TOLMETIN

Fetal Risk Summary

Tolmetin is a nonsteroidal anti-inflammatory drug (NSAID) used for the relief of the signs and symptoms of rheumatoid arthritis, juvenile arthritis, and osteoarthritis. It is the same subclass (acetic acids) as three other NSAIDs (diclofenac, indomethacin, and sulindac).

Tolmetin is not teratogenic in rats and rabbits (1,2). The doses used in some of the studies were up to 1.5 times the maximum clinical dose based on a body weight of 60 kg (2).

It is not known if tolmetin crosses the human placenta. The molecular weight of the sodium salt (about 315) is low enough, however, that passage to the fetus should be expected.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 99 newborns had been exposed to tolmetin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (1.0%) infant had a major birth defect (four expected) consisting of a cardiovascular defect (one expected) and polydactyly (none 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 (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). These drugs also have been shown to inhibit labor and prolong pregnancy, both in humans (5) (see also Indomethacin) and in animals (6). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including tolmetin, 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

Tolmetin is excreted into breast milk (2,9). In the 4 hours following a single 400-mg oral dose, milk levels varied from 0.06 to 0.18 µg/mL with the highest concentration occurring at 0.67 hour. Milk:plasma ratios were 0.005–0.007. The clinical significance of these levels to the nursing infant is unknown. The American Academy of Pediatrics considers tolmetin to be compatible with breast feeding (10).

References

1. Nishimura K, Fukagawa S, Shigematsu K, Makumoto K, Terada Y, Sasaki H, Nanto T, Tatsumi H. Teratogenicity study of tolmetin sodium in rabbits. (Japanese) Iyakuhin Kenkyu 1977;8:158–64. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:625.
2. Product information. Tolectin. Ortho-McNeil Pharmaceutical, 2001.
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. 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 Witorsch RJ, editor. 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.
9. Sagraves R, Waller ES, Goehrs HR. Tolmetin in breast milk. Drug Intell Clin Pharm 1985;19:55–6.
10. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into breast milk. Pediatrics 1994;93:137–50.