Effects of galcanezumab on human fetal development are unknown. Exclusion from entering clinical studies included

• pregnant women, and
• lactating women.4

Women and men with reproductive potential were required to use a reliable method of birth control during the clinical studies and for 5 months following the final dose. Pregnancy was a criterion for permanent discontinuation from all galcanezumab studies.4

Pregnancy events were evaluated across the phase 2 and phase 3 galcanezumab migraine prevention studies.

As of the end of the safety follow-up period on September 4, 2018, there were 21 women (total female exposure: N=2183) exposed to galcanezumab who became pregnant during their migraine prevention study participation. Summary of Pregnancies: Mothers in Migraine Prevention Clinical Trials Exposed to Galcanezumab During Pregnancy summarizes the outcome for those pregnancies.4

There were 2 pregnancies in partners of male patients exposed to galcanezumab during their participation in a study (Summary of Pregnancies: Fetal Exposure During Migraine Prevention Trials via Fathers Exposed to Galcanezumab).4

Of the 2 pregnancies,

• 1 was carried to term and delivered with a notable infant outcome of congenital ankyloglossia. During pregnancy, the mother experienced gestational hypertension (no treatment given), marginal cord insertion (no issue with delivery), and vasopressive syncopal episode with no treatment or residual sequelae.
• the second was carried to term and resulted in a normal outcome.4

There are no adequate data on the effect on fertility with the use of galcanezumab in humans, as patients of reproductive potential were required to use birth control during the studies.4

Galcanezumab was administered to rats at subcutaneous doses of up to 250 mg/kg  (representing exposures 4-18 times the highest proposed clinical dose of 300 mg). No adverse effect was observed on fertility parameters such as

• reproductive organs
• estrous cycle
• sperm analysis, or
• mating and fertility.4

Embryofetal development studies conducted in rats and rabbits at exposures greater than expected clinically revealed no evidence of harm to the developing fetus.4

In offspring exposed to galcanezumab in utero and through lactation at exposures greater than expected clinically in the prenatal and postnatal development study in rats, there were no effects on

• survival
• growth
• sexual maturation
• behavior, or
• reproduction.4

There is no information on which to base a recommendation for a washout period for those who are receiving galcanezumab and are planning to become pregnant.

Galcanezumab is an IgG4 monoclonal antibody and is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.4,6

The t_1/2 of galcanezumab is 27 days.4,6

Clinicians should use their clinical judgment in determining the most appropriate approach in a patient treated with galcanezumab who is planning to become pregnant.

Through March 27, 2021, Medical Dictionary for Regulatory Activities (MedDRA) terms related to pregnancy and lactation that have been reported in the Eli Lilly and Company spontaneous adverse event database are provided in Galcanezumab Postmarketing Reporting Rates Through 27 March 2021.

Postmarketing data do not necessarily represent the rate of occurrence of an adverse event (AE) in a treated population, but they represent a reporting rate of a particular AE to the company. Spontaneous reporting of AEs can be highly variable and is not appropriately controlled clinical information on which to base an assessment of whether a particular drug product is the causal agent of an event.7

Spontaneous reporting has limited use due to

• lack of control population
• under-reporting or reporting bias, and
• missing or incomplete information regarding medical history or concomitant medications.7

The World Health Organization (WHO) published a report of postmarketing pregnancy events reported by patients receiving either erenumab, galcanezumab, or fremanezumab through December 31, 2019.8 Reports classified in the "Pregnancy and neonatal topics" standard MedDRA query (SMQ; MedDRA version 22.1) were retrieved from the WHO pharmacovigilance database of safety reports of suspected adverse drug reactions (VigiBase). This analysis included 94 safety reports from the specified SMQ, of which 31 were associated with galcanezumab, and of those 28 were safety reports reporting only drug exposure. The remaining 3 reports comprised 1 report of spontaneous abortion, and 2 reports of a maternal adverse drug reaction. Based on the VigiBase data, the WHO review of the use of calcitonin gene-related peptide monoclonal antibodies in pregnancy and lactation did not identify

• specific maternal toxicities
• patterns of major birth defects, or
• increased reporting of spontaneous abortion.8

There are limited data from the use of galcanezumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.9

Human immunoglobulin (IgG) is known to cross the placental barrier. As a precautionary measure, it is preferable to avoid the use of galcanezumab during pregnancy.9

It is unknown whether galcanezumab is excreted in human milk. Human IgG is known to be excreted in breast milk during the first days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to breast-fed infants cannot be excluded during this short period. Afterwards, use of galcanezumab could be considered during breast-feeding only if clinically needed.9

The effect of galcanezumab on human fertility has not been evaluated. Fertility studies in animals do not indicate harmful effects with respect to male and female fertility.9

No effects on fertility parameters such as oestrous cycle, sperm analysis, or mating and reproductive performance were observed in rats that were administered galcanezumab (exposures approximately 4 to 20 times the human exposure at 240 mg). In male fertility study, right testis weight was significantly reduced at exposures to 4 times the human exposure at 240 mg.9

At Gestational Day 20, an increase in the number of foetuses and litters with short ribs and a decrease in the mean number of ossified caudal vertebrae occurred in the rat embryo-foetal toxicity development study at an exposure approximately 20 times the human exposure at 240 mg. These findings were noted at no maternal toxicity and were considered to be related to galcanezumab but non-adverse.9

At Gestational Day 29, in rabbit embryo-foetal development toxicity study skull anomaly was found in one male foetus from mother treated with galcanezumab at an exposure approximately 33 times the human exposure at 240 mg.9

There are insufficient human data to establish the safety of galcanezumab during pregnancy or in women exposed via a male partner treated with galcanezumab.4