Regulatory Decision Summary for neffy

The purpose of this New Drug Submission was to seek marketing approval for neffy, an epinephrine nasal spray intended for the emergency treatment of anaphylaxis in adults and pediatric patients weighing 30 kg or greater.

The accepted indication is equivalent to that used for comparable epinephrine autoinjector products currently marketed for the treatment of anaphylaxis in Canada.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

neffy nasal spray is a novel needle-free epinephrine product intended for the emergency treatment of anaphylaxis. While epinephrine has been the only recommended first-line treatment for anaphylaxis for several decades, its administration for this purpose has required either intramuscular or subcutaneous injections, or intravenous administration. The only currently approved epinephrine products intended for at-home anaphylaxis treatment in Canada are the epinephrine autoinjectors, administered by thigh muscle injections. The 2 milligram (mg) epinephrine dose for neffy was developed to be equivalent to the commonly used adult and pediatric dose of 0.3 mg epinephrine delivered by the currently approved epinephrine autoinjectors.

As it is not ethically or practically feasible to conduct controlled efficacy studies in patients experiencing anaphylaxis, the sponsor has submitted Phase I clinical studies that investigated the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the neffy nasal spray in comparison to established intramuscular epinephrine anaphylaxis treatments. Only a limited number of Phase I clinical studies, focusing on PK variables, have been conducted for the epinephrine autoinjectors. Their marketing approvals have been based primarily on established clinical practice. No optimal PK characteristics have been demonstrated for any epinephrine product for the treatment of anaphylaxis. As such, rather than using bioequivalence as the basis of approval for neffy, a PK bracketing approach accepted by the United States Food and Drug Administration was used to demonstrate comparability to currently approved epinephrine injection products.

In healthy adults, neffy administration produced PK exposure values at least as high as needle and syringe intramuscular injections of the standard 0.3 mg epinephrine dose. However, patients experiencing anaphylaxis can have nasal symptoms that may affect absorption. These symptoms overlap to some extent with symptoms experienced in allergic rhinitis. In a study of adults experiencing nasal congestion and oedema following induction of allergic rhinitis, plasma epinephrine concentrations were lower compared to intramuscular epinephrine injections beyond approximately 20 minutes post-dose. However, initial epinephrine absorption was rapid with the nasal spray and the systemic exposure over the first half hour was comparable between the different routes of administration. Both clinical and nonclinical testing (in dogs with induced anaphylaxis) indicated that nasal oedema can, in fact, promote epinephrine absorption. Repeat dose neffy administration produced epinephrine plasma concentrations at least equivalent to repeat dose needle and syringe injections in subjects experiencing rhinitis symptoms. The epinephrine exposure values were sustained well beyond the first 20 minutes post-dose in this case. Repeat dosing to the same nostril produced higher sustained epinephrine plasma concentrations, and same side dosing was included as a recommendation in the final labelling of the Instructions for Use for cases where a second dose is needed. Pharmacokinetic modeling and the results of a single pediatric study supported a similar posology between adults and pediatric patients weighing at least 30 kg.

The PD endpoints used as surrogate markers of efficacy were blood pressure (BP) and heart rate (HR). In healthy subjects, both BP and HR increased by magnitudes comparable to or greater than epinephrine autoinjector or needle and syringe intramuscular epinephrine injections over at least the first two hours post-dose. Corresponding to the reduced PK exposure values observed beyond 20 minutes under rhinitis conditions, increases in BP and HR were only observed at early time points following a single dose of neffy under rhinitis conditions. However, these PD responses were more sustained and comparable to intramuscular epinephrine injections following the repeat dose administration of neffy. This supports the appropriateness of the nasal spray, including in cases where a second dose is warranted due to ongoing anaphylaxis symptoms.

No treatment-related serious side effects were observed in any of the clinical studies for neffy. Unique side effects with neffy included those related to the use of a nasal spray (e.g. nasal discomfort, runny nose) and were transient and mild. Labelled precautions for the use of neffy are in line with those of the epinephrine autoinjectors. These include, for example, recommendations of cautious use for patients with heart disease or narrow-angle glaucoma. However, as with the epinephrine autoinjectors, there are no absolute contraindications that would prevent the use of neffy in a life-threatening allergic situation.

To facilitate the absorption of epinephrine using a nasal spray, the neffy formulation includes a permeation enhancer, dodecyl maltoside (DDM). As DDM has not previously been approved for use in Canada, toxicology studies were provided to support its safety. While novel to Canada, the DDM excipient has been approved for use in several nasal sprays in the United States and is approved for use in higher amount and in a nasal spray indicated for children as young as 6 years of age in the United States. No clinical or nonclinical studies provided by the sponsor indicated that the use of DDM in the neffy nasal spray presented an additional risk.

Review of the quality information included an assessment of manufacturing information for the novel DDM excipient. The information filed in support of DDM was found to be acceptable. No other issues were identified in the quality review. The chemistry and manufacturing information submitted has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

The device used for the administration of the neffy nasal spray solution is not novel to Canada, as the same device is already approved for the emergency administration of naloxone. Its use in administering epinephrine in an emergency situation is appropriate.

The final labelling and Product Monograph were considered acceptable.

The sponsor’s clinical data provides sufficient information to indicate that the systemic exposures and pharmacodynamic effects of epinephrine delivered by neffy nasal spray are sufficiently similar to those of the currently approved emergency-use epinephrine products in Canada. As such, neffy is expected to provide benefits similar to the epinephrine autoinjectors for the emergency treatment of anaphylaxis.

Overall, the benefit-harm-uncertainty profile was favourable for neffy 2 mg/0.1 milliliter (mL) solution nasal spray for the authorized indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

For further details about neffy, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.