VENLAFAXINE

Fetal Risk Summary

Venlafaxine, an antidepressant structurally unrelated to other available antidepressants, was approved by the FDA in December 1993. Although the mechanism of action of this agent and its active metabolite is unknown, it is believed to be related to the potentiation of neurotransmitter activity in the brain. Venlafaxine is a potent inhibitor of neuronal reuptake of serotonin and norepinephrine, and a weak inhibitor of dopamine reuptake.

Reproduction studies in rats and rabbits at doses up to 2.5 and 4 times the maximum recommended human daily dose based on body surface area (MRHD), respectively, did not reveal teratogenicity (1). When rats were given the same maximum dose during pregnancy through weaning, however, there was a decrease in pup weight and an increased number of stillbirths and pup deaths during the first 5 days of lactation. The no-effect dose for pup mortality was 0.25 times the MRHD (1).

A 1994 review of venlafaxine included citations of data from the clinical trials of this drug involving its use during gestation in 10 women for periods ranging from 10 to 60 days (2), apparently during the 1st trimester. No adverse effects of the exposure were observed in four of the infants (information not provided for the other six exposed pregnancies).

Except for the report above, no publications describing the use of venlafaxine during human pregnancy have been located. The FDA has not received any reports of adverse pregnancy outcomes involving the use of the drug during gestation (personal communication, F. Rosa, FDA, 1996).

Breast Feeding Summary

Venlafaxine is excreted into human breast milk. A 1998 study measured the excretion of venlafaxine and its active metabolite, O-desmethylvenlafaxine, in the milk of three breast-feeding women (3). The three mothers, started on the antidepressant after delivery, had been taking a stable dose (3.04–8.18 mg/kg/day) for 0.23–5 months. The age of the infants ranged from 0.37 to 6 months. The mean milk:plasma (M:P) ratio (in two cases based on area under the concentration curve [12 hours], in one on a single point) for the parent drug was 4.14 (range 3.26–5.18), whereas it was 3.06 (range 2.93–3.19) for the metabolite. The mean infant doses for venlafaxine and metabolite were 3.49% and 4.08% of the mother's weight-adjusted dose, respectively. Venlafaxine was not detected in infant plasma, but the median infant metabolite plasma concentration was 100 µg/L (range 23–225 µg/L). The mean total infant dose was 7.57% (range 4.74%–9.23%). No adverse effects in the suckling infants were noted. Because of the relatively high infant dose in comparison to other antidepressants, the investigators recommended that close observation of the infant for short-term adverse effects (e.g., agitation, insomnia, poor feeding, or failure to thrive) was required (3).

The long-term effects on neurobehavior and cognitive development from exposure to potent serotonin reuptake inhibitors during a period of rapid central nervous system development have not been adequately studied. The American Academy of Pediatrics considers the effects of other antidepressants on the nursing infant to be unknown, although they may be of concern (4).

References

1. Product information. Effexor. Wyeth-Ayerst Pharmaceuticals, 2000.
2. Ellingrod VL, Perry PJ. Venlafaxine: a heterocyclic antidepressant. Am J Hosp Pharm 1994;51:3033–46.
3. Ilett KF, Hackett LP, Dusci LJ, Roberts MJ, Kristensen JH, Paech M, Groves A, Yapp P. Distribution and excretion of venlafaxine and O-desmethylvenlafaxine in human milk. Br J Clin Pharmacol 1998;45:459–62.
4. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.