Pregnancy & Lactation : הריון/הנקה

4.6 FERTILITY, PREGNANCY AND LACTATION
Effects on fertility
No studies on the effect on fertility have been conducted with indacaterol, glycopyrronium and mometasone furoate in combination. In single-agent studies, no adverse effects on fertility were observed in male and female rats given indacaterol by subcutaneous injection at doses up to 2 mg/kg/day or glycopyrronium bromide at subcutaneous doses up to 1.5 mg/kg/day, yielding systemic exposure hundreds of times higher than in patients. As with other corticosteroids, at exposure levels associated with marked signs of systemic corticosteroid toxicity, mometasone furoate had progestogenic effects on the female reproductive tract and mammary glands. However, fertility was unimpaired in a reproductive toxicity study carried out in rats.

Use in pregnancy
Risk Summary
There are insufficient data from the use of Enerzair Breezhaler or its individual components (indacaterol, glycopyrronium and mometasone furoate) in pregnant women to determine whether there is a risk.

Indacaterol and glycopyrronium were not teratogenic in rats and rabbits following subcutaneous or inhalation administration respectively (see Animal data). In animal reproduction studies with pregnant mice, rats and rabbits, mometasone furoate caused increased foetal malformations and decreased foetal survival and growth.

Enerzair Breezhaler should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus.

Clinical Considerations
Disease-associated maternal and/or embryo/foetal risk
In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.
ENE API JUL22 V2.1                                                         Australian PI Dec2021 Labour and Delivery
Information related to indacaterol
Like other medicinal products containing beta2-adrenergic agonists, indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle.

Information related to glycopyrronium
In pregnant women undergoing Caesarean section, 86 minutes after a single intramuscular injection of 0.006 mg/kg glycopyrronium bromide, the concentration of glycopyrronium in the umbilical venous (0.28 (0.25) ng/ml) and in the umbilical arterial (0.18 (0.11) ng/ml) plasma were low (clinically insignificant).

Animal data
The combination of indacaterol, glycopyrronium and mometasone furoate has not been studied in pregnant animals.

Indacaterol
Indacaterol was not teratogenic at subcutaneous doses up to 1 mg/kg/day in rats and 3 mg/kg/day in rabbits (yielding more than 180-and 1000-times, respectively, the AUC in humans at 150 μg/day). An increase in the incidence of a rib skeletal variation and retarded ossification were observed in the rabbit at 3 mg/kg/day, possibly secondary to maternal toxicity; embryo foetal development was unaffected in the species at 1 mg/kg/day (relative exposure, >400). Impaired learning and decreased fertility were observed in the pups of rats given indacaterol at a subcutaneous dose of 1 mg/kg/day during pregnancy and lactation (relative exposure, approximately 160; unaffected at 0.3 mg/kg/day, associated with a relative exposure level of 63). The potential risk for humans is unknown.

Glycopyrronium
Glycopyrronium was not teratogenic in rats or rabbits following inhalational administration at doses up to 3.05 and 3.5 mg/kg/day in the respective species (yielding plasma AUC values approximately 570-times and 200-times higher than in patients at the maximum recommended human dose).
Glycopyrronium and its metabolites did not significantly cross the placental barrier of pregnant mice, rabbits and dogs. Published data for glycopyrronium in animals do not indicate any reproductive toxicity issues. Fertility and pre- and post-natal development were not affected in rats.

Mometasone furoate
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Effects noted were umbilical hernia in rats, cleft palate in mice and gallbladder agenesis, umbilical hernia and flexed front paws in rabbits. There were also reductions in maternal body weight gains, effects on foetal growth (lower foetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice. In rats, subcutaneous mometasone furoate at 15 micrograms/kg prolonged gestation and difficult labor occurred with a reduction in offspring survival and body weight.

Use in lactation
There is no information available on the presence of indacaterol, glycopyrronium or mometasone in human milk, on the effects on a breastfed child, or on the effects on milk production. Other inhaled 
ENE API JUL22 V2.1                                                          Australian PI Dec2021 corticosteroids, similar to mometasone furoate, are transferred into human milk. Indacaterol, glycopyrronium and mometasone furoate have been detected in the milk of lactating rats.
Glycopyrronium reached up to 10-fold higher concentrations in the milk of lactating rats than in the blood of the dam after intravenous administration. Reduced body weight gain was observed in pups of rats treated with indacaterol or glycopyrronium, while impaired learning and decreased fertility were observed in pups of rats treated with indacaterol during pregnancy and lactation.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Enerzair Breezhaler and any potential adverse effects on the breast-fed child from Enerzair Breezhaler or from the underlying maternal condition.