ROFECOXIB

Fetal Risk Summary

Rofecoxib is a second-generation nonsteroidal anti-inflammatory drug (NSAID) that inhibits prostaglandin synthesis via the inhibition of cyclooxygenase-2 (COX-2). At therapeutic concentrations, it does not inhibit, as do first-generation NSAIDs, the cyclooxygenase-1 (COX-1) isoenzyme. It is indicated for the relief of the signs and symptoms of osteoarthritis, acute pain, and primary dysmenorrhea (1). Rofecoxib is in the same NSAID subclass (COX-2) as celecoxib.

In animal reproduction studies with rats and rabbits, rofecoxib caused peri- and post-implantation losses and reduced embryo and fetal survival at doses approximately 9 and 2 times, respectively, the human exposure based on area under the 24-hour concentration curve (HE) at 25 mg/day, or 3 and <1 times, respectively, the HE at 50 mg/day (1). These effects are a natural consequence of inhibition of prostaglandin synthesis. No teratogenicity was observed in rats at doses 28 and 10 times the HE at 25 and 50 mg/day. In rabbits, a slight, non–statistically significant increase in the incidence of vertebral malformations was seen at doses 1 and <1 times the HE at 25 and 50 mg/day. In pregnant rats administered a single dose of rofecoxib, a decrease in the diameter of the ductus arteriosus was seen at all doses used (lowest dose tested: 2 and <1 times the HE at 25 and 50 mg/day). At 10 and 3 times the HE at 25 and 50 mg/day, rofecoxib did not cause a significantly delayed labor or parturition in rats (1).

It is not known if rofecoxib crosses the human placenta. The molecular weight (about 314) is low enough that transfer to the fetus should be expected. Rofecoxib crosses the placenta in rats and rabbits (1).

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).

Data from the Merck Pregnancy Registry for Vioxx (rofecoxib), as of July 31, 2000, include 11 exposed pregnancies (3). In another six, the cases remain blinded (the subjects may have received rofecoxib, placebo, or a comparative drug). Four pregnancies were exposed during a clinical trial with outcomes of two normal live born infants, one 1st trimester SAB, and one outcome pending. Six pregnancies were reported prospectively to the Registry. The outcomes in these cases were two normal live-born infants, one lost to follow-up, and three pregnancies ongoing. Finally, one pregnancy was reported retrospectively to the Registry that ended in the birth of a healthy baby (3).

Constriction of the ductus arteriosus in utero is a pharmacologic consequence arising from the use of prostaglandin synthesis inhibitors during pregnancy (see also Indomethacin) (4). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (4). First-generation NSAIDs have been shown to inhibit labor and prolong gestation, both in humans (5) (see also Indomethacin) and in animals (6). Although animal studies with rofecoxib did not show this effect, it is not known if humans would be similarly unaffected. Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including rofecoxib, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (7,8). 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 rofecoxib during human lactation have been located. The molecular weight (about 314) is low enough that excretion into breast milk should be expected. The drug is excreted in the milk of lactating rats at concentrations similar to those in the plasma (1). At a maternal dose approximately 18 times the HE at 25 mg/day (6 times the HE at 50 mg/day), there was an increase in nursing pup mortality and a decrease in pup body weight. The effects on a human nursing infant from exposure to rofecoxib in breast milk are unknown. 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 rofecoxib (about 17 hours) and the absence of clinical pharmacologic data in infants suggest that this agent should be avoided during nursing.

References

1. Product information. Vioxx. Merck, 2001.
2. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. Br Med J 2001;322:266–70.
3. Merck Pregnancy Registry for VIOXX (rofecoxib). First Annual Report. October 5, 2000.
4. Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.
5. Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:809–20.
6. Powell JG, Cochrane RL. The effects of a number of non-steroidal anti-inflammatory compounds on parturition in the rat. Prostaglandins 1982;23:469–88.
7. Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In Wilorsch RJ, ed. Reproductive Toxicology. 2nd ed. New York, NY: Raven Press, 1995:175–93.
8. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.