AHFS Class:

• Calcitonin Gene-related Peptide (CGRP) Antagonists 28:32.12

Generic Name(s):

• Eptinezumab

Molecular Formula:

• C₆₃₅₂H₉₈₃₈N₁₆₉₄O₁₉₉₂S₄₆

Eptinezumab-jjmr, a recombinant humanized immunoglobulin G₁ (IgG₁) monoclonal antibody specific for calcitonin gene-related peptide (CGRP) ligand, is an antimigraine agent.1,10,13

Preventive Treatment of Migraine

Eptinezumab-jjmr is used for the preventive treatment of migraine in adults.1,2,3 In clinical studies, eptinezumab prophylaxis substantially reduced monthly migraine days in patients with episodic or chronic migraine when compared with placebo.1,2,3

Efficacy and safety of eptinezumab for the preventive treatment of migraine have been established in 2 randomized, double-blind, placebo-controlled, multicenter studies (PROMISE-I and PROMISE-II]) in adults with a history of migraine according to the International Classification of Headache Disorders, third edition, beta version (ICHD-3 beta) diagnostic criteria.1,2,3 PROMISE-I included patients with episodic migraine (experiencing at least 4 migraine days but not more than 14 headache days per month) and PROMISE-II included patients with chronic migraine (experiencing at least 8 migraine days and 15-26 headache days per month).1,2,3 Both studies evaluated eptinezumab dosages of 100 mg and 300 mg administered by IV infusion once every 3 months.1,2,3 PROMISE-I also evaluated an eptinezumab dosage of 30 mg once every 3 months, which was not included in the efficacy and safety analyses.2 Patients were permitted to use acute headache treatments, including antimigraine agents (e.g., selective serotonin type 1 [5-hydroxytryptamine type 1; 5-HT₁] receptor agonists [triptans], ergot alkaloids) as needed during both studies.1,2,3 In PROMISE-I, regular use of preventive headache treatments (except short-term prophylactic treatment for menstrual migraine) was not permitted.2 In PROMISE-II, patients were allowed to continue stable regimens of preventive antimigraine therapy (with the exception of onabotulinumtoxinA).1,3 Use of opiates or barbiturate (e.g., butalbital)-containing preparations could not exceed 4 days per month.1,2,3 Both studies excluded patients with a history of cardiovascular disease (hypertension, ischemic heart disease), neurological disease, or cerebrovascular disease.1 The primary efficacy endpoint in both studies was the change from baseline in mean monthly migraine days over the first 12 weeks of treatment.1,2,3 Secondary endpoints included the percentages of patients with 50% or greater and 75% or greater reductions from baseline in monthly migraine days over the first 12 weeks of treatment.1,2,3

In PROMISE-I, 665 patients with episodic migraine received eptinezumab 100 mg, eptinezumab 300 mg, or placebo by IV infusion every 3 months for 12 months; over 94% of patients completed the 12-week, double-blind treatment phase.1,2 From a mean baseline of approximately 8.6 migraine days per month, monthly migraine days were reduced by 3.9 or 4.3 days in patients who received eptinezumab 100 or 300 mg, respectively, compared with a reduction of 3.2 days in patients receiving placebo.1,2 Reductions in monthly migraine days were evident within the first month of eptinezumab treatment and were sustained throughout 6 months of treatment.1,2 Substantially greater proportions of patients receiving either dosage of eptinezumab achieved a 50% or greater reduction in mean migraine days per month compared with placebo recipients, and a greater proportion of patients receiving the 300-mg dosage achieved a 75% or greater reduction in monthly migraine days compared with those receiving placebo.1 Fewer patients receiving either dosage of eptinezumab experienced a migraine on most days during the first 7 days of treatment compared with those receiving placebo.1

In PROMISE-II, 1072 patients with chronic migraine received eptinezumab 100 mg, eptinezumab 300 mg, or placebo by IV infusion every 3 months for 6 months; over 97% of patients completed the 12-week, double-blind treatment phase.1,3 From a mean baseline of approximately 16.1 migraine days per month, monthly migraine days were reduced by 7.7 or 8.2 days in patients who received eptinezumab 100 or 300 mg, respectively, compared with a reduction of 5.6 days in patients receiving placebo.1,3 Reductions in monthly migraine days were evident within the first month of eptinezumab treatment and were sustained through 6 months of treatment.1 Substantially greater proportions of patients receiving either dosage of eptinezumab achieved a 50% or greater and 75% or greater reduction in mean migraine days per month compared with placebo recipients.1,3 In addition, fewer patients receiving either dosage of eptinezumab experienced a migraine on individual days within the first 7 days of treatment compared with those receiving placebo.1

Clinical Perspective

The American Headache Society (AHS) has published expert consensus statements on integrating new migraine treatments into clinical practice.12,23 AHS states that eptinezumab and other anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies offer a number of advantages over some oral migraine preventive therapies, including no need for dosage escalation, rapid onset of therapeutic activity (within days to weeks), demonstrated efficacy after failure of prior preventive treatments or in combination with oral preventive treatments, minimal risk of adverse drug interactions, and favorable overall tolerability profiles.12,23 However, the potential benefit of using newer therapies such as the anti-CGRP monoclonal antibodies over established therapies should be considered on an individual basis; in some cases, a combination of newer and older treatments as well as complex or nontraditional approaches may be required.23 AHS has established a criteria for initiating treatment with anti-CGRP monoclonal antibodies based on a balance of cost-effective considerations and access to care; according to this criteria, use of anti-CGRP monoclonal antibodies may be appropriate when patients with migraine are unable to tolerate and/or have an inadequate response to an 8-week trial of at least 2 oral preventive therapies (e.g., topiramate, valproate, β-adrenergic blocking agents, tricyclic antidepressants, selective serotonin- and norepinephrine-reuptake inhibitors).12,23

Similar to other commercially available antimigraine agents, eptinezumab is unlikely to achieve complete migraine freedom, but substantial reductions in migraine frequency were observed in controlled clinical trials.1,2,3,4

Administration

Eptinezumab-jjmr is administered only by IV infusion.1 The drug should not be administered by rapid IV injection (e.g., IV push or bolus).1

Eptinezumab-jjmr is commercially available as an injection concentrate containing 100 mg/mL in single-dose vials that must be diluted prior to IV infusion.1

Single-dose vials of eptinezumab injection concentrate should be stored at 2-8°C and in the original carton to protect the drug from light until time of use.1 The vials should not be frozen or shaken.1

Eptinezumab should not be mixed with or administered through the same IV infusion set with other drugs.1 Diluted solutions of the drug should be administered through a separate IV line using a 0.2- or 0.22-µm inline or add-on sterile filter.1 After the infusion is complete, the IV line should be flushed with 20 mL of 0.9% sodium chloride injection.1

Dilution

Prior to IV infusion, commercially available eptinezumab-jjmr injection concentrate must be diluted using proper aseptic technique.1

The injection concentrate and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration.1 The injection concentrate should be clear or slightly opalescent and colorless to brownish-yellow; the drug should be discarded if the solution is cloudy or discolored, or if visible particles are present.1

To prepare a 100-mg dose, 1 mL of eptinezumab injection concentrate should be withdrawn from a single-dose vial (containing 100 mg/mL of eptinezumab) using a sterile needle and syringe and added to a polyvinyl chloride (PVC), polyethylene, or polyolefin infusion bag containing 100 mL of 0.9% sodium chloride injection.1

To prepare a 300-mg dose, a total of 3 mL of eptinezumab injection concentrate should be withdrawn from 3 single-dose vials (containing 100 mg/mL of eptinezumab) using a sterile needle and syringe and added to a polyvinyl chloride (PVC), polyethylene, or polyolefin infusion bag containing 100 mL of 0.9% sodium chloride injection.1

The diluted solution should be mixed completely by gentle inversion and should not be shaken.1 Diluted solutions of eptinezumab must be administered by IV infusion within 8 hours after preparation.1 If the infusion is not administered immediately, the diluted solution should be stored at room temperature (20-25°C).1 The diluted infusion solution should not be frozen.1

Single-dose vials of eptinezumab injection concentrate contain no preservatives and are intended for single use only; any unused portion remaining in the vial should be discarded.1

Rate of Administration

IV infusions of eptinezumab should be given over approximately 30 minutes.1

Dosage

Preventive Treatment of Migraine

For the preventive treatment of migraine in adults, the recommended dosage of eptinezumab-jjmr is 100 mg by IV infusion every 3 months.1 A higher dosage of 300 mg by IV infusion every 3 months may be considered in some patients.1 There does not appear to be a need for dosage titration with eptinezumab; therapy may be initiated with either the 100- or 300-mg dose.12

The risk of adverse drug interactions with eptinezumab appears to be minimal.1,4,12 When initiating therapy with eptinezumab or another anti-calcitonin gene-related peptide (CGRP) monoclonal antibody in a patient who is already receiving a preventive treatment for migraine, the American Headache Society (AHS) recommends adding the anti-CGRP monoclonal antibody to the existing antimigraine regimen and not making other changes until the clinical efficacy of the anti-CGRP monoclonal antibody is determined.12

Clinical experience with anti-CGRP monoclonal antibody therapy indicates that some patients who do not experience a response to anti-CGRP monoclonal antibody therapy following the first dose may respond within 4 weeks after the second dose or within 4-8 weeks after the third dose.12 Therefore, the AHS recommends assessing the clinical efficacy of eptinezumab and other anti-CGRP monoclonal antibodies that are administered every 3 months (e.g., fremanezumab) 6 months after initiating treatment and continuing therapy only if treatment benefits have been observed with the drug by that time.12

Special Populations

The manufacturer makes no specific dosage recommendations for geriatric patients or patients with hepatic or renal impairment.1

Contraindications

• Serious hypersensitivity to eptinezumab or to any excipients in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including angioedema, urticaria, facial flushing, and rash, have been reported in patients receiving eptinezumab during clinical trials.1 Most of the reactions reported to date occurred during IV infusion of the drug and were not serious, but often led to discontinuance of therapy or required treatment.1 However, serious hypersensitivity reactions may occur.1

If a hypersensitivity reaction occurs, discontinuance of eptinezumab should be considered and appropriate therapy initiated.1

The manufacturer states that the vial stoppers of eptinezumab-jjmr vials are not made with natural rubber latex.1

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with eptinezumab therapy.1 Immunogenicity has been evaluated in 2 placebo-controlled studies (PROMISE-I and PROMISE-II) in patients receiving eptinezumab (100 or 300 mg IV every 3 months).1 In a study of up to 56 weeks' duration, anti-eptinezumab antibodies were detected in 92 of 447 patients (20.6%) who received the drug and antibodies with neutralizing activity were detected in 38 of the 92 patients (41.3%).1 In a study of up to 32 weeks' duration, anti-eptinezumab antibodies were detected in 129 of 706 (18.3%) of patients and antibodies with neutralizing activity were detected in 45 of the 129 patients (34.9%).1 In an open-label study with 84 weeks of treatment, anti-eptinezumab antibodies were detected in 23 of 128 patients (18%) receiving eptinezumab, and 9 of the 23 patients (39%) developed antibodies with neutralizing activity.1 Although available data do not demonstrate an effect of anti-eptinezumab antibody development, including neutralizing antibodies, on the safety or efficacy of eptinezumab, the data currently are too limited to make definitive conclusions.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risk associated with the use of eptinezumab in pregnant women.1 In animal studies, no adverse developmental effects were observed following IV administration of eptinezumab throughout the period of organogenesis in rabbits and rats or throughout pregnancy and lactation in rats at systemic exposures greater than those expected clinically.1

The estimated rate of major birth defects and miscarriage among deliveries to women with migraine (2.2-2.9 and 17%, respectively) are similar to rates reported in women without migraine.1 Clinicians should be aware that published data suggest that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.1

Lactation

It is not known whether eptinezumab is distributed into human milk.1 The effects of the drug on breast-fed infants or on milk production also are unknown.1 The manufacturer states that the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for eptinezumab and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Pediatric Use

The manufacturer states that the safety and efficacy of eptinezumab have not been established in pediatric patients.1

Pending further clinical experience with the use of anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies in pediatric patients, the Pediatric and Adolescent Headache special interest group of the American Headache Society (AHS) recommends that anti-CGRP monoclonal antibodies should be considered mainly for use in postpubertal adolescents† with relatively frequent migraines (i.e., 8 or more headache days per month) who have moderate to severe disability associated with migraine (e.g., PedMIDAS score of 30 or more) and in whom at least 2 preventive therapies (including pharmacologic and nonpharmacologic therapies and dietary supplements) have failed.11 For younger pediatric patients† with severe chronic migraine that is refractory to multiple preventive therapies, these experts recommend that anti-CGRP monoclonal antibodies be considered only in carefully selected patients with close monitoring (e.g., pubertal status, bone health, linear growth, weight, body mass index [BMI], infectious complications).11

Geriatric Use

Clinical trials of eptinezumab did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

Hepatic impairment is not expected to substantially affect the pharmacokinetics of eptinezumab.1 Formal pharmacokinetic studies of eptinezumab have not been conducted in patients with hepatic impairment.1 Population pharmacokinetic analysis from clinical studies with the drug did not reveal a difference in the pharmacokinetics of eptinezumab in patients with hepatic impairment compared with those with normal hepatic function.1

Renal Impairment

Renal impairment is not expected to substantially affect the pharmacokinetics of eptinezumab.1 Formal pharmacokinetic studies of eptinezumab have not been conducted in patients with renal impairment.1 Population pharmacokinetic analysis from clinical studies with the drug did not reveal a difference in the pharmacokinetics of eptinezumab in patients with renal impairment compared with those with normal renal function.1

Common Adverse Effects

Adverse reactions reported in ≥2% of patients receiving eptinezumab-jjmr for preventive treatment of migraine in clinical studies and ≥2% more frequently than with placebo include nasopharyngitis and hypersensitivity reactions.1

The risk of clinically important drug interactions with eptinezumab appears to be minimal.1,4,12 Eptinezumab is not metabolized by cytochrome P-450 (CYP) enzymes.1 In addition, eptinezumab, a monoclonal antibody, is unlikely to affect drug-metabolizing enzymes or drug transport systems.4 Therefore, pharmacokinetic interactions with drugs affecting or metabolized by CYP enzymes or substrates of various drug transport systems are not expected.1,4

Sumatriptan

Concomitant administration of eptinezumab-jjmr (single 300-mg IV infusion over approximately 1 hour) and sumatriptan (single 6-mg subcutaneous dose) did not substantially affect the pharmacokinetics of either drug.1

Description

Eptinezumab is a humanized immunoglobulin G₁ (IgG₁) monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) ligand and blocks its binding with the CGRP receptor.1,9,10,13 The drug is produced using recombinant DNA technology in Pichia pastoris yeast cells.1,13

CGRP is a potent vasodilator and pain-signaling neuropeptide that has been associated with migraine pathophysiology.7,9,10,18 CGRP and its receptors are located at sites that are relevant to migraine development such as the trigeminal neurons and are also widely distributed throughout the central and peripheral nervous systems as well as in nonneuronal tissues throughout the body.7,9,10,11,18

Increased serum CGRP concentrations have been observed in individuals during acute migraine attacks (with or without aura) and IV infusion of CGRP has been shown to induce migraines in patients with a history of migraines.7,9,10,18 Eptinezumab binds to the CGRP ligand and blocks its interaction with the CGRP receptor.1,9,10,13 Because of their large molecular size, however, anti-CGRP monoclonal antibodies are considered unlikely to cross the blood-brain barrier in substantial amounts and probably antagonize CGRP function peripherally rather than centrally within the nervous system.11,13,18

Eptinezumab exhibits linear and dose-proportional pharmacokinetics with IV dosages of 100-300 mg.1 Peak plasma concentrations occur at the end of the IV infusion.4 Following IV administration every 3 months, the mean accumulation ratio is 1.2; steady-state plasma concentrations of eptinezumab are attained after the first dose.1,4 Metabolism of eptinezumab is expected to be mediated by proteolytic degradation into small peptides and amino acids.1 The elimination half-life of the drug is approximately 27 days.1

Age, sex, race, body weight, and body mass index (BMI) do not have clinically important effects on the pharmacokinetics of eptinezumab.1,4

Advice to Patients

• Importance of advising patients to read the manufacturer's patient information.1
• Importance of informing patients that hypersensitivity reactions, including angioedema, urticaria, facial flushing, and rash, may occur.1 Patients should immediately contact their healthcare provider if signs or symptoms of a hypersensitivity reaction occur.1
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Lundbeck Seattle BioPharmaceuticals, Inc. Vyepti^® (eptinezumab-jjmr) injection prescribing information. Bothell, WA; 2020 Feb.

2. Ashina M, Saper J, Cady R et al. Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia . 2020; 40:241-254. [PubMedCentral][PubMed 32075406]

3. Lipton RB, Goadsby PJ, Smith J et al. Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology . 2020; 94:e1365-e1377. [PubMedCentral][PubMed 32209650]

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761119Orig1s000: Clinical pharmacology review(s). From FDA website. [Web]

7. Hargreaves R, Olesen J. Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class. Headache . 2019; 59:951-970. [PubMed 31020659]

9. Edvinsson L, Haanes KA, Warfvinge K et al. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol . 2018; 14:338-350. [PubMed 29691490]

10. Schuster NM, Rapoport AM. Calcitonin gene-related peptide-targeted therapies for migraine and cluster headache: A review. Clin Neuropharmacol . 2017 Jul/Aug; 40:169-174. [PubMed 28644160]

11. Szperka CL, VanderPluym J, Orr SL et al. Recommendations on the use of anti-CGRP monoclonal antibodies in children and adolescents. Headache . 2018; 58:1658-69. [PubMed 30324723]

12. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache . 2019; 59:1-18. [PubMed 30536394]

13. Raffaelli B, Reuter U. The biology of monoclonal antibodies: focus on calcitonin gene-related peptide for prophylactic migraine therapy. Neurotherapeutics . 2018; 15:324-35. [PubMed 29616494]

18. Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache . 2017; 57:47-55. [PubMed 28485848]

23. Ailani J, Burch RC, Robbins MS et al. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache . 2021; 61:1021-1039. [PubMed 34160823]