Reimbursement Recommendation

Intranasal epinephrine (Neffy)

Indication: Emergency treatment of allergic reactions (anaphylaxis) due to insect stings or bites, foods, medicinal products and other allergens as well as idiopathic or exercise induced anaphylaxis in adult and pediatric patients who weigh 30 kg or greater

Sponsor: ALK-Abelló Pharmaceuticals Inc.

Final recommendation: Reimburse with conditions

What Is the Reimbursement Recommendation for Neffy?

Canada’s Drug Agency (CDA-AMC) recommends that Neffy be reimbursed by public drug plans for the emergency treatment of allergic reactions (anaphylaxis) due to insect stings or bites, foods, medicinal products, and other allergens, as well as idiopathic or exercise-induced anaphylaxis, in adult and pediatric patients who weigh 30 kg or greater, if certain conditions are met.

Why Did CDA-AMC Recommend Reimbursement?

Evidence from 5 studies (the EPI-15, EPI-16, EPI-17, EPI-18, and EPI-10 studies) showed that treatment with Neffy achieved plasma epinephrine concentrations and time to peak within the range observed with EpiPen and intramuscular (IM) epinephrine, with corresponding transient increases in blood pressure and heart rate in adults and children with type I allergies, adults with allergic rhinitis, and healthy adults. However, none of the studies evaluated Neffy in patients experiencing anaphylaxis or assessed whether Neffy improved outcomes that are important to patients, including symptom resolution, avoidance of hospitalization, and prevention of symptoms suddenly coming back. As a result, it is not completely certain if Neffy provides similar benefits and harms to EpiPen when used to treat anaphylaxis. Nevertheless, there is enough physiological evidence to expect that the effects will be comparable.

Based on the observed pharmacological profile and assumption of similar effects, the Canadian Drug Expert Committee (CDEC) determined that Neffy demonstrates acceptable clinical value versus EpiPen or IM epinephrine for the treatment of allergic reactions including anaphylaxis in adults and pediatric patients who weigh 30 kg or greater. This determination was sufficient for CDEC to recommend that Neffy be reimbursed. Given that Neffy is expected to be an alternative treatment option to EpiPen, acceptable clinical value refers to at least comparable value versus EpiPen.

Which Patients Are Eligible for Coverage?

Neffy should only be covered for adults and pediatric patients who weigh 30 kg or greater with severe type I allergic reactions, including anaphylaxis. Eligibility should be broadly the same as for EpiPen.

What Are the Conditions for Reimbursement?

Neffy should be reimbursed based on the criteria used by each public drug plan for initiation, renewal, discontinuation, and prescribing of epinephrine autoinjectors, and if the drug program cost of Neffy does not exceed the drug program cost of the least costly epinephrine autoinjector.

Review Background

• Disease background: Type I allergic reactions include conditions such as asthma, rhinitis, conjunctivitis, dermatitis, anaphylaxis, and allergies to food or drugs. Anaphylaxis is the most serious complication of type I allergic reactions and can affect many organ systems in a life-threatening way. Anaphylaxis affects up to 1 in 20 people worldwide, and in Canada, emergency visits for anaphylaxis nearly doubled between 2006 and 2014.

• Indication and reimbursement request: Intranasal epinephrine (IE) (Neffy) has undergone Health Canada review for emergency treatment of type I allergic reactions, including anaphylaxis, in adult and pediatric patients who weigh 30 kg or greater. The sponsor is seeking reimbursement as per the proposed Health Canada indication.

• Drug under review: IE is an adrenergic agonist that acts on both alpha- and beta-adrenergic receptors to counteract the pathophysiological processes of anaphylaxis. It is available as a nasal spray for intranasal (IN) administration, and the dosage recommended in the product monograph is 2 mg administered into 1 nostril. In the absence of clinical improvement or if symptoms worsen after the initial treatment, a second dose may be administered in the same nostril with a second nasal spray, starting 5 minutes after the first dose.

• Treatment costs: At the submitted price of $327.42 per 2-pack unit, the annual cost of IE is expected to be $179.27 per patient, based on the Health Canada–recommended dosage and assumptions about device shelf life, number of anaphylactic episodes, units dispensed per refill, and device utilization during anaphylactic episodes.

• Tailored review process: This application was reviewed through the tailored review process. When submitting an application for a tailored review, the sponsor does not claim added clinical benefit with the drug under review versus the most appropriate comparators. A subcommittee of the relevant expert committee deliberates on and, when there is unanimous agreement, issues the recommendation for tailored review applications. The focus of the subcommittee deliberations is on whether the submitted evidence supports that the drug under review demonstrates comparable clinical benefit and harms to 1 or more appropriate comparators, and whether the evidence supports the drug being reimbursed in accordance with the existing reimbursement criteria for the most appropriate comparators.

Highlights of Input From Interested Parties

The patient group (Food Allergy Canada) noted the following regarding impacts of the disease, unmet needs, and important outcomes:

• Beyond the immediate health risks, anaphylaxis imposes continuous vigilance, constant risk assessment (particularly for children), lifestyle restrictions, and emotional and social burdens for patients and their families.

• Treatment of anaphylaxis is suboptimal, as epinephrine is underused: only 21% of children and 7% of adults worldwide receive epinephrine before arriving at the hospital.

• Current experience with EpiPen highlights barriers including needle phobia, bulkiness, temperature sensitivity, expiry concerns, and social stigma, which may complicate and delay epinephrine administration during emergencies.

• The most important treatment goals for patients with type I allergic reactions including anaphylaxis are to ensure timely recognition and treatment of anaphylaxis and to guarantee reliable access to and administration of epinephrine.

• Patients noted that reliable epinephrine options that are needle-free, reliable, and easy-to-use options that can withstand extreme temperatures and can fit in a pocket or wallet are needed.

The clinician group (the Canadian Society of Allergy and Clinical Immunology) and a clinical expert consulted by Canada’s Drug Agency (CDA-AMC) noted the following regarding unmet needs arising from the disease and place in therapy for the drug under review:

• Patients are reluctant to use EpiPen given its invasive administration, the inconvenience of carrying it, the fact that it is temperature sensitive, the potential for accidental digital injection, lacerations in children due to “fighting” administration, and its relatively short shelf life.

• The clinician group and the clinical expert noted that IE could address many of the challenges associated with EpiPen.

• The clinician group and the clinical expert input suggested that IE will be an alternative to injectable epinephrine for patients at risk of anaphylaxis. IE is expected to be used as a first-line option, or to switch from EpiPen due to its needle-free, easy-to-use design.

The participating public drug programs raised potential implementation issues related to considerations for initiation, renewal, discontinuation, and prescribing of therapy, as well as generalizability of trial populations to broader populations.

Recommendation

As per the procedures for tailored reviews, a subcommittee of the Canadian Drug Expert Committee (CDEC) initially reviewed this submission but could not come to a unanimous agreement on a recommendation. Consequently, the review was deferred to the full CDEC committee.

With a vote of 11 to 5, CDEC recommends that IE be reimbursed for the emergency treatment of allergic reactions (anaphylaxis) due to insect stings or bites, foods, medicinal products, and other allergens, as well as idiopathic or exercise-induced anaphylaxis, in adult and pediatric patients who weigh 30 kg or greater, only if the conditions listed in Table 1 are met.

Table 1: Reimbursement Conditions and Reasons

CDA-AMC = Canada’s Drug Agency; IE = intranasal epinephrine; IM = intramuscular.

Rationale for the Recommendation

Clinical Value

CDEC deliberated on whether the evidence submitted by the sponsor supported IE demonstrating comparable clinical benefit and harms to 1 or more appropriate comparators in patients with type I allergic reactions, including anaphylaxis. Based on the totality of the presented clinical evidence, CDEC concluded that IE is expected to provide comparable clinical benefits and harms relative to EpiPen and therefore has acceptable clinical value.

Evidence from 5 trials (the EPI-15 [N = 59], EPI-16 [N = 36], EPI-17 [N = 45], EPI-18 [N = 43], and EPI-10 [N = 16] studies) showed that treatment with IE resulted in epinephrine delivery, as demonstrated by pharmacokinetic (PK) and pharmacodynamic (PD) profiles that were descriptively comparable with those observed following IM epinephrine or EpiPen in healthy volunteers or study participants at risk of type I allergic reactions, including anaphylaxis. In the EPI-16, EPI-17, and EPI-18 studies, PK and PD responses following IE administration were similar to or greater than those observed with IM epinephrine, both under normal and induced rhinitis conditions, and with staff-administered injection or self-administration. Direct comparison with EpiPen was conducted only in the EPI-15 study, in which EpiPen showed a faster rise in plasma drug concentration (time of maximum plasma concentration) compared with IE and IM epinephrine, but this did not translate into faster PD effects. The PK and PD profiles in the pediatric study (the EPI-10 study) were similar to those observed in the adult studies; however, the pediatric data should be considered exploratory and noncomparative, given the small sample size and lack of a comparator.

CDEC concluded that IE was associated with a higher proportion of nasal discomfort, headache, and throat irritation than IM epinephrine. However, no serious adverse events, deaths, or treatment-related withdrawals were reported, and the observed adverse events were generally mild and consistent with the known safety profile of epinephrine administered intranasally.

CDEC acknowledged that the submitted evidence consisted primarily of small, short-duration phase I PK and PD studies conducted under controlled conditions, in participants who were not experiencing severe allergy symptoms. Patient-important outcomes, including symptom resolution, avoidance of hospitalization, and prevention of biphasic reactions, were not directly assessed, and evidence evaluating usability (cognitive, behavioural, and functional) during anaphylaxis or under real-world conditions was not available. CDEC also noted that no prespecified thresholds for clinically meaningful PK or PD differences or formal statistical analyses were available. During the reconsideration meeting, CDEC considered the sponsor's rationale regarding the accepted regulatory framework for epinephrine delivery products and the ethical and practical challenges associated with conducting comparative efficacy studies during anaphylaxis. CDEC acknowledged that PK and PD results were generally situated within the efficacy bracket delimited by EpiPen and IM epinephrine. Taking the totality of the submitted evidence into account, including the consistency of the PK and PD findings across studies, the established pharmacology of epinephrine, and acceptance of PK and PD evidence for epinephrine delivery products, CDEC concluded that the bioavailability and physiological effects of IE are sufficiently similar to those of EpiPen and IM epinephrine to support the conclusion of comparable clinical value.

Further information on the CDEC discussion around clinical value is provided in the Summary of Deliberation section.

Developing the Recommendation

The determination of acceptable clinical value was sufficient for CDEC to recommend reimbursement of IE.

Because CDEC recommended that IE be reimbursed, CDEC also deliberated on whether reimbursement conditions should be added to address important economic considerations, health system impacts, or social and ethical considerations, or to ensure clinical value is realized. The resulting reimbursement conditions, with accompanying reasons and implementation guidance, are stated in Table 1.

Summary of Deliberation

CDEC considered all domains of value of the deliberative framework before developing its recommendation: clinical value, unmet clinical need, distinct social and ethical considerations, economic considerations, and impacts on health systems. For further information on the domains of value, refer to Expert Committee Deliberation at Canada’s Drug Agency.

CDEC considered the following key discussion points, organized by the 5 domains of value.

The sponsor requested reconsideration of the initial draft recommendation not to reimburse IE for the emergency treatment of allergic reactions (anaphylaxis) due to insect stings or bites, foods, medicinal products, and other allergens, as well as idiopathic or exercise-induced anaphylaxis, in adults and pediatric patients weighing 30 kg or greater. The sponsor's request raised 3 issues related to the interpretation of the PK and PD evidence, the role of IM epinephrine in establishing comparable clinical value, and the consideration of unmet clinical need and distinct social and ethical factors during committee deliberations. These issues were discussed by CDEC.

Clinical Value

• Appropriate comparators: During the initial and reconsideration meetings, CDEC noted that only 1 of the included trials compared IE with EpiPen. All studies compared IE with IM epinephrine except the pediatric study, which had no comparator. CDEC noted that IM epinephrine is administered by health care professionals in the hospital setting and does not reflect real-world circumstances in which patients or caregivers typically self-administer epinephrine. During the reconsideration meeting, CDEC acknowledged that IM epinephrine injection is a reference clinical intervention and can be considered a comparator for use in the framework accepted by regulators. In the latter, IM epinephrine and EpiPen act as boundaries in a bracketing approach whose purpose is to establish whether IE efficacy falls within a range of acceptable PK and PD values.

• Efficacy versus EpiPen: During the initial and reconsideration meetings, CDEC noted that evidence on the comparative efficacy of IE came from 5 phase I PK and PD studies (the EPI-15, EPI-16, EPI-17, EPI-18, and EPI-10 studies), none of which enrolled patients experiencing anaphylaxis or type I allergic reactions for which epinephrine is typically indicated. Across the included studies, IE demonstrated PK and PD profiles broadly comparable to IM epinephrine. In the EPI-16, EPI-17, and EPI-18 studies, PK and PD responses following IE were comparable to or greater than those of IM epinephrine under normal and induced rhinitis conditions, including with self-administration. Direct comparison with EpiPen only occurred in the EPI-15 study, in which IE produced PK (maximum plasma concentration, time of maximum plasma concentration, area under the curve) and PD (systolic blood pressure, diastolic blood pressure, and heart rate) responses that were within or above the range observed with EpiPen. EpiPen reached peak concentration faster without translating into faster PD effects. The pediatric data (from the EPI-10 study) were exploratory, noncomparative, and limited by the small sample size (N = 16). Because only 1 study included EpiPen, conclusions about comparability relied on extrapolation from IM epinephrine data, introducing uncertainty, particularly given the absence of prespecified thresholds for meaningful PK and PD differences and the lack of statistical analyses.

• Clinical importance of treatment effects: During the initial committee meeting, CDEC discussed the uncertainty regarding whether the observed PK and PD findings translated into clinically meaningful benefits for patients, who prioritize reliable and rapid symptom resolution, avoidance of hospitalization, and prevention of biphasic reactions during anaphylaxis. During the reconsideration meeting, CDEC considered the sponsor's request that the evidentiary standard applied was inconsistent with the historical development and regulatory evaluation of epinephrine products, and acknowledged that PK and PD evidence has been accepted by regulatory agencies for epinephrine delivery products because randomized efficacy studies in anaphylaxis are difficult to conduct. Taking the totality of the submitted evidence into account, including the established pharmacology of epinephrine, the consistency of the PK and PD findings across studies, and the accepted regulatory framework for epinephrine products, CDEC concluded that the PK and PD profile of IE was comparable to that of EpiPen and IM epinephrine to support the expectation of comparable clinical value.

• Certainty of the evidence: During the initial and reconsideration meetings, CDEC concluded that the certainty of the evidence was very low. All studies were phase I PK or PD trials with no evaluation of patient- and clinician-identified important outcomes for patients experiencing anaphylaxis or type I allergic reactions for which epinephrine is typically indicated. There was substantial interindividual variability in PK and PD parameters, and no prespecified thresholds for clinically meaningful differences or formal statistical analyses were provided. Generalizability was limited by the exclusion of important patient groups, including younger children, individuals with severe asthma or cardiovascular disease, and those receiving treatment with beta blockers. In addition, the median weight of the 16 participants in the EPI-10 study was ██ kg, which limits the generalizability of evidence to all individuals weighing more than 30 kg.

• Safety precautions: CDEC acknowledged that the PK and PD evidence is considered sufficient within the regulatory framework to support the expected efficacy of IE. However, given the limitations of the submitted studies, including the short duration and sample size, the safety of IE compared to EpiPen and IM epinephrine is uncertain. In addition, patients with nasal passage abnormalities that could interfere with nasal spray administration, severe or uncontrolled asthma, or cardiovascular comorbidities or abnormal electrocardiograms, as well as those receiving beta-blocker therapy, were excluded from the submitted studies. Therefore, there remains uncertainty regarding the generalizability of the available efficacy and safety evidence of IE to these populations, and caution should be advised when prescribing IE to these patients.

• Additional clinical considerations: During the initial and reconsideration meetings, CDEC noted that IE was associated with a higher proportion of adverse events than comparators, most commonly nasal discomfort, headache, and throat irritation. The clinical expert consulted for the review noted that harms such as mild nasal irritation would be a reasonable trade-off if a needle-free formulation improved timely administration of epinephrine. This was supported by the input from the patient group, which emphasized that patients prefer transient nasal irritation to the risks associated with IM epinephrine. Although no deaths or serious adverse events were reported, the short follow-up duration (██ █████) limited the ability to detect rare or delayed harms. All studies were conducted under controlled conditions and did not evaluate usability during type I allergic reactions, including anaphylaxis, which was considered important by patients, or in individuals with nasal abnormalities or relevant comorbidities.

• Addressing gaps: During the initial committee meetings, CDEC identified the absence of evidence evaluating important patient outcomes during type I allergic reactions, including anaphylaxis, as an important evidence gap. During the reconsideration meeting, CDEC considered the sponsor's rationale regarding the accepted evidentiary framework for epinephrine products and the ethical and practical challenges associated with conducting comparative efficacy studies during anaphylaxis. CDEC accepted the submitted evidence as sufficient for a positive recommendation under the tailored review framework. However, the committee acknowledged that uncertainty remained regarding patient-important outcomes, and noted that additional evidence evaluating IE under conditions that closely reflect anaphylaxis, including controlled challenge settings or real-world use, could further increase certainty regarding outcomes such as symptom resolution and biphasic reactions. CDEC also considered patient group input that real-world evidence could help determine whether the anticipated advantages of IE translate into increased carriage and administration of epinephrine when needed and improved outcomes.

• Clinical value: Based on the totality of the submitted evidence, CDEC determined that there is some uncertainty as to whether IE provides clinical value comparable to EpiPen, given that patient-important outcomes were not assessed. However, CDEC noted that, in view of the constraints associated with evaluating clinical outcomes during anaphylaxis, the available PK and PD evidence — together with the established pharmacology of epinephrine — was sufficient to support the expectation that IE would provide clinical value comparable to IM epinephrine and EpiPen.

Unmet Clinical Need

• Unmet need: In the reconsideration meeting, CDEC discussed the sponsor’s request to further consider unmet clinical need and distinct social and ethical factors during committee deliberations. However, in product variation tailored reviews, the deliberation is focused on comparability and not incremental value or unmet need, and thus CDEC did not further deliberate on these aspects.

• Deliberation on significant unmet clinical need: CDEC reviewed the considerations for unmet clinical need. Given that deliberations for tailored reviews have a specific focus, further deliberation on whether there was significant unmet clinical need was not required.

Distinct Social and Ethical Considerations

• Deliberation on significant nonclinical need or health inequity: CDEC reviewed the considerations for unmet nonclinical need and health inequity. CDEC acknowledged the unmet clinical needs and social and ethical issues associated with EpiPen, including needle aversion, stigma, portability issues, limited shelf life, and risk of product shortage. As mentioned previously, deliberations for tailored reviews have a specific focus, and further deliberation on whether the drug under review addresses a significant unmet nonclinical need or health inequity was not required.

Economic Considerations

• Cost of IE versus relevant comparators: Based on the submitted price of $327.42 per 2-pack unit, the annual drug acquisition cost of IE is estimated to be $179.27 per patient. The sponsor derived the annual drug acquisition cost per patient based on assumptions regarding device shelf life, estimated annual number of anaphylactic episodes, units dispensed per refill, probability of device utilization during anaphylactic episodes, and device disposal. Using publicly available list prices for comparators, the annual cost of IE is expected to be higher than the associated annual cost of an epinephrine autoinjector.

• Other considerations: The committee noted that IE could generate additional wastage, given that it is packaged as a 2-pack unit, and that the product monograph recommends that patients always maintain access to 2 units. Specifically, if only 1 unit of IE is used during an episode, patients would still need to refill the prescription to ensure continuous access to a full 2-pack and to ensure adequate coverage in emergency situations. This may result in some patients possessing an additional unit, which may generate more wastage than an epinephrine autoinjector, which can be acquired by unit.

Impacts on Health Systems

• Anticipated budget impact: The sponsor estimated that the budget impact of reimbursing IE for emergency treatment of type I allergic reactions, including anaphylaxis, in adult and pediatric patients who weigh 30 kg or greater will be $460,000 over the first 3 years of reimbursement compared to the amount currently spent on epinephrine autoinjector 0.3 mg, with an estimated expenditure of $12 million on IE over this period. CDA-AMC was unable to provide a more robust estimate owing to a lack of reliable input; however, scenario analyses suggest the budget impact could reach up to $12 million over the first 3 years. The incremental cost to the drug plans will depend on the total eligible patient population, market share, and number of epinephrine autoinjector units dispensed per refill.

Sources of Information Used by the Committee

To make its recommendation, CDEC considered the following information (links to the full documents for the review can be found on the project web page):

• the CDA-AMC review of the clinical and pharmacoeconomic evidence related to IE submitted by the sponsor (refer the Main Report and Supplemental Material document)

• the sponsor’s comments on the draft report and the CDA-AMC responses

• patients' perspectives gathered by 1 patient group, Food Allergy Canada (refer to the Patient and Clinician Group Input document)

• input from 1 clinician group, the Canadian Society of Allergy and Clinical Immunology (refer to the Patient and Clinician Group Input document)

• input from public drug programs that participate in the reimbursement review process (refer to the Supplemental Material document)

• input from 1 clinical expert with expertise in the management of anaphylaxis consulted by CDA-AMC.

Request for Reconsideration

The sponsor filed a request for reconsideration of the draft recommendation for IE for the emergency treatment of allergic reactions (anaphylaxis) due to insect stings or bites, foods, medicinal products and other allergens, as well as idiopathic or exercise-induced anaphylaxis, in adult and pediatric patients who weigh 30 kg or greater. In their request, the sponsor identified the following issues:

• The sponsor stated that the evidentiary standard applied by CDEC was inconsistent with accepted regulatory and scientific practice for epinephrine delivery devices. The sponsor requested that CDEC reconsider its conclusion regarding the comparable clinical value of IE relative to EpiPen, noting that the clinical development program was based on PK and PD evidence developed in consultation with regulatory authorities, and that randomized comparative efficacy studies in anaphylaxis are not considered feasible or necessary.

• The sponsor stated that IM epinephrine is a clinically relevant comparator for establishing the clinical value of IE and that evidence comparing IE with IM epinephrine should not be considered only as extrapolation to EpiPen. The sponsor requested that CDEC recognize IM epinephrine alongside EpiPen as a clinically relevant comparator and reconsider its conclusions regarding the comparable clinical value of IE.

• The sponsor stated that CDEC did not appropriately consider unmet clinical need and distinct social and ethical considerations, including barriers associated with currently available epinephrine autoinjectors that may delay epinephrine administration. The sponsor requested that CDEC explicitly consider these factors when reassessing the clinical value of IE.

In the meeting to discuss the sponsor’s request for reconsideration, CDEC considered the following information:

• information submitted as part of the sponsor’s request for reconsideration

• information from the initial submission related to the issues identified by the sponsor

• feedback from 2 clinical specialists with expertise in diagnosing and treating patients with type I allergic reactions, including anaphylaxis

• feedback on the draft recommendation from 1 patient group (Food Allergy Canada)

• feedback on the draft recommendation from 2 clinician groups (the Canadian Society of Allergy and Clinical Immunology as well as the Children’s Hospital of Eastern Ontario [CHEO] and CHEO Research Institute)

• feedback on the draft recommendation from the public drug programs that participate in the reimbursement review process

• feedback on the draft recommendation from the sponsor.

All feedback received in response to the draft recommendation is available on the CDA-AMC project web page.

CDEC Information

Members of the Committee

Dr. Peter Jamieson (Chair), Dr. Kerry Mansell (Vice-Chair), Sally Bean, Daryl Bell, Dan Dunsky, Dr. Ran Goldman, Dr. Trudy Huyghebaert, Dr. Dennis Ko, Dr. Christine Leong, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Nicholas Myers, Dr. Krishnan Ramanathan, Dr. Marco Solmi, Carla Velastegui, Dr. Edward Xie, and Dr. Peter Zed

A subcommittee composed of 4 CDEC members was convened. None had a conflict of interest that precluded their participation.

Subcommittee meeting date: November 26, 2025

Initial committee meeting date: December 17, 2025

Regrets: Two expert committee members did not attend.

Conflicts of interest: None

Reconsideration meeting date: July 23, 2026

Regrets: None

Conflicts of interest: None