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).

Does Emgality® ▼ (galcanezumab) cause injection site pain?

Injection site-related adverse events were the most frequently reported adverse events in the phase 3 studies. Most events were mild to moderate and did not lead to discontinuation

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UK_cFAQ_GLC102_INJECTION_SITE_PAIN
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Injection Site Related Events in the Summary of Product Characteristics

The reported adverse drug reactions for 120 mg and 240 mg in migraine clinical trials were

  • injection site pain (10.1 %/11.6 %),
  • injection site reactions (9.9 %/14.5 %).1
  • The recommended dose is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.1 Please note that the results of a maintenance dose of 240 mg galcanezumab 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.

With regard to Injection site reactions, the most frequently reported terms (≥ 1 %) were:

  • Injection site reaction
  • Injection site erythema
  • Injection site pruritus
  • Injection site bruising
  • Injection site swelling.1

The majority of events related to the injection site were mild to moderate and less than 0.5 % of patients exposed to galcanezumab during the phase 3 studies discontinued the treatment due to an injection site reaction.1

The majority of injection site reactions were reported within 1 day and on average resolved within 5 days. In 86 % of the patients reporting injection site pain, the event occurred within 1 hour of injection and resolved on average in 1 day.1

One percent of the patients exposed to galcanezumab during the phase 3 studies experienced severe pain at the injection site.1

Description of Analysis Set

Injection site-related AEs were evaluated in phase 3 galcanezumab studies including

  • 2 randomized, double-blind, placebo-controlled, 6-month episodic migraine prevention studies (EVOLVE-1 and EVOLVE-2)2,3
  • 1 randomized, double-blind, placebo-controlled, 3-month chronic migraine prevention study with an optional 9-month open-label extension phase (REGAIN)4 
  • 1 randomized, double-blind, placebo-controlled 3-month migraine prevention study with an optional 3-month open-label extension phase in patients with episodic or chronic migraine who had not benefited from multiple previous migraine preventive treatments (CONQUER), and5,6
  • a 12-month, open-label safety study in patients with episodic or chronic migraine (CGAJ).7

The recommended dose of galcanezumab is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.1 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.

In addition, injection site-related AEs from a phase 2 double-blind, placebo-controlled 6-month study in Japanese patients with episodic migraine (study CGAN) are also summarized.8

The long-term analysis set discussed below includes galcanezumab-treated patients from the

  • double-blind and open-label extension phase of REGAIN (month 0-12), and
  • 12-month open-label safety study, CGAJ.9

There were differences in the device and who administered the injections between EVOLVE-1, EVOLVE-2, REGAIN, CONQUER, study CGAJ, and study CGAN as shown in Device and Injection Administration in Galcanezumab Migraine Prevention Studies.

Device and Injection Administration in Galcanezumab Migraine Prevention Studies

In study...

Patients received...

SQ injectionsa were administered...

With a volume of...

By...

Using the following device...

EVOLVE-1, EVOLVE-2, REGAIN2-4,10

2 SQ injectionsb

monthly

1 mLc

investigative site personnel

prefilled syringe

CGAJ7,11

1 or 2 SQ injectionsd

monthly

1 mLc

self-administratione

prefilled syringe or autoinjectorf

CONQUER4,6

1 or 2 SQ injectionsg

monthly

1 mLc

investigative site personnel

prefilled syringe

CGAN8,10

1 or 2 SQ injectionsb

monthly

1 mLc

investigative site personnel

prefilled syringe

Abbreviation: SQ = subcutaneous.

aPossible injection-sites included the abdomen, thigh, upper arm, or buttocks.

bEVOLVE-1, EVOLVE-2, REGAIN, and CGAN: patients received 2 injections of 1 mL each via SQ injection at each visit. Patients received either galcanezumab 120 mg (2 injections of galcanezumab 120 mg as loading dose at first dosing visit, followed by 1 injection each of galcanezumab 120 mg and placebo at all subsequent dosing visits), galcanezumab 240 mg (2 injections of galcanezumab 120 mg), or placebo (2 placebo injections).

cEach injection was 1 mL.

dCGAJ: Patients randomized to the galcanezumab 120-mg dose received an initial loading dose of 240 mg (2 SQ injections of 120 mg each; 1 mL each) and 1 injection of 120 mg at each subsequent dosing visit. Patients randomized to the galcanezumab 240-mg dose received 2 SQ injections of 120 mg at each dosing visit.

eInvestigative site personnel administered the first injection. Self/caregiver administration started at the second injection visit after the loading dose administration by site staff and review of instructions for use for self-administration.

fPatients were switched from the prefilled syringe device to the autoinjector device. The device switch started after all patients had completed at least month 9 of the study, and 179 patients in study CGAJ received ≥1 galcanezumab dose using the autoinjector. Patients had up to 3-months exposure with the autoinjector.

gCONQUER: At the beginning of double-blind treatment, patients received either galcanezumab 120 mg (2 injections of galcanezumab 120 mg as loading dose at first dosing visit, followed by 1 injection of galcanezumab 120 mg at all subsequent dosing visits), or placebo (2 placebo injections at the first dosing visit, followed by 1 injection of placebo at subsequent dosing visits). At the beginning of open-label treatment, all patients received 2 injections to allow for blinded 240-mg loading dose of galcanezumab at month 3. Specifically, patients randomized to placebo during double-blind treatment received a loading dose of galcanezumab 240 mg, and patients randomized to galcanezumab during double-blind treatment received 1 injection of galcanezumab 120 mg and 1 injection of placebo.

Migraine Prevention: Treatment-Emergent Reports of Injection-Site Pain

Migraine Prevention: Incidence of Injection Site Pain

Injection site pain was the most frequently reported TEAE in

During double-blind treatment (Summary of Injection-Site-Related AEs During Double-Blind Treatment: Migraine Prevention), injection-site pain was reported in a greater percentage of patients

  • in the placebo group (5.7%) compared with the galcanezumab group (2.2%) in CONQUER and
  • in the galcanezumab treatment groups (6.1%-7.0%) compared with placebo (1.3%) in the CGAN study.8,10

During open-label treatment in CONQUER (patients who received up to 6 months of galcanezumab treatment in addition to patients on placebo in the double-blind treatment phase who received galcanezumab during open-label treatment), the incidence of injection-site pain was 4.4%.10

Summary of Injection-Site-Related AEs During Double-Blind Treatment: Migraine Prevention6,8-10

 

Patients With ≥1 Injection-Site-Related TEAE
n/N (%)

Injection Site Paina
n/N (%)

EVOLVE-1, EVOLVE-2, REGAINb

PBO

183/1451 (12.6)

138/1451 (9.5)

GMB 120 mg

128/705 (18.2)c

71/705 (10.1)

GMB 240 mg

166/730 (22.7)cd

85/730 (11.6)

CONQUERe

PBO

23/230 (10.0)

13/230 (5.7)

GMB 120 mg

16/232 (6.9)

5/232 (2.2)

CGANf

PBO

13/230 (5.7)

3/230 (1.3)

GMB 120 mg

30/115 (26.1)c

7/115 (6.1)cg

GMB 240 mg

45/114 (39.5)h

8/114 (7.0)h

Abbreviations: AE = adverse event; GMB = galcanezumab; MedDRA = Medical Dictionary for Regulatory Activities; PBO = placebo; TEAE = treatment-emergent adverse event.

aPreferred term.

bAll AEs listed in the MedDRA version 19.1 high-level term of "injection site reactions" were analyzed.

cp<.001 vs PBO.

dp=.033 vs GMB 120 mg.

eAdverse events related to injection-sites were defined using terms from the MedDRA version 22.0 high-level term of "Injection site reactions."

fAdverse events related to injection-sites were defined using terms from the MedDRA version 21.1 high-level term of "Injection site reactions."

gp<.05 vs GMB 120 mg.

hp<.05 vs PBO.

Migraine Prevention: Serious Adverse Events and Discontinuations

No events of injection-site pain were reported as an SAE in any of the studies (EVOLVE-1, EVOLVE-2, REGAIN, CONQUER, CGAJ, or CGAN).7,9,10,12 

During double-blind treatment In EVOLVE-1, EVOLVE-2, and REGAIN, 1 galcanezumab-treated patient discontinued due to injection site pain (moderate in severity).9

There were no discontinuations due to injection site pain during CONQUER, CGAN, or open-label treatment in the long-term analysis.10

Migraine Prevention: Characterization of Injection Site Pain

Reports of injection site pain during double-blind treatment in EVOLVE-1, EVOLVE-2, and REGAIN 

  • were reported as "injection site burning" in 50% of events
  • were mostly mild to moderate in severity
  • had an onset within 60 minutes of injection in >84% of patients, and
  • resolved in 1.4 days on average.9 

The percentage of patients reporting severe injection site pain in EVOLVE-1, EVOLVE-2, and REGAIN was comparable among all galcanezumab- and placebo-treated patients (1.1% and 1.2%, respectively).9

There were no reports of severe injection-site pain during double-blind treatment in CONQUER and CGAN. Most events occurred during administration of the injection and were self-limiting in nature.8,10,12 

During open-label treatment, injection-site pain occurred mostly on the day of injection. Severe TEAEs of injection-site pain were reported by

  • 4 patients (0.9%) in CONQUER, and
  • 5 patients (1.9%) in CGAJ.10

There were no severe TEAEs of injection-site pain reported during open-label treatment in REGAIN.10

Migraine Prevention: Injection-Site Reactions by Anti-Drug Antibody Status

A post hoc analysis of EVOLVE-1, EVOLVE-2, REGAIN, and CGAJ studies reported no evidence that injection-site-related AEs were mediated by TE ADA in galcanezumab-treated patients. No specific injection-site-related AEs were reported exclusively in TE ADA+ patients.9,13

Postmarketing Spontaneous Reports

Through 27 March 2020, the MedDRA term of injection site pain has been uncommonly reported in the Eli Lilly and Company spontaneous AE database. Uncommonly reported is defined as an AE that has been reported at an estimated rate of ≥0.1% and <1% according to the reporting system information.10

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.14

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.14

Prevention and Management of Injection Site Pain

Safe practices for administering SQ injections include

  • leaving the medication sit at room temperature for 30 minutes prior to injection
  • washing hands
  • cleaning and drying the site prior to injection
  • rotation of injection sites
  • not injecting into areas where the skin is tender, bruised, red, or hard, and 
  • not massaging or rubbing the site after injection.15,16

Comfort Measures

In the CONQUER study, staff were encouraged to administer comfort measures, such as cold compress, ice pack, or topical anesthetic cream, to the injection-site prior to or after the injection at their clinical discretion as needed.12  

The percentage of patients who used comfort measures around the time of injection was low and similar between treatment groups during double-blind treatment: Comfort Measures Used at Injection-Sites During Double-Blind Treatment: CONQUER. The most frequently used comfort measure was application of an ice pack.10

Comfort Measures Used at Injection-Sites During Double-Blind Treatment: CONQUER10,12

 

PBO
M=916
n (%)

GMB 120 mg
M=918
n (%)

Comfort measures used before injection

12 (1.3)

15 (1.6)

Ice pack

10 (1.1)

15 (1.6)

Cold compress

2 (0.2)

0 (0.0)

Topical anesthetic or analgesic cream

0 (0.0)

0 (0.0)

Comfort measures used after injection

23 (2.5)

29 (3.2)

Ice pack

19 (2.1)

27 (2.9)

Cold compress

4 (0.4)

2 (0.2)

Topical anesthetic or analgesic cream

0 (0.0)

0 (0.0)

Abbreviations: GMB = galcanezumab; M = number of injections used for the analysis population; PBO = placebo.

Although management of injection site-related AEs was not outlined in the phase 3 study protocols (EVOLVE-1, EVOLVE-2, REGAIN, CGAJ for migraine prevention or CGAL and CGAM for cluster headache), premedication was not prohibited.10

Concomitant medications including acetaminophen (paracetamol) and NSAIDs were permitted. Other concomitant medications such a topical steroids and topical or oral antihistamines were not prohibited. The use of oral steroids was prohibited.10

Management of injection site-related AEs in the EVOLVE-1, EVOLVE-2, REGAIN, CGAJ, CGAL, and CGAM studies was at the discretion of the study investigators.10 The decision whether to pre-medicate a patient prior to galcanezumab injection should be made at the discretion of the prescribing physician.

Factors for Injection-Site Pain and Adverse Events

Injection-site pain and AEs following SQ injection might vary depending on patient-related factors, properties of the compound, and the cellular dynamics at the site of injection.9,17 Examples include

  • injection speed (injection-site pain with fast injections)
  • patient differences in pain tolerance
  • formulation temperature (should ideally be close to body temperature)
  • type of injectable device (prefilled syringe or autoinjector)
  • injection volume (ideally should be ≤3 mL)
  • physiologic pH, and
  • excipients.9

In EVOLVE-1, EVOLVE-2, and REGAIN, a similar incidence of injection-site pain was observed during short-term exposure between placebo- and galcanezumab-treated patients. This may explain the possibility that formulation-based factors could have resulted in injection-site pain, including

  • a nonphysiological pH of less than 7 (galcanezumab pH is 5.3-6.3), and
  • the presence of polysorbate 80.9

Other inactive excipients in the galcanezumab formulation include L-histidine, histidine hydrochloride monohydrate, and sodium chloride.9

Therapeutic Indication

Galcanezumab is indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month.1

The recommended dose is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.1

References

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

2Stauffer 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

3Skljarevski 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

4Detke 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

5Detke HC, Reuter U, Lucas C, et al. Galcanezumab in patients with treatment-resistant migraine: results from the open-label phase of the CONQUER phase 3 trial. Eur J Neurol. 2020;27(suppl 1):298. Congress of the European Academy of Neurology abstract EPR2071. https://doi.org/10.1111/ene.14307

6Mulleners 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

7Camporeale 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

8Sakai F, Ozeki A, Skljarevski V. Efficacy and safety of galcanezumab for prevention of migraine headache in Japanese patients with episodic migraine: a phase 2 randomized controlled clinical trial. Cephalalgia Rep. 2020;3:251581632093257. http://dx.doi.org/10.1177/2515816320932573

9Stauffer VL, Wang S, Bonner J, et al. Evaluation of injection-site-related adverse events with galcanezumab: a post hoc analysis of phase 3 studies in participants with migraine. BMC Neurol. 2020;20(1):194. https://doi.org/10.1186/s12883-020-01775-4

10Data on file, Eli Lilly and Company and/or one of its subsidiaries.

11Stauffer VL, Sides R, Lanteri-Minet M, et al. Comparison between prefilled syringe and autoinjector devices on patient-reported experiences and pharmacokinetics in galcanezumab studies. Patient Prefer Adherence. 2018;12:1785-1795. http://dx.doi.org/10.2147/ppa.s170636

12Stauffer VL, Lanteri-Minet M, García-Azorín D, et al. Characterization of injection-site reactions from the CONQUER study of galcanezumab in patients with treatment-resistant migraine. Cephalalgia. 2020;40(suppl 1):18-110. Migraine Trust Virtual 2020 - Digital Symposium abstract MTV20-DP-053. https://doi.org/10.1177/0333102420962305

13Martinez JM, Hindiyeh N, Anglin G, et al. Assessment of immunogenicity from galcanezumab phase 3 trials in patients with episodic or chronic migraine. Cephalalgia. 2020;40(9):978-989. https://doi.org/10.1177/0333102420920642

14Goldman 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

15Ogston-Tuck S. Subcutaneous injection technique: an evidence-based approach. Nurs Stand. 2014;29(3):53-58. http://dx.doi.org/10.7748/ns.29.3.53.e9183

16EMGALITY [patient package insert]. Eli Lilly and Company: Indianapolis, IN; 2019.

17Workman B. Safe injection techniques. Nurs Stand. 1999;13(39):47-53. https://doi.org/10.7748/ns1999.06.13.39.47.c2623

Glossary

AE = adverse event

MedDRA = Medical Dictionary for Regulatory Activities

NSAID = nonsteroidal anti-inflammatory drug

SAE = serious adverse event

SQ = subcutaneous

TE ADA = treatment-emergent anti-drug antibodies

TEAE = treatment-emergent adverse event

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: 12 November 2020


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