Abstract
A new product, Epinephrine HFA, is being considered by the Food and Drug Administration (FDA) for marketing approval as a nonprescription bronchodilator inhaler for the treatment of the “temporary relief of mild symptoms of intermittent asthma in adults and children 12 years of age and older.” This product would serve as a replacement for Primatene® Mist, which was removed from the market in December 2011 in accordance with the requirements of the Montreal Protocol to phase out chlorofluorocarbon (CFC) propellants. The Nonprescription Drugs Advisory Committee and the Pulmonary-Allergy Drugs Advisory Committee met in early 2014 to review the clinical data. The data indicate that Epinephrine HFA provides improvement in lung function at the proposed doses and that no clinically important safety issues were observed. There were, however, concerns that the device could malfunction and that the dose-counter could lose accuracy. These device issues are significant for a drug that could be used for life-threatening symptoms of asthma. All study data presented are publically available from the FDA website at www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/ucm380890.htm for the February 24, 2014, meeting.
A
In July 2013, Armstrong Pharmaceuticals submitted an NDA for Epinephrine HFA (hydrofluroalkane) MDI to serve as a replacement for Primatene® Mist, and the data were reviewed by a joint meeting of the Nonprescription Drugs Advisory Committee and the Pulmonary-Allergy Drugs Advisory Committee in February 2014. The product name would be Primatene® Mist HFA. The proposed indication is for one to two inhalations (125 μg/inhalation) for the “temporary relief of mild symptoms of intermittent asthma in adults and children 12 years of age and older.” Key differences with the HFA versus CFC formulations are: the HFA product is a suspension, whereas the CFC product was a solution, and thus requires shaking prior to use; it requires cleaning and priming prior to each use to prevent clogging (a problem seen with other HFA products3,4 though also noted for the CFC product 5 ); it contains a dose indicator (the CFC product did not); it is indicated for patients 12 years and older (vs. 4 years and older for the CFC product); it achieves higher blood levels; and dosing may be repeated every 4 hours for a maximum of eight inhalations per day (the CFC product instructions were less specific 5 ). The committees reviewed efficacy (including dose selection), safety, and device performance. They were asked to determine if the risk/benefit profile was supportive of nonprescription use of Epinephrine HFA for the temporary relief of mild asthma symptoms of intermittent asthma.
Efficacy was assessed during dose selection trials, pharmacokinetic studies, and efficacy and safety trials (12 weeks). The dose-ranging and pharmacokinetic studies were conducted in adults with asthma and healthy adults respectively. The 12-week efficacy and safety trial was conducted in patients with asthma aged 12–75 years. There was a 4-week efficacy and safety study in children aged 4–11 years, but these data were not included in the submission.
In the adult dose-ranging trial placebo controlled cross-over trial, participants (N=30) had to have a baseline FEV1 of 50–85% predicted with reversibility of at least 15% after Primatene® Mist administration. Single doses of Epinephrine HFA ranging from 1×90 μg/inhalation to 2×125 μg/inhalation were compared to Primatene® Mist 1×and 2×220 μg/inhalation, and placebo; FEV1 was measured for 360 minutes after dosing. The primary endpoint was mean area under the curve (AUC) of the percent change from baseline FEV1. This trial demonstrated dose ordering especially at the lower doses with no consistent dose ordering above 125 μg for Epinephrine HFA. Thus, a dose of 125 μg/inhalation was chosen for the primary efficacy trial. When the pharmacokinetic studies were performed using 10 inhalations of 125 μg/inhalation Epineprine HFA and 220 μg/inhalation Primatene® Mist (a large number inhalations were required to obtain measurable plasma concentrations), the AUC and maximum plasma concentration were 37% higher and 4.7 times greater, respectively, with Epineprine HFA. The clinical relevance of this finding was further explored in the primary efficacy trial.
The primary efficacy trial compared Epinephrine HFA (two inhalations of 125 μg/inhalation) to Primatene® Mist (two inhalations of 220 μg/inhalation) and placebo given four times daily for 12 weeks, randomized in a 4:1:1 (N=120:30:30) manner, respectively. Participants had to be clinically stable with an FEV1 of 50–90% predicted and demonstrated reversibility of at least 12% after two inhalations of 220 μg/inhalation Primatene® Mist. Albuterol was provided for as-needed use. The primary endpoint was mean AUC of the percent change in FEV1 from same-day baseline (0–360 minutes post-dose) at day 1 and week 12. Both Epinephrine HFA and Primatene® Mist had similar differences in AUC from placebo at day 1 and week 12, and both were significantly greater than placebo (Fig. 1). The time to peak bronchodilator effect and duration of bronchodilator effect was similar for the two products at approximately 1 hour and 1.4 hours, respectively. Adolescents (vs. adults) and women (vs. men) tended to have nearly twice the difference in AUC from placebo with Epinephrine HFA compared with Primatene® Mist at week 12. Not surprisingly, those with a baseline FEV1 of <80% predicted had a greater AUC versus placebo response after Epineprine HFA compared to those with higher lung function.
Serial FEV1, 0–360 minutes post-dose on day 1 and week 12. Data presented by the FDA at the Joint Meeting of the Nonprescription Drugs Advisory Committee and Pulmonary-Allergy Drugs Advisory Committee February 25, 2014. www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/ucm386673.htm. FDA, Food and Drug Administration.
Safety data were derived from the 12-week efficacy study, which was followed by a 12-week extension trial with the same dose regimen for a total of 6 months exposure data. Adverse events of interest included tremor, chest discomfort, chest pain, tachycardia, heart rate increase, and QTC prolongation. Tremor was observed more frequently in the Epineprine HFA group compared to Primatene® Mist, which may reflect the higher plasma concentrations and AUC with the former (Table 1). Chest discomfort occurred more frequently in the Epinephrine HFA group, but five of the nine events were from two participants. A review by the FDA Division of Cardiovascular and Renal Products noted that while overall there was no cardiovascular safety signal, data from the high doses in the dose-ranging studies suggest that increases in systolic blood pressure and heart rate could be significant in some patients who overuse Epinephrine HFA acutely. In addition, in the primary efficacy trial, there were more events of heart rate increase of more than 20 beats per minute in Epinephrine HFA group than either the placebo or Primatene® Mist arms.
Data presented by the FDA at the Joint Meeting of the Nonprescription Drugs Advisory Committee and Pulmonary-Allergy Drugs Advisory Committee February 25, 2014.
The post-marketing experience with Primatene® Mist has been unremarkable for cardiovascular events and death in more than 50 years of nonprescription use. Unlike the epidemics of asthma deaths that occurred in the early 1960s in England and Wales with the introduction of isoproterenol,6–8 and in the 1970s in New Zealand after the introduction of fenoterol,8,9 no such increase was observed in the United States after the introduction of Primatene® Mist in 1967. The FDA undertook a careful review of the FDA Adverse Event Reporting System (FAERS) data, the manufacturer's database, and publications to identify adverse effects related to Primatene® Mist. The inadequacies of the FAERS are well known and include the voluntariness, limited clinical information, reporting biases, duplicate reporting, and inability to determine incidence rates. Examination of the FAERS over 16 years (an estimated 66 million Primatene® Mist products were sold) identifed 389 adverse events reported with use, of which 25 reports were in children. The reports were similar to those in adults and included lack of effect, worsening of asthma, and mild cardiac-related adverse events (palpitations and chest discomfort). Two deaths in children were reported, but in one case it was not clear that the death was precipitated by Primatene® Mist use. The manufacturer's data identifed 179 adverse events, which were of the same scope as FAERS, with one report of death in a child that was reported years after the death ocurred. A literature search found a review of 286 adverse events from 1975 to 1997, including 13 deaths, though it was not clear if use of Primatene® Mist was related to any of the deaths.
Several issues with the Epineprine HFA device were identified by the FDA. The device consists of a 14 mL anodized aluminum canister with a 50 μL metering valve and a 160-count dose indicator. The dose indicator is glued to the bottom of the canister rather than being integrated with the actuator. The dose counter counts down in 20 dose increments, and when 20 or fewer doses remain, the indicator is displayed in red. If the MDI is dropped, the dose counter is no longer reliable, and patients are required to keep track of the number of doses remaining. At the conclusion of the primary efficacy trial, the manufacturer reported that 7% of the devices were reported as malfunctioning. Of this 7%, 21% malfunctioned due to clogging and 12% were reported not to dispense properly; the nature of the problems with the remaining devices was not reported to the FDA or Advisory Committees. The FDA considered a 7% malfunction rate to be excessively high and suggested that the device poses a significant risk to users who could use it in times of an asthma emergency. The FDA also had concerns about the number of devices that undercounted the number of doses used. This is problematic because a device that undercounts will lead the user to believe falsely there is more drug remaining in the canister than is actually present.
The available data on the clinical response to Epinephrine HFA presented to the FDA advisory committees indicated that the product provides clinically important bronchodilation that is similar to that observed with Primatene® Mist and greater than placebo. In addition, the rate of cardiovascular and other adverse events are low and likely are consistent that observed in more than 50 years of Primatene® Mist use. Even the higher blood concentrations with Epinephrine HFA did not translate into more observed adverse events. The problem with the product appears to be the device. Clogging is known to occur with HFA products, but it is not clear if Epinephrine HFA has a higher rate than other asthma medication inhalers. The dose counter problems could be solved by having a counter integrated into the actuator, but additional clinical trial data would be required before approval.
The committee heard many impassioned pleas by asthma patients to bring inhaled epinephrine back onto the nonprescription market. There is considerable resistance by the medical community to allow patients to self-manage symptoms through the availability of a nonprescription bronchodilator inhaler medication due to the perception that patients will delay or not seek regular care in a healthcare setting. However, the same argument could be made against allowing patients with mild intermittent asthma to have access to an albuterol inhaler for a 12-month prescription period. Such a patient would typically use albuterol infrequently, but in times of an exacerbation could overuse albuterol, resulting in death, as has been recently reported.10,11 Patients with asthma should have ready access to medications to relieve symptoms. It seems that there is little excess risk of harm by having a nonprescription reliever medication available to the public for treatment of mild asthma symptoms based on historical experience of more than 50 years with Primatene® Mist that is substantively different from the morbidity and mortality risks associated with prescription short-acting bronchodilators.
Footnotes
Author Disclosure Statement
No competing financial interests exist.