Entacapone

When ATH:
N04BX02

Pharmacological action

Pharmacological action – antiparkinsonian. COMT Inhibitor.

Entacapone is a new class of drugs - inhibitors catechol-O-methyltransferase (KOMT). This drug is reversible, specific and mainly peripherally acting, which has been designed for simultaneous use with levodopa. Entacapone, inhibiting the enzyme COMT, inhibits metabolic degradation of levodopa, and turning it into a 3-O-methyldopa (3-UMD). This leads to an increase in the bioavailability of levodopa and increase the amount of levodopa, reaching the brain. Action entacapone confirmed by clinical studies, where it was shown, that the combined use of entacapone with levodopa increases the "on" time for 16% and reduces the "off" on 24%.

Entacapone inhibits the enzyme COMT predominantly in peripheral tissues. Inhibition of erythrocyte COMT clearly depends on the concentration in the plasma entacapone, indicating the reversible nature of COMT inhibition.

Pharmacokinetics

The absorption of entacapone is characterized by significant variability. The maximum plasma concentration (C max ) It reached approximately 1 hour after taking the tablets entacapone, contains 200 mg. The drug is largely metabolized in the "first pass" through the liver. After oral bioavailability of entacapone is about 35%. Food does not significantly affect the absorption of entacapone.

Entacapone is rapidly distributed to the peripheral tissues. The volume of distribution at steady state is 20 l. About 92% the dose is excreted in the b-phase, half-life is very short and is 30 minutes.

Entacapone has a high degree of binding to plasma proteins, mostly to albumin. Once the therapeutic concentration range of the unbound fraction in human plasma is about 2%. The therapeutic range of concentrations of entacapone does not displace due to proteins other drugs, characterized by a high degree of binding (eg, warfarin, salicylic acid, phenylbutazone, or diazepam). The substances in therapeutic or higher concentrations, in turn, not to displace any significant degree of entacapone due to plasma proteins.

A small amount of entacapone, which (E)-isomer, It turns into (FROM)-isomer. (E)-isomer of 95% the magnitude of the area under the curve "concentration-time" (AUC) entacapone. Remaining 5% up (FROM)-isomer, and trace amounts of other metabolites.

About 80-90% of the dose is excreted in the feces of entacapone (Although clinical trials, conducted in humans, these data have not yet been fully confirmed). About 10-20% the drug is excreted in urine, and mainly (95%) as conjugates with glucuronic acid. Unmodified entacapone found in urine in trace amounts only. Among the metabolites found in the urine only 1% represented by the compounds, formed as a result of oxidation reactions. The total clearance of entacapone is about 800 ml / min.

Pharmacokinetic parameters of entacapone in adults young and old alike. The metabolism of entacapone is slowed in patients with mild and moderate hepatic impairment, which leads to the increase of its plasma concentrations in the suction phase, and a phase elimination. Renal impairment does not affect the pharmacokinetics of entacapone. Nonetheless, in the treatment of patients, hemodialysis, It should take into account the need for lengthening the intervals between doses of the drug.

Testimony

As a complement to therapy with levodopa / benserazide or levodopa / carbidopa.

For the treatment of patients with Parkinson's disease and motor fluctuations end of dose where, when the application of the above combined preparations does not lead to stabilization of the.

Dosage regimen

Entacapone appointed interior, simultaneously with each dose of levodopa / carbidopa or levodopa / benserazide. In the case of simultaneous use of entacapone with levodopa instructions for use of these drugs are not changed.

Entacapone can be taken with food, and fasting.

One tablet, contains 200 mg entacapone, taken together with each dose of the drug, consisting of levodopa and a dopa decarboxylase inhibitor.

Entacapone enhances the effects of levodopa. Concerning, to reduce the side effects of levodopa, dopaminergic (including dyskinesias, nausea, vomiting and hallucinations) in the first days and weeks after initiation of therapy entacapone often necessary correction dosing regimen of levodopa. The daily dose of levodopa should be reduced by about 10-30%, both by increasing the intervals between doses, and / or by reducing single dose, guided by the clinical status of the patient.

In the event of termination of treatment entacapone, to achieve adequate control of the symptoms of Parkinson's disease must be 'corrected dosing regimen of other antiparkinsonian drugs, especially levodopa .

Under the influence of entacapone bioavailability of levodopa from standard levodopa / benserazide increases several more (on 5-10%), than levodopa / carbidopa. Therefore, early treatment entacapone patients, take the drug levodopa / benserazide, It may require a significant reduction in the dose of levodopa.

In renal failure the pharmacokinetics of entacapone does not change, Consequently, there is no need to change dosage. Patients, hemodialysis, must be, However, bear in mind the possibility of increasing the intervals between doses of the drug.

For elderly patients correction mode is not required.

Side effect

Often – dyskinesia, nausea, and discoloration of urine (urine may acquire a reddish-brown color, this phenomenon is harmless.

Often – diarrhea, increased effects of Parkinson's disease, dizziness , stomach ache, insomnia, dry mouth, fatigue, hallucinations, constipation, dystonia, increased perspiration, giperkineziya , headache, leg cramps, disorientation, nightmares, drop, orthostatic hypotension, expressed dizziness and tremor.

Most adverse events, caused by entacapone, associated with increased dopaminergic activity and are usually observed at the start of treatment. By reducing levodopa dose decreases the severity and frequency of occurrence of these phenomena.

Entacapone caused adverse effects are usually mild or moderately expressed. The reason for stopping treatment entacapone adverse events were usually from the gastrointestinal tract (eg, diarrhea, 2,5%) and dopaminergic symptoms (eg, dyskinesias, 1,7%).

When using entacapone, compared to placebo, more often observed such phenomena as dyskinesia (27%), nausea (11%), diarrhea (8%), stomach ache (7%) and dry mouth (4,2%).

Some adverse events, Taki how dyskinesia, nausea and abdominal pain, may occur more frequently when higher doses of entacapone (1,4-2,0 g per day), than when using lower doses.

There are reports of a slight decrease in hemoglobin levels , hematocrit, and red blood cells during treatment with entacapone. The basis of this mechanism may lie reduce iron absorption from the gastrointestinal tract. During prolonged (6 months) treatment entacapone a clinically significant decrease in hemoglobin was observed in 1,5% patients.

There are rare reports of clinically significant increases in liver enzymes.

Contraindications

Hypersensitivity.

Pregnancy.

Lactation.

Abnormal liver function.

Pheochromocytoma (because of the increased risk of hypertensive crisis).

Concomitant use of entacapone with non-selective MAO inhibitors (MAO-A and MAO-B) eg, phenelzine, tranylcypromine.

The simultaneous use of a combination of entacapone and selective inhibitor of MAO-A selective MAO-B inhibitor.

Notes a history of neuroleptic malignant syndrome and / or rhabdomyolysis, not associated with the trauma.

Age to 18 years (in the absence of clinical data for this age group).

Pregnancy and lactation

As experience with entacapone in pregnant women has not, prescribed the drug during pregnancy should not be.

Cautions

Patients with Parkinson's disease rarely rhabdomyolysis marked by severe dyskinesias or neuroleptic malignant syndrome (NMS). There were no reports of similar phenomena in the case of entacapone were reported.

NMS, including rhabdomyolysis and hyperthermia, It is characterized by motor symptoms (rigidity, myoclonus, tremor), changes in the psyche and consciousness (excitation, disorientation, coma ), disorders of the autonomic nervous system (tachycardia, unstable blood pressure) and increased levels of creatinine phosphokinase (CPK) serum. In some cases, there may be only a few of these symptoms.

In controlled studies,, where suddenly canceled entacapone, There were no cases of rhabdomyolysis or CSN. Nonetheless, since rare cases of NMS in patients with Parkinson's disease have been reported with the sudden cancellation of other dopaminergic drugs, doctors should be careful when canceling entacapone. If you need to cancel entacapone, it should be done slowly. If, despite the slow abolition, symptoms do occur, You may need to increase the dose of levodopa .

Entacapone, due to its mechanism of action, may alter the metabolism and increase the effects of drugs, containing a catechol group. Therefore, entacapone should be used with caution in patients, undergoing treatment with, metabolized with the participation of catechol-O-methyltransferase (KOMT), eg, such as rimiterol, Isoprenaline , adrenaline , noradrenaline, Dopamine , doʙutamin , alpha-methyldopa, and apomorphine.

Entacapone is always used as an adjunct to levodopa treatment . Hence, Cautions, related to levodopa therapy, must be considered in the treatment of entacapone. Under the influence of entacapone bioavailability of levodopa from standard levodopa / benserazide increases by 5-10% better, than levodopa / carbidopa. In this regard, with the addition of entacapone to levodopa treatment / benserazide more likely to meet the unwanted side effects of dopaminergic. To reduce levodopa due to the dopaminergic side effects often require dose adjustment of levodopa in the first days or weeks after starting treatment entacapone, taking into account the clinical condition of the patient.

Entacapone can enhance levodopa-induced orthostatic hypotension. Caution is required when assigning patients entacapone, take other medicines, which may cause orthostatic hypotension.

In clinical studies, it was noted, that unwanted dopaminergic effects, eg, dyskinesia, were more common in patients, receiving entacapone and dopamine agonists (such as bromocriptine ), selegiline or amantadine , compared to patients, receiving placebo along with entacapone. Early treatment entacapone may require adjustment of doses of other antiparkinsonian drugs.

Drug Interactions

The simultaneous use of entacapone with selegiline (a selective inhibitor of MAO-B), but the daily dose of selegiline must not exceed 10 mg.