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Aspirin / caffeine / propoxyphene Pregnancy and Breastfeeding Warnings

Aspirin / caffeine / propoxyphene is also known as: Darvon Compound 32, Darvon Compound-65, PC-CAP, Propoxyphene Compound 65

Aspirin / caffeine / propoxyphene Pregnancy Warnings

The frequency of fetal exposure to aspirin reported in many studies may be underestimated because aspirin (and other salicylates) occur in many over-the-counter preparations and women may fail to recall taking aspirin and over-the-counter drugs. A study of the use of low-dose aspirin (60 mg per day) to prevent and treat preeclampsia in 9364 pregnant women (the Collaborative Low-dose Aspirin Study in Pregnancy--CLASP) did "not support routine prophylactic or therapeutic administration of antiplatelet therapy in pregnancy to all women at increased risk of preeclampsia or IUGR." In that study, no excess of intraventricular hemorrhage, neonatal bleeds, or mortality attributable to bleeding were observed. The investigators did identify a possible role for low-dose aspirin in the treatment of early-onset preeclampsia severe enough to need very preterm delivery. Another study of low-dose aspirin (follow-up from the Italian Study of Aspirin in Pregnancy) has suggested that "low dose aspirin in pregnancy is safe with respect to the risks of malformation and of major impairment in development at 18 months of age." High-dose aspirin (2 g per day) has been associated with stillbirths, cerebral hemorrhage, oculoauriculovertebral dysplasia, neonatal salicylate toxicity, constricted ductus arteriosus, cyclopia, and neonatal acidosis. Some cases of congenital heart defects have been reported. However, a case control study of aspirin use in the first trimester concluded that aspirin "does not increase the risk of congenital heart defects in relation to that of other structural malformations." In a study of 2817 fertile women, no evidence of adverse effects from caffeine was found. The fecundability ratio (adjusted for known risk factors for time to conceive) was 1.03 between fertile women who consumed more than 7000 mg caffeine per month and those who consumed 500 mg or less per month. Furthermore, caffeine was not associated with infertility in 1818 infertile women and their primiparous controls. In another study (n=441) no evidence was found that moderate caffeine use increased the risk of spontaneous abortion, intrauterine growth retardation, or microcephaly. In most cases of congenital malformations in infants exposed to propoxyphene, other drugs were also used during pregnancy and a clear association between propoxyphene use and the malformations has not been established. Some of the specific malformations described in case reports of infants exposed to propoxyphene (and often other drugs) have included: prune perineum, Pierre Robin syndrome, arthrogryposis, severe caudal dysplasia, micrognathia, microcephaly, ductus arteriosus persistens, cataract, benign tumors, club foot, and limb reduction defects. The Collaborative Perinatal Project identified 686 mother-child pairs with first trimester exposure to propoxyphene and observed 31 malformed children. (In that group, 34.4 malformed children were expected.) A study of Michigan Medicaid patients identified 1029 neonates exposed in utero to propoxyphene and observed 41 malformed children (personal communication, Franz Rosa, MD, Food and Drug Administration, 1994). (In that group, 43 malformed children were expected.) Neonatal propoxyphene withdrawal symptoms include irritability, hypertonicity, jitteriness, increased temperature, tremors, increased appetite, diarrhea and high-pitched cry.

Aspirin has not been formally assigned to a pregnancy category. NSAID use during the third trimester of pregnancy should be avoided due to effects on the fetal cardiovascular system (closure of the ductus arteriosus). Aspirin use in pregnancy has been associated with alterations in both maternal and fetal hemostasis. In addition, high doses of aspirin have been associated with increased perinatal mortality, intrauterine growth retardation, and teratogenic effects. Increased maternal bleeding can occur during delivery when aspirin is used 1 week prior to and/or during labor and delivery. Prolonged gestation and labor have been reported due to aspirin's inhibition of prostaglandin. Caffeine has been assigned to pregnancy category B by the FDA. Both human and animal studies have failed to reveal evidence of significant mutagenic or carcinogenic effects. Caffeine crosses the placenta. Fetal blood and tissue levels in the fetus are similar to those in the mother. Caffeine has been reported to be an animal teratogen only with doses high enough to cause toxicity in the mother. In 1980, the Food and Drug Administration issued an advisory (based primarily on animal evidence) which stated that pregnant women should limit there intake of caffeine to a minimum. Propoxyphene has not been formally assigned to a pregnancy category by the FDA. Several case reports have described infants exposed to propoxyphene in utero who were born with a variety of congenital malformations. Withdrawal symptoms have also been reported in neonates whose mothers took propoxyphene during pregnancy. There are no controlled data in human pregnancy. Aspirin/caffeine/propoxyphene should only be given during the first two trimesters pregnancy when there are no alternatives and benefit outweighs risk. Aspirin/caffeine/propoxyphene is considered contraindicated during the third trimester pregnancy.

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Aspirin / caffeine / propoxyphene Breastfeeding Warnings

Aspirin is excreted into human milk in small amounts. Peak milk salicylate levels have been reported at nine hours after maternal dosing (and measured at 1.1 mg/dL). Use of large doses of aspirin can result in rashes, platelet abnormalities, and bleeding in nursing infants. Because of a single case report of metabolic acidosis, the American Academy of Pediatrics characterizes aspirin as a drug that has been "associated with significant effects on some nursing infants and should be given to nursing mothers with caution." Caffeine is excreted into human milk in small amounts. Adverse effects in the nursing infant are unlikely. However, irritability and poor sleep patterns have been reported in nursing infants. The amount of caffeine generally found in caffeinated beverages is considered to usually be compatible with breast-feeding by the American Academy of Pediatrics. Because caffeine is excreted into human milk and because caffeine is metabolized slowly by nursing infants, consumption of more than moderate levels of caffeine by nursing mothers is not recommended. Propoxyphene and its active metabolite, norpropoxyphene, are excreted into human breast milk in small amounts. The clinical effects in breast-fed infants have not been described. Propoxyphene is considered compatible with breast-feeding by the American Academy of Pediatrics.

See references

References for pregnancy information

  1. Mills JL, Holmes LB, Aarons JH, Simpson JL, Brown ZA, Jovanovic-Peterson LG, Conley MR, Graubard BI, Knopp RH, Metzger BE "Moderate caffeine use and the risk of spontaneous abortion and intrauterine growth retardation [see comments." JAMA 269 (1993): 593-7
  2. "Clasp: a randomised trial lf low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women." Lancet 343 (1994): 619-29
  3. Eskenazi B "Caffeine during pregnancy: grounds for concern? [editorial; comment]." JAMA 270 (1993): 2973-4
  4. Schoenfeld A, Bar Y, Merlob P, Ovadia Y "NSAIDs: maternal and fetal considerations." Am J Reprod Immunol 28 (1992): 141-7
  5. Ente G, Mehra MC "Neonatal withdrawal from propoxyphene hydrochloride." N Y State J Med 78 (1978): 2084-5
  6. "Product Information. Darvon Compound-65 (ASA/caffeine/propoxyphene)." aaiPharma, Wilmington, NC.
  7. "Product Information. Bayer aspirin (aspirin)." Bayer, West Haven, CT.
  8. Quillian 2d, Dunn CA "Neonatal drug withdrawal from propoxyphene." JAMA 235 (1976): 2128
  9. Parazzini F, Bortolus R, Chatenoud L, Restelli S, Benedetto C "Follow-up of children in the italian study of aspirin in pregnancy." Lancet 343 (1994): 1235
  10. Ringrose CA "The hazard of neurotropic drugs in the fertile years." Can Med Assoc J 106 (1972): 1058
  11. Barrow MV, Souder DE "Propoxyphene and congenital malformations." JAMA 217 (1971): 1551-2
  12. Heinonen O, Slone D, Shapiro S; Kaufman DW ed. "Birth Defects and Drugs in Pregnancy." Littleton, MA: Publishing Sciences Group, Inc. (1977): 297
  13. Koren G, Pastuszak A, Ito S "Drugs in pregnancy." N Engl J Med 338 (1998): 1128-37
  14. Tyson HK "Neonatal withdrawal symptoms associated with maternal use of propoxyphene hydrochloride (Darvon)." J Pediatr 85 (1974): 684-5
  15. Briggs GG, Freeman RK, Yaffe SJ.. "Drugs in Pregnancy and Lactation. 5th ed." Baltimore, MD: Williams & Wilkins (1998):
  16. Williams DA, Weiss T, Wade E, Dignan P "Prune perineum syndrome: report of a second case." Teratology 28 (1983): 145-8
  17. "Product Information. Darvon (propoxyphene)." Lilly, Eli and Company, Indianapolis, IN.
  18. Strode SW "Propoxyphene dependence and withdrawal." Am Fam Physician 32 (1985): 105-8
  19. Poskitt EM, Hensey OJ, Smith CS "Alcohol, other drugs and the fetus." Dev Med Child Neurol 24 (1982): 596-602
  20. Karlowicz MG, White LE "Severe intracranial hemorrhage in a term neonate associated with maternal acetylsalicylic acid ingestion." Clin Pediatr (Phila) 32 (1993): 740-3
  21. Klein RB, Blatman S, Little GA "Probable neonatal propoxyphene withdrawal: a case report." Pediatrics 55 (1975): 882-4
  22. Joesoef MR, Beral V, Rolfs RT, Aral SO, Cramer DW "Are caffeinated beverages risk factors for delayed conception? [see comments." Lancet 335 (1990): 136-7
  23. Golden NL, King KC, Sokol RJ "Propoxyphene and acetaminophen. Possible effects on the fetus." Clin Pediatr (Phila) 21 (1982): 752-4

References for breastfeeding information

  1. Erickson SH, Oppenheim GL "Aspirin in breast milk." J Fam Pract 8 (1979): 189-90
  2. Kunka RL, Yong CL, Ladik CF, Bates TR "Liquid chromatographic determination of propoxyphene and norpropoxyphene in plasma and breast milk." J Pharm Sci 74 (1985): 103-4
  3. "Product Information. Bayer aspirin (aspirin)." Bayer, West Haven, CT.
  4. "Product Information. Darvon Compound-65 (ASA/caffeine/propoxyphene)." aaiPharma, Wilmington, NC.
  5. Kunka RL, Venkataramanan R, Stern RM, Ladik CF "Excretion of propoxyphene and norpropoxyphene in breast milk." Clin Pharmacol Ther 35 (1984): 675-80
  6. Committee on Drugs, 1992 to 1993 "The transfer of drugs and other chemicals into human milk." Pediatrics 93 (1994): 137-50

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