Is Emgality®▼ (galcanezumab) safe in pregnancy and lactation?

Information from Summary of Product Characteristics

Fertility, pregnancy and lactation

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 .¹

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.¹

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.¹

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.¹

Preclinical Data

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.¹

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.¹

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.¹

There are insufficient human data to establish the safety of galcanezumab during pregnancy or in women exposed via a male partner treated with galcanezumab.²

Pregnancies in Galcanezumab Clinical Trials

Galcanezumab has been studied in migraine prevention.^3-5Pregnancy events are summarized below.

Please note that the results of a maintenance dose of 240 mg galcanezumab once monthly are also included in this response. Even though this dose has been tested in pivotal studies, it has not been approved and therefore is not recommended.

Summary of Pregnancies in Migraine Prevention Trials

Migraine Prevention: Clinical Trial Inclusion and Exclusion Criteria

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

• pregnant women, and

• lactating women.²

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.²

Maternal Exposure to Galcanezumab in Migraine Prevention Trials

As of 04 September 2018, there were 21 women (total female exposure: N=2183) exposed to galcanezumab who became pregnant during their migraine prevention study participation. Table 1 summarizes the outcome for those pregnancies.²

Normal Outcome

Ten infants were carried to term and delivered without evidence of fetal adverse effect (normal outcome).²

One of the 10 term infants

• was born to a woman with gestational diabetes

• was delivered at 37 weeks, and

• experienced postpartum low blood glucose that resolved with no further complication.²

Premature Birth

Two pregnancies resulted in premature birth due to pre-eclampsia.²

One infant was

• delivered via cesarean section at 34 weeks and 5 days gestation, and 

• did not experience any complications.²

The mother's elevated blood pressure did not continue after delivery.²

The second infant was

• delivered via cesarean section at 31 weeks gestation

• treated in the neonatal intensive care unit

• progressed without complication, and

• was discharged without obvious long-term effects or ongoing treatments.²

The mother recovered without complication.²

Abortion

There were 3 pregnancies that resulted in abortion including

• 1 spontaneous abortion which occurred directly after the patient was assaulted during a domestic dispute

• a patient of advanced maternal age (41 years), and

• a missed abortion, thought to be a probable blighted ovum in a patient with a history of smoking and 2 previous failed pregnancies.²

Other

Five patients were lost to follow-up, and 1 pregnancy was electively terminated.²

Table 1. Summary of Pregnancies: Mothers in Migraine Prevention Clinical Trials Exposed to Galcanezumab During Pregnancy²

Outcome	Number of Events (n)	Percent (%) of Total Female Exposurea
Normal Outcome	10	0.46
Premature birth	2	0.09
Abortion spontaneous (n=2); abortion missed (n=1)	3	0.14
Elective termination	1	0.05
Lost to follow-up	5	0.23
Overall exposure via mother	21	0.96%

Abbreviation: n = number of patients within each specific category.

^a Total Female Exposure = 2183.

Paternal Exposure to Galcanezumab in Migraine Prevention Trials

There were 2 pregnancies in partners of male patients exposed to galcanezumab during their participation in a study (Table 2).²

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.²

Table 2. Summary of Pregnancies: Fetal Exposure During Migraine Prevention Trials via Fathers Exposed to Galcanezumab²

Outcome	Number of Events (n)
Normal Outcome	1
Exposure via father (infant with ankyloglossia)a	1
Premature birth	0
Abortion spontaneous (n=0); miscarriage of partner (n=0)	0
Elective termination	0
Lost to follow-up	0
Outcome pending	0
Overall exposure via father	2

Abbreviation: n = number of patients within each specific category.

^a Total Female Exposure = 2183.

Lactation

There are no data on

• the presence of galcanezumab in human milk

• the effects on the breastfed infant, or

• the effects on milk production.²

Planning to Become Pregnant

Effect on Fertility (Preclinical Data)

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.²

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.²

Effect on Fetus (Preclinical Data)

Embryofetal development studies conducted in rats and rabbits at exposures greater than expected clinically revealed no evidence of harm to the developing fetus.²

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.²

Washout Period

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.^2,6

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

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

Postmarketing Spontaneous Reports

Through September 27, 2020, the MedDRA term of maternal exposure during pregnancy has been rarely reported in the Eli Lilly and Company spontaneous AE database. Rarely reported is defined as an AE that has been reported at an estimated rate between ≥0.01% and <0.1% according to the reporting system information.²

Exposure during pregnancy, fetal exposure during pregnancy, maternal exposure before pregnancy, maternal exposure during breastfeeding, or maternal exposure timing unspecified, as well as paternal exposure during pregnancy have been very rarely reported. Very rarely reported is defined as an AE that has been reported at an estimated rate of <0.01%.²

Postmarketing data do not necessarily represent the rate of occurrence of an 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

Postmarketing Spontaneous Reports From the WHO Pharmacovigilance Database

The 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" 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 CGRP mAbs in pregnancy and lactation did not identify

• specific maternal toxicities

• patterns of major birth defects, or

• increased reporting of spontaneous abortion.⁸

Pregnancy Registry

Information regarding the galcanezumab pregnancy registry is available at: http://www.encepp.eu/encepp/viewResource.htm?id=32855

References

1. Emgality [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3. Stauffer VL, Dodick DW, Zhang Q, et al. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080-1088. http://dx.doi.org/10.1001/jamaneurol.2018.1212

4. Skljarevski V, Matharu M, Millen BA, et al. Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442-1454. http://dx.doi.org/10.1177/0333102418779543

5. Detke HC, Goadsby PJ, Wang S, et al. Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018;91(24):e2211-e2221. http://dx.doi.org/10.1212/WNL.0000000000006640

6. Kielbasa W, Helton DL. A new era for migraine: Pharmacokinetic and pharmacodynamic insights into monoclonal antibodies with a focus on galcanezumab, an anti-CGRP antibody. Cephalalgia. 2019;39(10):1284-1297. http://dx.doi.org/10.1177/0333102419840780

7. Goldman SA. Limitations and strengths of spontaneous reports data. Clin Ther. 1998;20(suppl 3):C40-C44. http://dx.doi.org/10.1016/S0149-2918(98)80007-6

8. Noseda R, Bedussi F, Gobbi C, et al. Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: analysis of the WHO pharmacovigilance database. Cephalalgia. Published online January 12, 2021. http://dx.doi.org/10.1177/0333102420983292

Glossary

AE = adverse event

CGRP = calcitonin gene-related peptide

IgG = immunoglobulin G

mAb = monoclonal antibody

MedDRA = Medical Dictionary for Regulatory Activities

MRHD = maximum recommended human dose

SMQ = standard MedDRA query

WHO = World Health Organization

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.