Antidepressant
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 3rd Trimester
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of desvenlafaxine in human pregnancy have been located. The drug is the major active metabolite of venlafaxine that has some human pregnancy data (see also Venlafaxine). Neither the animal reproduction nor the limited human pregnancy experience with venlafaxine and other serotonin–norepinephrine reuptake inhibitors (SNRIs) suggest a major risk for structural anomalies. However, SNRIs and selective serotonin reuptake inhibitors (SSRIs) have been associated with spontaneous abortions, low birth weight, and prematurity. Exposure in the latter part of pregnancy has been associated with neonatal serotonin syndrome, neonatal behavioral syndrome (withdrawal including seizures), possible sustained abnormal neurobehavior beyond the neonatal period, and respiratory distress. These symptoms are consistent with a direct toxic effect, drug discontinuance syndrome, or a serotonin syndrome. Persistent pulmonary hypertension of the newborn (PPHN) is an additional potential risk, but confirmation is needed.
FETAL RISK SUMMARY
Desvenlafaxine, available as immediate- and extended-release formulations, is in the same antidepressant subclass of SNRIs as duloxetine, milnacipran, and venlafaxine. Desvenlafaxine is indicated for the treatment of major depressive disorder. It undergoes partial metabolism to apparently inactive metabolites. Plasma protein binding is low (30%) and the mean terminal half-life is about 11 hours (1).
Reproduction studies have been conducted in rats and rabbits. When these species were given desvenlafaxine during organogenesis, no evidence of structural anomalies was observed with doses up to 10 and 15 times, respectively, the human dose of 100 mg/day based on BSA (HD). However, fetal weights were decreased in rats, with a no-effect dose 10 times the HD. Exposure of rats throughout gestation and lactation was associated with decreased pup weights and increased pup deaths during the first 4 days of lactation. The cause of the deaths was not known. The no-effect dose for pup mortality was 10 times the HD. Postweaning growth and reproductive performance of the offspring were not affected by maternal treatment at a dose 29 times the HD (1).
Desvenlafaxine was not carcinogenic in 2-year studies in mice and rats. Assays and studies for mutagenic and clastogenic effects also were negative. Reduced fertility was observed in male and female rats given doses about 10 times the HD. There was no effect on fertility with doses that were about 3 times the HD (1).
At term, desvenlafaxine crosses the human placenta (2). This is consistent with the molecular weight (about 381 for the nonhydrated form), low plasma protein binding, moderately long terminal half-life, and the toxicity observed in newborns. Although placental transfer of the drug has not been studied at other times, exposure of the embryo–fetus should be expected throughout gestation.
The use of desvenlafaxine late in the pregnancy may result in functional and behavioral deficits in the newborn infant. The observed toxicities with SNRIs and SSRIs include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. The clinical features are consistent with either a direct toxic effect or drug discontinuation syndrome and, occasionally, may resemble a serotonin syndrome. The complications may require prolonged hospitalization, respiratory support, and tube feeding (1). (See Venlafaxine for additional information.)
BREASTFEEDING SUMMARY
Consistent with the molecular weight (about 381 for the nonhydrated form), low plasma protein binding (30%), and moderately long elimination half-life (about 11 hours), desvenlafaxine is excreted into breast milk. (See also Venlafaxine.)
A 1998 study measured the excretion of venlafaxine and its active metabolite desvenlafaxine in the milk of three breastfeeding 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 ages of the infants were 0.37–6 months. The mean milk:plasma (M:P) ratio (in two cases based on AUC and 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 mcg/L (range 23–225 mcg/L). The mean total infant dose was 7.57% (range 4.74%–9.23%). No adverse effects in the infants were noted. Because of the relatively high infant dose in comparison with other antidepressants, it was 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).
A 2002 study determined the milk:plasma (M:P) ratios based on AUC and infant doses of venlafaxine and its metabolite desvenlafaxine in six mothers (mean age 34.5 years and weight 84.3 kg) and their seven nursing infants (mean age 7.0 months and weight 7.3 kg) (4). The median venlafaxine dose was 244 mg/day. The mean M:P ratios for the drug and its metabolite were 2.5 (range 2.0–3.2) and 2.7 (range 2.3–3.2), respectively, whereas the mean maximum milk concentrations were 1161 and 796 mcg/L, respectively. Using an estimated milk production rate of 150 mL/kg/day, the mean infant exposure expressed as a percentage of the weight-adjusted maternal dose was 3.2% (95% confidence interval [CI] 1.7–4.7) for venlafaxine and 3.2% (95% CI 1.9–4.9) for desvenlafaxine. Venlafaxine was detected in the plasma of one infant (5 mcg/L), whereas desvenlafaxine was detected in four infants (range 3–38 mcg/L). All of the infants were healthy (4).
In a 2009 report, 13 women taking venlafaxine (mean dose 194.3 mg/day) and their nursing infants (mean age about 21 weeks) were studied (5). The highest venlafaxine and desvenlafaxine concentrations in milk occurred 8 hours after maternal ingestion. For combined venlafaxine plus desvenlafaxine, the mean M:P ratio was 2.75, and the theoretical infant dose was 0.208 mg/kg/day. The relative infant dose as a percentage of the mother’s weight-adjusted dose was 8.1%. The theoretical and relative infant doses for desvenlafaxine were 1.97 and 2.24 times higher than those for venlafaxine. No adverse effects were observed or reported in the infants (5).
A study of a woman taking desvenlafaxine 250 mg/day and amisulpride (an atypical antipsychotic not available in the United States) 100 mg/day for depression and nursing her 5-month-old infant was reported in 2010 (6). The absolute (theoretical) infant doses of the two drugs were 294 and 183 mcg/kg/day, respectively. The relative infant doses as a percentage of the mother’s weight-adjusted doses were 7.8% and 6.1%, respectively. The infant was achieving expected developmental progress for age and no adverse effects were noted (6).
In a 2011 study of 10 women taking desvenlafaxine (50–150 mg/day) and their nursing infants (mean age 4.3 months, range 0.9–12.7 months), 8 of whom were exclusively breastfed, no adverse effects were noted in the infants (7). The mean theoretical infant dose was 85 mcg/kg/day and the relative infant dose as a percentage of the mother’s weight-adjusted dose was 6.8%.
Maternal plasma concentrations of desvenlafaxine and venlafaxine determine the amount of drug excreted into milk. In this regard, a 2009 study appears to have important implications for choosing which agent to use in a lactating woman (8). The study evaluated the effect of cytochrome P450 2D6 extensive metabolizer (EM) or poor metabolizer (PM) status on the pharmacokinetics of single doses of venlafaxine extended release and desvenlafaxine in healthy adults. The maximum plasma concentrations and AUC of desvenlafaxine were statistically similar in the two groups. In contrast, venlafaxine concentrations and AUC were significantly higher in the PM phenotype compared with the EM phenotype, whereas the desvenlafaxine concentrations and AUC were significantly lower in the PM group (8).
In summary, the available data suggest that exposure to desvenlafaxine from milk does not represent a major risk to a nursing infant. However, nursing preterm and newborn infants were not involved in the above studies and they should be closely observed for excessive sedation and appropriate weight gain if the agent is used by the mother. Additional studies, especially long-term follow-up of exposed infants, are warranted.
References
1.Product information. Pristiq. Wyeth, 2011.
2.Rampono J, Simmer K, Ilett KF, Hackett LP, Doherty DA, Elliot R, Kok CH, Coenen A, Forman T. Placental transfer of SSRI and SNRI antidepressants and effects on the neonate. Pharmacopsychiatry 2009;42:95–100.
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.Ilett KF, Kristensen JH, Hackett LP, Paech M, Kohan R, Rampono J. Distribution of venlafaxine and its O-desmethyl metabolite in human milk and their effects in breastfed infants. Br J Clin Pharmacol 2002;53:17–22.
5.Newport DJ, Ritchie JC, Knight BT, Glover BA, Zach EB, Stowe ZN. Venlafaxine in human breast milk and nursing infant plasma: determination of exposure. J Clin Psychiatry 2009;70:1304–10.
6.Ilett KF, Watt F, Hackett LP, Kohan R, Teoh S. Assessment of infant dose through milk in a lactating woman taking amisulpride and desvenlafaxine for treatment-resistant depression. Ther Drug Monit 2010;32:704–7.
7.Rampono J, Teoh S, Hackett LP, Kohan R, Ilett KF. Estimation of desvenlafaxine transfer into milk and infant exposure during its use in lactating women with postnatal depression. Arch Womens Ment Health 2011;14:49–53.
8.Preskorn S, Patroneva A, Silman H, Jiang Q, Isler JA, Burczynski ME, Ahmed S, Paul J, Nichols AI. Comparison of the pharmacokinetics of venlafaxine extended release and desvenlafaxine in extensive and poor cytochrome P450 2D6 metabolizers. J Clin Psychopharmacol 2009;29:39–43.