Drugs in Pregnancy and Lactation: Tenth Edition

FLURBIPROFEN

Nonsteroidal Anti-inflammatory

PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters

BREASTFEEDING RECOMMENDATION: Compatible

PREGNANCY SUMMARY

No reports describing the use of flurbiprofen during human pregnancy have been located. 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) (1). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (1,2). Women attempting to conceive should not use any prostaglandin synthetase inhibitor, including flurbiprofen, because of the findings in various animal models that indicate these agents block blastocyst implantation (3,4). Moreover, as noted below, nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with spontaneous abortions (SABs) and congenital malformations. The absolute risk for these defects, however, appears to be low.

FETAL RISK SUMMARY

Flurbiprofen is an NSAID that shares the same precautions for human pregnancy use as other NSAIDs. It is in the same subclass (propionic acids) as five other agents (fenoprofen, ibuprofen, ketoprofen, naproxen, and oxaprozin). Flurbiprofen is used in the treatment of arthritis and is available in an ocular formulation for inhibition of intraoperative miosis. No teratogenic effects were observed in mice, rats, and rabbits administered this drug during gestation (5).

Like other NSAIDs, systemic use of flurbiprofen in rats has been associated with prolonged gestation, fetal growth restriction, and decreased fetal survival (6). In one study of pregnant rats, flurbiprofen inhibition of parturition appeared to be dose-related (7).

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 (8). 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 SABs. (A similar study, also published in 2001, failed to find a relationship, in general, between NSAIDs and congenital malformations, but did find a significant association with cardiac defects and orofacial clefts (9), In addition, a 2003 study found a significant association between exposure to NSAIDs in early pregnancy and SABs (10) (see Ibuprofen for details on these three studies).

A brief 2003 editorial on the potential for NSAID-induced developmental toxicity concluded that NSAIDs, and specifically those with greater cyclooxygenase 2 (COX-2) affinity, had a lower risk of this toxicity in humans than aspirin (11). Two reviews, both on antirheumatic drug therapy in pregnancy, recommended that if an NSAID was needed, agents with short elimination adult half-lives should be used at the maximum tolerated dosage interval, using the smallest effective dose, and that therapy should be stopped within 8 weeks of the expected delivery date (12,13). Flurbiprofen has a short plasma elimination half-life (5.7 hours), but other factors, such as its toxicity profile, need to be considered.

BREASTFEEDING SUMMARY

Very small amounts of flurbiprofen are excreted into breast milk (14,15). In 10 nursing mothers, at least 1 month postpartum, a single 100-mg oral dose of flurbiprofen was administered and milk and blood samples were obtained over a 48-hour period (14). The average peak plasma concentration (14.7 mcg/mL) occurred at 1.5 hours with a mean half-life of 5.8 hours. The average peak milk concentration was 0.09 mcg/mL with an average of 0.05% (range 0.03%–0.07%) of the maternal dose recovered in breast milk. Breastfeeding was discontinued during and after the study.

In a multiple dosing study, 12 lactating women, 3–5 days after delivery, were administered nine doses of flurbiprofen over a 3-day period (50 mg 4 times daily) (15). Paired milk and plasma samples were obtained at several times during the period and after the last dose. The mean maternal plasma half-life of the drug was 4.8 hours. Flurbiprofen milk concentrations were less than 0.05 mcg/mL in 10 of the mothers. In the remaining two mothers, only three of their milk samples contained flurbiprofen: 0.06, 0.07, and 0.08 mcg/mL. The authors concluded that these small amounts were safe for a nursing infant. The mothers did not breastfeed their infants (15).

The small amounts of flurbiprofen recovered from transitional and mature breast milk seem to indicate that the risk posed by flurbiprofen to a nursing infant is slight, if it exists at all. One reviewer classified flurbiprofen as one of several low-risk alternatives, because of its short adult serum half-life and toxicity profile compared with other similar agents, if an NSAID was required while nursing (16). Other reviewers have also stated that flurbiprofen can be safely used during breastfeeding (17,18). Ibuprofen, another NSAID in the same subclass as flurbiprofen, is considered compatible with breastfeeding by the American Academy of Pediatrics (see Ibuprofen).

References

1.Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.

2.Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, Epstein MF. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 1996;97:658–63.

3.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.

4.Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.

5.Product information. Ansaid. The Upjohn Company, 1995.

6.Product information. Ocufen. Allergan America, 1987.

7.Powell JG Jr, Cochrane RL. The effects of a number of non-steroidal anti-inflammatory compounds on parturition in the rat. Prostaglandins 1982;23:469–88.

8.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.

9.Ericson A, Kallen BAJ. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001;15:371–5.

10.Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. Br Med J 2003;327:368–71.

11.Tassinari MS, Cook JC, Hurtt ME. NSAIDs and developmental toxicity. Birth Defects Res B Dev Reprod Toxicol 2003;68:3–4.

12.Needs CJ, Brooks PM. Antirheumatic medication in pregnancy. Br J Rheumatol 1985;24:282–90.

13.Ostesen M. Optimisation of antirheumatic drug treatment in pregnancy. Clin Pharmacokinet 1994;27:486–503.

14.Cox SR, Forbes KK. Excretion of flurbiprofen into breast milk. Pharmacotherapy 1987;7:211–5.

15.Smith IJ, Hinson JL, Johnson VA, Brown RD, Cook SM, Whitt RT, Wilson JT. Flurbiprofen in post-partum women: plasma and breast milk disposition. J Clin Pharmacol 1989;29:174–84.

16.Anderson PO. Medication use while breast feeding a neonate. Neonatal Pharmacol Q 1993;2:3–14.

17.Goldsmith DP. Neonatal rheumatic disorders. View of the pediatrician. Rheum Dis Clin North Am 1989;15:287–305.

18.Needs CJ, Brooks PM. Antirheumatic medication during lactation. Br J Rheumatol 1985;24:291–7.



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