Emgality ® (galkanezumab)

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Emgality® ▼ (galcanezumab): Smärta vid injektionsstället

Injektionsplatsrelaterade biverkningar var de vanligaste rapporterade biverkningarna i fas 3-studierna. De flesta händelser var milda till måttliga och ledde inte till avbrott

Information On Injection Site Related Events

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 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

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, 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, 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.

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

  • EVOLVE-1, EVOLVE-2, and REGAIN, with a similar incidence between patients treated with galcanezumab (pooled 10.9%) or placebo (9.5%) (Table 2), and

  • the long-term analysis set comprising of the open-label study CGAJ and the open-label treatment phase of REGAIN (8.1% galcanezumab pooled).9 

During double-blind treatment, injection site pain was reported in a greater percentage of patients

  • in the placebo group compared with the galcanezumab group in CONQUER (Table 3), and

  • in the galcanezumab treatment groups compared with placebo in the CGAN study (Table 4).8,10

Table 2. Summary of Injection Site-Related AEs During Phase 3 Double-Blind Treatment: EVOLVE-1, EVOLVE-2, REGAIN9,10

Eventab

PBO
N=1451
n (%)

GMB 120 mg
N=705
n (%)

GMB 240mg
N=730
n (%)

GMB Pooled
N=1435
n (%)

Patients with ≥1 TEAE

183 (12.6)

128 (18.2)c

166 (22.7)cd

294 (20.5)c

Injection site pain

138 (9.5)

71 (10.1)

85 (11.6)

156 (10.9)

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

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

b Preferred term.

c p<.001 vs placebo.

d p=.033 vs GMB 120 mg.

Table 3. Summary of Injection Site-Related AEs: CONQUER Study5,6,10

 

PBO
N=230
n (%)

GMB 120 mg
N=232
n (%)

GMB 120 mg
N=457
n (%)

Eventab

Double-Blind Treatment Phase

Open-Label Treatment Phasec

Patients with ≥1 TEAE

23.0 (10.0)

16 (6.9)

50 (10.9)

Injection site pain

13 (5.7)

5 (2.2)

20 (4.4)

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

a Preferred term.

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

c 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.

Table 4. Summary of Injection Site-Related AEs: Phase 2 Study in Japanese Patients8,10

Eventab

PBO
N=230
n (%)

GMB 120 mg
N=115
n (%)

GMB 240 mg
N=114
n (%)

Patients with ≥1 TEAE

13 (5.7)

30 (26.1)c

45 (39.5)dc

Patients with ≥1 TEAE, excluding injection site pain

12 (5.22)

27 (23.5)c

43 (37.7)dc

Injection site pain

3 (1.3)

7 (6.1)e

8 (7.0)e

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

a Preferred term.

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

c p<.001 vs placebo.

d p<.05 vs GMB 120 mg.

e p<.05 vs placebo.

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

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

During open-label treatment, severe TEAEs of injection site pain also occurred mostly on the day of injection and were reported by

  • 4 patients (0.9%) in CONQUER,

  • 5 patients (1.9%) in CGAJ, and

  • 21 patients (2.1%) 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, including injection site pain, were reported exclusively in TE ADA+ patients.9,12

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.13

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.13

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.14,15

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.10 

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.10

Table 5. Comfort Measures Used at Injection Sites During Double-Blind Treatment: CONQUER10

 

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.

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

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. 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. 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

13. 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

14. 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

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

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.

Datum fӧr senaste ӧversyn 2020 M07 31


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