EMGALITY: Package Insert and Label Information

EMGALITY- galcanezumab injection, solution
Eli Lilly and Company

1 INDICATIONS AND USAGE

1.1 Migraine

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

1.2 Episodic Cluster Headache

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

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing for Migraine

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.

2.2 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.

2.3 Important Administration Instructions

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 or single-dose prefilled syringe, including aseptic technique [see How Supplied/Storage and Handling (16.2) and Instructions for Use]:

  • 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 [see Dosage Forms and Strengths (3) and How Supplied/Storage and Handling (16.1)]. 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.
  • Both the prefilled pen and prefilled syringe are single-dose and deliver the entire contents.

3 DOSAGE FORMS AND STRENGTHS

EMGALITY is a sterile clear to opalescent, colorless to slightly yellow to slightly brown solution available as follows:

  • Injection: 120 mg/mL in a single-dose prefilled pen
  • Injection: 120 mg/mL in a single-dose prefilled syringe
  • Injection: 100 mg/mL in a single-dose prefilled syringe

4 CONTRAINDICATIONS

EMGALITY is contraindicated in patients with serious hypersensitivity to galcanezumab-gnlm or to any of the excipients [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 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), Adverse Reactions (6.1), and Patient Counseling Information (17)]. Hypersensitivity reactions can occur days after administration and may be prolonged.

6 ADVERSE REACTIONS

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

  • Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.1)]

6.1 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.

Migraine

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 Clinical Studies (14.1)]. 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.

Adverse Reaction EMGALITY 120 mg Monthly (N=705) % Placebo Monthly (N=1451) %
Injection site reactionsa 18 13

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 Clinical Studies (14.2)]. 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.

6.2 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-gnlm 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 anti-galcanezumab-gnlm antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro ligand-binding 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-gnlm 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 EMGALITY-treated patients developed anti-galcanezumab-gnlm antibodies, most of whom tested positive for neutralizing antibodies.

Although anti-galcanezumab-gnlm 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.

6.3 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) and Warnings and Precautions (5.1)].

Skin and Subcutaneous Tissue Disorders — Rash.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of EMGALITY in pregnant women. Administration of galcanezumab-gnlm 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).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% — 4% and 15% — 20%, respectively. The estimated rate of major birth defects (2.2% — 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

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-gnlm 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 (Cave, ss ) 38 or 18 times that in humans at the recommended human dose (RHD) for migraine (120 mg) or episodic cluster headache (300 mg), respectively. Administration of galcanezumab-gnlm (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 Cave, ss 64 or 29 times that in humans at 120 mg or 300 mg, respectively.

Administration of galcanezumab-gnlm (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 Cave, ss 34 or 16 times that in humans at 120 mg or 300 mg, respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of galcanezumab-gnlm 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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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.

11 DESCRIPTION

Galcanezumab-gnlm is a humanized IgG4 monoclonal antibody specific for calcitonin-gene related peptide (CGRP) ligand. Galcanezumab-gnlm is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. Galcanezumab-gnlm is composed of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains and has an overall molecular weight of approximately 147 kDa.

EMGALITY (galcanezumab-gnlm) injection is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow to slightly brown solution, for subcutaneous use. EMGALITY is supplied in a 1 mL single-dose prefilled pen to deliver 120 mg of galcanezumab-gnlm or a 1 mL single-dose prefilled syringe to deliver 100 mg or 120 mg of galcanezumab-gnlm. Each mL of solution contains 100 mg or 120 mg of galcanezumab-gnlm; L-histidine (0.5 mg); L-histidine hydrochloride monohydrate (1.5 mg); Polysorbate 80 (0.5 mg); Sodium Chloride (8.8 mg); Water for Injection, USP. The pH range is 5.3 — 6.3.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

Galcanezumab-gnlm 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-gnlm, the time to maximum concentration was about 5 days.

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

Distribution

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

Metabolism and Elimination

Galcanezumab-gnlm 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-gnlm 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-gnlm 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-gnlm.

Patients with Renal or Hepatic Impairment

Renal and hepatic impairment are not expected to affect the pharmacokinetics of galcanezumab-gnlm. Population pharmacokinetic analysis of integrated data from the galcanezumab-gnlm clinical studies revealed that creatinine clearance did not affect the pharmacokinetics of galcanezumab-gnlm 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-gnlm.

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

Drug Interaction Studies

P450 Enzymes

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

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