Clomipramine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Clomipramine can elevate prolactin levels and sometimes induce galactorrhea. Small clinical studies suggest that treatment with clomipramine and other tricyclic antidepressants may reduce libido and cause erectile and ejaculatory dysfunction in males and delayed orgasm or anorgasmia in females. In other case reports, men using clomipramine and other tricyclics reported painful ejaculation. This side effect disappeared when the drugs were discontinued.

Effects on developmental toxicity

Description of key information

Clomipramine did not produce an increase in malformations in rats and mice, but treatment of pregnant rats with this drug has been associated with behavioral changes in the offspring. These effects may be due to changes in cerebral cortex neurotransmitters.

[Reprotox for Clomipramine. REPROTOX® Database: Klasco RK: REPROTOX® Database. Truven Health Analytics, Greenwood Village, Colorado.]

Toxicity to reproduction: other studies

Description of key information

Human pregnancy reports

In humans there has been concern that clomipramine and other tricyclic antidepressants cause congenital malformations with specific attention focused on limb reduction defects. However, a large-scale study failed to show a preponderance of clomipramine users among mothers of children with congenital limb defects. In a series of 134 pregnancies exposed to clomipramine, 20 underwent voluntary abortion, 22 miscarried, four were stillborn, and three infants were born with a malformation. These figures are similar to what would be anticipated in the general population, although the number of stillbirths may be somewhat high. A study of antidepressant use from the Swedish Medical Birth Register

identified an association between clomipramine use during pregnancy and congenital heart disease in the offspring. The odds ratio (95% CI) was 1.87 (1.16-2.99). Ventricular and atrial septal defects showed the strongest associations among the individual malformations. This information was presented in a letter-to-the-editor that had been prompted by reports of congenital heart disease in infants exposed prenatally to paroxetine (#3590).

Neonatal complications

In case reports and one case series on infants exposed to clomipramine during all or part of pregnancy, drug exposure was associated with transient neonatal complications including lethargy, hypotonia, cyanosis, jitteriness, irregular respiration with respiratory acidosis, and hypothermia. These toxic effects may be related to the anticholinergic properties of this drug. In one case, premature birth occurred four days after maternal clomipramine was abruptly discontinued, raising the concern that intrauterine withdrawal in the fetus precipitated the premature birth. Also, nortriptyline, a congener of clomipramine, has been associated with urinary retention in one newborn. Three infants who had neonatal complications following third trimester and perinatal exposure to clomipramine (200 mg/d) showed normal neurobehavioral development at 4 months, 6 months, and 18 months, respectively. In vivo placental passage of clomipramine and its metabolite desmethylclomipramine was demonstrated in seven patients. The dose range was 50-175 mg/d. The mean (SD) ratio of umbilical cord blood concentration to maternal serum concentration was 0.60 (0.50) for clomipramine and 0.80 (0.60) for the metabolite. Four of the 7 cases had obstetrical or neonatal complications (labored breathing, aspiration, premature rupture of membranes, pregnancy induced hypertension), but there was no apparent association between complications and maternal blood or umbilical cord blood concentrations of either the parent compound or the metabolite.

Eleven pregnant women who took clomipramine (37/5-125 mg/d) throughout pregnancy were prospectively enrolled in a study to

assess neonatal complications and clomipramine metabolism in the neonate (40). Mothers were excluded if they used drugs of abuse

but not if they used nicotine or alcohol. The authors reported that 3 of the 11 developed pre-eclampsia (yielding late preterm deliveries in 2 cases), 1 other had gestational diabetes and another had pre-existing diabetes. Four infants were delivered by cesarean section. One mother-infant pair was excluded due to protocol violation. Of the 10 infants remaining, 7 had neonatal complications observed within 48 hours (sleep disturbance, poor feeding, tremors, respiratory difficulties, and hyperactive Moro reflex) including 2 infants with severe tachycardia and

cyanosis, and 1 had no complications. Information about neonatal adaptation for the remaining two neonates was not given. The authors did not specify which infants been exposed to other psychotropic medications or to nicotine, nor which infants had neonatal complications following maternal pregnancy complications. The average half-life for clomipramine in neonates was 42 hours while the half-life in adults is 20 hours.

The number and severity of neonatal complications did not correlate with serum concentrations of clomipramine or desmethylclomipramine or whether the infant was breastfed. No congenital malformations were detected in any of the 11 infants at the 20 week ultrasound or at delivery.

Neurobehavioral testing of 80 children with antenatal exposure to tricyclic antidepressants (of whom 10 had been exposed to clomipramine) showed no differences in IQ or behavior compared to 55 children with exposure to fluoxetine (#1898) or 84 children without antidepressant exposure during gestation.

The children ranged in age from 16 to 86 months at the time of testing.

Effects on or via lactation

Many tricyclic antidepressants enter human milk. There is a report on 4 infants exposed by this route to clomipramine, none of whom had measurable serum levels of the drug or its metabolites and none of whom showed abnormal behavior attributable to the drug exposure. Three additional case reports document the presence of clomipramine in human milk, but did not measure infant serum levels. Normal development was reported in a 24 month old child who had been exposed to clomipramine via breastfeeding from age 9 to 13 weeks (maternal dose 175 mg/d).  In 1994, the American Academy of Pediatrics classified clomipramine as compatible with breastfeeding but later stated that the Committee believed it should be included with other tricyclic antidepressants among those agents that may be of concern when used while breastfeeding.

[Reprotox for clomipramine. REPROTOX® Database: Klasco RK: REPROTOX® Database. Truven Health Analytics, Greenwood Village, Colorado.]

Limited evidence indicates that use of clomipramine during breastfeeding is acceptable. For women who were taking clomipramine during pregnancy, the amount of drug in breastmilk may be insufficient to prevent neonatal withdrawal symptoms in breastfed infants. For use as an antidepressant, clomipramine may be less desirable than other antidepressants that have been studied more thoroughly.

[Lactmed for clomipramine. Drugs and Lactation Database [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm]

Justification for classification or non-classification

Available data are inconclusive for the classification of the substance.