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

Content overview

Injection site-related adverse drug reactions from the Summary of Product Characteristics

Description of Migraine Analysis Set

Migraine Prevention: Injection Site-Related Adverse Events

Postmarketing Spontaneous Reports

Prevention and Management of Injection Site-related Adverse Events

References

Appendix

Injection site-related adverse drug reactions from the Summary of Product Characteristics

Injection site pain or reactions

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 included in this response. 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

Pruritus

Pruritus is a common adverse reaction of galcanezumab. Pruritus was reported by 0.7 % and 1.2 % of patients with 120 mg and 240 mg galcanezumab, respectively.¹

Urticaria

Urticaria is an uncommon adverse reaction of galcanezumab. Urticaria was reported by 0.3 % and 0.1 % of patients with 120 mg and 240 mg galcanezumab, respectively.¹

While urticaria is uncommon, serious cases of urticaria have been reported in galcanezumab clinical studies. ¹

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Description of Migraine 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), and^5,6

• 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 Table 1.

Table 1. 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.

^a Possible injection-sites included the abdomen, thigh, upper arm, or buttocks.

^b EVOLVE-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).

^c Each injection was 1 mL.

^d CGAJ: 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.

^e Investigative 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.

^f Patients 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.

^g CONQUER: 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.

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Migraine Prevention: Injection Site-Related Adverse Events

Migraine Prevention: Incidence of Injection Site-Related Adverse Events

Injection-site-related AEs occurred in significantly more galcanezumab-treated patients than placebo in

• EVOLVE-1, EVOLVE-2, and REGAIN (20.5% galcanezumab pooled vs 12.6% placebo) (Table 7),⁹ and

• the phase 2 study in Japanese patients (32.8% galcanezumab pooled vs 5.7% placebo) (Table 9).¹⁰

In the CONQUER study, injection site-related AEs occurred more frequently in placebo-treated patients (10%) than galcanezumab-treated patients (6.9%) during the double-blind treatment phase (Table 8).⁶

Injection-site-related AEs were reported by 21.8% of galcanezumab-treated patients in the long-term analysis set (REGAIN and CGAJ).⁹

Most Commonly Reported Injection Site-Related Adverse Events

The most commonly reported injection site-related AE was

• injection site pain in EVOLVE-1, EVOLVE-2, and REGAIN (10.9% galcanezumab pooled, 9.5% placebo), and the long-term analysis set (8.1% galcanezumab pooled),⁹ and

• injection site erythema in CONQUER (3.5% galcanezumab 120 mg, 2.6% placebo) and CGAN (21.0% galcanezumab pooled, 2.2% placebo).¹⁰

These results are summarized in Table 7, Table 8, and Table 9 in the Appendix.

Migraine Prevention: Serious Adverse Events and Discontinuations

No SAEs related to injection-sites were reported in any of the studies (EVOLVE-1, EVOLVE-2, REGAIN, CONQUER, CGAJ, or CGAN).^7,9,10,12,13 

Discontinuation due to an injection site-related AE during double-blind, placebo-controlled treatment occurred at an incidence of <0.5% in the EVOLVE-1, EVOLVE-2, and REGAIN studies, and only in galcanezumab-treated patients,^9,12 and <1% in the long-term analysis.⁹

In the EVOLVE-1, EVOLVE-2, and REGAIN studies, injection site-related AEs resulting in study discontinuation were

• moderate unspecified injection site reaction (n=4)

• moderate injection site pain (n=1)

• severe injection site erythema (n=1), and

• moderate injection site swelling (n=1).⁹

All discontinuations due to injection site-related AEs resolved without sequelae.¹⁰

During the CONQUER study, there were no discontinuations due to an injection-site-related AE during double-blind treatment and 1 patient discontinued due to injection-site erythema during open-label treatment.^10,13

In the long-term analysis set, 9 patients discontinued due to injection-site-related AEs during open-label treatment. All discontinuations were observed following multiple doses of galcanezumab.⁹

In the CGAN study, 2 galcanezumab-treated patients (240 mg) reported severe injection site reactions, but only 1 patient discontinued as a result. These were 

• injection site erythema and injection site pruritus (discontinued due to the injection site erythema), and

• injection site pruritus, injection site erythema, and injection site induration (did not discontinue).⁸

Migraine Prevention: Characterization of Injection Site-Related Adverse Events

The majority of patients reporting injection-site-related AEs (excluding pain) had events that

• were mild to moderate in severity

• occurred on the day of treatment administration, and

• resolved, either on the same day or a few days afterward.^7-10,12,13

In EVOLVE-1, EVOLVE-2, and REGAIN, all the 67 galcanezumab-treated patients who reported a non-specified AE of injection site reaction had at least 1 follow-up form completed to further characterize the unspecified injection site reaction: Table 2.⁹

Table 2. Characterization of Nonspecific Injection-Site Reactions^a Reported by Galcanezumab-Treated Patients During Double-Blind Treatment: EVOLVE-1, EVOLVE-2, REGAIN^9,10

	GMB 120 mg n=22	GMB 240 mg n=45
Pain	81%	71%
Itching	59%	60%
Rash or redness	59%	84%
Hardening of the injection site	59%	44%

Abbreviation: GMB = galcanezumab.

^a A nonspecified adverse event of injection-site reaction: some sites recorded the adverse event of “injection site reaction” without further qualification while others were more specific in recording the symptom the patient reported at the site of the injection.

In CONQUER, each injection-site reaction was characterized based on a series of follow-up questions. Overall, 12.5% of galcanezumab-treated patients reported an injection-site reaction which was assessed using the injection-site reaction follow-up form: Table 3.¹³ More details were collected on the follow-up questions in the CONQUER study compared to the EVOLVE-1, EVOLVE-2, and REGAIN studies.

Table 3. Characterization of Injection-Site Reactions Reported by Galcanezumab-Treated Patients in the CONQUER Study¹³

Injection-Site Reaction	GMB-Treated Timea N=457 n (%)
Patients with >1 record of ISR follow-up form	57 (12.47)
Pain
Mild	27 (5.9)
Moderate	8 (1.8)
Severe	2 (0.4)
Erythema
Very mild	20 (4.4)
Clearly red	17 (3.7)
Bright red	3 (0.7)
Pruritus
Mild	15 (3.3)
Moderate	3 (0.7)
Severe	1 (0.2)
Induration
Barely noticeable	10 (2.2)
Slight	3 (0.7)
Moderate	5 (1.1)
Severe	3 (0.7)
Edema
Mild	7 (1.5)
Moderate	5 (1.1)
Severe	5 (1.1)

Abbreviation: GMB = galcanezumab; ISR = injection-site reaction.

^a Patients were treated for up to 6 months with GMB (3 months double-blind/3 months open-label) or up to 3 months GMB (3 months placebo in double-blind/3 months GMB in open-label).

In the CONQUER study, most patients received either 3 or 6 monthly injections over the course of 6 months, and the reporting of injection-site reactions did not increase with the number of doses.¹³

In the long-term analysis set, the reporting of injection-site reactions (excluding pain) by galcanezumab-treated patients did not increase with multiple dose administrations. Overall, 81% of patients received 9 doses or more of galcanezumab and most patients reported 1 to 3 events with monthly injections over 9 to 12 months.⁹

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.^9,14

In TE ADA+ patients who reported injection-site-related AEs (Table 4)

• 1 patient reported injection-site inflammation before the development of TE ADA which did not recur after the detection of titer increase of antibodies, and

• 2 patients had already detectable TE ADA before reporting injection-site rash.¹⁴

Table 4. Injection-Site-Related AEs and ADA in Galcanezumab-Treated Patients: Cases That Met Flagging for Further Review^a in Phase 3 Migraine Prevention Studies¹⁴

Preferred Term	TE ADA Status	N	n (%)
Injection site rash	Yes	92	2 (2.2%)
	No	1562	10 (0.6%)
Injection site inflammation	Yes	92	1 (1.1%)
	No	1562	1 (0.1%)

Abbreviations: ADA = antidrug antibodies; AE = adverse event; N = number of patients in the analysis population; n = number of patients within each specific category; TE ADA = treatment-emergent anti-drug antibody.

^a Criteria for case level review were based on odds ratio and p value from the Cochran-Mantel-Haenszel test that compared the proportions of patients with ≥1 preferred term related to injection-sites between TE ADA+ and TE ADA- patients, stratified by study. Events with an odds ratio >2.0 or p≤.05 met flagging criteria for further review.

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Postmarketing Spontaneous Reports

Through March 27, 2020, MedDRA terms related to injection-site reactions that have been reported in the Eli Lilly and Company spontaneous AE database are provided in Table 5.¹⁰

Table 5. Galcanezumab Postmarketing Reporting Rates of Injection-Site Reactions^a Through 27 March 2020¹⁰

Uncommonly Reported (≥0.1% and <1%)	Rarely Reported (≥0.01% and <0.1%)	Very Rarely Reported (<0.01%)
injection site erythema, injection site pain, injection site pruritus, injection site reaction, injection site swelling	injection site bruising, injection site discomfort, injection site hemorrhage, injection site hypersensitivity, injection site induration, injection site injury, injection site irritation, injection site mass, injection site rash, injection site urticaria, injection site warmth	injection site cellulitis, injection site coldness, injection site discoloration, injection site dryness, injection site exfoliation, injection site extravasation, injection site hematoma, injection site hyperesthesia, injection site hypoesthesia, injection site infection, injection site joint erythema, injection site inflammation, injection site laceration, injection site macule, injection site nodule, injection site edema, injection site pallor, injection site papule, injection site paresthesia, injection site plaque, injection site pustule, injection site scab, injection site scar, injection site vesicles

Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities.

^a MedDRA preferred terms.

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

• under-reporting or reporting bias, and

• missing or incomplete information regarding medical history or concomitant medications.¹⁵

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Prevention and Management of Injection Site-related Adverse Events

Safe practices for administering SQ injections include

• leaving the medication to 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.^10,16,17

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.¹³  

The percentage of patients who used comfort measures around the time of injection was low and similar between treatment groups during double-blind treatment: Table 6. The most frequently used comfort measure was application of an ice pack.¹⁰

Table 6. Comfort Measures Used at Injection-Sites During Double-Blind Treatment: CONQUER^10,13

	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 premedicate 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.^9,18 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

As noted in Table 7, 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

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References

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

2. 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

3. 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

4. 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

5. Detke 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

6. Mulleners 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

7. Camporeale 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

8. Sakai 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

9. Stauffer 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

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

11. Stauffer 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

12. Bangs 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

13. Stauffer 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

14. Martinez 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

15. 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

16. Ogston-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

17. Emgality [instructions for use, pre-filled syringe]. Eli Lilly Nederland B.V., The Netherlands.

18. Workman 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

Appendix

Migraine Prevention: Summary of Injection Site-Related Adverse Events

Table 7. Summary of Injection-Site-Related AEs During Phase 3 Double-Blind Treatment: EVOLVE-1, EVOLVE-2, REGAIN^a9,10

Eventbc	PBO N=1451 n (%)	GMB 120 mg N=705 n (%)	GMB 240 mg N=730 n (%)	GMB Pooled N=1435 n (%)
Patients with ≥1 TEAE	183 (12.6)	128 (18.2)d	166 (22.7)de	294 (20.5)d
Patients with ≥1 TEAE, excluding injection site painf	60 (4.1)	70 (9.9)d	106 (14.5)dg	176 (12.3)d
Injection site pain	138 (9.5)	71 (10.1)	85 (11.6)	156 (10.9)
Unspecified injection site reaction	14 (1.0)	22 (3.1)d	45 (6.2)dh	67 (4.7)d
Injection site erythema	20 (1.4)	20 (2.8)i	29 (4.0)d	49 (3.4)d
Injection site pruritus	2 (0.1)	15 (2.1)d	24 (3.3)d	39 (2.7)d
Injection site bruising	9 (0.6)	4 (0.6)	10 (1.4)	14 (1.0)
Injection site swelling	1 (0.1)	8 (1.1)d	4 (0.6)j	12 (0.8)k
Injection site rash	2 (0.1)	6 (0.9)l	4 (0.6)	10 (0.7)m
Injection site induration	1 (0.1)	3 (0.4)	3 (0.4)	6 (0.4)
Injection site discomfort	3 (0.2)	3 (0.4)	2 (0.3)	5 (0.4)
Injection site hematoma	7 (0.5)	1 (0.1)	3 (0.4)	4 (0.3)
Injection site hypersensitivity	0 (0.0)	1 (0.1)	3 (0.4)n	4 (0.3)o
Injection site mass	0 (0.0)	3 (0.4)p	0 (0.0)	3 (0.2)
Injection site hemorrhage	2 (0.1)	1 (0.1)	1 (0.1)	2 (0.1)
Injection site inflammation	0 (0.0)	1 (0.1)	1 (0.1)	2 (0.1)
Injection site irritation	3 (0.2)	1 (0.1)	1 (0.1)	2 (0.1)
Injection site urticaria	1 (0.1)	1 (0.1)	1 (0.1)	2 (0.1)
Injection site discoloration	0 (0.0)	0 (0.0)	1 (0.1)	1 (0.1)
Injection site edema	1 (0.1)	1 (0.1)	0 (0.0)	1 (0.1)
Injection site papule	0 (0.0)	1 (0.1)	0 (0.0)	1 (0.1)
Injection site vesicles	0 (0.0)	0 (0.0)	1 (0.1)	1 (0.1)
Injection site warmth	1 (0.1)	0 (0.0)	0 (0.0)	0 (0.0)

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

^a Prefilled syringe was used in these trials.

^b Preferred term.

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

^d p<.001 vs PBO.

^e p=.033 vs GMB 120 mg.

^f Most frequently reported terms (not less than 1.5% of all preferred terms which included: injection site reaction, injection site erythema, and injection site pruritus).

^g p=.008 vs GMB 120 mg.

^h p=.006 vs GMB 120 mg.

ⁱ p=.017 vs PBO.

^j p=.028 vs PBO.

^k p=.002 vs PBO.

^l p=.011 vs PBO.

^m p=.02 vs PBO.

ⁿ p=.015 vs PBO.

^o p=.044 vs PBO.

^p p=.012 vs PBO.

Table 8. Summary of Injection-Site-Related AEs: CONQUER Study^a5,6,10

	PBO N=230 n (%)	GMB 120 mg N=232 n (%)	GMB 120 mg N=457 n (%)
Eventbc	Double-Blind Treatment Phase		Open-Label Treatment Phased
Patients with ≥1 TEAE	23.0 (10.0)	16 (6.9)	50 (10.9)
Injection site erythema	6 (2.6)	8 (3.5)	19 (4.2)
Injection site pain	13 (5.7)	5 (2.2)	20 (4.4)
Injection site pruritus	0 (0.0)	3 (1.3)	9 (2.0)
Injection site edema	0 (0.0)	2 (0.9)	3 (0.7)
Injection site discoloration	1 (0.4)	1 (0.4)	3 (0.7)
Injection site hypersensitivity	0 (0.0)	1 (0.4)	1 (0.2)
Injection site induration	4 (1.7)	1 (0.4)	5 (1.1)
Injection site paresthesia	3 (1.3)	1 (0.4)	3 (0.7)
Injection site swelling	0 (0.0)	1 (0.4)	2 (0.4)
Injection site bruising	4 (1.7)	0 (0.0)	2 (0.4)
Injection site hematoma	1 (0.4)	0 (0.0)	1 (0.2)
Injection site reaction	6 (2.6)e	0 (0.0)	8 (1.8)
Injection site inflammation	NR	NR	1 (0.2)
Injection site irritation	NR	NR	1 (0.2)
Injection site rash	NR	NR	1 (0.2)
Injection site vesicles	NR	NR	1 (0.2)
Injection site warmth	NR	NR	1 (0.2)

Abbreviations: AE = adverse event; GMB = galcanezumab; MedDRA = Medical Dictionary for Regulatory Activities; NR = not reported; PBO = placebo; TEAE = treatment-emergent adverse event.

^a Prefilled syringe was used in this study.

^b Preferred term.

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

^d Galcanezumab-treated population: patients who received up to 6 months of GMB treatment in addition to patients on PBO in the double-blind treatment phase who received GMB during open-label treatment.

^e p=.015 vs GMB 120 mg.

Table 9. Summary of Injection-Site-Related AEs: Phase 2 Study^a in Japanese Patients With Episodic Migraine^8,10

Eventbc	PBO N=230 n (%)	GMB 120 mg N=115 n (%)	GMB 240 mg N=114 n (%)	GMB Pooled N=229 n (%)
Patients with ≥1 TEAE	13 (5.7)	30 (26.1)d	45 (39.5)de	75 (32.8)d
Patients with ≥1 TEAE, excluding injection site pain	12 (5.2)	27 (23.5)d	43 (37.7)df	70 (30.6)d
Injection site erythema	5 (2.2)	17 (14.8)d	31 (27.2)dg	48 (21.0)d
Injection site pruritus	0 (0.0)	10 (8.7)d	23 (20.2)dh	33 (14.4)d
Injection site swelling	3 (1.3)	12 (10.4)d	12 (10.5)d	24 (10.5)d
Injection site pain	3 (1.3)	7 (6.1)i	8 (7.0)j	15 (6.6)k
Injection site induration	1 (0.4)	3 (2.6)	3 (2.6)	6 (2.6)
Injection site inflammation	0 (0.0)	3 (2.6)l	0 (0.0)	3 (1.3)
Injection site rash	2 (0.9)	0 (0.0)	3 (2.6)	3 (1.3)
Injection site warmth	0 (0.0)	2 (1.7)	1 (0.9)	3 (1.3)
Injection site bruising	4 (1.7)	2 (1.7)	0 (0.0)	2 (0.9)
Injection site mass	0 (0.0)	1 (0.9)	1 (0.9)	2 (0.9)
Injection site urticaria	0 (0.0)	1 (0.9)	1 (0.9)	2 (0.9)
Injection site dermatitis	0 (0.0)	0 (0.0)	1 (0.9)	1 (0.4)
Injection site eczema	0 (0.0)	0 (0.0)	1 (0.9)	1 (0.4)
Injection site hemorrhage	1 (0.4)	1 (0.9)	0 (0.0)	1 (0.4)
Injection site discoloration	1 (0.4)	0 (0.0)	0 (0.0)	0 (0.0)
Injection site discomfort	1 (0.4)	0 (0.0)	0 (0.0)	0 (0.0)
Injection site reaction	1 (0.4)	0 (0.0)	0 (0.0)	0 (0.0)

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

^a Prefilled syringe was used in this study.

^b Preferred term.

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

^d p<.001 vs PBO.

^e p=.035 vs GMB 120 mg.

^f p=.022 vs GMB 120 mg.

^g p=.024 vs GMB 120 mg.

^h p=.015 vs GMB 120 mg.

ⁱ p=.018 vs PBO.

^j p=.008 vs PBO.

^k p=.004 vs PBO.

^l p=.036 vs PBO.

▼ 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.