Diclofenac Sodium and Misoprostol (Page 7 of 11)

8.2 Lactation

Risk Summary

No lactation studies have been conducted with diclofenac sodium and misoprostol; however, limited published literature reports that diclofenac and the active metabolite of misoprostol are present in breast milk [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac sodium and misoprostol and any potential adverse effects on the breastfed infant from the diclofenac sodium and misoprostol or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status for females of reproductive potential within 2 weeks prior to initiating diclofenac sodium and misoprostol.

Contraception

Females

Diclofenac sodium and misoprostol can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with diclofenac sodium and misoprostol.

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac, a component of diclofenac sodium and misoprostol, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1)]. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac sodium and misoprostol, in women who have difficulties conceiving or who are undergoing investigation of infertility.

8.4 Pediatric Use

Safety and effectiveness of diclofenac sodium and misoprostol in pediatric patients have not been established.

8.5 Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].

Of the more than 2,100 subjects in clinical studies with diclofenac sodium and misoprostol, 25% were 65 and over, while 6% were 75 and over. In studies with diclofenac, 31% of subjects were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Diclofenac is known to be substantially excreted by the kidney, and the risk of toxic reactions to diclofenac sodium and misoprostol may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].

Based on studies in the elderly, no adjustment of the dose of diclofenac sodium and misoprostol is necessary in the elderly for pharmacokinetic reasons [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14) and Clinical Pharmacology (12.3)], although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging.

10 OVERDOSAGE

The toxic dose of diclofenac sodium and misoprostol has not been determined. However, signs of overdosage from the components of the product have been described.

Diclofenac

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)].

Clinical signs that may suggest diclofenac sodium overdose include GI complaints, confusion, drowsiness, or general hypotonia.

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

Misoprostol

The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of GI discomfort being reported. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia.

Diclofenac Sodium and Misoprostol Delayed-Release Tablets

Symptoms of overdosage with diclofenac sodium and misoprostol delayed-release tablets should be treated with supportive therapy. In case of acute overdosage, gastric lavage is recommended. Induced diuresis may be beneficial because diclofenac sodium and misoprostol metabolites are excreted in the urine. The effect of dialysis or hemoperfusion on the elimination of diclofenac sodium (99% protein bound) and misoprostol acid remains unproven. The use of oral activated charcoal may help to reduce the absorption of diclofenac sodium and misoprostol.

For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

11 DESCRIPTION

Diclofenac sodium and misoprostol delayed-release tablets, USP are a combination product containing diclofenac sodium, USP an NSAID with analgesic properties, and misoprostol, USP a gastrointestinal (GI) mucosal protective prostaglandin-1 (PGE1) analog. Diclofenac sodium and misoprostol delayed-release tablets, USP are white to off-white, round, biconvex tablets, and approximately 11 mm in diameter. Each tablet consists of an enteric-coated core containing 50 mg or 75 mg diclofenac sodium, USP (equivalent to 46.39 mg or 69.58 mg of diclofenac, respectively) surrounded by an outer mantle containing 0.2 mg misoprostol, USP.

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

C14 H10 Cl2 NO2 Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt.

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

C22 H38 O5 [M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate.

Inactive ingredients in diclofenac sodium and misoprostol delayed-release tablets include: colloidal silicon dioxide, crospovidone, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid and ethyl acrylate copolymer dispersion, microcrystalline cellulose, povidone K-30, sodium hydroxide, corn starch, talc, and triethyl citrate.

12 CLINICAL PHARMACOLOGY

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