Pregnancy & Lactation : הריון/הנקה

4.6       Fertility, pregnancy and lactation

Effects on Fertility
Dietary administration of clonazepam to male and female rats was associated with a reduced pregnancy rate and impaired pup survival at doses of 60 mg/m2/day or greater (4-fold the maximal recommended human dose [MRHD]); the no effect dose was 6 mg/m2/day (less than clinical exposure).

In a two-generation fertility study in which clonazepam was given orally to rats at 10 and 100 mg/kg/day, there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning. The lowest dose tested is approximately 5 and 24 times the maximum recommended human dose (MRHD) of 20 mg/day for seizure disorders and 4 mg/day for panic disorder, respectively, on a body surface area (mg/m2) basis.


Use in Pregnancy
The risk of a mother with epilepsy giving birth to a baby with an abnormality is about three times that of the normal population. Some of this risk is due to the anticonvulsant medicines taken. Mothers taking more than one anticonvulsant medicine might have a higher risk of having a baby with a malformation than mothers taking one medicine.

Overall the risk of having an abnormal child is far outweighed by the dangers to the mother and foetus of uncontrolled convulsions. It is therefore recommended that: women on anticonvulsant medicines receive pre-pregnancy counselling with regard to the risk of foetal abnormalities;anticonvulsant should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose;
 folic acid supplement (5 mg) should be commenced four weeks prior to and continue for twelve weeks after conception;
 specialist prenatal diagnosis including detailed midtrimester ultrasound should be offered.

Clonazepam is a benzodiazepine. These medicines cross the placenta and appear in the foetus and may, after continuous administration during a large part of pregnancy, give rise to hypotonia, reduced respiratory function and hypothermia in the newborn child. Withdrawal symptoms in newborn infants have occasionally been reported with this class of medicines.

Oral administration of clonazepam during the period of organogenesis has elicited a low, nondose-related incidence of a similar pattern of malformations in rabbits (cleft palate, open eyelids, fused sternebrae, limb defects) and mice (exencephaly, central nervous system defects) at doses less than MRHD. These effects were not observed in rats at oral doses more than 20-fold MRHD. The clinical significance of these findings is unknown.

The lowest dose tested is less than the maximum recommended human dose (MRHD) of 20 mg/day for seizure disorders and similar to the MRHD of 4 mg/day for panic disorder, on a mg/m2 basis. Reductions in maternal weight gain occurred at doses of 5 mg/kg/day or greater and reduction in embryofetal growth occurred in one study at a dose of 10 mg/kg/day.

No adverse maternal or embryofetal effects were observed in mice or rats following oral administration of clonazepam during organogenesis of doses up to 15 or 40 mg/kg/day, respectively (4 and 20 times the MRHD of 20 mg/day for seizure disorders and 20 and 100 times the MRHD of 4 mg/day for panic disorder, respectively, on a mg/m2 basis).

Withdrawal symptoms in newborn infants have been reported with benzodiazepines.

Use in Lactation
Rivotril must not be given to nursing women. Rivotril is excreted in human breast milk, and may cause drowsiness and feeding difficulties in the infant. If there is a compelling reason for use, breastfeeding should be discontinued.