Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1.Pharmacodynamic properties

Pharmacotherapeutic group (ATC code): M01BX

Diclofenac/misoprostol is a fixed combination of a nonsteroidal, anti-inflammatory drug with analgesic properties, and a gastroduodenal mucosal protective prostaglandin E1 analog.

Diclofenac has been shown to have anti-inflammatory and analgesic properties. The mechanism of action is thought to be related to inhibition of prostaglandin synthetase.

Misoprostol is a synthetic prostaglandin E1 analog that enhances several of the factors that maintain gastroduodenal mucosal integrity. It inhibits both stimulated and unstimulated gastric acid secretion.
Misoprostol also maintains gastric mucosal blood flow, and increases duodenal bicarbonate and gastric mucus secretion.

Misoprostol decreases pepsin output, gastric acid output, and gastric fluid volume under basal and under some stimulated conditions.

Pharmacokinetic Properties

5.2.Pharmacokinetic properties

Diclofenac/ misoprostol
The pharmacokinetic profiles of diclofenac and misoprostol administered as the fixed combination are similar to the profiles when the two drugs are administered as separate tablets. No pharmacokinetic interaction between the two drugs has been observed following multiple dosing , apart from a slight decrease in diclofenac sodium Cmax when administered concomitantly with misoprostol.
There was no accumulation of diclofenac or misoprostol acid in plasma following repeated doses of diclofenac/misoprostol.

Diclofenac
In man, orally administered diclofenac is rapidly and almost completely absorbed and distributed to the blood, liver and kidneys and is highly protein bound in the plasma. Plasma concentrations show a linear relationship to the amount of drug administered and no accumulation occurs provided that the recommended dosage intervals are observed. The elimination half-life (t1/2) is 1 to 2 hours. Diclofenac metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver. Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered diclofenac with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Forty percent (40%) to 60% of the drug and its metabolites (conjugates of the 3N-, 4N- and 5N –hydroxy derivatives of diclofenac) are eliminated in the urine and the balance through biliary excretion.

Misoprostol
Orally administered misoprostol is rapidly and extensively metabolized to the free acid, which is the principal pharmacologically active metabolite in the blood. The elimination half-life (t1/2) is about 20-30 minutes. Single doses show a linear relationship with dose over the range of 200 to 400 mcg. Plasma steady state was achieved within two days. Approximately 73% of the administered dose is excreted in the urine, mainly as biologically inactive metabolites. In patients with mild-to-moderate renal impairment, t1/2, Cmax, and AUC were increased compared to controls, but there was no clear correlation between the degree of renal impairment and AUC. In patients with total renal failure, AUC was approximately doubled in four of six patients, suggesting that in these patients diclofenac/ misoprostol therapy should be started at the lower end of the dosing range (See section 4.2 Posology and method of administration).

The serum protein binding of misoprostol acid is less than 90 % and is concentration-independent in the therapeutic range.