galcanezumab: prescribing information – dosing, contraindications, interactions, side effects

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

Treatment should be initiated by physicians experienced in the diagnosis and treatment of migraine.

Posology

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

Patients should be instructed to inject a missed dose as soon as possible and then resume monthly dosing.

The treatment benefit should be assessed within 3 months after initiation of treatment. Any further decision to continue treatment should be taken on an individual patient basis. Evaluation of the need to continue treatment is recommended regularly thereafter.

Elderly (≥ 65 years)
There is limited information in subjects aged ≥ 65 years. No dose adjustment is required as the pharmacokinetics of galcanezumab are not affected by age.

Renal impairment/hepatic impairment
No dose adjustment is required in patients with mild to moderate renal impairment or hepatic impairment (see section 5.2).

Paediatric population
The safety and efficacy of galcanezumab in children aged 6 to 18 years have not yet been established.
No data are available.

There is no relevant use of galcanezumab in children below the age of 6 years for the prevention of migraine.

Method of administration

Subcutaneous use.

A patient may self-inject galcanezumab by following the Instructions for Use. Galcanezumab is to be injected subcutaneously in the abdomen, thigh, back of the upper arm, or in the gluteal region. After training, patients may self-inject galcanezumab if a healthcare professional determines that it is appropriate. Comprehensive instructions for administration are given in the Package Leaflet.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

Over 2 500 patients were exposed to galcanezumab in migraine prophylaxis studies supporting the initial registration of galcanezumab. Over 1 400 patients were exposed to galcanezumab during the double-blind treatment phase of the placebo-controlled phase 3 studies. 279 patients were exposed for 12 months.

The reported adverse drug reactions for 120 mg and 240 mg in the migraine clinical trials were injection site pain (10.1 %/11.6 %), injection site reactions (9.9 %/14.5 %), vertigo (0.7 %/1.2 %), constipation (1.0 %/1.5 %), pruritus (0.7 %/1.2 %) and urticaria (0.3 %/0.1 %). Most of the reactions were mild or moderate in severity. Less than 2.5 % of patients in these studies discontinued due to adverse reactions.

Tabulated list of adverse reactions

Table 1. List of adverse reactions in clinical studies and post-marketing reports Frequency estimate: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000).

System organ class

Very common
Common
Uncommon
Rare
Immune system disorders

Anaphylaxis
Angioedema
Ear and labyrinth disorders

Vertigo

Gastrointestinal disorders

Constipation

Skin and subcutaneous tissue disorders

Pruritus
Rash
Urticaria

General disorders and administration site conditions
Injection site pain
Injection site reactionsa

a Most frequently reported terms (≥ 1 %) were: Injection site reaction, Injection site erythema, Injection site pruritus, Injection site bruising, Injection site swelling.

Description of selected adverse reactions

Injection site pain or reactions
The majority of reactions 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. 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 reaction occurred within 1 hour of injection and resolved on average in 1 day. One percent of the patients exposed to galcanezumab during the phase 3 studies experienced severe pain at the injection site.

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

Immunogenicity
In the clinical studies, the incidence of anti-drug antibody development during the double-blind treatment phase was 4.8 % in patients receiving galcanezumab once monthly (all but one of whom had in vitro neutralizing activity). With 12 months of treatment, up to 12.5 % of galcanezumab-treated patients developed anti-drug antibodies, most of which were of low titre and tested positive for neutralising activity in vitro. However, the presence of anti-drug antibodies did not affect the pharmacokinetics, efficacy, or safety of galcanezumab.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Cardiovascular risk

Patients with certain major cardiovascular diseases were excluded from clinical studies (see section 5.1). No safety data are available in these patients.

Serious hypersensitivity

Serious hypersensitivity reactions including cases of anaphylaxis, angioedema and urticaria have been reported (see section 4.8). Serious hypersensitivity reactions may occur within 1 day after galcanezumab administration, however cases with a delayed onset (ranging from more than 1 day to 4 weeks after administration) have been reported. In some cases, hypersensitivity reactions had a prolonged duration. If a serious hypersensitivity reaction occurs, administration of galcanezumab should be discontinued immediately and appropriate therapy initiated (see section 4.3). Patients should be informed on the possibility of a delayed onset hypersensitivity reaction and instructed to contact their physician.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per 120 mg dose, that is to say essentially “sodium-free”.

No drug interaction studies were conducted. No pharmacokinetic drug interactions are expected based on the characteristics of galcanezumab.

Pregnancy

There are limited data from the use of galcanezumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Human immunoglobulin (IgG) is known to cross the placental barrier. As a precautionary measure, it is preferable to avoid the use of galcanezumab during pregnancy.

Breast-feeding

It is unknown whether galcanezumab is excreted in human milk. Human IgG is known to be excreted in breast milk during the first days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to breast-fed infants cannot be excluded during this short period.
Afterwards, use of galcanezumab could be considered during breast-feeding only if clinically needed.

Fertility

The effect of galcanezumab on human fertility has not been evaluated. Fertility studies in animals do not indicate harmful effects with respect to male and female fertility (see section 5.3).

Galcanezumab may have a minor influence on the ability to drive and use machines. Vertigo may occur following the administration of galcanezumab (see section 4.8).

Doses up to 600 mg have been administered subcutaneously to humans without dose-limiting toxicity.
In case of an overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: analgesics, calcitonin gene-related peptide (CGRP) antagonists, ATC code: N02CD02

Mechanism of action

Galcanezumab is a humanised IgG4 monoclonal antibody that binds calcitonin gene-related peptide (CGRP) thus preventing its biological activity. Elevated blood concentrations of CGRP have been associated with migraine attacks. Galcanezumab binds to CGRP with high affinity (KD = 31 pM) and high specificity (> 10 000-fold vs related peptides adrenomedullin, amylin, calcitonin and intermedin).

Clinical efficacy and safety

The efficacy and safety of galcanezumab has been studied in 3 phase 3, randomized, placebo- controlled, double-blind studies in adult patients (N = 2 886). The 2 episodic migraine studies (EVOLVE-1 and EVOLVE-2) enrolled patients who met International Classification of Headache Disorders (ICHD) criteria for a diagnosis of migraine with or without aura with 4-14 migraine headache days per month. The chronic migraine study (REGAIN) enrolled patients who met ICHD criteria for chronic migraine with ≥ 15 headache days per month, of which at least 8 had the features of migraine. Patients with recent acute cardiovascular events (including MI, unstable angina, CABG, stroke, DVT) and/or those deemed to be at serious cardiovascular risk were excluded from the galcanezumab clinical trials. Patients > 65 years of age were also excluded.

Patients received placebo, galcanezumab 120 mg/month (with an initial loading dose of 240 mg for the first month) or galcanezumab 240 mg/month and were allowed to use medication for the acute treatment of migraine. Across the 3 studies, patients were predominantly female (> 83 %) with a mean age of 41 years, and an average migraine history of 20 to 21 years. Approximately one-third of patients across the studies had at least 1 prior failure on a migraine prophylactic treatment for efficacy reasons and approximately 16 % of patients across the studies had at least 2 prior failure on a prophylactic treatment for efficacy reasons.

Absorption

Based on a population pharmacokinetic (PK) analysis, following a loading dose of 240 mg the maximum serum concentration (Cmax) of galcanezumab was approximately 30 μg/mL (27 % coefficient of variation, (CV)) and the time to Cmax was 5 days postdose.

Monthly doses of 120 mg or 240 mg achieved a steady-state Cmax (Cmax, ss) of approximately 28 μg/mL (35 % CV) or 54 μg/mL (31 % CV), respectively. The galcanezumab Cmax, ss at monthly doses of 120 mg is achieved after the 240 mg loading dose.

Injection site location (abdomen, thigh, buttocks and arm) did not significantly influence the absorption of galcanezumab.

Distribution

Based on a population PK analysis, the apparent volume of distribution of galcanezumab was 7.3 L.

Biotransformation

As a humanised IgG4 monoclonal antibody, galcanezumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

Elimination

Based on a population PK analysis, the apparent clearance of galcanezumab was approximately 0.008 L/hour and the half life of galcanezumab was 27 days.

Linearity/non-linearity

Galcanezumab exposure increases proportionally with dose.

Based on a population PK analysis that included doses ranging from 5 – 300 mg, the rate of absorption, apparent clearance and apparent volume of distribution was independent of dose.

Age, sex, weight, race, ethnicity

No dose adjustment is needed on the basis of age (18 to 65 years), sex, weight, race or ethnicity as there was no clinically meaningful effect of these factors on the apparent clearance or apparent volume of distribution of galcanezumab.

Renal or hepatic impairment