CELECOXIB

Fetal Risk Summary

Celecoxib is a second-generation nonsteroidal antiinflammatory agent (NSAID) that inhibits prostaglandin synthesis via the inhibition of cyclooxygenase-2 (COX-2). It is in the same NSAID subclass (COX-2 inhibitors) as rofecoxib. At therapeutic concentrations, it does not inhibit, as do first-generation NSAIDs, the cyclooxygenase-1 (COX-1) isoenzyme. Celecoxib is indicated for the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis (1).

Celecoxib was not mutagenic or clastogenic in Chinese hamster ovary cells or clastogenic in an in vivo micronucleus test in rat bone marrow (1). Administration to female rats of oral doses (50 mg/kg/day (about 6 times the maximum recommended human dose [MRHD] based on AUC at 200 mg twice a day) resulted in pre-implantation and post-implantation losses and reduced embryo/fetal survival, a natural consequence of its inhibition of prostaglandin synthesis (1).

Teratogenicity studies have been conducted in rats and rabbits (1). In pregnant rats, a dose-related increase in diaphragmatic hernias was observed in one of two studies at doses of (30 mg/kg/day) (about 6 times the MRHD). No teratogenic effects occurred in pregnant rabbits dosed at 60 mg/kg/day (equal to the MRHD), but at (150 mg/kg/day (approximately 2 times the MRHD), an increased incidence of fetal alterations (fused ribs and fused, misshapen sternebrae) was observed (1). No evidence of delayed labor or parturition at doses up to 100 mg/kg (approximately 7 times the MRHD) was observed in rats (1).

No reports describing the placental transfer of celecoxib have been located. The molecular weight (about 381), however, is low enough that passage to the fetus should be expected. Celecoxib metabolism is mediated by the cytochrome P450 2C9 enzyme, resulting in at least three inactive metabolites (1). Women in whom metabolism by this enzyme is known or suspected to be deficient may have abnormally high plasma levels of celecoxib and, thus, more of the drug will be available for placental transfer.

A combined 2001 population-based observational cohort study and a case-control study estimated the risk of adverse pregnancy outcome from the use of NSAIDs (2). The use of NSAIDs during pregnancy was not associated with congenital malformations, preterm delivery, or low birth weight, but a positive association was discovered with spontaneous abortions (SABs) (see Ibuprofen for details).

The use of first-generation NSAIDs during the latter half of pregnancy has been associated with oligohydramnios and premature closure of the ductus arteriosus (e.g., see Indomethacin) (3). Persistent pulmonary hypertension of the newborn may occur if NSAIDs are used in the 3rd trimester close to delivery (3). These drugs also have been shown to inhibit labor and prolong pregnancy, both in humans (4) and in animals (5). Similar effects should be expected if celecoxib is used during the 3rd trimester or close to delivery. Women attempting to conceive should not used any prostaglandin synthesis inhibitor, including celecoxib, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (6,7). Moreover, as noted above, NSAIDs have been associated with SABs.

[*Risk Factor D if used in 3rd trimester or near delivery.]

Breast Feeding Summary

No reports describing the use of celecoxib during human lactation have been located. The drug is excreted in the milk of lactating rats in concentrations similar to those measured in plasma (1). Although several first-generation NSAIDs are considered low-risk during nursing (e.g., see Diclofenac, Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Ketorolac, and Tolmetin), the relatively long adult serum half-life of celecoxib (11.2 hours) and the absence of clinical pharmacologic data in infants suggest that this agent should be avoided during nursing.

References

1. Product information. Celebrex. G.D. Searle, 1999.
2. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal antiinflammatory drugs: population based observational study and case-control study. Br Med J 2001;322:266–70.
3. Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.
4. Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:809–20.
5. Powell JG, Cochrane RL. The effects of a number of non-steroidal antiinflammatory compounds on parturition in the rat. Prostaglandins 1982;23:469–88.
6. Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In Witorsch RJ, ed. Reproductive Toxicology. 2nd ed. New York, NY:Raven Press, 1995:175–93.
7. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.