Galcanezumab

EMGALITY ® is a calcitonin-gene related peptide antagonist indicated in adults for the: preventive treatment of migraine. ( 1.1 ) treatment of episodic cluster headache. ( 1.2 )

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.

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 Injection: 120 mg/mL solution in a single-dose prefilled pen ( 3 ) Injection: 120 mg/mL solution in a single-dose prefilled syringe ( 3 ) Injection: 100 mg/mL solution in a single-dose prefilled syringe ( 3 )

EMGALITY is contraindicated in patients with serious hypersensitivity to galcanezumab-gnlm or to any of the excipients [see Warnings and Precautions ( 5.1 )] . EMGALITY is contraindicated in patients with serious hypersensitivity to galcanezumab-gnlm or to any of the excipients. ( 4 )

Hypersensitivity Reactions: If a serious hypersensitivity reaction occurs, discontinue administration of EMGALITY and initiate appropriate therapy. Hypersensitivity reactions can occur days after administration, and may be prolonged. ( 5.1 ) Constipation with Serious Complications: Serious complications of constipation may occur. ( 5.2 ) Hypertension: New-onset or worsening of pre-existing hypertension may occur. ( 5.3 ) Raynaud's Phenomenon: New-onset or worsening of pre-existing Raynaud's phenomenon may occur. ( 5.4 )

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.

5.2 Constipation with Serious Complications Constipation with serious complications has been reported following the use of monoclonal antibody CGRP antagonists, including EMGALITY, in the postmarketing setting. There were cases with monoclonal antibody CGRP antagonists that required hospitalization, including cases where surgery was necessary. In a majority of these cases, the onset of constipation was reported after the first dose; however, patients have also presented with constipation later on in treatment. The monoclonal antibody CGRP antagonist was discontinued in many of the reported cases of constipation with serious complications. Monitor patients treated with EMGALITY for severe constipation and manage as clinically appropriate. The concurrent use of medications that reduce gastrointestinal motility may increase the risk for more severe constipation and the potential for constipation-related complications.

5.3 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.

5.4 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.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] Constipation with Serious Complications [see Warnings and Precautions ( 5.2 )] Hypertension [see Warnings and Precautions ( 5.3 )] Raynaud's Phenomenon [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (incidence ≥2% and at least 2% greater than placebo) in EMGALITY clinical studies were injection site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 reactions a 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. Gastrointestinal Disorders — Constipation [see Warnings and Precautions ( 5.2 )] Immune System Disorders — Anaphylaxis, angioedema [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] Skin and Subcutaneous Tissue Disorders — Rash Vascular Disorders — Hypertension [see Warnings and Precautions ( 5.3 )] , Raynaud's Phenomenon [see Warnings and Precautions ( 5.4 )]

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EMGALITY during pregnancy. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-833-464-4724 or by contacting the company at www.migrainepregnancyregistry.com. 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 (C ave, 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 C ave, 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 C ave, 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.

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