Narcotic Agonist Analgesic
PREGNANCY RECOMMENDATION: No Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of tapentadol in human pregnancy have been located. The drug caused significant embryo–fetal developmental toxicity in two animal species but always in the presence of maternal toxicity. In general, occasional use of narcotic agonist analgesics in pregnancy is considered low risk. However, tapentadol, as with other agents in this class, has the potential for abuse and such use could cause embryo–fetal harm. Respiratory depression of the newborn is a potential complication if the drug is used close to birth. A narcotic antagonist, such as naloxone, should be readily available to reverse neonatal respiratory depression if present.
FETAL RISK SUMMARY
Tapentadol is an oral centrally acting synthetic analgesic. It is indicated for the relief of moderate to severe acute pain in patients 18 years of age or older. Similar to other mu-opioid agonists, tapentadol has addictive properties and may be sought by drug abusers. The drug is extensively metabolized to inactive metabolites. Plasma protein binding is low (about 20%), whereas the average terminal half-life is 4 hours (1).
Reproduction studies have been conducted in rats and rabbits. No teratogenic effects were observed during organogenesis in rats given SC doses resulting in plasma exposures up to the plasma exposure at the maximum recommended human dose of 700 mg/day based on AUC (MRHD). The highest dose caused significant maternal toxicity and was associated with embryo–fetal toxicity that included transient delays in skeletal maturation (i.e., reduced ossification). Exposures up to 1.7 times the MRHD during late gestation and early postnatal period did not influence physical or reflex development, the outcome of neurobehavioral tests or reproductive parameters. However, at maternal toxic exposures, treatment-related developmental delay was observed, including incomplete ossification, significant reductions in pup body weights and weight gains, and increased pup mortality (1).
During organogenesis, rabbits received SC doses resulting in plasma exposures that were 0.2–1.85 times the MRHD. At exposures ≥0.6 times the MRHD, embryo–fetal toxicity was observed that consisted of reduced fetal viability, skeletal delays and other variations, and multiple malformations (gastroschisis/thoracogastroschisis, amelia/phocomelia, and cleft palate). Malformations observed at exposures that were 1.85 times the MRHD were ablepharia, encephalopathy, and spina bifida. However, the exposures caused significant maternal toxicity and this may have caused the embryo–fetal toxicities, including malformations (1).
In 2-year studies for carcinogenicity, no increase in tumor incidence was observed in mice and rats. The drug was not mutagenic in several assays. A clastogenic effect was noted in one assay but was not confirmed in a repeat test or in vivo. In fertility tests in rats, plasma exposures up to 0.4 times the MRHD did not alter fertility at any dose level. However, maternal toxicity was observed at plasma exposures <0.4 times the MRHD that resulted in a decreased number of implantations and live conceptuses, and increased preimplantation and postimplantation losses (1).
It is not known if tapentadol crosses the human placenta. The molecular weight (about 222 for the free base), low plasma protein binding, and the terminal half-life suggest that the drug will reach the embryo–fetus.
BREASTFEEDING SUMMARY
No reports describing the use of tapentadol during human lactation have been located. The molecular weight (about 222 for the free base), low plasma protein binding (about 20%), and the average terminal half-life (4 hours) suggest that the drug will be excreted into breast milk. As with all basic drugs, accumulation in the more acidic milk, as compared with plasma, should occur with continuous dosing and result in milk:plasma ratios >1. The effect of this exposure on a nursing infant is unknown, but respiratory depression and other narcotic effects are a potential complication.
Reference
1.Product information. Nucynta. PriCara (Division of Ortho-McNeil-Janssen Pharmaceuticals), 2009.