Tips for searching:
• You have to select a product and type at least 2 words to activate the search
• Use only words that are specific to the information you are looking for
• Avoid typing questions or sentences
Please do not use this field to report adverse events or product complaints. Adverse events and product complaints should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow card in the Google play or Apple app store. Adverse events and product complaints should also be reported to Lilly: please call Lilly UK on 01256 315 000.
Emgality ® ▼ (galcanezumab)
This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. For current prescribing information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).
Is the incidence of constipation increased with Emgality® (galcanezumab) use?
Constipation was reported in ≤2% of galcanezumab-treated patients in phase 3 studies. Most events were mild or moderate in severity and no patients discontinued due to constipation. In a phase 4 study, no meaningful changes in GI transit rates were seen.
Content Overview
Summary of constipation with galcanezumab
Summary of constipation events in galcanezumab phase 3 migraine prevention studies
In the phase 3 migraine prevention studies, events of constipation
- were mostly mild to moderate in severity
- did not have a pattern of occurrence with regard to timing of injection, and
- did not lead to discontinuation in any patients.1
A summary of constipation events in the phase 3 migraine prevention studies can be found in Summary of constipation events in the phase 3 migraine prevention studies.
Biological plausibility of constipation with galcanezumab use
Calcitonin gene-related peptide (CGRP) is
- widely expressed throughout the central and peripheral nervous system,2 and
- primarily localized to C and A-delta sensory fibers and has a dual role in sensory (nociceptive) and efferent (effector) function.3
Calcitonin gene-related peptide and its receptors are also widely expressed in the enteric system and animal studies have suggested a role for CGRP in modulating intestinal neurotransmission, mobility, and secretion.4,5 Rodent studies have demonstrated alteration of gastrointestinal (GI) tract motility and secretions when given agents that antagonize CGRP or its receptors.5,6
A mouse study evaluating the effect of CGRP inhibition on GI transit time
Constipation related to blocking the CGRP receptor was evaluated in a mouse study of transgenic mice expressing the human receptor activity–modifying protein 1 (hRAMP1) subunit of the CGRP receptor complex. This study evaluated the effect of CGRP inhibition on GI transit time and found that the
- CGRP receptor antibody and small molecule CGRP receptor antagonist significantly inhibited GI transit time in the large intestine, and
- CGRP ligand antibody did not have a significant effect.6
Thus, it is plausible that modulating CGRP function may have potential impact on the human GI tract.6
Information from the summary of product characteristics
Constipation is a common adverse reaction of galcanezumab. Constipation was reported by 1.0 % and 1.5 % of patients with 120 mg and 240 mg galcanezumab, respectively.7
Summary of constipation events in the phase 3 migraine prevention studies
Galcanezumab has been studied in migraine prevention.8-12 Constipation events for each population are summarized separately below.
Galcanezumab has been studied in phase 3 randomized, double-blind, placebo-controlled studies in adult patients for the prevention of
The EVOLVE-1, EVOLVE-2, and REGAIN studies were the pivotal studies and safety results have been integrated resulting in a pooled analysis of 2886 adult patients, comprised of a total of 1435 patients that received monthly doses of galcanezumab (120 mg or 240 mg) administered subcutaneously.13
Results from CONQUER and CGAJ, the phase 3b open-label safety study, are provided to supplement the primary integrated safety analysis. In the CONQUER study, there was a total of 462 adult patients enrolled, with 232 patients that received monthly doses of galcanezumab 120 mg.11 In the 12-month open-label safety study, a total of 270 adult patients received monthly doses of galcanezumab (120 or 240 mg).12
The recommended dose of galcanezumab is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.7 The results of a maintenance dose of galcanezumab 240 mg once monthly are also described here. Even though this dose has been tested in pivotal studies, it has not been approved and therefore is not recommended.
Incidence and severity of constipation events: Migraine prevention studies
The incidence and severity of constipation during the phase 3 galcanezumab studies for migraine prevention is illustrated in The incidence of constipation events in galcanezumab phase 3 migraine prevention studies and The severity of constipation events in galcanezumab phase 3 migraine prevention studies .
One patient from the CONQUER study treated with galcanezumab reported
- an event of constipation with moderate severity after completing the double-blind phase, and
- not continuing in the open-label phase of the study as a result of the moderate constipation event.1
Figure 1 illustrates the number of constipation events reported in galcanezumab phase 3 migraine prevention studies.
Abbreviations: GMB = galcanezumab; PBO = placebo.
a Constipation events reported are from the double-blind treatment period.
b p<.05 vs placebo.
Figure 2 shows the severity of constipation events reported in galcanezumab phase 3 studies in migraine prevention.
Abbreviations: GMB = galcanezumab; PBO = placebo.
a Constipation events reported are from the double-blind treatment period.
Duration of constipation events: Migraine Prevention Studies
The duration of constipation events by treatment group in the EVOLVE-1, EVOLVE-2, and REGAIN studies is illustrated in Duration* of constipation events in the EVOLVE-1, EVOLVE-2, and REGAIN double-blind treatment phase 3 studies .
Persistent constipation was defined as resolution in >30 days.1 More patients treated with galcanezumab reported persistent constipation (n=6) than placebo (n=2). Three patients in the galcanezumab 120-mg dose group reported mild to moderate constipation that persisted for >90 days.1 These cases are summarized in Reports of Constipation That Persisted for >90 Days in the EVOLVE-1, EVOLVE-2, and REGAIN Studies.
Figure 3 illustrates the duration of constipation events in the EVOLVE-1, EVOLVE-2, and REGAIN pivotal studies that included 2886 adult patients suffering from episodic or chronic migraine. 1435 patients received a monthly doses of galcanezumab (120 mg or 240 mg) subcutaneous injections.13
Abbreviations: GMB = galcanezumab; PBO = placebo; TEAE = treatment-emergent adverse event.
* Duration for treatment-emergent constipation events was calculated only for those events with a documented start and end date.
Duration of Constipation |
Reported Term for AE |
Severity |
Details |
95 days |
Intermittent Constipation |
mild |
|
138 days |
Constipation |
mild |
|
183 days |
Obstipation |
moderate |
|
Abbreviations: AE = adverse event; PRN = as needed.
In the CONQUER study, 5 of the constipation events did not have a documented end date, thus duration data is available for only 5 of the 10 events reported.1 Those events with a documented end date had a duration of
- 14 and 43 days in the galcanezumab group, and
- between 3 and 14 days in the placebo group.1
In the 12-month open-label safety study, the 2 cases of constipation had a duration of ≤7 days.1
A phase 4 study of galcanezumab and erenumab to compare effects on GI motility
A phase 4, multicenter, randomized, single-blind clinical study in the United States in patients with episodic migraine was conducted to compare the effects on GI motility after an initial dose of a CGRP
- ligand antagonist (galcanezumab), or
- receptor antagonist (erenumab).14
Patients (N=65) were randomized in a 1:1 ratio to receive subcutaneous injections of
- galcanezumab 240 mg (n=33), or
- erenumab 140 mg (n=32).14
Gastrointestinal whole and regional transit times were assessed using a wireless motility capsule 1 week before and 2 weeks after administration of galcanezumab or erenumab.14
The primary endpoint of this study was change from baseline in colonic transit time (CTT) in hours at 2 weeks postdose. The secondary endpoints of this study were least squares (LS) mean change (in hours) from baseline at 2 weeks postdose in
- whole gut transit time (WGTT)
- gastric emptying time (GET)
- small bowel transit time (SBTT), and
- small and large bowel transit time (SLBTT).14
Tertiary objectives evaluated LS mean change between treatment groups GI whole and regional transit times.14
The primary and secondary endpoints evaluated the changes from baseline within each treatment group, while tertiary objectives evaluated changes between treatment groups.14
Other measures included
- GI Symptom Rating Scale (GSRS)
- Bristol Stool Form Scale (BSFS), and
- spontaneous bowel movement (SBM) evaluation.14
Baseline characteristics indicated significant GI transit time variability with minimal GI reported symptoms.14
The primary endpoint was not statistically significant; however, a numerical mean increase in CTT was observed in erenumab patients compared with baseline (mean [SD] at baseline: 33.8 [29.4] hours; LS mean [SE] change: 5.8 [5.7] hours; 95% CI: -5.7 to 17.2; p=.320), while galcanezumab decreased CTT compared with baseline (mean [SD] at baseline: 29.3 [24.5] hours; LS mean [SE] change: -5.3 [5.4] hours; 95% CI: -16.2 to 5.5; p=.328).14
Statistically significant results were not seen for the
- secondary endpoints (except for SBTT in the galcanezumab group; LS mean change decrease of 0.7 hours [p=.018]), or
- tertiary endpoints.14
Changes in baseline GI transit times for galcanezumab- and erenumab-treated patients can be found in Changes From Baseline in GI Transit Times in Hours in Galcanezumab- and Erenumab-Treated Patients.
CTT |
WGTT |
GET |
SBTT |
SLBTT |
|
Primary/Secondary Endpoints |
|||||
Galcanezumab (n=31) |
|||||
LS mean change (SE) |
-5.3 (5.4) |
-7.0 (5.6) |
-0.6 (1.0) |
-0.7 (0.3) |
-6.0 (5.4) |
95% CI |
(-16.2, 5.5) |
(-18.3, 4.3) |
(-2.5, 1.4) |
(-1.3, -0.1) |
(-16.7, 4.8) |
P value |
0.328 |
0.217 |
0.551 |
0.018 |
0.271 |
Erenumab (n=28) |
|||||
LS mean change (SE) |
5.8 (5.7) |
4.1 (6.0) |
-1.3 (1.0) |
-0.6 (0.3) |
5.2 (5.7) |
95% CI |
(-5.7, 17.2) |
(-7.9, 16.1) |
(-3.4, 0.7) |
(-1.2, 0.1) |
(-6.2, 16.5) |
P value |
0.320 |
0.494 |
0.206 |
0.085 |
0.367 |
Tertiary Endpoints (galcanezumab versus erenumab) |
|||||
LS mean change (SE) |
-11.1 (7.1) |
-11.2 (7.4) |
0.7 (1.3) |
-0.2 (0.4) |
-11.1 (7.0) |
95% CI |
(-25.4, 3.2) |
(-26.0, 3.7) |
(-1.8, 3.3) |
(-0.9, 0.6) |
(-25.2, 3.0) |
P value |
0.125 |
0.138 |
0.567 |
0.665 |
0.120 |
Abbreviations: CTT = colonic transit time; GET = gastric emptying time; LS = least squares; SBTT = small bowel transit time; SLBTT = small and large bowel transit time; WGTT = whole gut transit time.
Overall, compared with baseline, erenumab
- significantly reduced BSFS (LS mean change [SE] -0.5 [0.2]; p=.004)
- significantly reduced SBM (LS mean change [SE] -1.2 [0.5]; p=.012), and
- increased GSRS-constipation (LS mean change [SE] 0.3 [0.1]; p=.016).14
Overall, compared with baseline, galcanezumab increased GSRS-constipation (LS mean change [SE] 0.4 [0.1]; p=.002).14
No deaths, serious AEs, or discontinuations due to an AE were reported in the study.14
Although the primary endpoint of this study was not met, results for the secondary and tertiary endpoints suggest a potential mechanistic difference between ligand and receptor antagonism that may contribute to GI AEs in humans.14
Postmarketing Spontaneous Reports
Based on postmarketing spontaneous reports from the Eli Lilly and Company spontaneous AE database received through March 27, 2022,
- constipation was uncommonly reported (≥0.1% and <1%), and
- infrequent bowel movements and faeces hard were very rarely reported (<0.01%).1
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.15
Spontaneous reporting has limited use due to
- lack of control population
- underreporting or reporting bias, and
- missing or incomplete information regarding medical history or concomitant medications.15
References
1Data on file, Eli Lilly and Company and/or one of its subsidiaries.
2Goadsby PJ, Holland PR, Martins-Oliveira M, et al. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97(2):553-622. http://dx.doi.org/10.1152/physrev.00034.2015
3Russell FA, King R, Smillie SJ, et al. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099-1142. http://dx.doi.org/10.1152/physrev.00034.2013
4Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine. Pain. 2017;158(4):543-559. http://dx.doi.org/10.1097/j.pain.0000000000000831
5Cottrell GS, Alemi F, Kirkland JG, et al. Localization of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in human gastrointestinal tract. Peptides. 2012;35(2):202-211. http://dx.doi.org/10.1016/j.peptides.2012.03.020
6Johnson KW, Li X, Huang X, et al. Characterization of transit rates in the large intestine of mice following treatment with a CGRP antibody, CGRP receptor antibody, and small molecule CGRP receptor antagonists. Headache. 2022;62(7):848-857. https://dx.doi.org/10.1111/head.14336
7Emgality [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
8Stauffer 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
9Skljarevski 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
10Detke 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
11Mulleners WM, Kim BK, Láinez MJA, et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2020;19(10):814-825. http://dx.doi.org/10.1016/S1474-4422(20)30279-9
12Camporeale A, Kudrow D, Sides R, et al. A phase 3, long-term, open-label safety study of galcanezumab in patients with migraine. BMC Neurol. 2018;18(1):188. http://dx.doi.org/10.1186/s12883-018-1193-2
13Bangs ME, Kudrow D, Wang S, et al. Safety and tolerability of monthly galcanezumab injections in patients with migraine: integrated results from migraine clinical studies. BMC Neurol. 2020;20(1):25. https://doi.org/10.1186/s12883-020-1609-7
14Kudrow D, Nguyen L, Semler J, et al. A phase IV clinical trial of gastrointestinal motility in adult patients with migraine before and after initiation of a calcitonin gene-related peptide ligand (galcanezumab) or receptor (erenumab) antagonist. Headache. 2022;62(9):1164-1176. https://doi.org/10.1111/head.14390.
15Goldman 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
▼ 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.
Date of Last Review: 23 February 2022