of desipramine. Overall, the frequency of adverse events increased slightly. These adverse events were predictable based on the known adverse reactions to each of the three drugs individually. Therefore, caution should be exercised when desipramine is administered to Parkinson's disease patients being treated with Tolcapone tablets and levodopa/carbidopa.

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

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.

Tolcapone tablets are supplied as film-coated tablets containing 100 mg Tolcapone. The 100 mg beige to yellowish beige tablet is hexagonal and biconvex. Debossed on one side of the 100 mg tablet is TASMAR and the tablet strength (100), on the other side is a V.

Tolcapone tablets 100 mg: bottles of 90 (NDC 68682-938-90).

Storage

Store at controlled room temperature 20°C to 25°C (68°F to 77°F) in tight containers as defined in USP/NF.

Manufactured for:
Oceanside Pharmaceuticals, a division of
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA

Manufactured by:
Valeant Pharmaceuticals International, Inc.
Steinbach, MB R5G 1Z7, Canada

9461801-20001814

06/17

NDC 68682-938-90
Rx only

Tolcapone
Tablets

100 mg
90 Tablets

OCEANSIDE
PHARMACEUTICALS

In patients with moderate cirrhotic liver disease, clearance and Vd is reduced about 50%. Do not initiate therapy if the patient exhibits clinical evidence of active liver disease or 2 ALT or AST values greater than the ULN.

Tolcapone may be taken with or without food.