Tasmar (Tablets) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Rights Belong To

Valeant Global Acquisition Company, PTE. Ltd. (Switzerland)

ATC Code

N04BX01 (Tolcapone)

Active Substance

Tolcapone (Rec.INN registered by WHO)

Dosage Forms

	Tasmar	Film-coated tablets, 100 mg: 10, 20, 30, 60 or 100 pcs.
		Film-coated tablets, 200 mg: 10, 20, 30, 60 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from pale yellow to light yellow, hexagonal, biconvex, engraved with “ROCHE 100” on one side.

Excipients: calcium hydrogen phosphate, microcrystalline cellulose, povidone K-30, sodium starch glycolate, lactose, talc, magnesium stearate.

Coating composition: hypromellose, talc, yellow iron oxide, ethylcellulose aqueous dispersion, titanium dioxide, triacetin, sodium lauryl sulfate.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
100 pcs. – dark glass bottles (1) – cardboard packs.

Film-coated tablets from orange-yellow to brownish-yellow, hexagonal, biconvex, engraved with “ROCHE 200” on one side.

Excipients: calcium hydrogen phosphate, microcrystalline cellulose, povidone K-30, sodium starch glycolate, lactose, talc, magnesium stearate.

Coating composition: hypromellose, talc, yellow iron oxide, ethylcellulose aqueous dispersion, titanium dioxide, triacetin, sodium lauryl sulfate.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
100 pcs. – dark glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

COMT inhibitor. Drug used as part of combination therapy for Parkinson’s disease

Pharmacotherapeutic Group

COMT inhibitor

Pharmacological Action

A selective, reversible inhibitor of catechol-O-methyltransferase (COMT). When used concomitantly with levodopa and an aromatic amino acid decarboxylase inhibitor (AAADI), it stabilizes levodopa plasma levels by slowing the conversion of levodopa to 3-O-methyldopa. Tolcapone penetrates the blood-brain barrier well. Thus, COMT inhibition occurs both in the brain and peripherally. Stable plasma and brain concentrations of levodopa result in more constant dopaminergic stimulation of the brain, which increases treatment efficacy and allows for a reduction in the daily dose of levodopa.

When Tasmar is administered together with levodopa, the relative bioavailability of levodopa increases approximately 2-fold. This is due to a reduction in the total clearance of levodopa, leading to an increase in its terminal half-life. Usually, the mean maximum plasma concentration of levodopa and the time to reach it do not change. The drug’s effect begins after the first dose and is maintained with long-term use. The maximum effect of the drug is observed when tolcapone is used at a dose of 100-200 mg. When tolcapone was administered with levodopa/AAADI (benserazide or carbidopa), the plasma concentration of 3-O-methyldopa was significantly reduced and was dose-dependent. The effect of tolcapone on the pharmacokinetics of levodopa is the same for all dosage forms of levodopa/benserazide and levodopa/carbidopa preparations.

At the recommended therapeutic dose (100 and 200 mg three times daily), Tasmar, on average, reduces “off” time (“wearing-off phenomenon”) by 20-30% in patients with motor fluctuations receiving levodopa/AAADI. Tasmar allows for a significant reduction in the dose of levodopa in parkinsonian patients with motor fluctuations and reduces the need to increase the dose of levodopa in non-fluctuating patients.

In clinical studies lasting up to 1 year, the effect of Tasmar was maintained in both fluctuating and non-fluctuating patients.

Pharmacokinetics

Within the therapeutic range, the pharmacokinetics of tolcapone are linear and independent of concomitantly administered levodopa/AAADI preparations (benserazide and carbidopa).

Absorption

The drug is rapidly absorbed. The time to reach C_max of tolcapone in blood plasma is about 2 hours. The absolute bioavailability after oral administration is approximately 65%. When tolcapone is administered at a dose of 100 mg three times daily, C_max is about 3 µg/ml, and at a dose of 200 mg three times daily – 6 µg/ml. Food intake delays the absorption of tolcapone, but the relative bioavailability of the drug taken with food is 80-90%.

Distribution

No accumulation occurs when tolcapone is administered at 100 or 200 mg three times daily.

The V_d of tolcapone is 9 L. Tolcapone penetrates tissues insignificantly due to extensive binding to plasma proteins (more than 99.9%). In vitro studies have shown that Tolcapone binds primarily to serum albumin.

Metabolism and Excretion

Tolcapone is almost completely metabolized before being eliminated from the body. Only a very small amount of tolcapone (0.5% of the dose) is found unchanged in the urine. The main metabolic pathway of tolcapone is conjugation to form an inactive glucuronide. In addition, the drug is methylated by COMT (catechol-O-methyltransferase) to 3-O-methyltolcapone and metabolized by the CYP3A4 and CYP2A6 isoenzymes to a primary alcohol, which is then oxidized to form a carboxylic acid. Reduction to an amine with subsequent N-acetylation occurs to a lesser extent. After oral administration, 60% of the dose of the drug and its metabolites is excreted in the urine, 40% in the feces.

Tolcapone is characterized by a low extraction ratio (0.15) and moderate systemic clearance (7 L/h). The T_1/2 of the terminal phase of tolcapone is approximately 2 hours.

Pharmacokinetics in Special Clinical Cases

The pharmacokinetics of tolcapone do not change in moderate liver disease not accompanied by cirrhosis. However, in moderate cirrhosis, the clearance of free tolcapone decreases by almost 50%. As a result of this decrease, the mean concentration of unbound tolcapone may double.

The pharmacokinetics of tolcapone in patients with renal failure have not been studied separately. However, the relationship between tolcapone pharmacokinetics and renal function was studied in a population pharmacokinetic analysis within clinical trials. Data from over 400 patients confirmed that over a wide range of creatinine clearance (30-130 ml/min), the pharmacokinetics of tolcapone are independent of renal function. This can be explained by the fact that very little unchanged tolcapone is excreted in the urine, and its main metabolite, tolcapone glucuronide, is excreted both in urine and in bile (feces).

Indications

• As part of combination therapy with levodopa/benserazide and levodopa/carbidopa preparations in patients with idiopathic parkinsonism and motor fluctuations for whom levodopa is effective but symptoms are not adequately controlled by other available drugs, or who have contraindications to the use of alternative drugs.

ICD codes

Dosage Regimen

Tasmar is administered orally 3 times/day. Each day, the first dose of Tasmar should be taken together with the first dose of levodopa that day, and subsequent doses are taken approximately 6 and 12 hours later.

Tasmar can be taken with meals or between meals. It can be combined with all dosage forms of levodopa/benserazide and levodopa/carbidopa.

The recommended dose of Tasmar is 100 mg three times daily, always in combination with a levodopa/benserazide or levodopa/carbidopa preparation. Only in exceptional cases (when the expected increase in clinical benefit justifies the increased risk of liver adverse reactions) should the dose be increased to 200 mg three times daily. If increasing the drug dose to 200 mg three times daily is not accompanied by additional clinical benefits, the dose should be reduced back to 100 mg three times daily.

In clinical studies, in most patients taking the drug at a daily dose of more than 600 mg, as well as in patients with moderate and severe dyskinesias, the dose of levodopa had to be reduced. These factors, as well as the patient’s sensitivity to changes in levodopa doses, should be taken into account when deciding to reduce the daily dose of levodopa after starting Tasmar. The average reduction in the daily dose of levodopa in those patients who required it was approximately 30%. If the dose of Tasmar is increased to 200 mg three times daily, further adjustment of the levodopa dose may be required.

During treatment with Tasmar, the dose of levodopa should be adjusted to optimize the clinical benefits of combination therapy.

The maximum daily dose of 600 mg should not be exceeded, as this does not lead to an increase in efficacy.

Since an increase in levodopa concentration due to COMT suppression can occur after the first dose of the drug, an increase in the levodopa dose may also be required within the first few days after discontinuation of Tasmar.

Patients with mild or moderate renal impairment do not require dose adjustment. The safety of Tasmar in patients with severe renal impairment with CrCl < 30 ml/min has not been studied.

Adverse Reactions

Data from clinical studies

The most frequent adverse events observed with Tasmar more often than with placebo are dyskinesias (involuntary movements), nausea, sleep disturbances, anorexia, and diarrhea (leading to discontinuation of Tasmar). Diarrhea usually develops 2-4 months after the start of therapy. Its frequency was 8% and 10%. In patients receiving the drug at a dose of 100 mg and 200 mg, diarrhea was the reason for discontinuation in 5% and 6% of patients, respectively, while with placebo, diarrhea was the reason for discontinuation in 1% of patients.

Isolated cases of neuroleptic malignant syndrome (NMS), including rhabdomyolysis and hyperthermia, have been described following abrupt dose reduction or discontinuation of Tasmar and other concomitantly administered dopaminergic drugs. This syndrome is characterized by motor symptoms (muscle rigidity, myoclonus, tremor), changes in mental status (agitation, confusion, stupor, coma), fever, autonomic dysfunction (labile blood pressure, tachycardia), and increased serum CPK levels, which may occur due to myolysis. Although NMS may present with all of these symptoms, in some cases only some of them predominate. In rare cases, rhabdomyolysis occurs secondary to severe dyskinesias or NMS. A higher risk of NMS is characteristic of patients receiving multiple drugs that affect different metabolic pathways in the CNS (e.g., suppression or reduction of dopaminergic activity, COMT suppression, MAO suppression, serotonergic stimulation).

In 1% of patients receiving Tasmar 100 mg three times daily and in 3% of patients receiving 200 mg three times daily, a more than three-fold increase above the upper limit of normal ALT activity was observed. Women are twice as likely to have elevated transaminase levels. This increase usually occurred within 6-12 weeks after the start of treatment and was not accompanied by any clinical symptoms. In approximately half of the cases, ALT levels returned to baseline spontaneously while continuing treatment with Tasmar. In the remaining cases, its activity returned to baseline after drug discontinuation.

Rare cases of severe hepatocellular damage, including fulminant hepatitis with fatal outcome, have been reported.

Contraindications

• Liver disease or elevated liver enzymes above the upper limit of normal (because the risk of liver damage is increased);
• History of neuroleptic malignant syndrome, rhabdomyolysis, severe dyskinesias;
• Hypersensitivity to tolcapone or other components of the drug.

Tasmar should not be prescribed in combination with non-selective MAOIs (e.g., phenelzine and tranylcypromine). The combination of a type A MAO inhibitor with a type B MAO inhibitor is equivalent to non-selective inhibition of MAO activity, therefore both inhibitors cannot be prescribed together with Tasmar and levodopa.

Use in Pregnancy and Lactation

Tasmar is always prescribed in combination with levodopa preparations, which are known to cause skeletal and visceral malformations in rabbits. No clinical studies have been conducted on the use of Tasmar in pregnant women.

The use of Tasmar during pregnancy is possible only if the potential benefit to the mother outweighs the potential risk to the fetus.

Animal studies have shown that Tolcapone is excreted in breast milk. The safety of tolcapone for breastfed infants has not been established; therefore, a decision should be made to discontinue breastfeeding during treatment with Tasmar.

Use in Hepatic Impairment

Contraindicated in liver disease or when liver enzyme activity is elevated above the upper limit of normal (because the risk of liver damage is increased).

Use in Renal Impairment

Patients with mild or moderate renal impairment do not require dose adjustment. The safety of Tasmar in patients with severe renal impairment with CrCl less than 30 ml/min has not been studied.

Special Precautions

Given that Tasmar must be prescribed in combination with levodopa/benserazide and levodopa/carbidopa, the instructions for use of these medicinal products can also be used when they are used concomitantly with Tasmar.

Due to the risk of developing fulminant hepatitis, which can be fatal, Tasmar should not be considered a first-line drug in addition to levodopa/benserazide and carbidopa/benserazide. Considering the risk of liver damage and the fact that the symptomatic effect of Tasmar appears quite quickly, in patients who do not show significant clinical improvement within 3 weeks after starting treatment, the drug should be discontinued.

Liver function tests (AST, ALT activity) should be determined before starting treatment with Tasmar, then every 2 weeks during the first year of therapy, every 4 weeks for the next 6 months, and every 8 weeks thereafter. If the drug dose is increased to 200 mg three times daily, an additional check of liver function is necessary before this, and after that, monitoring of transaminase activity is carried out according to the above scheme.

If liver enzyme activity exceeds the ULN, the drug should be discontinued. It should also be discontinued and liver function immediately evaluated if complaints and clinical symptoms appear that suggest the development of hepatotoxicity or hepatitis (persistent nausea, weakness, drowsiness, loss of appetite, jaundice, dark urine, itching and pain in the right upper quadrant).

Dyskinesia, nausea, and other side effects of levodopa may be enhanced when taking Tasmar. They can be alleviated by reducing the dose of levodopa.

If symptoms of neuroleptic malignant syndrome occur after discontinuation of Tasmar, the attending physician should decide on increasing the dose of levodopa.

Tolcapone and its metabolites are yellow in color and may enhance the coloration of the patient’s urine, which is harmless.

Caution should be exercised when treating parkinsonian patients with severe renal failure (CrCl less than 30 ml/min). There are no data on the tolerability of tolcapone in this group of patients.

There are no data on the simultaneous use of Tasmar and type A MAO inhibitors, so drugs in such combination should be prescribed with caution.

When used concomitantly with Tasmar, selective type B MAO inhibitors (e.g., selegiline) should not be used in doses exceeding the recommended ones (e.g., 10 mg/day for selegiline).

Overdose

Symptoms: the maximum dose of tolcapone taken by a person was 800 mg three times daily, both with and without concomitant levodopa intake. In this case, the maximum plasma concentration of tolcapone averaged 30 µg/ml (for comparison – 3 µg/ml and 6 µg/ml when taking doses of 100 mg and 200 mg of tolcapone, respectively). In such cases, nausea, vomiting, and dizziness occurred, especially when levodopa was taken concomitantly.

Treatment: hospitalization is recommended. Supportive therapy is indicated. Based on the physicochemical properties of the compound, hemodialysis is not effective.

Drug Interactions

Although Tolcapone is highly bound to plasma proteins, in vitro studies have shown that at therapeutic concentrations the drug does not displace other drugs from their protein binding sites.

Tasmar may affect the pharmacokinetics of drugs metabolized by COMT. However, no effect on the pharmacokinetics of the COMT substrate carbidopa was observed. An interaction with benserazide was identified, which may lead to increased concentrations of benserazide and its active metabolite. The severity of this effect depends on the dose of benserazide. Plasma concentrations of benserazide after simultaneous administration of tolcapone and levodopa/benserazide-25 mg did not exceed the concentrations observed after taking levodopa/benserazide alone. After simultaneous administration of tolcapone and levodopa/benserazide-50 mg, the plasma concentration of benserazide may exceed that which usually occurs after taking levodopa and benserazide alone.

The effect of tolcapone on the pharmacokinetics of other drugs metabolized by COMT (such as α-methyldopa, dobutamine, apomorphine, epinephrine, isoproterenol and isoprenaline) has not been studied. When prescribing these drugs together with Tasmar, the issue of reducing their dose should be considered.

Having affinity for cytochrome P₄₅₀2C9 in vitro, Tolcapone may theoretically affect drugs whose clearance depends on this metabolic pathway (tolbutamide and warfarin). However, no such interaction has been found in practice. Since clinical information on the combination of warfarin and tolcapone is limited, coagulation parameters should be monitored when these drugs are taken concomitantly.

Drug interaction due to competition for glucuronidation is unlikely because the liver’s capacity for glucuronidation is very high. Tolcapone did not alter the pharmacokinetics of desipramine, despite the fact that glucuronidation is the primary metabolic pathway for both drugs.

Tolcapone did not affect the action of ephedrine (an indirect sympathomimetic), hemodynamic parameters, or plasma catecholamine levels, either at rest or during physical exercise. Since Tolcapone does not affect the tolerability of ephedrine, the simultaneous administration of this combination is possible.

When Tasmar was administered together with levodopa/carbidopa preparations and desipramine, no significant changes in blood pressure, heart rate, or plasma desipramine concentration were observed. The overall incidence of adverse events increased somewhat. These adverse events were predictable based on the known side effects of each of the three drugs individually. Therefore, caution should be exercised when prescribing desipramine to parkinsonian patients receiving Tasmar and levodopa preparations.

In clinical studies, the side effect profile in patients receiving Tasmar and levodopa was the same, regardless of the simultaneous use of selegiline (a type B MAO inhibitor). There are no data on the combination of Tasmar with type A MAO inhibitors.

Storage Conditions

List B. The drug should be stored out of the reach of children.

Shelf Life

The shelf life for film-coated tablets 100 mg is 5 years, for film-coated tablets 200 mg is 4 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.