NABUMETONE

Fetal Risk Summary

The nonsteroidal anti-inflammatory drug (NSAID), nabumetone, is used in the acute and chronic treatment of arthritis. Nabumetone is a prodrug that partially undergoes hepatic conversion to an active metabolite. It is in a NSAID subclass (naphthylalkanones) that contains no other agents.

The drug was not teratogenic in rats and rabbits but did produce toxicity similar to other agents in this class, including delayed parturition, dystocia, decreased fetal growth, and decreased fetal survival (1,2). Increased postimplantation loss in rats was observed at a dose equal to the average human exposure at the maximum recommended dose (1).

It is not known if nabumetone crosses the human placenta. The molecular weight (about 228) is low enough, however, that passage to the fetus should be expected.

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 (3). 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).

Constriction of the ductus arteriosus in utero is a pharmacologic consequence arising from the use of prostaglandin synthesis inhibitors during pregnancy, as is inhibition of labor, prolongation of pregnancy, and suppression of fetal renal function (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). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including nabumetone, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (5,6). 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 nabumetone during human lactation have been located. The molecular weight (about 228) is low enough that excretion into breast milk should be expected. The active metabolite is excreted into the milk of lactating rats (1).

One reviewer listed several NSAIDs (diclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, and tolmetin) that were considered safer alternatives to other agents (nabumetone not mentioned) if these drugs were required during nursing (7). Because of the long serum elimination half-life (³22.5 hours) of the active metabolite in adults and the unknown amounts of the drug that are excreted into milk, any of these choices are probably preferable.

References

1. Product information. Relafen. SmithKline Beecham Pharmaceuticals, 2001.
2. Toshiyaki F, Kadoh Y, Fujimoto Y, Tenshio A, Fuchigami K, Ohtsuka T. Toxicity study of nabumetone (iii)—teratological studies. Kiso to Rinsho 1988;22:2975–85. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:275–6.
3. 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.
4. Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.
5. Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In Witorsch RJ, editor. Reproductive Toxicology. 2nd ed. New York, NY: Raven Press, 1995:175–93.
6. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.
7. Anderson PO. Medication use while breast feeding a neonate. Neonatal Pharmacol Q 1993;2:3–14.