Antidepressant
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 3rd Trimester
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Duloxetine causes developmental toxicity in animals (growth restriction in rats and rabbits; behavior deficits and death in rats) at doses <10 times the maximum recommended human dose of 60 mg/day based on BSA (MRHD). No structural anomalies were observed in these species. The human data for duloxetine are limited and incomplete. However, the pharmacologic action of duloxetine is similar to that of venlafaxine and selective serotonin reuptake inhibitors (SSRIs). SSRIs and venlafaxine have been associated with developmental toxicities, including spontaneous abortions, low birth weight, prematurity, neonatal serotonin syndrome, neonatal behavioral syndrome (withdrawal), possible sustained abnormal neurobehavior beyond the neonatal period, respiratory distress, and persistent pulmonary hypertension of the newborn (PPHN). Some of these symptoms are thought to be consistent with a direct toxic effect, drug discontinuance syndrome, or a serotonin syndrome. If duloxetine is used in pregnancy, healthcare professionals are encouraged to call the toll-free number (800-670-6126) for information about patient enrollment in the Motherisk study.
FETAL RISK SUMMARY
Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). It has both antidepressant and central pain inhibitory action. Other drugs in the same class are desvenlafaxine, milnacipran, and venlafaxine. Duloxetine is extensively metabolized to inactive metabolites. The parent compound is highly bound (>90%) to plasma albumin and α1-acid glycoprotein. The elimination half-life is about 12 hours (range 8–17 hours) (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, there was no evidence of fetal structural defects at doses up to seven times the MRHD administered during organogenesis. However, fetal weights were decreased at this dose. The no-effect dose was twice the MRHD. When duloxetine was administered throughout gestation and lactation, pup survival to 1 day postpartum and pup body weights at birth and during lactation were decreased at a dose five times the MRHD. In addition, pup behavior was adversely affected as shown by increased reactivity (e.g., increased startle response to noise and decreased habituation of locomotor activity). No adverse effects were observed on postweaning growth and reproductive performance. In pregnant rabbits, no evidence of fetal structural defects was observed at doses up to 15 times the MRHD during organogenesis, but fetal growth restriction was noted. The no-effect dose was three times the MRHD (1).
Duloxetine crosses the human placenta, at least at term. In a 2009 case report, the cord blood duloxetine concentration about 14 hours after a 60-mg extended release dose was 65 mcg/L (2). This is consistent with the molecular weight (about 298 for the free base) and the long elimination half-life of the drug.
Approximately 10 women became pregnant in a study of duloxetine in the treatment of depression (3). Treatment was discontinued and no additional information was provided.
A 2007 review conducted a literature search to determine the risk of major congenital malformations after 1st trimester exposure to SSRIs and SNRIs (4). Fifteen controlled studies were analyzed. The data were adequate to suggest that citalopram, fluoxetine, sertraline, and venlafaxine were not associated with an increased risk of congenital defects. In contrast, the analysis did suggest an increased risk with paroxetine. The data were inadequate to determine the risk for the other SSRIs and SNRIs (4).
A case–control study, published in 2006, found that exposure to SSRIs in late pregnancy was associated with persistent pulmonary hypertension of the newborn (PPHN) (5) (see Paroxetine or other SSRIs). Although there were no exposures to duloxetine in this study, the action of duloxetine is similar enough to the SSRIs that it might cause the same effect.
A brief report in 2008 described a case of poor neonatal behavioral syndrome due to duloxetine (6). The 36-year-old mother had been treated with monotherapy duloxetine 90 mg/day during pregnancy. Her female infant was born at 38 weeks’ with Apgar scores of 7 and 9 (birth weight not provided). At delivery, the infant was blue, with minimal respiratory effort and oxygen saturation was in the 80s. Laboratory and other tests to determine the cause of the infant’s condition were normal. “Jerky rhythmic movements” or “twitchiness” and episodes of shaking began on day 3. The initial electroencephalogram (EEG) showed nonspecific encephalopathy, but a repeat test at 7 days was suggestive of subclinical seizures. The infant was treated with phenobarbital but continued occasional twitching. At 7 weeks, the EEG was normal and phenobarbital was discontinued. At age 2 years, the child is healthy with normal neurobehavioral development (6).
A 2009 report described the use of duloxetine during the second half of pregnancy (2). The 20-year-old woman, treated for depression, was taking 60 mg once daily (868 mcg/kg/day or 34 mg/m2). She gave birth to a healthy, 2.916-kg female infant at 38 weeks’. The Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. The concentration of duloxetine in the cord blood (see above) was greater than the mother’s peak plasma concentration obtained 6 hours after a dose 32 days after birth (see Breastfeeding Summary below). No evidence of developmental toxicity or other toxicity was observed in the infant (2).
Using the Lilly Safety System, a database for the collection, storage, and reporting of adverse events involving Lilly products, investigators identified 400 pregnancies (233 prospective; 167 retrospective) with known outcomes (7). The data collection period was from 2004 (drug approval) through October 2011. Of the prospectively reported cases, 170 (73%) were spontaneous reports, 58 (25%) were from clinical trials, and 5 (2%) involved post-marketing studies. In addition, 176 reports involving duloxetine from the FDA Adverse Events Reporting System through September 2011 were also examined. Analysis of the two data sources suggested that the frequency of abnormal outcomes were generally consistent with historic control rates in the general population (7).
BREASTFEEDING SUMMARY
Duloxetine is excreted into breast milk (2,8). A 2008 study conducted by the manufacturer described the use of duloxetine 40 mg every 12 hours for 3.5 days in six healthy women, at least 12 weeks postpartum, who had stopped nursing when the study was started (8). Seven paired milk and blood samples were collected on day 4 (probably at steady state). The mean milk:plasma ratio was 0.25 (90% confidence interval 0.18–0.35). The theoretical infant dose (TID) was 1.72 mcg/kg/day (range 0.59–3.05) and the mean maternal weight-adjusted dose was 1210 mcg/kg/day, resulting in a relative infant dose (RID) of 0.14% (range 0.068–0.249) (8).
In the case described in the Fetal Risk Summary, the mother exclusively breastfed her infant and, on day 32, milk and plasma samples (peak and trough) and a peak infant plasma sample were obtained (2). The milk:plasma ratios for the peak and trough collections were 1.2 and 1.3, respectively, whereas the drug was not detected in the infant plasma. The TID was 7.1 mcg/kg/day, whereas the mother’s weight-adjusted dose was 868 mcg/kg/day. This yielded an RID of 0.82%. No signs of toxicity were noted in the infant at any time (2).
A 2010 study using human and animal models found that drugs that disturb serotonin balance such as SSRIs and SNRIs can impair lactation (9). The authors concluded that mothers taking these drugs may need additional support to achieve breastfeeding goals.
The presence of duloxetine in milk is consistent with the molecular weight (about 298 for the free base) and long elimination half-life (12 hours). Moreover, because milk is relatively acidic compared with blood, the milk:plasma ratio that was >1 also is consistent. Although no toxicity was observed in the above case, the long-term effects of exposure to duloxetine and similar antidepressants have not been adequately studied. The long-term effects on neurobehavior and cognitive development from exposure to potent SNRIs and SSRIs during a period of rapid CNS development have not been adequately studied. Therefore, the best course is to avoid duloxetine, if possible, during nursing. The American Academy of Pediatrics classifies antidepressants as drugs for which the effect on nursing infants is unknown but may be of concern (10).
References
1.Product information. Cymbalta. Eli Lilly, 2006.
2.Briggs GG, Ambrose PJ, Ilett KF, Hackett LP, Nageotte MP, Padilla G. Use of duloxetine in pregnancy and lactation. Ann Pharmacother 2009;43:1898–902.
3.Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. Duloxetine in the long-term treatment of major depressive disorder. J Clin Psychiatry 2003;64:1237–44.
4.Bellantuono C, Migliarese G, Gentile S. Serotonin reuptake inhibitors in pregnancy and the risk of major malformations: a systematic review. Hum Psychopharmacol Clin Exp 2007;22:121–8.
5.Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579–87.
6.Eyal R, Yaeger D. Poor neonatal adaptation after in utero exposure to duloxetine. Am J Psychiatry 2008;165:651.
7.Hoog SL, Cheng Y, Elpers J, Dowsett SA. Duloxetine and pregnancy outcomes: safety surveillance findings. Int J Med Sci 2013;10:413–9.
8.Lobo ED, Loghin C, Knadler M, Quinlan T, Zhang L, Chappell J, Lucas R, Bergstrom RF. Pharmacokinetics of duloxetine in breast milk and plasma of healthy postpartum women. Clin Pharmacokinet 2008;47:103–9.
9.Marshall AM, Nommsen-Rivers LA, Hernandez LI, Dewey KG, Chantry CJ, Gregerson KA, Horseman ND. Serotonin transport and metabolism in the mammary gland modulates secretory activation and involution. J Clin Endocrin Metab 2010;95:837–46.
10.Committee on Drugs. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.