Emgality® ▼ (galcanezumab): Injection Site Reactions

Information from Summary of Product Characteristics

Injection site pain or reactions

Injection site pain and Injection site reactions are very common adverse reactions of galcanezumab.

• Injection site pain was reported by 10.1 % and 11.6 % of patients with 120 mg and 240 mg galcanezumab, respectively.

• Injection site reactions were reported by 9.9 % and 14.5 % of patients  with 120 mg and 240 mg galcanezumab, respectively.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

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)^5,6, and

• a 12-month, open-label safety study in patients with episodic or chronic migraine (CGAJ).⁷

Note: The recommended dose 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 to 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, and study CGAJ as shown in Table 1.

Table 1. Device and Injection Administration in Galcanezumab Migraine Prevention Studies

Abbreviation: SQ = subcutaneous.

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

^b EVOLVE-1, EVOLVE-2, and REGAIN: 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.

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 6),⁹ and 

• the phase 2 study in Japanese patients (32.8% galcanezumab pooled vs 5.7% placebo) (Table 8).¹²

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 7).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).¹²

These results are summarized in Table 6, Table 7, and Table 8 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).^7,9,12,14 

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,^9,14 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.¹²

There were no discontinuations due to an injection site-related AE during double-blind treatment in the CONQUER study.¹²

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 CONQUER study, 1 patient discontinued due to injection site erythema during open-label treatment.¹²

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 afterwards.^7-9,12,14

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 Non-Specific Injection Site Reactions Reported by Galcanezumab-Treated Patients During Double-Blind Treatment: EVOLVE-1, EVOLVE-2, REGAIN^9,12

Abbreviation: GMB = galcanezumab.

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.^9,15

In TE ADA+ patients who reported injection site-related AEs (Table 3), 

• 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.¹⁵

Table 3. Injection Site-Related AEs and ADA in Galcanezumab-Treated Patients: Cases That Met Flagging for Further Review^a in Phase 3 Migraine Prevention Studies¹⁵

Abbreviations: ADA = anti-drug antibodies; AE = adverse event; TE ADA = treatment-emergent anti-drug antibody.

^a Criteria for case level review was 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.

Postmarketing Spontaneous Reports

Through 27 March 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 4.¹²

Table 4. Galcanezumab Postmarketing Reporting Rates of Injection Site Reactions^a Through 27 March 2020¹²

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.¹⁶

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.¹⁶

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.^12,17,18

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: Table 5. The most frequently used comfort measure was application of an ice pack.¹²

Table 5. Comfort Measures Used at Injection Sites During Double-Blind Treatment: CONQUER¹²

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.¹²

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.¹²

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.¹² 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.^9,19 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 6, 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 non-physiological pH of less than 7 (galcanezumab pH is 5.3 to 6.3), and

• the presence of polysorbate 80.⁹

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

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. Poster presented at: 14th European Headache Federation (EHF Virtual); June 29-July 2, 2020.

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. Published online July 16, 2020. 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 Neurology. 2020;20(1):194. https://doi.org/10.1186/s12883-020-01775-4

10. 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

11. 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

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

13. 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

14. Bangs ME, Kudrow D, Wang S, et al. Safety and tolerability of monthly galcanezumab injections in patients with migraine: integrated results from migraine studies. BMC Neurol. 2020;20(1):25. http://dx.doi.org/10.1186/s12883-020-1609-7. Published correction appears in BMC Neurol. 2020;20(1):90. http://dx.doi.org/10.1186/s12883-020-01675-7

15. 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

16. 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

17. 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

18. Emgality [package insert]. Indianapolis, IN: Eli Lilly and Company; 2019.

19. Workman B. Safe injection techniques. Nurs Stand. 1999;13(39):47-53. http://www.ncbi.nlm.nih.gov/pubmed/10497490

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 6. Summary of Injection Site-Related AEs During Phase 3 Double-Blind Treatment: EVOLVE-1, EVOLVE-2, REGAIN^9,12a

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

^a Pre-filled 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 placebo.

^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 placebo.

^j p=.028 vs placebo.

^k p=.002 vs placebo.

^l p=.011 vs placebo.

^m p=.02 vs placebo.

ⁿ p=.015 vs placebo.

^o p=.044 vs placebo.

^p p=.012 vs placebo.

Table 7. Summary of Injection Site-Related AEs: CONQUER Study^5,6,12a

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

^a Pre-filled 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 galcanezumab treatment in addition to patients on placebo in the double-blind treatment phase who received galcanezumab during open-label treatment.

^e p=.015 vs GMB 120 mg.

Table 8. Summary of Injection Site-Related AEs: Phase 2 Study in Japanese Patients With Episodic Migraine^8,12a

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

^a Pre-filled 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 placebo.

^e p<.05 vs GMB 120 mg.

^f p<.05 vs placebo.

▼ 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.