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ARTHROTEC® (misoprostol, diclofenac sodium) Use in Specific Populations

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

ARTHROTEC is contraindicated in pregnant women [see Contraindications (4)].

There are no adequate and well-controlled studies of ARTHROTEC in pregnant women; however, there is information available about the active drug components of ARTHROTEC, misoprostol and diclofenac sodium. Administration of misoprostol to pregnant women can cause abortion, premature birth, or birth defects. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug's teratogenic mechanism has not been demonstrated. Use of NSAIDS, including diclofenac, during the third trimester of pregnancy increases the risk of premature closure of fetal ductus arteriosus [see Data]. There are clinical considerations when misoprostol and diclofenac are used in pregnant women [see Clinical Considerations]. In reproduction studies with pregnant rabbits, there were no skeletal or visceral malformations when the combination of diclofenac sodium and misoprostol was administered during organogenesis at doses less than the maximum recommended human doses (MRHD); however, embryotoxicity was observed at this exposure [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. If a woman becomes pregnant while taking ARTHROTEC, discontinue the drug and advise the woman of the potential risks to her and to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

Maternal Adverse Reactions

Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Misoprostol has been used to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its approved indication. A major adverse effect of these uses is hyperstimulation of the uterus. Uterine rupture, amniotic fluid embolism, severe bleeding, shock, and maternal death have been reported when misoprostol was administered to pregnant women to induce labor to induce abortion beyond the eight week of pregnancy. Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation. ARTHROTEC, which contains 200 mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet of misoprostol. Abortions caused by misoprostol may be incomplete.

Cases of amniotic fluid embolism, which resulted in maternal and fetal death, have been reported with use of misoprostol during pregnancy. Severe vaginal bleeding, retained placenta, shock, and pelvic pain have also been reported. These women were administered misoprostol vaginally and/or orally over a range of doses. If a woman is or becomes pregnant while taking this drug, the drug should be discontinued and the patient apprised of the potential hazard to the fetus.

ARTHROTEC is contraindicated in pregnant women [see Contraindications (4)].

Fetal/Neonatal Adverse Reactions

Misoprostol

Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Use of misoprostol for the induction of labor in the third trimester was associated with uterine hyperstimulation with resulting changes in the fetal heart rate (fetal bradycardia) and fetal death. ARTHROTEC is contraindicated in pregnant women [see Contraindications (4)].

Diclofenac

Diclofenac may cause premature closure of the ductus arteriosus in a fetus [see Warnings and Precautions (5.10)].

Labor or Delivery

There are no studies on the effects of ARTHROTEC or diclofenac during labor or delivery. In animal studies, NSAIDS, including diclofenac, are known to inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. In humans, some case reports and studies have associated misoprostol with risk of stillbirth, uterine hyperstimulation, perineal tear, amniotic fluid embolism, severe bleeding, shock, uterine rupture and death.

Data

Human Data

Misoprostol

Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.

Diclofenac

Data from observational studies regarding potential embryo-fetal risks of NSAID use (including diclofenac) in the first or second trimesters of pregnancy are inconclusive. However, use of NSAIDS (including diclofenac) during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Animal Data

The reproductive and developmental effects of both the combination of diclofenac sodium and misoprostol and each component of ARTHROTEC alone have been studied in animals. In all studies there was no evidence of teratogenicity. In an oral teratology study in pregnant rabbits, ARTHROTEC was administered at dose combinations (diclofenac and misoprostol, 250:1 ratio) up to 10 mg/kg/day diclofenac sodium (120 mg/m2/day, 0.8 times the recommended maximum human dose based on body surface area) and 0.04 mg/kg/day misoprostol (0.48 mg/m2/day, 0.8 times the recommended maximum human dose based on body surface area) and there was no evidence of teratogenicity. At the high dose, there was evidence of embryotoxicity (resorption and decreased fetal body weight) and maternal toxicity (decreased food intake and weight gain).

In oral teratology studies with misoprostol in pregnant rats at doses up to 1.6 mg/kg/day (9.6 mg/m2/day, 16 times the recommended maximum human dose based on body surface area) and pregnant rabbits at doses up to 1.0 mg/kg/day (12 mg/m2/day, 20 times the recommended maximum human dose based on body surface area), there was no evidence of teratogenicity.

In oral teratology studies with diclofenac sodium in pregnant mice at doses up to 20 mg/kg/day (60 mg/m2/day, 0.4 times the recommended maximum human dose based on body surface area), pregnant rats at doses up to 10 mg/kg/day (60 mg/m2/day, 0.4 times the recommended maximum human dose based on body surface area) and pregnant rabbits at doses up to 10 mg/kg/day (120 mg/m2/day, 0.8 times the recommended maximum human dose based on body surface area), there was no evidence of teratogenicity.

8.2 Lactation

Risk Summary

No lactation studies have been conducted with ARTHROTEC; 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 ARTHROTEC and any potential adverse effects on the breastfed infant from the ARTHROTEC 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 ARTHROTEC.

Contraception

Females

ARTHROTEC 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 ARTHROTEC.

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including ARTHROTEC, 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 ARTHOTEC, in women who have difficulties conceiving or who are undergoing investigation of infertility.

8.4 Pediatric Use

Safety and effectiveness of ARTHROTEC 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, 5.13)].

Of the more than 2,100 subjects in clinical studies with ARTHROTEC, 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 ARTHROTEC 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 ARTHROTEC is necessary in the elderly for pharmacokinetic reasons [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13) 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.

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