Analgesic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of ziconotide in human pregnancy have been located. Ziconotide is indicated for long-term intrathecal (IT) therapy and, as such, any exposure would occur throughout gestation. However, clinically significant amounts do not appear to reach the plasma during continuous IT infusions. The small amounts that are in the systemic circulation are metabolized in organ tissues to peptide fragments and free amino acids. Moreover, animal reproduction studies in two species suggest that the risk to the human embryo or fetus is low. Although the absence of human pregnancy experience prevents a more complete assessment, the risk to the embryo–fetus appears to be low. If a woman requires IT therapy with ziconotide, the benefit to her appears to far outweigh the unknown risk to her developing baby.
FETAL RISK SUMMARY
Ziconotide, a 25-amino-acid polypeptide, is a synthetic equivalent of a naturally occurring conopeptide found in the piscivorous marine snail, Conus magus. The hydrophilic peptide is given as an IT infusion for the management of severe chronic pain in patients for whom IT therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapy, or IT morphine (1). The terminal half-life in the cerebrospinal fluid (CSF) is about 4.5 hours (range 2.9–6.5 hours). About 50% of ziconotide is bound to plasma proteins, but metabolism to peptide fragments and individual free amino acids occurs in organs, such as the kidney, liver, lung, and muscle, not in the CSF or blood. The biologic activity of the metabolic products has not been determined. Although ziconotide should not be given IV, minimal amounts of the drug (<1%) were recovered from the urine after an IV infusion (1).
During constant IT infusions at rates ranging from 0.1 to 7 mcg/hr, plasma concentrations were below the level of detection (0.04 ng/mL) in slightly more than half of the patients. More patients had detectable plasma concentrations when higher doses were used (1).
Reproduction studies have been conducted in rats and rabbits. Ziconotide caused embryo death in pregnant rats given continuous IV infusions about 700 times higher than the expected plasma exposure resulting from the maximum recommended human daily IT dose of 0.8 mcg/hr (19.2 mcg/day) (MRHD). No structural defects were observed in rats and rabbits given continuous IV infusions during organogenesis that were up to about 26,000 and 940 times higher, respectively, than the expected plasma exposure resulting from the MRHD. Maternal toxicity (decreased body weight gain and food consumption) was observed at all dose levels. In rats, maternal toxicity, at doses about ≥8900 times higher than the expected plasma exposure resulting from the MRHD, resulted in reduced fetal weight and delayed ossification of the pubic bones. The no-observed-adverse-effect level (NOAEL) for embryo–fetal development in rats and rabbits was about 400 and 940 times higher, respectively, than the expected plasma exposure from the MRHD.
In prenatal and postnatal studies in rats, continuous IV infusions up to about 3800 times higher than the expected plasma exposure resulting from the MRHD had no effect on pup development or reproductive performance. Maternal toxicity, as noted above, was observed at all dose levels.
It is not known if ziconotide crosses the human placenta. The molecular weight (2639) and the very low plasma concentrations suggest that little, if any, drug will reach the embryo or fetus.
BREASTFEEDING SUMMARY
No reports describing the use of ziconotide during human lactation have been located. Ziconotide is a 25-amino-acid polypeptide with a molecular weight of 2639. Although excretion into milk is possible, only small, probably clinically insignificant amounts of ziconotide appear in the plasma during IT infusions. It is not known if the drug would be detectable in breast milk. The risk to a nursing infant appears to be negligible.
Reference
1.Product information. Prialt. Elan Pharmaceuticals, 2005.