ARTHROTEC (diclofenac sodium and misoprostol enteric-coated tablets) Action And Clinical Pharmacology

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Mechanism of Action

ARTHROTEC (diclofenac sodium plus misoprostol) is a combination of a nonsteroidal anti-inflammatory drug (NSAID) with a mucosal protective synthetic analog of prostaglandin E1.
Diclofenac inhibits prostaglandin synthesis by interfering with the action of prostaglandin synthetase. This inhibitory effect may partially explain its actions, both therapeutic and adverse.
Misoprostol has been shown to inhibit both basal and stimulated gastric acid secretion. In addition, increases in gastric mucosal blood flow, duodenal bicarbonate secretion and gastric mucus secretion have all been observed following treatment with misoprostol. It is not known whether the ability of misoprostol to prevent gastric and duodenal ulcers is the result of its antisecretory effect, its mucosal protective effect, or both.


The pharmacokinetic profiles of diclofenac and misoprostol administered alone are similar to the profiles when they are coadministered as separate tablets, or given as ARTHROTEC (diclofenac sodium plus misoprostol). No pharmacokinetic interaction between the two drugs has been observed following either single or multiple doses.

There was no accumulation of diclofenac or misoprostol acid in plasma following repeated doses of ARTHROTEC.

Table 1 Summary of Mean ARTHROTEC Pharmacokinetic Parameters
D = Diclofenac; M = Misoprostol acid











Single dose of ARTHROTEC 50, Healthy Male Subjects,  N=36







Single dose of ARTHROTEC 75, Healthy Male and Female Subjects, N=35








Orally administered diclofenac is rapidly and almost completely absorbed.

Orally administered misoprostol is also rapidly and extensively absorbed.

With ARTHROTEC the effect of food on the bioavailability of the diclofenac and misoprostol components is similar to that reported for the individual drugs. The times of peak concentration (Tmax) for diclofenac and misoprostol are prolonged by approximately 50% and 100% respectively, while the peak concentrations (Cmax) are decreased by about 25% for diclofenac and 50% for misoprostol: the AUC for diclofenac is decreased by approximately 60%, while that of misoprostol is increased by about 25%.


Diclofenac is highly but reversibly bound in the plasma. Following administration of enteric-coated tablets there is high between- and within-subject variability in the plasma concentrations of diclofenac, particularly if the tablets are taken with food. However, the plasma concentrations show a linear relationship to the amount of drug administered and no accumulation occurs provided that the recommended dosage intervals are observed.

There is high variability in plasma levels of misoprostol acid, but mean values after single doses show a linear relationship with dose over the range of 200 to 400 µg. No accumulation has been found in multiple dose studies and plasma steady state was achieved within two days.


Diclofenac metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver.
Diclofenac undergoes single and multiple hydroxylation and methoxylation, producing 3'-, 4'-, 5-hydroxy, 4'-5-hydroxy and 3'-hydroxy-4'-methoxy derivatives of diclofenac. These phenolic metabolites are largely inactive, and (along with the parent compound) are mostly converted to glucuronide conjugates.

Misoprostol undergoes rapid metabolism to misoprostol acid.


The half-life of diclofenac is 1 to 2 hours. Forty to 60% of the drug and its metabolites are eliminated in the urine and the balance in the bile.
Misoprostol acid is quickly eliminated (elimination half-life of approximately 30 minutes). Approximately 70% of the dose of misoprostol is excreted in the urine, mainly as biologically inactive metabolites.

Special Populations and Conditions


The kinetics and metabolism of diclofenac do not appear to be affected by age.
In the elderly, the AUC of misoprostol acid is increased by roughly 40%.

Poor CYP2C9 Metabolizers:

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 (see DRUG INTERACTIONS – Overview).

Hepatic Insufficiency:

The kinetics and metabolism of diclofenac do not appear to be affected by hepatic impairment.
Misoprostol does not affect the hepatic mixed function oxidase (cytochrome P-450) enzyme system in animals. In a study of people with mild to moderate hepatic impairment, mean misoprostol acid AUC and Cmax showed approximately double the mean values obtained in healthy people. Three people who had the lowest antipyrine and lowest indocyanine green clearance values had the highest misoprostol acid AUC and Cmax values.

Renal Insufficiency:

Differences in the pharmacokinetics of diclofenac (50 mg intravenously) have not been detected in studies of patients with renal impairment (N=5, creatinine clearance 3 to 42 mL/min). In these patients, AUC values and elimination rates were comparable to those in healthy people.

Following oral administration of misoprostol in patients with mild-to-moderate renal impairment, there was no significant effect on the pharmacokinetic profile compared to normal subjects. However, in anuric patients, an approximate doubling of Cmax, AUC and t1/2 of misoprostol acid has been observed compared to normal subjects.