Chemical formula: C₁₄H₁₁NO₅ Molecular mass: 273.241 g/mol PubChem compound: 4659569
Tolcapone interacts in the following cases:
The combination of MAO-A and MAO-B inhibitors is equivalent to non-selective 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.
Patients with severe renal impairment (creatinine clearance <30 ml/min) should be treated with caution. No information on the tolerability of tolcapone in these populations is available.
In rats and rabbits, embryo-foetal toxicity was observed after tolcapone administration. The potential risk for humans is unknown.
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 co-administration 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 α-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 tolcapone.
Since tolcapone interferes with the metabolism of catecholamines, interactions with other drugs affecting catecholamine levels are theoretically possible.
When tolcapone 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 reactions increased slightly. These adverse reactions were predictable based on the known adverse reactions to each of the three drugs individually. Therefore, caution should be exercised when potent noradrenaline uptake inhibitors such as desipramine, maprotiline, or venlafaxine are administered to Parkinson’s disease patients being treated with tolcapone and levodopa preparations.
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 relevant interactions involving cytochrome CYP2C9 appear unlikely.
Since clinical information is limited regarding the combination of warfarin and tolcapone, coagulation parameters should be monitored when these drugs are co-administered.
In clinical trials, diarrhoea developed in 16% and 18% of patients receiving tolcapone 100 mg tid and 200 mg tid respectively, compared to 8% of patients receiving placebo. Diarrhoea associated with tolcapone usually began 2 to 4 months after initiation of therapy. Diarrhoea led to withdrawal of 5% and 6% of patients receiving tolcapone 100 mg tid and 200 mg tid respectively, compared to 1 % of patients receiving placebo.
Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments such as tolcapone in association with levodopa. Review of treatment is recommended if such symptoms develop.
There are no adequate data from the use of tolcapone in pregnant women. Therefore, tolcapone should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
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 tolcapone.
In rats and rabbits, embryo-foetal toxicity was observed after tolcapone administration. The potential risk for humans is unknown.
No studies on the effects of tolcapone on the ability to drive and use machines have been performed. There is no evidence from clinical studies that tolcapone adversely influences a patient’s ability to drive and use machines. However patients should be advised that their ability to drive and operate machines may be compromised due to their Parkinson’s disease symptoms.
Tolcapone, as a COMT inhibitor, is known to increase the bioavailability of the co-adminstered levodopa. The consequent increase in dopaminergic stimulation can lead to the dopaminergic side effects observed after treatment with COMT inhibitors. Patients being treated with Levodopa and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved.
The most commonly observed adverse reactions associated with the use of tolcapone, occurring more frequently than in placebo-treated patients are listed below. However, tolcapone, 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 reactions commonly leading to discontinuation of tolcapone in clinical trials was diarrhoea.
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 (cannot be estimated from the available data)
Experience with tolcapone obtained in parallel placebo-controlled randomised studies in patients with Parkinson’s disease is shown in the following list, which lists adverse reactions with a potential relationship to tolcapone.
Summary of potentially tolcapone-related adverse reactions, with crude incidence rates for the phase III placebo-controlled studies:
Common: Upper respiratory tract infection
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)
Very common: Dyskinesia, Dystonia, Headache, Dizziness, Somnolence, Orthostatic complaints
Rare: Neuroleptic Malignant Syndrome, Symptom Complex
Common: Hypokinesia, Syncope
Very common: Nausea, Diarrhoea
Common: Vomiting, Constipation, Xerostomia, Abdominal pain, Dyspepsia
Very common: Anorexia
Common: Sweating increased
Common: Urine discoloration
Common: Chest pain, Influenza like illness
Uncommon: Hepatocellular injury, in rare cases with fatal outcome*
Common: Increase of alanine aminotransferase (ALT)
* Adverse reactions for which no frequency could be derived from clinical studies (i.e. where a specific adverse reaction was not observed in clinical trials but was reported post-marketing only) are indicated by an asterisk (*), and the frequency category has been calculated according to EU Guideline.
Increases to more than three times the upper limit of normal (ULN) in alanine aminotransferase (ALT)occurred in 1% of patients receiving tolcapone 100 mg three times daily, and 3% of patients at 200 mg three times daily. Increases were approximately two times more likely in females. The increases usually appeared within 6 to 12 weeks of starting treatment, and were not associated with any clinical signs or symptoms. In about half the cases, transaminase levels returned spontaneously to baseline values whilst patients continued tolcapone treatment. For the remainder, when treatment was discontinued, transaminase levels returned to pre-treatment levels.
Rare cases of severe hepatocellular injury resulting in death have been reported during marketed use.
Isolated cases of patients with symptoms suggestive of Neuroleptic Malignant Syndrome Symptom Complex have been reported following reduction or discontinuation of tolcapone and following introduction of tolcapone when this was accompanied by a significant reduction in other concomitant dopaminergic medications. In addition, rhabdomyolysis, secondary to NMS or severe dyskinesia, has been observed.
Tolcapone and its metabolites are yellow and can cause a harmless intensification in the colour of the patient’s urine.
Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments such as tolcapone in association with Levedopa.
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