EMGALITY is indicated for the preventive treatment of migraine in adults.

Posology

Recommanded Dosing

The recommended dosage of EMGALITY is 240 mg (two consecutive subcutaneous injections of 120 mg each) once as a loading dose, followed by monthly doses of 120 mg injected subcutaneously.

If a dose of EMGALITY is missed, administer as soon as possible. Thereafter, EMGALITY can be scheduled monthly from the date of the last dose.

Method of administration

EMGALITY is for subcutaneous use only.

EMGALITY is intended for patient self-administration. Prior to use, provide proper training to patients and/or caregivers on how to prepare and administer EMGALITY using the single-dose prefilled pen, including aseptic technique:

• Protect EMGALITY from direct sunlight.
• Prior to subcutaneous administration, allow EMGALITY to sit at room temperature for 30 minutes. Do not warm by using a heat source such as hot water or a microwave.
• Do not shake the product.
• Inspect EMGALITY visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use EMGALITY if it is cloudy or there are visible particles.
• Administer EMGALITY in the abdomen, thigh, back of the upper arm, or buttocks subcutaneously. Do not inject into areas where the skin is tender, bruised, red, or hard.
• The prefilled pen is single-dose and delivers the entire contents.

Hypersensitivity Reactions

Hypersensitivity reactions, including dyspnea, urticaria, and rash, have occurred with EMGALITY in clinical studies and the postmarketing setting. Cases of anaphylaxis and angioedema have also been reported in the postmarketing setting. If a serious or severe hypersensitivity reaction occurs, discontinue administration of EMGALITY and initiate appropriate therapy [see Contraindications (4.3) and Undesirable effects (4.6)]. Hypersensitivity reactions can occur days after administration, and may be prolonged.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of EMGALITY did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

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

Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of EMGALITY in pregnant women. Administration of galcanezumab to rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation at plasma exposures greater than that expected clinically did not result in adverse effects on development (see Animal Data).

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.

Data

Animal Data

When galcanezumab was administered to female rats by subcutaneous injection in two studies (0, 30, or 100 mg/kg; 0 or 250 mg/kg) prior to and during mating and continuing throughout organogenesis, no adverse effects on embryofetal development were observed. The highest dose tested (250 mg/kg) was associated with a plasma exposure (C_{ave, ss}) 38 times that in humans at the recommended human dose (RHD) of 120 mg. Administration of galcanezumab (0, 30, or 100 mg/kg) by subcutaneous injection to pregnant rabbits throughout the period of organogenesis produced no adverse effects on embryofetal development. The higher dose tested was associated with a plasma (C_{ave, ss}) 64 times that in humans at the RHD.

Administration of galcanezumab (0, 30, or 250 mg/kg) by subcutaneous injection to rats throughout pregnancy and lactation produced no adverse effects on pre- and postnatal development. The higher dose tested was associated with a plasma C_{ave, ss} 34 times that in humans at the RHD.

Breast-feeding

Risk Summary

There are no data on the presence of galcanezumab in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EMGALITY and any potential adverse effects on the breastfed infant from EMGALITY or from the

underlying maternal condition.

There are no known effects on the ability to drive or use machines associated with the use of galcanezumab.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hypersensitivity Reactions [see Contraindications (4.3) and Special warnings and precautions for use (4.4)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of EMGALITY has been evaluated in 2586 patients with migraine who received at least one dose of EMGALITY, representing 1487 patient-years of exposure. Of these, 1920 patients were exposed to EMGALITY once monthly for at least 6 months, and 526 patients were exposed for 12 months.

In placebo-controlled clinical studies (Studies 1, 2, and 3), 705 patients received at least one dose of EMGALITY 120 mg once monthly, and 1451 patients received placebo, during 3 months or 6 months of double-blind treatment [see Pharmacodynamic properties (5.1)]. Of the EMGALITY-treated patients, approximately 85% were female, 77% were white, and the mean age

was 41 years at study entry. The most common adverse reaction was injection site reactions. In Studies 1, 2, and 3, 1.8% of patients discontinued double-blind treatment because of adverse events. Table 1 summarizes the adverse reactions that occurred within up to 6 months of treatment in the migraine studies.

Table 1: Adverse Reactions occurring in Adults with Migraine with an Incidence of at least 2% for EMGALITY and at least 2% Greater than Placebo (up to 6 Months of Treatment) in Studies 1, 2, and 3

^a Injection site reactions include multiple related adverse event terms, such as injection site pain, injection site reaction, injection site erythema, and injection site pruritus.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies to galcanezumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

The immunogenicity of EMGALITY has been evaluated using an in vitro immunoassay for the detection of binding antigalcanezumab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro ligandbinding immunoassay was performed to detect neutralizing antibodies.

In controlled studies with EMGALITY up to 6 months (Study 1, Study 2, and Study 3), the incidence of anti-galcanezumab antibody development was 4.8% (33/688) in patients receiving EMGALITY once monthly (32 out of 33 of whom had in vitro neutralizing activity). With 12 months of treatment in an open-label study, up to 12.5% (16/128) of EMGALITYtreated patients developed anti-galcanezumab antibodies, most of whom tested positive for neutralizing antibodies.

Although anti-galcanezumab antibody development was not found to affect the pharmacokinetics, safety or efficacy of EMGALITY in these patients, the available data are too limited to make definitive conclusions.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of EMGALITY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to EMGALITY exposure.

Immune System Disorders — Anaphylaxis, angioedema [see Contraindications (4.3) and Special warnings and precautions for use (4.4)]. Skin and Subcutaneous Tissue Disorders — Rash.

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 below.

To report any side effect(s):

The National Pharmacovigilance Center (NPC)

·        Fax: +966-11-205-7662

·        SFDA Call Center: 19999

·        E-mail: npc.drug@sfda.gov.sa

·        Website: https://ade.sfda.gov.sa/

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.

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

Mechanism of action

Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor.

Pharmacodynamic effects

There are no relevant data on the pharmacodynamic effects of galcanezumab.

Clinical efficacy and safety

The efficacy of EMGALITY was evaluated as a preventive treatment of episodic or chronic migraine in three multicenter, randomized, double-blind, placebo-controlled studies: two 6-month studies in patients with episodic migraine (Studies 1 and 2) and one 3-month study in patients with chronic migraine (Study 3).

Episodic Migraine

Studies 1 (NCT02614183) and 2 (NCT02614196) included adults with a history of episodic migraine (4 to 14 migraine days per month). All patients were randomized in a 1:1:2 ratio to receive once-monthly subcutaneous injections of EMGALITY 120 mg, EMGALITY 240 mg, or placebo. All patients in the 120 mg EMGALITY group received an initial 240 mg loading dose. Patients were allowed to use acute headache treatments, including migraine-specific medications

(i.e., triptans, ergotamine derivatives), NSAIDs, and acetaminophen during the study.

The studies excluded patients on any other migraine preventive treatment, patients with medication overuse headache, patients with ECG abnormalities compatible with an acute cardiovascular event and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening.

The primary efficacy endpoint for Studies 1 and 2 was the mean change from baseline in the number of monthly migraine headache days over the 6-month treatment period. Key secondary endpoints included response rates (the mean percentages of patients reaching at least 50%, 75%, and 100% reduction from baseline in the number of monthly migraine headache days over the 6-month treatment period), the mean change from baseline in the number of monthly migraine headache days with use of any acute headache medication during the 6-month treatment period, and the impact of migraine on daily activities, as assessed by the mean change from baseline in the average Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive domain score during the last 3 months of treatment (Months 4 to 6). Scores are scaled from 0 to 100, with higher scores indicating less impact of migraine on daily activities.

In Study 1, a total of 858 patients (718 females, 140 males) ranging in age from 18 to 65 years, were randomized. A total of 703 patients completed the 6-month double-blind phase. In Study 2, a total of 915 patients (781 female, 134 male) ranging in age from 18 to 65 years, were randomized. A total of 785 patients completed the 6-month double-blind phase. In Study 1 and Study 2, the mean migraine frequency at baseline was approximately 9 migraine days per month, and was similar across treatment groups.

EMGALITY 120 mg demonstrated statistically significant improvements for efficacy endpoints compared to placebo over the 6-month period, as summarized in Table 2. EMGALITY treatment with the 240 mg once-monthly dose showed no additional benefit over the EMGALITY 120 mg once-monthly dose.

Table 2: Efficacy Endpoints in Studies 1 and 2

^a N = 189 for EMGALITY 120 mg and N = 377 for placebo in Study 1; N = 213 for EMGALITY 120 mg and N = 396 for placebo in Study 2.

* p<0.001

Figure 1: Change from Baseline in Monthly Migraine Headache Days in Study 1^a

^a Least-square means and 95% confidence intervals are presented.

Figure 2: Change from Baseline in Monthly Migraine Headache Days in Study 2^a  

^a Least-square means and 95% confidence intervals are presented.

Figure 3 shows the distribution of change from baseline in the mean number of monthly migraine headache days in bins of 2 days, by treatment group, in Study 1. A treatment benefit over placebo for EMGALITY is seen across a range of changes from baseline in monthly migraine headache days.

Figure 3: Distribution of Change from Baseline in Mean Monthly Migraine Headache Days over Months 1 to 6 by Treatment Group in Study 1

Figure 4 shows the distribution of change from baseline in the mean number of monthly migraine headache days in bins of 2 days, by treatment group, in Study 2. A treatment benefit over placebo for EMGALITY is seen across a range of changes from baseline in monthly migraine headache days.

Figure 4: Distribution of Change from Baseline in Mean Monthly Migraine Headache Days over Months 1 to 6 by Treatment Group in Study 2

Chronic Migraine

Study 3 (NCT02614261) included adults with a history of chronic migraine (≥15 headache days per month with ≥8 migraine days per month). All patients were randomized in a 1:1:2 ratio to receive once-monthly subcutaneous injections of EMGALITY 120 mg, EMGALITY 240 mg, or placebo over a 3-month treatment period. All patients in the 120 mg EMGALITY group received an initial 240 mg loading dose.

Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives), NSAIDs, and acetaminophen. A subset of patients (15%) was allowed to use one concomitant migraine preventive medication. Patients with medication overuse headache were allowed to enroll.

The study excluded patients with ECG abnormalities compatible with an acute cardiovascular event, and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening.

The primary endpoint was the mean change from baseline in the number of monthly migraine headache days over the 3-month treatment period. The secondary endpoints were response rates (the mean percentages of patients reaching at least 50%, 75% and 100% reduction from baseline in the number of monthly migraine headache days over the 3-month treatment period), the mean change from baseline in the number of monthly migraine headache days with use of any acute headache medication during the 3-month treatment period, and the impact of migraine on daily activities as assessed by the mean change from baseline in the MSQ v2.1 Role Function-Restrictive domain score at Month 3. Scores are scaled from 0 to 100, with higher scores indicating less impact of migraine on daily activities.

In Study 3, a total of 1113 patients (946 female, 167 male) ranging in age from 18 to 65 years, were randomized. A total of 1037 patients completed the 3-month double-blind phase. The mean number of monthly migraine headache days at baseline was approximately 19.

EMGALITY 120 mg demonstrated statistically significant improvement for the mean change from baseline in the number of monthly migraine headache days over the 3-month treatment period, and in the mean percentage of patients reaching at least 50% reduction from baseline in the number of monthly migraine headache days over the 3-month treatment period, as summarized in Table 3. EMGALITY treatment with the 240 mg once-monthly dose showed no additional benefit over the EMGALITY 120 mg once-monthly dose.

Table 3: Efficacy Endpoints in Study 3

^a N = 252 for EMGALITY 120 mg and N = 494 for placebo.

* p<0.001

Study 3 utilized a sequential testing procedure to control the Type-I error rate for the multiple secondary endpoints. Once a secondary endpoint failed to reach the required level for statistical significance, formal hypothesis testing was terminated for subsequent endpoints, and p-values were considered nominal only. In Study 3, EMGALITY 120 mg was not significantly better than placebo for the proportion of patients with ≥75% or 100% reduction in migraine headache days. Patients treated with EMGALITY 120 mg showed a nominally greater reduction in the number of monthly migraine headache days that acute medication was taken (-4.7 for EMGALITY 120 mg vs. -2.2 for placebo; nominal p-value <0.001), and the mean change from baseline in the MSQ Role Function-Restrictive Domain score at Month 3 was nominally greater in patients treated with EMGALITY 120 mg than in patients on placebo (21.8 for EMGALITY 120 mg vs. 16.8 for placebo; nominal p-value <0.001).

Figure 5: Change from Baseline in Monthly Migraine Headache Days in Study 3^a

^a Least-square means and 95% confidence intervals are presented.

Figure 6 shows the distribution of change from baseline in the mean number of monthly migraine headache days for the 3-month study period in bins of 3 days by treatment group. A treatment benefit over placebo for EMGALITY is seen across a range of changes from baseline in monthly migraine headache days.

Figure 6: Distribution of Change from Baseline in Mean Monthly Migraine Headache Days over Months 1 to 3 by Treatment Group in Study 3

Galcanezumab exhibits linear pharmacokinetics and exposure increases proportionally with doses between 1 and 600 mg.

A loading dose of 240 mg achieved the serum galcanezumab steady-state concentration after the first dose. A dose of 300 mg monthly would achieve steady-state concentration after the fourth dose. The time to maximum concentration is 5 days, and the elimination half-life is 27 days.

There was no difference in pharmacokinetic parameters between healthy volunteers,  patients with episodic or chronic migraine, and patients with episodic cluster headache.

Absorption

Following a subcutaneous dose of galcanezumab, the time to maximum concentration was about 5 days.

Injection site location did not significantly influence the absorption of galcanezumab.

Distribution

The apparent volume of distribution (V/F) of galcanezumab was 7.3 L (34% Inter Individual Variability [IIV]).

Metabolism and Elimination

Galcanezumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

The apparent clearance (CL/F) of galcanezumab was 0.008 L/h and the elimination half-life of galcanezumab was 27 days.

Specific Populations

Age, Sex, Weight, Race, Ethnicity

The pharmacokinetics of galcanezumab were not affected by age, sex, race, or subtypes of migraine spectrum (episodic or chronic migraine), or headache diagnosis (migraine vs. episodic cluster headache) based on a population pharmacokinetics analysis. Body weight has no clinically relevant effect on the pharmacokinetics of galcanezumab.

Patients with Renal or Hepatic Impairment

Renal and hepatic impairment are not expected to affect the pharmacokinetics of galcanezumab. Population pharmacokinetic analysis of integrated data from the galcanezumab clinical studies revealed that creatinine clearance did not affect the pharmacokinetics of galcanezumab in patients with mild or moderate renal impairment. Patients with severe renal impairment (creatinine clearance <30 mL/min) have not been studied. Based on a population PK analysis, bilirubin concentration did not significantly influence the CL/F of galcanezumab.

No dedicated clinical studies were conducted to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of galcanezumab.

Drug Interaction Studies

P450 Enzymes

Galcanezumab is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of galcanezumab has not been assessed.Mutagenesis

Genetic toxicology studies of galcanezumab have not been conducted. Impairment of Fertility

When galcanezumab (0, 30, or 250 mg/kg) was administered to male rats by subcutaneous injection prior to and during mating, no adverse effects on fertility was observed. The higher dose tested was associated with a plasma exposure (C_{ave, ss}) 8 times that in humans at the recommended human dose (RHD) of 120 mg. When galcanezumab was administered to female rats by subcutaneous injection in two studies (0, 30, or 100 mg/kg; 0 or 250 mg/kg) prior to and during mating and continuing throughout organogenesis, no adverse effects on fertility were observed. The highest dose tested (250 mg/kg) was associated with a plasma C_{ave, ss} 38 times that in humans at the RHD.

• L-histidine [0.5 mg/mL, 0.5 mg]
• L-histidine hydrochloride monohydrate [1.5 mg/mL, 1.5mg]
• Polysorbate 80 [0.5 mg/mL 0.5 mg] [E433]
• Sodium Chloride [8.8 mg/mL, 8.8 mg]
• Water for Injection

Total sodium content per 1 mL of product approximately 3.5 mg

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

• Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect EMGALITY from light until use.
• Do not freeze.
• Do not shake.
• EMGALITY may be stored out of refrigeration in the original carton at temperatures up to 30°C (86°F) for up to 7 days. Once stored out of refrigeration, do not place back in the refrigerator.
• If these conditions are exceeded, EMGALITY must be discarded.
• Discard the EMGALITY single-dose prefilled pen after use in a puncture-resistant container.

EMGALITY injection is a sterile, preservative-free, clear and colorless to slightly yellow solution available in a single-dose prefilled pen manufactured to deliver 120 mg galcanezumab. EMGALITY is not made with natural rubber latex.

EMGALITY is supplied as:

Not all pack sizes may be marketed.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.