Episodic Cluster Headache

EMGALITY is indicated for the treatment of episodic cluster headache in adults.

Posology

Recommended Dosing for Episodic Cluster Headache

The recommended dosage of EMGALITY is 300 mg (three consecutive subcutaneous injections of 100 mg each) at the onset of the cluster period, and then monthly until the end of the cluster period.

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

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 syringe, 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 syringe 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.

Hypertension

Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists, including EMGALITY, in the postmarketing setting. Some of the patients who developed new-onset hypertension had risk factors for hypertension. There were cases requiring initiation of pharmacological treatment for hypertension and, in some cases, hospitalization. Hypertension may occur at any time during treatment but was most frequently reported within 7 days of therapy initiation. EMGALITY was discontinued in many of the reported cases.

Monitor patients treated with EMGALITY for new-onset hypertension or worsening of pre-existing hypertension, and consider whether discontinuation of EMGALITY is warranted if evaluation fails to establish an alternative etiology or blood pressure is inadequately controlled.

Raynaud’s Phenomenon

Development of Raynaud’s phenomenon and recurrence or worsening of pre-existing Raynaud’s phenomenon have been reported in the postmarketing setting following the use of CGRP antagonists, including EMGALITY. In reported cases with monoclonal antibody CGRP antagonists, symptom onset occurred after a median of 71 days following dosing. Many of the cases reported serious outcomes, including hospitalizations and disability, generally related to debilitating pain. In most reported cases, discontinuation of the CGRP antagonist resulted in resolution of symptoms.

EMGALITY should be discontinued if signs or symptoms of Raynaud’s phenomenon develop, and patients should be evaluated by a healthcare provider if symptoms do not resolve. Patients with a history of Raynaud’s phenomenon should be monitored for, and informed about the possibility of, worsening or recurrence of signs and symptoms.

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}) 18 times that in humans at the recommended human dose (RHD) for episodic cluster headache (300 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} 29 times that in humans at 300 mg.

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} 16 times that in humans at 300 mg,.

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)].

• Vascular Disorders: Hypertension, Raynaud’s phenomenon [see 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.

Episodic Cluster Headache

EMGALITY was studied for up to 2 months in a placebo-controlled trial in patients with episodic cluster headache (Study 4) [see Pharmacodynamic properties (5.1)]. A total of 106 patients were studied (49 on EMGALITY and 57 on placebo). Of the EMGALITY-treated patients, approximately 84% were male, 88% were white, and the mean age was 47 years at study entry. Two EMGALITY-treated patients discontinued double-blind treatment because of adverse events.

Overall, the safety profile observed in patients with episodic cluster headache treated with EMGALITY 300 mg monthly is consistent with the safety profile in migraine patients.

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 Special warnings and precautions for use (4.4)]

Skin and Subcutaneous Tissue Disorders — Rash.

Vascular Disorders — Hypertension [see Special warnings and precautions for use (4.4)]

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.

Please report adverse drug events to:

The National Pharmacovigilance Centre (NPC):

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 Studies

Episodic Cluster Headache

The efficacy of EMGALITY was evaluated for the treatment of episodic cluster headache in a randomized, 8-week, double-blind, placebo-controlled study (Study 4).

Study 4 (NCT02397473) included adults who met the International Classification of Headache Disorders 3rd edition (beta version) diagnostic criteria for episodic cluster headache and had a maximum of 8 attacks per day, a minimum of one attack every other day, and at least 4 attacks during the prospective 7-day baseline period. All patients were randomized in a 1:1 ratio to receive once-monthly subcutaneous injections of EMGALITY 300 mg or placebo. Patients were allowed to use certain specified acute/abortive cluster headache treatments, including triptans, oxygen, acetaminophen, and NSAIDs during the study.

The study excluded patients on other treatments intended to reduce the frequency of cluster headache attacks; patients with medication overuse headache; patients with ECG abnormalities compatible with an acute cardiovascular event or conduction delay; and patients with a history of myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening. In addition, patients with any history of stroke, intracranial or carotid aneurysm, intracranial hemorrhage, or vasospastic angina; clinical evidence of peripheral vascular disease; or diagnosis of Raynaud’s disease were excluded.

The primary efficacy endpoint for Study 4 was the mean change from baseline in weekly cluster headache attack frequency across Weeks 1 to 3. A secondary endpoint was the percentage of patients who achieved a response (defined as a reduction from baseline of 50% or greater in the weekly cluster headache attack frequency) at Week 3.

In Study 4, a total of 106 patients (88 males, 18 females) ranging in age from 19 to 65 years were randomized and treated. A total of 90 patients completed the 8-week double-blind phase. In the prospective baseline phase, the mean number of weekly cluster headache attacks was 17.5, and was similar across treatment groups.

EMGALITY 300 mg demonstrated statistically significant improvements for efficacy endpoints compared to placebo, as summarized in Table 2.

Table 2: Efficacy Endpoints in Study 4

Figure 1: Mean Change in Weekly Cluster Headache Attack Frequency over Weeks 1 to 3 in Study 4^a

^a   Abbreviations: BL = baseline; LS = least square; SE = standard error.

Figure 2 shows the distribution of the average percent change from baseline in weekly cluster headache attack frequency across Weeks 1 to 3 in bins of 25%, by treatment group, in Study 4.

Figure 2: Distribution of the Average Percent Change from Baseline in Weekly Cluster Headache Attack Frequency over Weeks 1 to 3 in Study 4^a

^a       N = number of intent to treat patients with non-missing average percentage change from baseline in weekly cluster headache attack frequency over weeks 1 to 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-gnlm 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 approximately 27 days.

Specific Populations

Age, Sex, Weight, Race, Ethnicity

The pharmacokinetics of galcanezumab were not affected by age, sex, race, 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})4 times that in humans at the recommended human dose (RHD) for episodic cluster headache (300 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} 18 times that in humans at 300 mg.

·         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

Not applicable for subcutaneous single-dose product.

•     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 syringe after use in a puncture-resistant container.

EMGALITY injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow to slightly brown solution for subcutaneous administration.

The primary container closure system for galcanezumab injection is a 1-mL-long clear glass

syringe barrel with small round flange, 27G special thin wall x 1/2" staked needle, and closed

with a barrier film laminated elastomeric plunger and rigid needle shield.

EMGALITY is supplied as follows:

No special requirements for disposal.

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

PATIENT COUNSELING INFORMATION

Advise the patient to read the approved patient labeling (Patient Information and Instructions for Use).

Instructions on Self-Administration: Provide guidance to patients and/or caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the prefilled pen or prefilled syringe correctly [see Instructions for Use]. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use EMGALITY.

Hypersensitivity Reactions: Inform patients about the signs and symptoms of hypersensitivity reactions and that these reactions can occur with EMGALITY. Advise patients to seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reactions [see Special warnings and precautions for use (4.4)]

Hypertension: Inform patients that hypertension can develop or pre-existing hypertension can worsen with EMGALITY, and that they should contact their healthcare provider if they experience elevation in their blood pressure [see Special warnings and precautions for use (4.4)]

Raynaud's Phenomenon: Inform patients that Raynaud's phenomenon can develop or worsen with EMGALITY. Advise patients to discontinue EMGALITY and contact their healthcare provider if they experience signs or symptoms of Raynaud's phenomenon [see Special warnings and precautions for use (4.4)]