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Arthrotec (Diclofenac Sodium / Misoprostol) - Description and Clinical Pharmacology

 
 



ARTHROTEC®
(diclofenac sodium/misoprostol) tablets

DESCRIPTION

ARTHROTEC (diclofenac sodium/misoprostol) is a combination product containing diclofenac sodium, a nonsteroidal anti-inflammatory drug (NSAID) with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin E1 analog. ARTHROTEC oral tablets are white to off-white, round, biconvex and approximately 11 mm in diameter. Each tablet consists of an enteric-coated core containing 50 mg (ARTHROTEC 50) or 75 mg (ARTHROTEC 75) diclofenac sodium surrounded by an outer mantle containing 200 mcg misoprostol.

Diclofenac sodium is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium is freely soluble in methanol, soluble in ethanol and practically insoluble in chloroform and in dilute acid. Diclofenac sodium is sparingly soluble in water. Its chemical formula and name are:

  C14H10Cl2NO2Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt.

Misoprostol is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are:

  C22H38O5 [M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate.

Inactive ingredients in ARTHROTEC include: colloidal silicon dioxide; crospovidone; hydrogenated castor oil; hypromellose; lactose; magnesium stearate; methacrylic acid copolymer; microcrystalline cellulose; povidone (polyvidone) K-30; sodium hydroxide; starch (corn); talc; triethyl citrate.

CLINICAL PHARMACOLOGY

Pharmacodynamics and pharmacokinetics of diclofenac sodium

Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID). In pharmacologic studies, diclofenac sodium has shown anti-inflammatory, analgesic and antipyretic properties. The mechanism of action of diclofenac sodium, like other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Diclofenac sodium is completely absorbed from the GI tract after fasting, oral administration. The diclofenac sodium in ARTHROTEC is in a pharmaceutical formulation that resists dissolution in the low pH of gastric fluid but allows a rapid release of drug in the higher pH environment of the duodenum. Only 50% of the absorbed dose is systemically available due to first pass metabolism. Peak plasma levels are achieved in 2 hours (range 1–4 hours), and the area under the plasma concentration curve (AUC) is dose proportional within the range of 25 mg to 150 mg. Peak plasma levels are less than dose-proportional and are approximately 1.5 and 2.0 mcg/mL for 50 mg and 75 mg doses, respectively.

Plasma concentrations of diclofenac sodium decline from peak levels in a biexponential fashion, with the terminal phase having a half-life of approximately 2 hours. Clearance and volume of distribution are about 350 mL/min and 550 mL/kg, respectively. More than 99% of diclofenac sodium is reversibly bound to human plasma albumin.

Diclofenac sodium is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Approximately 65% of the dose is excreted in the urine and 35% in the bile.

Conjugates of unchanged diclofenac account for 5–10% of the dose excreted in the urine and for less than 5% excreted in the bile. Little or no unchanged unconjugated drug is excreted. Conjugates of the principal metabolite account for 20–30% of the dose excreted in the urine and for 10–20% of the dose excreted in the bile.

Conjugates of three other metabolites together account for 10–20% of the dose excreted in the urine and for small amounts excreted in the bile. The elimination half-life values for these metabolites are shorter than those for the parent drug. Urinary excretion of an additional metabolite (half-life = 80 hours) accounts for only 1.4% of the oral dose. The degree of accumulation of diclofenac metabolites is unknown. Some of the metabolites may have activity.

Pharmacodynamics and pharmacokinetics of misoprostol

Misoprostol is a synthetic prostaglandin E1 analog with gastric antisecretory and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis. A deficiency of prostaglandins within the gastric and duodenal mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by NSAIDs.

Misoprostol can increase bicarbonate and mucus production, but in humans this has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to tell whether the ability of misoprostol to reduce the risk of gastric and duodenal ulcers is the result of its antisecretory effect, its mucosal protective effect, or both.

In vitro studies on canine parietal cells using titrated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereo-specific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained.

Misoprostol produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor intrinsic factor output.

Effects on gastric acid secretion

Misoprostol, over the range of 50–200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter-lived, and only the 200 mcg dose had substantial effects on nocturnal secretion or on histamine- and meal-stimulated secretion.

Orally administered misoprostol is rapidly and extensively absorbed, and it undergoes rapid metabolism to its biologically active metabolite, misoprostol acid. Misoprostol acid in ARTHROTEC reaches a maximum plasma concentration in about 20 minutes and is, thereafter, quickly eliminated with an elimination t1/2 of about 30 minutes. There is high variability in plasma levels of misoprostol acid between and within studies, but mean values after single doses show a linear relationship with dose of misoprostol over the range of 200 to 400 mcg. No accumulation of misoprostol acid was found in multiple-dose studies, and plasma steady state was achieved within 2 days. The serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range.

After oral administration of radio-labeled misoprostol, about 70% of detected radioactivity appears in the urine. Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food, and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid; this effect does not appear to be clinically important.

Pharmacokinetic studies also showed a lack of drug interaction with antipyrine or propranolol given with misoprostol. Misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart.

Pharmacokinetics of ARTHROTEC

The pharmacokinetics following oral administration of a single dose (see Table 1) or multiple doses of ARTHROTEC (diclofenac sodium/misoprostol) to healthy subjects under fasted conditions are similar to the pharmacokinetics of the two individual components.

Table 1
SD:      Standard deviation of the mean
AUC:  Area under the curve
Cmax:   Peak concentration
tmax:    Time to peak concentration
MISOPROSTOL ACID Mean (SD)
Treatment (n=36) Cmax (pg/mL) tmax (hr) AUC (0–4h)
(pg∙hr/mL)
ARTHROTEC 50441 (137)0.30 (0.13)266 (95)
Cytotec®478 (201)0.30 (0.10)295 (143)
ARTHROTEC 75304 (110)0.26 (0.09)177 (49)
Cytotec290 (130)0.35 (0.12)176 (58)
DICLOFENAC Mean (SD)
Treatment (n=36) Cmax(ng/mL) tmax (hr) AUC (0–12h)
(ng∙hr/mL)
ARTHROTEC 501207 (364)2.4 (1.0)1380 (272)
Voltaren®1298 (441)2.4 (1.0)1357 (290)
ARTHROTEC 752025 (2005)2.0 (1.4)2773 (1347)
Voltaren2367 (1318)1.9 (0.7)2609 (1185)

The rate and extent of absorption of both diclofenac sodium and misoprostol acid from ARTHROTEC 50 and ARTHROTEC 75 are similar to those from diclofenac sodium and misoprostol formulations each administered alone.

Neither diclofenac sodium nor misoprostol acid accumulated in plasma following repeated doses of ARTHROTEC given every 12 hours under fasted conditions. Food decreases the multiple-dose bioavailability profile of ARTHROTEC 50 and ARTHROTEC 75.

Special populations

A 4-week study, comparing plasma level profiles of diclofenac (50 mg bid) in younger (26–46 years) versus older (66–81 years) adults, did not show differences between age groups (10 patients per age group). In a multiple-dose (bid) crossover study of 24 people aged 65 years or older, the misoprostol contained in ARTHROTEC did not affect the pharmacokinetics of diclofenac sodium.

Differences in the pharmacokinetics of diclofenac have not been detected in studies of patients with renal (50 mg intravenously) or hepatic impairment (100 mg oral solution). In patients with renal impairment (N=5, creatinine clearance 3 to 42 mL/min), AUC values and elimination rates were comparable to those in healthy people. In patients with biopsy-confirmed cirrhosis or chronic active hepatitis (variably elevated transaminases and mildly elevated bilirubins, N=10), diclofenac concentrations and urinary elimination values were comparable to those in healthy people.

Pharmacokinetic studies with misoprostol in patients with varying degrees of renal impairment showed an approximate doubling of t1/2, Cmax and AUC compared to healthy people. In people over 64 years of age, the AUC for misoprostol acid is increased.

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.

CLINICAL STUDIES

Osteoarthritis

Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of osteoarthritis.

Rheumatoid arthritis

Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of rheumatoid arthritis.

Upper gastrointestinal safety

Diclofenac, and other NSAIDs, have caused serious gastrointestinal toxicity, such as bleeding, ulceration and perforation of the stomach, small intestine or large intestine. Misoprostol has been shown to reduce the incidence of endoscopically diagnosed NSAID-induced gastric and duodenal ulcers. In a 12-week, randomized, double-blind, dose-response study, misoprostol 200 mcg administered qid, tid or bid, was significantly more effective than placebo in reducing the incidence of gastric ulcer in OA and RA patients using a variety of NSAIDs. The tid regimen was therapeutically equivalent to misoprostol 200 mcg qid with respect to the prevention of gastric ulcers. Misoprostol 200 mcg given bid was less effective than 200 mcg given tid or qid. The incidence of NSAID-induced duodenal ulcer was also significantly reduced with all three regimens of misoprostol compared to placebo (see Table 2).

Table 2
Misoprostol 200 mcg Dosage Regimen
Placebobidtidqid
N=1623; 12 weeks
Gastric ulcer11%6% 1 3%3%
Duodenal ulcer6%2%3%1%

1 Misoprostol significantly different from placebo (p<0.05)

Results of a study in 572 patients with osteoarthritis demonstrate that patients receiving ARTHROTEC have a lower incidence of endoscopically defined gastric ulcers compared to patients receiving diclofenac sodium (see Table 3).

Table 3
Osteoarthritis patients with history of ulcer or erosive disease (N=572), 6 weeksIncidence of ulcers
GastricDuodenal
ARTHROTEC 50 tid3% 1 6%
ARTHROTEC 75 bid4%3%
diclofenac sodium 75 mg bid11%7%
placebo3%1%

1 Statistically significantly different from diclofenac (p<0.05)

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