MECLOFENAMATE

Drugs in Pregnancy and Lactation.

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Name: MECLOFENAMATE
Class: Nonsteroidal Anti-inflammatory
Risk Factor:    B*

Fetal Risk Summary

The nonsteroidal anti-inflammatory drug (NSAID) meclofenamate sodium is used in the treatment of acute and chronic pain, arthritis, and primary dysmenorrhea. It is in the same NSAID subclass (fenamates) as mefenamic acid.

Reproduction studies in mice, rats, and rabbits during organogenesis found no teratogenic effects (1,2 and 3), but postimplantation losses were observed in rats (3). Although apparently not reported, animal reproductive toxicities observed with other agents in the class, such as prolonged gestation, dystocia, intrauterine growth retardation, and decreased fetal and neonatal survival, should also be expected with meclofenamate.

It is not known if meclofenamate crosses the human placenta. The molecular weight of the free acid (about 313) 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, 166 newborns had been exposed to meclofenamate during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Six (3.6%) major birth defects were observed (seven expected), including one cardiovascular defect (two expected) and one oral cleft (three expected). No anomalies were observed in four other categories of defects (spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. These data do not support an association between the drug and congenital defects.

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 (4). 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).

Two reviews, both on antirheumatic drug therapy in pregnancy, recommended that if a NSAID was needed, agents with short elimination adult half-lifes should be used at the maximum tolerated dosage interval, using the lowest effective dose, and that therapy should be stopped within 8 weeks of the expected delivery date (5,6). Meclofenamate has a short plasma elimination half-life (2 hrs), but other factors, such as its toxicity profile, need to be considered.

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) (7). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (7). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including meclofenamate, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (8,9). 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 meclofenamate sodium during lactation have been located. The molecular weight of the free acid (about 313) suggests that the drug will be excreted into breast milk. The effects of this exposure on a nursing infant are unknown, but other NSAIDs are considered compatible with breast feeding by the American Academy of Pediatrics (see Ibuprofen and Indomethacin).

References

  1. Product information. Meclomen. Parke-Davis, 1993.
  2. Schardein JL, Blatz AT, Woosley ET, Kaump DH. Reproduction studies on sodium meclofenamate in comparison to aspirin and phenylbutazone. Toxicol Appl Pharmacol 1969;15:46–55. As cited in Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, Inc., 1993:131.
  3. Petrere JA, Humphrey RR, Anderson JA, Fitzgerald JE, De La Iglesia FA. Studies on reproduction in rats with meclofenamate sodium, a nonsteroidal antiinflammatory agent. Fund Appl Toxicol 1985;5:665–71. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore,MD: Johns Hopkins University Press, 1992:244–5.
  4. 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.
  5. Needs CJ, Brooks PM. Antirheumatic medication in pregnancy. Br J Rheumatol 1985;24:282–90.
  6. Ostensen M. Optimisation of antirheumatic drug treatment in pregnancy. Clin Pharmacokinet 1994;27:486–503.
  7. Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.
  8. 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.
  9. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.

Index