- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyOne 200 mg tablet is taken with each levodopa/dopa decarboxylase inhibitor dose. The maximum recommended dose is 200 mg ten times daily, i.e. 2,000 mg of entacapone. Entacapone enhances the effects of levodopa. Hence, to reduce levodopa-related dopaminergic adverse reactions, e.g. dyskinesias, nausea, vomiting and hallucinations, it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating entacapone treatment. The daily dose of levodopa should be reduced by about 10-30% by extending the dosing intervals and/or by reducing the amount of levodopa per dose, according to the clinical condition of the patient.If entacapone treatment is discontinued, it is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms.Entacapone increases the bioavailability of levodopa from standard levodopa/benserazide preparations slightly (5-10%) more than from standard levodopa/carbidopa preparations. Hence, patients who are taking standard levodopa/benserazide preparations may need a larger reduction of levodopa dose when entacapone is initiated.
Patients with renal impairmentRenal insufficiency does not affect the pharmacokinetics of entacapone and there is no need for dose adjustment. However, for patients who are receiving dialysis therapy, a longer dosing interval may be considered (see section 5.2).
Patients with hepatic impairmentSee section 4.3.
Older peopleNo dosage adjustment of entacapone is required for older people.
Paediatric populationThe safety and efficacy of Comtess in children below age 18 have not been established. No data are available.
Method of administrationEntacapone is administered orally and simultaneously with each levodopa/carbidopa or levodopa/benserazide dose. Entacapone can be taken with or without food (see section 5.2).
PregnancyNo overt teratogenic or primary foetotoxic effects were observed in animal studies in which the exposure levels of entacapone were markedly higher than the therapeutic exposure levels. As there is no experience in pregnant women, entacapone should not be used during pregnancy.
Breast-feedingIn animal studies entacapone was excreted in milk. The safety of entacapone in infants is unknown. Women should not breast-feed during treatment with entacapone.
Summary of the safety profileThe most frequent adverse reactions caused by entacapone relate to the increased dopaminergic activity and occur most commonly at the beginning of treatment. Reduction of levodopa dosage decreases the severity and frequency of these reactions. The other major class of adverse reactions are gastrointestinal symptoms, including nausea, vomiting, abdominal pain, constipation and diarrhoea. Urine may be discoloured reddish-brown by entacapone, but this is a harmless phenomenon.Usually the adverse reactions caused by entacapone are mild to moderate. In clinical studies the most common adverse reactions leading to discontinuation of entacapone treatment have been gastrointestinal symptoms (e.g. diarrhoea, 2.5%) and increased dopaminergic adverse reactions of levodopa (e.g. dyskinesias, 1.7%).Dyskinesias (27%), nausea (11%), diarrhoea (8%), abdominal pain (7%) and dry mouth (4.2%) were reported significantly more often with entacapone than with placebo in pooled data from clinical studies involving 406 patients taking the medicinal product and 296 patients taking placebo.Some of the adverse reactions, such as dyskinesia, nausea, and abdominal pain, may be more common with the higher doses (1,400 to 2,000 mg per day) than with the lower doses of entacapone.
Tabulated list of adverse reactionsThe following adverse reactions, listed below in Table 1, have been accumulated both from clinical studies with entacapone and since the introduction of entacapone into the market.
Table 1. Adverse drug reactions*
|Common:||Insomnia, hallucinations, confusion, paroniria|
|Nervous system disorders|
|Common:||Parkinsonism aggravated, dizziness, dystonia, hyperkinesia|
|Common:||Ischaemic heart disease events other than myocardial infarction (e.g. angina pectoris)|
|Common:||Diarrhoea, abdominal pain, dry mouth, constipation, vomiting|
|Rare:||Hepatic function tests abnormal|
|Not known:||Hepatitis with mainly cholestatic features (see section 4.4.)|
|Skin and subcutaneous tissue disorders|
|Rare:||Erythematous or maculopapular rash|
|Not known:||Skin, hair, beard and nail discolourations|
|Renal and urinary disorders|
|Very common:||Urine discoloration|
|General disorders and administration site conditions|
|Common:||Fatigue, sweating increased, fall|
|Very rare:||Weight decrease|
Description of selected adverse reactionsEntacapone in association with levodopa has been associated with isolated cases of excessive daytime somnolence and sudden sleep onset episodes.Impulse control disorders: 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 Comtess in association with levodopa (see section 4.4).Isolated cases of NMS have been reported following abrupt reduction or discontinuation of entacapone and other dopaminergic treatments.Isolated cases of rhabdomyolysis have been reported.Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: IrelandHPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie e-mail: email@example.com United KingdomYellow Card Scheme Website: www.mhra.gov.uk/yellowcard
Clinical studiesIn two phase III double-blind studies in a total of 376 patients with Parkinson's disease and end-of-dose motor fluctuations, entacapone or placebo was given with each levodopa/dopa decarboxylase inhibitor dose. The results are given in Table 2. In study I, daily ON time (hours) was measured from home diaries and in study II, the proportion of daily ON time.
Table 2. Daily ON time (Mean ±SD)
|Study I: Daily On time (h)|
|Entacapone (n=85)||Placebo (n=86)||Difference|
|Week 8-24||10.7±2.2||9.4±2.6||1 h 20 min (8.3%) CI95% 45 min, 1 h 56 min|
|Study II: Proportion of daily On time (%)|
|Entacapone (n=103)||Placebo (n=102)||Difference|
|Week 8-24||66.8±14.5||62.8±16.80||4.5% (0 h 35 min) CI95% 0.93%, 7.97%|
General characteristics of the active substance
AbsorptionThere are large intra- and interindividual variations in the absorption of entacapone.The peak concentration (Cmax) in plasma is usually reached about one hour after ingestion of a 200 mg entacapone tablet. The substance is subject to extensive first-pass metabolism. The bioavailability of entacapone is about 35% after an oral dose. Food does not affect the absorption of entacapone to any significant extent.
DistributionAfter absorption from the gastrointestinal tract, entacapone is rapidly distributed to the peripheral tissues with a distribution volume of 20 litres at steady state (Vdss). Approximately 92 % of the dose is eliminated during ß-phase with a short elimination half-life of 30 minutes. The total clearance of entacapone is about 800 ml/min.Entacapone is extensively bound to plasma proteins, mainly to albumin. In human plasma the unbound fraction is about 2.0% in the therapeutic concentration range. At therapeutic concentrations, entacapone does not displace other extensively bound substances (e.g. warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it displaced to any significant extent by any of these substances at therapeutic or higher concentrations.
BiotransformationA small amount of entacapone, the (E)-isomer, is converted to its (Z)-isomer. The (E)-isomer accounts for 95% of the AUC of entacapone. The (Z)-isomer and traces of other metabolites account for the remaining 5%.Data from in vitro studies using human liver microsomal preparations indicate that entacapone inhibits cytochrome P450 2C9 (IC504 µM). Entacapone showed little or no inhibition of other types of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19) (see section 4.5).
EliminationThe elimination of entacapone occurs mainly by non-renal metabolic routes. It is estimated that 80-90% of the dose is excreted in faeces, although this has not been confirmed in man. Approximately 10-20% is excreted in urine. Only traces of entacapone are found unchanged in urine. The major part (95%) of the product excreted in urine is conjugated with glucuronic acid. Of the metabolites found in urine only about 1% have been formed through oxidation.
Characteristics in patientsThe pharmacokinetic properties of entacapone are similar in both young people and older people. The metabolism of the medicinal product is slowed in patients with mild to moderate liver insufficiency (Child-Pugh Class A and B), which leads to an increased plasma concentration of entacapone in both the absorption and elimination phases (see section 4.3). Renal impairment does not affect the pharmacokinetics of entacapone. However, a longer dosing interval may be considered for patients who are receiving dialysis therapy.
Orion Pharma (UK) Limited
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