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 and

• a 12-month, open-label safety study in patients with episodic or chronic migraine (CGAJ).⁵

The results below are focused primarily on the findings from EVOLVE-1, EVOLVE-2, and REGAIN.⁶

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. Device and Injection Administration in Phase 3 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.

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.

Injection Site-related Adverse Events

Injection site-related AEs occurred in significantly more galcanezumab-treated patients than placebo (Table 2).^6,10

Table 2. Summary of Injection Site-Related AEs During Phase 3 Double-Blind Treatment: Migraine Prevention^9,10

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

^a Preferred term.

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

^c p<.001 vs placebo.

^d p=.033 vs GMB 120 mg.

^e 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).

^f p=.008 vs GMB 120 mg.

^g p=.006 vs GMB 120 mg.

^h p=.017 vs placebo.

ⁱ p=.028 vs placebo.

^j p=.002 vs placebo.

^k p=.011 vs placebo.

^l p=.02 vs placebo.

^m p=.015 vs placebo.

ⁿ p=.044 vs placebo.

^o p=.012 vs placebo.

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.

Serious Adverse Events and Discontinuations

No SAEs related to injection sites were reported in the phase 3 double-blind studies.¹⁰

Discontinuation due to an injection site-related AE occurred

• at an incidence of <0.5%, and

• only in galcanezumab-treated patients during double-blind, placebo-controlled treatment.^6,9

All discontinuations due to injection site-related AEs resolved without sequelae.⁹

Characterization of Injection Site-related Adverse Events

In the phase 3 studies 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, on average, in 5 days.^9,10

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 injection site reaction: Table 3.⁹

Table 3. Characterization of Non-Specific Injection Site Reactions Reported by Galcanezumab-Treated Patients During Double-Blind Treatment: Migraine Prevention⁹

Abbreviation: GMB = galcanezumab.

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.

Open-label Safety Study CGAJ

In the long-term, open-label safety study (CGAJ), the frequency of galcanezumab-treated patients experiencing injection site-related AEs was greater (pooled, 33.0%) than the frequency observed in the double-blind studies (pooled, 20.5%).⁹

The frequency of the following injection site-related AEs in galcanezumab-treated patients (120 mg and 240 mg pooled) was greater than the frequency observed in the double-blind studies including,

• injection site pain (18.52%)

• injection site reaction (10.37%)

• injection site erythema (6.67%)

• injection site bruising (4.81%)

• injection site hematoma (2.96%), and

• injection site induration (2.22%).^5,9

No difference was observed between the galcanezumab dose groups in overall incidence of ≥1 injection site-related AE.⁹

In CGAJ, the injection site-related AEs

• were mostly mild to moderate in severity, and

• resulted in discontinuation for 5 patients (1.9%).^5,9

Of the 5 patients who discontinued,

• 4 patients discontinued after ≥6 self-administration dosing visits, and

• 1 patient who had a severe injection site reaction discontinued after the 10th dosing visit due to progressive swelling around the site of injection, with rash and pain that progressed from the previous injection that lasted a few days.⁵ 

No SAEs related to injection sites were reported.⁹

Exposure Adjusted Incidence Rate

Exposure-adjusted incidence rates are a measure of whether TEAEs occur at an increased frequency with increased treatment duration.⁹

The EAIRs for injection site pain, injection site reaction, injection site erythema and injection site pruritus in study CGAJ were compared to EVOLVE-1, EVOLVE-2, and REGAIN. Compared to EVOLVE-1, EVOLVE-2, and REGAIN, the EAIRs in CGAJ for

• injection site pain and injection site pruritus for the galcanezumab pooled group were lower (32.50 vs 25.54; 7.41 vs 3.06), and

• injection site reaction and injection site erythema were similar (12.85 vs 12.85; 9.34 vs 8.15).⁹

EAIR is equal to 100 times the number of patients experiencing the event divided by event-specific total patient-year-at-risk.⁹

Prevention and Management of Injection Site-related Adverse Events

Although management of injection site-related AEs was not outlined in the phase 3 study protocols for either indication, premedication was not prohibited.⁹ 

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.⁹

Management of injection site-related AEs in the studies was at the discretion of the study investigators.⁹ The decision whether to pre-medicate a patient prior to galcanezumab injection should be made at the discretion of the prescribing physician.

Injection site pain and AEs following SQ injection might vary depending on the properties of the compound and the cellular dynamics at the site of injection.¹² 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.^13,14

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. Camporeale A, Kudrow D, Sides R, et al. A phase 3, long-term, open-label safety study of galcanezumab in patients with migraine. BMC Neurology. 2018;18(1):188. http://dx.doi.org/10.1186/s12883-018-1193-2

6. Stauffer VL, Wang S, Bangs M, et al. Phase 3 safety data from studies comparing galcanezumab and placebo in patients with episodic and chronic migraine. Poster presented at: European Academy of Neurology (EAN) – 4^th Congress; June 16-19, 2018; Lisbon, Portugal.

7. 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

8. 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

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

10. Stauffer VL, Wang S, Carter JN, et al. Evaluation of injection site related adverse events from the phase 3 placebo controlled trials of galcanezumab for migraine prevention. Poster presented at: Migraine Trust International Symposium (MTIS) – 17^th Biennial Meeting; September 6-9, 2018; London, United Kingdom.

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

13. 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

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

Glossary

AE = adverse event

EAIR = exposure-adjusted incidence rate

NSAID = nonsteroidal anti-inflammatory drug

SAE = serious adverse event

SQ = subcutaneous

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.