Tasmar · 4.5 Interaction with other medicinal products and other forms of interaction · 2

HOS-083313 · has-adverse-reaction-information · PDF-Seite 7

The most commonly observed adverse reactions associated with the use of Tasmar, occurring more frequently than in placebo-treated patients are listed in the table below. However, Tasmar, as a COMT inhibitor, is known to increase the bioavailability of the co-administered levodopa. The consequent increase in dopaminergic stimulation can lead to the dopaminergic side effects observed after treatment with COMT inhibitors. The most common of these are increased dyskinesia, nausea, vomiting, abdominal pain, syncope, orthostatic complains, constipation, sleep disorders, somnolence, hallucination. The only adverse reaction commonly leading to discontinuation of Tasmar in clinical trials was diarrhoea (see section 4.4). 7 Very common (≥1/10) Common (≥1/100 to < 1/10) Uncommon (≥1/1,000 to < 1/100) Rare (≥1/10,000 to < 1/1,000) Very rare (<1/10,000) Not known (frequency cannot be estimated from the available data) Experience with Tasmar obtained in parallel placebo-controlled randomised studies in patients with Parkinson’s disease is shown in the following table, which lists adverse reactions with a potential relationship to Tasmar. Summary of potentially Tasmar-related adverse reactions, with crude incidence rates for the phase III placebo-controlled studies: System organ class Incidence Adverse Events Infections and infestations Common Upper respiratory tract infection Psychiatric disorders Very common Sleep disorder Dreaming excessive Somnolence Confusion Hallucination Rare Impulse control disorders* (Libido increased, hypersexuality, pathological gambling, compulsive spending or buying, binge eating, compulsive eating (see section 4.4)) Nervous system disorders Very common Dyskinesia Dystonia

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HOS-083319 · has-adverse-reaction-information · PDF-Seite 19

The most commonly observed adverse reactions associated with the use of Tasmar, occurring more frequently than in placebo-treated patients are listed in the table below. However, Tasmar, as a COMT inhibitor, is known to increase the bioavailability of the co-administered levodopa. The consequent increase in dopaminergic stimulation can lead to the dopaminergic side effects observed after treatment with COMT inhibitors. The most common of these are increased dyskinesia, nausea, vomiting, abdominal pain, syncope, orthostatic complains, constipation, sleep disorders, somnolence, hallucination. 19 The only adverse reaction commonly leading to discontinuation of Tasmar in clinical trials was diarrhoea (see section 4.4). Very common (≥1/10) Common (≥1/100 to < 1/10) Uncommon (≥1/1,000 to < 1/100) Rare (≥1/10,000 to < 1/1,000) Very rare (<1/10,000) Not known (frequency cannot be estimated from the available data) Experience with Tasmar obtained in parallel placebo-controlled randomised studies in patients with Parkinson’s disease is shown in the following table, which lists adverse reactions with a potential relationship to Tasmar. Summary of potentially Tasmar-related adverse reactions, with crude incidence rates for the phase III placebo-controlled studies: System organ class Incidence Adverse Events Infections and infestations Common Upper respiratory tract infection Psychiatric disorders Very common Sleep disorder Dreaming excessive Somnolence Confusion Hallucination Rare Impulse control disorders* (Libido increased, hypersexuality, pathological gambling, compulsive spending or buying, binge eating, compulsive eating (see section 4.4)) Nervous system disorders Very common Dyskinesia Dystoni

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HOS-083315 · has-contraindication-information · PDF-Seite 16

• Hypersensitivity to tolcapone or any of its other ingredients listed in section 6.1. • Evidence of liver disease or increased liver enzymes. • Severe dyskinesia. • A previous history of Neuroleptic Malignant Syndrome (NMS) Symptom Complex and/or nontraumatic rhabdomyolysis or hyperthermia. • Phaeochromocytoma. • Treatment with non-selective mono amino oxidase (MAO) inhibitors.

HOS-083309 · has-contraindication-information · PDF-Seite 4

• Hypersensitivity to tolcapone or any of its other ingredients listed in section 6.1. • Evidence of liver disease or increased liver enzymes. • Severe dyskinesia. • A previous history of Neuroleptic Malignant Syndrome (NMS) Symptom Complex and/or nontraumatic rhabdomyolysis or hyperthermia. • Phaeochromocytoma. • Treatment with non-selective mono amino oxidase (MAO) inhibitors.

HOS-083314 · has-indication-information · PDF-Seite 14

Tasmar is indicated in combination with levodopa/benserazide or levodopa/carbidopa for use in patients with levodopa-responsive idiopathic Parkinson’s disease and motor fluctuations, who failed to respond to or are intolerant of other catechol-O-methyltransferase (COMT) inhibitors (see section 5.1). Because of the risk of potentially fatal, acute liver injury, Tasmar should not be considered as a firstline adjunct therapy to levodopa/benserazide or levodopa/carbidopa (see sections 4.4 and 4.8). Since Tasmar should be used only in combination with levodopa/benserazide and levodopa/carbidopa, the prescribing information for these levodopa preparations is also applicable to their concomitant use with Tasmar.

HOS-083308 · has-indication-information · PDF-Seite 2

Tasmar is indicated in combination with levodopa/benserazide or levodopa/carbidopa for use in patients with levodopa-responsive idiopathic Parkinson’s disease and motor fluctuations, who failed to respond to or are intolerant of other catechol-O-methyltransferase (COMT) inhibitors (see section 5.1). Because of the risk of potentially fatal, acute liver injury, Tasmar should not be considered as a firstline adjunct therapy to levodopa/benserazide or levodopa/carbidopa (see sections 4.4 and 4.8). Since Tasmar should be used only in combination with levodopa/benserazide and levodopa/carbidopa, the prescribing information for these levodopa preparations is also applicable to their concomitant use with Tasmar.

HOS-083311 · has-interaction-information · PDF-Seite 6

Tasmar, as a COMT inhibitor, is known to increase the bioavailability of the co-administered levodopa. The consequent increase in dopaminergic stimulation can lead to the dopaminergic adverse reactions observed after treatment with COMT inhibitors. The most common of these are increased dyskinesia, nausea, vomiting, abdominal pain, syncope, orthostatic complains, constipation, sleep disorders, somnolence, hallucination. Levodopa has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with levodopa. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines (see section 4.7). Furthermore a reduction of levodopa dose or termination of therapy may be considered. Catechols and other drugs metabolised by catechol-O-methyltransferase (COMT) Tolcapone may influence the pharmacokinetics of drugs metabolised by COMT. No effects were seen on the pharmacokinetics of the COMT substrate carbidopa. An interaction was observed with benserazide, which may lead to increased levels of benserazide and its active metabolite. The magnitude of the effect was dependent on the dose of benserazide. The plasma concentrations of benserazide observed after co-administration of tolcapone and benserazide-25 mg/levodopa were still within the range of values observed with levodopa/benserazide alone. On the other hand, after coadministration of tolcapone and benserazide-50 mg/levodopa the benserazide plasma concentrations could be increased above the levels usually observed with levodopa/benserazide alone. The effect of tolcapone on the pharmacokinetics of other drugs metabolised by COMT such as -methyldopa, dobutamine, apomorphine, adrenaline and isoprenaline have not been evaluated. The prescriber should be observant of adverse reactions caused by putative increased plasma levels of these drugs when combined with Tasmar. Effect of tolcapone on the metabolism of other drugs Due to its affinity for cytochrome CYP2C9 in vitro, tolcapone may interfere with drugs whose clearance is dependent on this metabolic pathway, such as tolbutamide and warfarin. In an interaction study, tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically rel

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HOS-083317 · has-interaction-information · PDF-Seite 18

Tasmar, as a COMT inhibitor, is known to increase the bioavailability of the co-administered levodopa. The consequent increase in dopaminergic stimulation can lead to the dopaminergic adverse reactions observed after treatment with COMT inhibitors. The most common of these are increased dyskinesia, nausea, vomiting, abdominal pain, syncope, orthostatic complains, constipation, sleep disorders, somnolence, hallucination. Levodopa has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with levodopa. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines (see section 4.7). Furthermore a reduction of levodopa dose or termination of therapy may be considered. Catechols and other drugs metabolised by catechol-O-methyltransferase (COMT) Tolcapone may influence the pharmacokinetics of drugs metabolised by COMT. No effects were seen on the pharmacokinetics of the COMT substrate carbidopa. An interaction was observed with benserazide, which may lead to increased levels of benserazide and its active metabolite. The magnitude of the effect was dependent on the dose of benserazide. The plasma concentrations of benserazide observed after co-administration of tolcapone and benserazide-25 mg/levodopa were still within the range of values observed with levodopa/benserazide alone. On the other hand, after coadministration of tolcapone and benserazide-50 mg/levodopa the benserazide plasma concentrations could be increased above the levels usually observed with levodopa/benserazide alone. The effect of tolcapone on the pharmacokinetics of other drugs metabolised by COMT such as -methyldopa, dobutamine, apomorphine, adrenaline and isoprenaline have not been evaluated. The prescriber should be observant of adverse reactions caused by putative increased plasma levels of these drugs when combined with Tasmar. Effect of tolcapone on the metabolism of other drugs Due to its affinity for cytochrome CYP2C9 in vitro, tolcapone may interfere with drugs whose clearance is dependent on this metabolic pathway, such as tolbutamide and warfarin. In an interaction study, tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically rel

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HOS-083318 · has-pregnancy-information · PDF-Seite 19

Pregnancy There are no adequate data from the use of tolcapone in pregnant women. Therefore, Tasmar should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Breast-feeding In animal studies, tolcapone was excreted into maternal milk. The safety of tolcapone in infants is unknown; therefore, women should not breast-feed during treatment with Tasmar. Fertility In rats and rabbits, embryo-foetal toxicity was observed after tolcapone administration (see section 5.3). The potential risk for humans is unknown.

HOS-083312 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are no adequate data from the use of tolcapone in pregnant women. Therefore, Tasmar should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Breast-feeding In animal studies, tolcapone was excreted into maternal milk. The safety of tolcapone in infants is unknown; therefore, women should not breast-feed during treatment with Tasmar. Fertility In rats and rabbits, embryo-foetal toxicity was observed after tolcapone administration (see section 5.3). The potential risk for humans is unknown.

HOS-083316 · has-warning-information · PDF-Seite 16

Tasmar therapy should only be initiated by physicians experienced in the management of advanced Parkinson’s disease, to ensure an appropriate risk-benefit assessment. Tasmar should not be prescribed until there has been a complete informative discussion of the risks with the patient. Tasmar should be discontinued if substantial clinical benefits are not seen within 3 weeks of the initiation of the treatment regardless of dose. Liver injury Because of the risk of rare but potentially fatal acute liver injury, Tasmar is only indicated for use in patients with levodopa-responsive idiopathic Parkinson’s disease and motor fluctuations, who failed to respond to or are intolerant of other COMT inhibitors. Periodic monitoring of liver enzymes cannot reliably predict the occurrence of fulminant hepatitis. However, it is generally believed that early detection of medicine-induced hepatic injury along with immediate withdrawal of the suspect medication enhances the likelihood for recovery. Liver injury has most often occurred between 1 month and 6 months after starting treatment with Tasmar. Additionally late onset hepatitis after approximately 18 months of treatment has been reported rarely. It should also be noted that female patients may have a higher risk of liver injury (see section 4.8). Before starting treatment: If liver function tests are abnormal or there are signs of impaired liver function, Tasmar should not be prescribed. If Tasmar is to be prescribed, the patient should be informed about the signs and symptoms which may indicate liver injury, and to contact the physician immediately. During treatment: Liver function should be monitored every 2 weeks for the first year of therapy, every 4 weeks for the next 6 months and every 8 weeks thereafter. If the dose is increased to 200 mg tid, liver enzyme monitoring should take place before increasing the dose and then be re-initiated following the sequence of frequencies as above. Treatment should be immediately discontinued if ALT and/or AST exceed the upper limit of normal or if symptoms or signs suggesting the onset of hepatic failure (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, right upper quadrant tenderness) develop. If treatment is discontinued: Patients who show evidence of acute liver injury while on Tasmar and are withdrawn from the medicinal product may be at increased risk for liver injury if Tasmar is reintroduced. Accordingly, such patients should not be co

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HOS-083310 · has-warning-information · PDF-Seite 4

Tasmar therapy should only be initiated by physicians experienced in the management of advanced Parkinson’s disease, to ensure an appropriate risk-benefit assessment. Tasmar should not be prescribed until there has been a complete informative discussion of the risks with the patient. Tasmar should be discontinued if substantial clinical benefits are not seen within 3 weeks of the initiation of the treatment regardless of dose. Liver injury Because of the risk of rare but potentially fatal acute liver injury, Tasmar is only indicated for use in patients with levodopa-responsive idiopathic Parkinson’s disease and motor fluctuations, who failed to respond to or are intolerant of other COMT inhibitors. Periodic monitoring of liver enzymes cannot reliably predict the occurrence of fulminant hepatitis. However, it is generally believed that early detection of medicine-induced hepatic injury along with immediate withdrawal of the suspect medication enhances the likelihood for recovery. Liver injury has most often occurred between 1 month and 6 months after starting treatment with Tasmar. Additionally late onset hepatitis after approximately 18 months of treatment has been reported rarely. It should also be noted that female patients may have a higher risk of liver injury (see section 4.8). Before starting treatment: If liver function tests are abnormal or there are signs of impaired liver function, Tasmar should not be prescribed. If Tasmar is to be prescribed, the patient should be informed about the signs and symptoms which may indicate liver injury, and to contact the physician immediately. During treatment: Liver function should be monitored every 2 weeks for the first year of therapy, every 4 weeks for the next 6 months and every 8 weeks thereafter. If the dose is increased to 200 mg tid, liver enzyme monitoring should take place before increasing the dose and then be re-initiated following the sequence of frequencies as above. Treatment should be immediately discontinued if ALT and/or AST exceed the upper limit of normal or if symptoms or signs suggesting the onset of hepatic failure (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, right upper quadrant tenderness) develop. If treatment is discontinued: Patients who show evidence of acute liver injury while on Tasmar and are withdrawn from the medicinal product may be at increased risk for liver injury if Tasmar is reintroduced. Accordingly, such patients should not be co

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