fda arthrotec

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 ) fda arthrotec.

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 fda arthrotec.

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

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

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

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 fda arthrotec. (See WARNINGS ) fda arthrotec. In such patients, ARTHROTEC may be prescribed if thepatient:

has had a negative serum pregnancy test within 2 weeks prior to beginning therapy fda arthrotec.
is capable of complying with effective contraceptive measures fda arthrotec.
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 fda arthrotec.
will begin ARTHROTEC only on the second or third day of the next normal menstrualperiod fda arthrotec.

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 fda arthrotec. ARTHROTECoral tablets are white to off-white, round, biconvex and approximately 11 mmin diameter fda arthrotec. 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 fda arthrotec.

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

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

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

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

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 fda arthrotec.

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

Diclofenac sodium is completely absorbed from the GI tract after fasting, oraladministration fda arthrotec. 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 fda arthrotec. Only 50% of the absorbeddose is systemically available due to first pass metabolism fda arthrotec. 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 fda arthrotec. Peak plasmalevels are less than dose proportional and are approximately 1.5 and 2.0 mcg/mLfor 50 mg and 75 mg doses, respectively fda arthrotec.

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

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

Conjugates of unchanged diclofenac account for 5-10% of the dose excreted inthe urine and for less than 5% excreted in the bile fda arthrotec. Little or no unchangedunconjugated drug is excreted fda arthrotec. 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 fda arthrotec.

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

Pharmacodynamics and pharmacokinetics of misoprostol
Misoprostol is a synthetic prostaglandin E 1 analog with gastric antisecretoryand (in animals) mucosal protective properties fda arthrotec. NSAIDs inhibit prostaglandinsynthesis fda arthrotec. 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 fda arthrotec.

Misoprostol can increase bicarbonate and mucus production, but in humans thishas been shown at doses 200 mcg and above that are also antisecretory fda arthrotec. 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 fda arthrotec.

In vitro studies on canine parietal cells using tritiated misoprostol acidas the ligand have led to the identification and characterization of specificprostaglandin receptors fda arthrotec. Receptor binding is saturable, reversible, and stereospecific fda arthrotec. 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 fda arthrotec. Receptor-site affinityfor misoprostol correlates well with an indirect index of antisecretory activity fda arthrotec. It is likely that these specific receptors allow misoprostol taken with foodto be effective topically, despite the lower serum concentrations attained fda arthrotec.

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

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 fda arthrotec. Activity is apparent 30 minutes after oral administration and persists for atleast 3 hours fda arthrotec. 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 fda arthrotec.

Orally administered misoprostol is rapidly and extensively absorbed, and itundergoes rapid metabolism to its biologically active metabolite, misoprostolacid fda arthrotec. 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 fda arthrotec. 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 fda arthrotec. No accumulationof misoprostol acid was found in multiple-dose studies, and plasma steady statewas achieved within 2 days fda arthrotec. The serum protein binding of misoprostol acid isless than 90% and is concentration-independent in the therapeutic range fda arthrotec.

After oral administration of radiolabeled misoprostol, about 70% of detectedradioactivity appears in the urine fda arthrotec. 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 fda arthrotec. Clinical trialswere conducted with concomitant antacid; this effect does not appear to be clinicallyimportant fda arthrotec.

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

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 fda arthrotec.

Table 1 fda arthrotec. 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 fda arthrotec.

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

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) fda arthrotec. 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 fda arthrotec.

Differences in the pharmacokinetics of diclofenac have not been detected instudies of patients with renal (50 mg intravenously) or hepatic impairment (100mg oral solution) fda arthrotec. In patients with renal impairment (N=5, creatinine clearance3 to 42 mL/min), AUC values and elimination rates were comparable to those inhealthy people fda arthrotec. 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 fda arthrotec.

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 fda arthrotec. In people over 64 years of age, the AUC for misoprostol acidis increased fda arthrotec.

Misoprostol does not affect the hepatic mixed function oxidase (cytochromeP-450) enzyme system in animals fda arthrotec. 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 fda arthrotec. Three people who had thelowest antipyrine and lowest indocyanine green clearance values had the highestmisoprostol acid AUC and C max values fda arthrotec.

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