arthrotec 75

CONTRAINDICATIONS AND WARNINGS
ARTHROTEC (diclofenac sodium/misoprostol) ADMINISTRATION BY ANY ROUTE IS CONTRAINDICATED,BECAUSE ITS MISOPROSTOL COMPONENT CAN CAUSE ABORTION, IN WOMEN WHO ARE PREGNANT(See WARNINGS and PRECAUTIONS ) arthrotec 75.

Anecdotal reports have been received, primarily from Brazil, of congenital anomaliesand reports of fetal death in pregnancies in which misoprostol has been usedas an abortifacient arthrotec 75.

PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVETHE DRUG TO OTHERS arthrotec 75.

UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL WAS ADMINISTERED INTRAVAGINALLYIN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE FIRST TRIMESTEROF PREGNANCY arthrotec 75.

UTERINE PERFORATION HAS BEEN REPORTED FOLLOWING ADMINISTRATION OF COMBINEDVAGINAL-AND-ORAL MISOPROSTOL IN PREGNANT WOMEN TO INDUCE ABORTION arthrotec 75. IN EACH OFTHESE REPORTED CASES, THE GESTATIONAL AGE OF THE PREGNANCIES WAS UNKNOWN arthrotec 75.

ARTHROTEC should not be used in women of childbearing potential unless thepatient requires nonsteroidal anti-inflammatory drug (NSAID) therapy and isat high risk of developing gastric or duodenal ulceration or for developingcomplications from gastric or duodenal ulcers associated with the use of theNSAID arthrotec 75. (See WARNINGS ) arthrotec 75. In such patients, ARTHROTEC may be prescribed if thepatient:

has had a negative serum pregnancy test within 2 weeks prior to beginning therapy arthrotec 75.
is capable of complying with effective contraceptive measures arthrotec 75.
has received both oral and written warnings of the hazards of misoprostol, therisk of possible contraception failure, and the danger to other women of child-bearingpotential should the drug be taken by mistake arthrotec 75.
will begin ARTHROTEC only on the second or third day of the next normal menstrualperiod arthrotec 75.

DESCRIPTION
ARTHROTEC is a combination product containing diclofenac sodium, a nonsteroidalanti-inflammatory drug (NSAID) with analgesic properties, and misoprostol, agastrointestinal (GI) mucosal protective prostaglandin E 1 analog arthrotec 75. ARTHROTECoral tablets are white to off-white, round, biconvex and approximately 11 mmin diameter arthrotec 75. Each tablet consists of an enteric-coated core containing 50 mg(ARTHROTEC 50) or 75 mg (ARTHROTEC 75) diclofenac sodium surrounded by an outermantle containing 200 mcg misoprostol arthrotec 75.

Diclofenac sodium is a phenylacetic acid derivative that is a white to off-white,virtually odorless, crystalline powder arthrotec 75. Diclofenac sodium is freely solublein methanol, soluble in ethanol and practically insoluble in chloroform andin dilute acid arthrotec 75. Diclofenac sodium is sparingly soluble in water arthrotec 75. Its chemicalformula and name are:

C 14 H 10 Cl 2 NO 2 Na [M.W arthrotec 75. = 318.14] 2-[ (2, 6-dichlorophenyl) amino] benzeneaceticacid, monosodium salt arthrotec 75.

Misoprostol is a water-soluble, viscous liquid that contains approximatelyequal amounts of two diastereomers arthrotec 75. Its chemical formula and name are:

C 22 H 38 O 5 [M.W arthrotec 75. = 382.54] (±)methyl 11(alpha), 16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate arthrotec 75.

Inactive ingredients in ARTHROTEC include: colloidal silicon dioxide; crospovidone;hydrogenated castor oil; hydroxypropyl methylcellulose; lactose; magnesium stearate;methacrylic acid copolymer; microcrystalline cellulose; povidone (polyvidone)K-30; sodium hydroxide; starch (corn); talc; triethyl citrate arthrotec 75.

CLINICAL PHARMACOLOGY
Pharmacodynamics and pharmacokinetics
of diclofenac sodium
Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID) arthrotec 75. In pharmacologicstudies, diclofenac sodium has shown anti-inflammatory, analgesic and antipyreticproperties arthrotec 75. The mechanism of action of diclofenac sodium, like other NSAIDs,is not completely understood but may be related to prostaglandin synthetaseinhibition arthrotec 75.

Diclofenac sodium is completely absorbed from the GI tract after fasting, oraladministration arthrotec 75. The diclofenac sodium in ARTHROTEC is in a pharmaceutical formulationthat resists dissolution in the low pH of gastric fluid but allows a rapid releaseof drug in the higher pH environment of the duodenum arthrotec 75. Only 50% of the absorbeddose is systemically available due to first pass metabolism arthrotec 75. Peak plasma levelsare achieved in 2 hours (range 1-4 hours), and the area under the plasma concentrationcurve (AUC) is dose proportional within the range of 25 mg to 150 mg arthrotec 75. Peak plasmalevels are less than dose proportional and are approximately 1.5 and 2.0 mcg/mLfor 50 mg and 75 mg doses, respectively arthrotec 75.

Plasma concentrations of diclofenac sodium decline from peak levels in a biexponentialfashion, with the terminal phase having a half-life of approximately 2 hours arthrotec 75. Clearance and volume of distribution are about 350 mL/min and 550 mL/kg, respectively arthrotec 75. More than 99% of diclofenac sodium is reversibly bound to human plasma albumin arthrotec 75.

Diclofenac sodium is eliminated through metabolism and subsequent urinary andbiliary excretion of the glucuronide and the sulfate conjugates of the metabolites arthrotec 75. Approximately 65% of the dose is excreted in the urine and 35% in the bile arthrotec 75.

Conjugates of unchanged diclofenac account for 5-10% of the dose excreted inthe urine and for less than 5% excreted in the bile arthrotec 75. Little or no unchangedunconjugated drug is excreted arthrotec 75. Conjugates of the principal metabolite accountfor 20-30% of the dose excreted in the urine and for 10-20% of the dose excretedin the bile arthrotec 75.

Conjugates of three other metabolites together account for 10-20% of the doseexcreted in the urine and for small amounts excreted in the bile arthrotec 75. The eliminationhalf-life values for these metabolites are shorter than those for the parentdrug arthrotec 75. Urinary excretion of an additional metabolite (half-life = 80 hours) accountsfor only 1.4% of the oral dose arthrotec 75. The degree of accumulation of diclofenac metabolitesis unknown arthrotec 75. Some of the metabolites may have activity arthrotec 75.

Pharmacodynamics and pharmacokinetics of misoprostol
Misoprostol is a synthetic prostaglandin E 1 analog with gastric antisecretoryand (in animals) mucosal protective properties arthrotec 75. NSAIDs inhibit prostaglandinsynthesis arthrotec 75. A deficiency of prostaglandins within the gastric and duodenal mucosamay lead to diminishing bicarbonate and mucus secretion and may contribute tothe mucosal damage caused by NSAIDs arthrotec 75.

Misoprostol can increase bicarbonate and mucus production, but in humans thishas been shown at doses 200 mcg and above that are also antisecretory arthrotec 75. It istherefore not possible to tell whether the ability of misoprostol to preventgastric and duodenal ulcers is the result of its antisecretory effect, its mucosalprotective effect, or both arthrotec 75.

In vitro studies on canine parietal cells using tritiated misoprostol acidas the ligand have led to the identification and characterization of specificprostaglandin receptors arthrotec 75. Receptor binding is saturable, reversible, and stereospecific arthrotec 75. The sites have a high affinity for misoprostol, for its acid metabolite, andfor other E type prostaglandins, but not for F or I prostaglandins and otherunrelated compounds, such as histamine or cimetidine arthrotec 75. Receptor-site affinityfor misoprostol correlates well with an indirect index of antisecretory activity arthrotec 75. It is likely that these specific receptors allow misoprostol taken with foodto be effective topically, despite the lower serum concentrations attained arthrotec 75.

Misoprostol produces a moderate decrease in pepsin concentration during basalconditions, but not during histamine stimulation arthrotec 75. It has no significant effecton fasting or postprandial gastrin nor intrinsic factor output arthrotec 75.

Effects on gastric acid secretion: Misoprostol, over the range of 50-200 mcg,inhibits basal and nocturnal gastric acid secretion, and acid secretion in responseto a variety of stimuli, including meals, histamine, pentagastrin, and coffee arthrotec 75. Activity is apparent 30 minutes after oral administration and persists for atleast 3 hours arthrotec 75. In general, the effects of 50 mcg were modest and shorter lived,and only the 200-mcg dose had substantial effects on nocturnal secretion oron histamine-and meal-stimulated secretion arthrotec 75.

Orally administered misoprostol is rapidly and extensively absorbed, and itundergoes rapid metabolism to its biologically active metabolite, misoprostolacid arthrotec 75. Misoprostol acid in ARTHROTEC reaches a maximum plasma concentration inabout 20 minutes and is, thereafter, quickly eliminated with an eliminationt 1/2 of about 30 minutes arthrotec 75. There is high variability in plasma levels of misoprostolacid between and within studies, but mean values after single doses show a linearrelationship with dose of misoprostol over the range of 200 to 400 mcg arthrotec 75. No accumulationof misoprostol acid was found in multiple-dose studies, and plasma steady statewas achieved within 2 days arthrotec 75. The serum protein binding of misoprostol acid isless than 90% and is concentration-independent in the therapeutic range arthrotec 75.

After oral administration of radiolabeled misoprostol, about 70% of detectedradioactivity appears in the urine arthrotec 75. Maximum plasma concentrations of misoprostolacid are diminished when the dose is taken with food, and total availabilityof misoprostol acid is reduced by use of concomitant antacid arthrotec 75. Clinical trialswere conducted with concomitant antacid; this effect does not appear to be clinicallyimportant arthrotec 75.

Pharmacokinetic studies also showed a lack of drug interaction with antipyrineor propranolol given with misoprostol arthrotec 75. Misoprostol given for 1 week had no effecton the steady state pharmacokinetics of diazepam when the two drugs were administered2 hours apart arthrotec 75.

Pharmacokinetics of ARTHROTEC
The pharmacokinetics following oral administration of a single dose (see Table1) or multiple doses of ARTHROTEC (diclofenac sodium/misoprostol) to healthysubjects under fasted conditions are similar to the pharmacokinetics of thetwo individual components arthrotec 75.

Table 1 arthrotec 75. MISOPROSTOL ACID Mean (SD)
Treatment
(n=36) C max
(pg/mL) t max
(hr) AUC (0-4 h)
(pg·hr/mL)
ARTHROTEC 50 441 (137) 0.30 (0.13) 266 (95)
Cytotec ® 478 (201) 0.30 (0.10) 295 (143)
ARTHROTEC 75 304 (110) 0.26 (0.09) 177 (49)
Cytotec 290 (130) 0.35 (0.12) 176 (58)
DICLOFENAC Mean (SD)
Treatment
(n=36) C max
(ng/mL) t max
(hr) AUC (0-12 h)
(ng·hr/mL)
ARTHROTEC 50 1207 (364) 2.4 (1.0) 1380 (272)
Voltaren ® 1298 (441) 2.4 (1.0) 1357 (290)
ARTHROTEC 75 2025 (2005) 2.0 (1.4) 2773 (1347)
Voltaren 2367 (1318) 1.9 (0.7) 2609 (1185)
SD: Standard deviation of the mean
AUC: Area under the curve
C max : Peak concentration
t max : Time to peak concentration

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

Neither diclofenac sodium nor misoprostol acid accumulated in plasma followingrepeated doses of ARTHROTEC given every 12 hours under fasted conditions arthrotec 75. Fooddecreases the multiple-dose bioavailability profile of ARTHROTEC 50 and ARTHROTEC75 arthrotec 75.

Special populations

A 4-week study, comparing plasma level profiles of diclofenac (50 mg bid) inyounger (26-46 years) versus older (66-81 years) adults, did not show differencesbetween age groups (10 patients per age group) arthrotec 75. In a multiple-dose (bid) cross-overstudy of 24 people aged 65 years or older, the misoprostol contained in ARTHROTECdid not affect the pharmacokinetics of diclofenac sodium arthrotec 75.

Differences in the pharmacokinetics of diclofenac have not been detected instudies of patients with renal (50 mg intravenously) or hepatic impairment (100mg oral solution) arthrotec 75. In patients with renal impairment (N=5, creatinine clearance3 to 42 mL/min), AUC values and elimination rates were comparable to those inhealthy people arthrotec 75. In patients with biopsy-confirmed cirrhosis or chronic activehepatitis (variably elevated transaminases and mildly elevated bilirubins, N=10),diclofenac concentrations and urinary elimination values were comparable tothose in healthy people arthrotec 75.

Pharmacokinetic studies with misoprostol in patients with varying degrees ofrenal impairment showed an approximate doubling of t 1/2 , C max and AUC comparedto healthy people arthrotec 75. In people over 64 years of age, the AUC for misoprostol acidis increased arthrotec 75.

Misoprostol does not affect the hepatic mixed function oxidase (cytochromeP-450) enzyme system in animals arthrotec 75. In a study of people with mild to moderatehepatic impairment, mean misoprostol acid AUC and C max showed approximatelydouble the mean values obtained in healthy people arthrotec 75. Three people who had thelowest antipyrine and lowest indocyanine green clearance values had the highestmisoprostol acid AUC and C max values arthrotec 75.

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