Inspections, Compliance, Enforcement, and Criminal Investigations
Nephron Pharmaceuticals Corp. 9/24/13
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
555 Winderley Place, Suite 200
Maitland, Florida 32751
w/ DELIVERY CONFIRMATION
September 24, 2013
Lou Kennedy, CEO
Nephron Pharmaceuticals Corporation
4121 SW 34th Street
Orlando, FL 32811
Dear Ms. Kennedy:
This letter concerns your firm’s marketing of the over-the-counter (OTC) drug product Asthmanefrin (NDC 0487-2784), a bronchodilator containing the active ingredient racepinephrine hydrochloride. Asthmanefrin is marketed both in the Asthmanefrin Starter Kit, which contains 10 Asthmanefrin vials co-packaged with the EZ Breathe Atomizer, a continuous battery powered atomizer, and in the Asthmanefrin Refill, which contains 30 Asthmanefrin vials. The directions for use for Asthmanefrin, as provided on the labels of both the Asthmanefrin Starter Kit and Asthmanefrin Refill, state that the Asthmanefrin vials are to be administered via an atomizer such as the EZ Breathe Atomizer.
As labeled, Asthmanefrin is a drug within the meaning of sections 201(g)(1)(B) and (C) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. §§ 321(g)(1)(B) and (C)] because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and because it is intended to affect the structure or function of the body. Specifically, the product labeling, including the outer carton label for the Asthmanefrin Starter Kit and Asthmanefrin Refill, states that these products are intended for the temporary relief of mild symptoms of intermittent asthma, including wheezing, tightness of chest, and shortness of breath.
In addition, based on the active ingredient and the claims made for this product, Asthmanefrin is a "new drug" within the meaning of section 201(p) of the Act [21 U.S.C. § 321(p)] because it is not generally recognized as safe and effective for its labeled uses. Drug products intended for indications such as those for which Asthmanefrin is labeled have been evaluated and determined by FDA to be generally recognized as safe and effective under the final monograph for Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for OTC use, 21 CFR Part 341 (OTC bronchodilator final monograph).
The OTC bronchodilator final monograph, however, does not include racepinephrine hydrochloride for use as a bronchodilator using a continuous atomizer such as the EZ Breathe Atomizer. See 21 CFR 341.76. Moreover, we are not aware of any other evidence establishing a product such as Asthmanefrin being generally recognized as safe and effective when directed for use with a continuous atomizer such as the EZ Breathe Atomizer.
Under sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)], a new drug may not be introduced or delivered for introduction into interstate commerce unless an application approved by FDA under either section 505(b) or (j) of the Act [21 U.S.C. § 355(b) or (j)] is in effect for the product. Based upon our information, there is no FDA-approved application on file for Asthmanefrin. The marketing of this product without an approved application constitutes a violation of these provisions of the Act.
Furthermore, the Center for Devices and Radiological Health has reviewed your website, http://www.nephronpharm.com/, and links on your website (http://www.ezbreatheatomizer.com/ and http://www.asthmanefrin.com/), and has determined that the EZ Breathe Atomizer is adulterated under section 501(f)(1)(B) of the Act [21 U.S.C. § 351(f)(1)(B)], because your firm does not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act [21 U.S.C. § 360e(a)], or an approved application for an investigational device exemption (IDE) under section 520(g) of the Act [21 U.S.C. § 360j(g)] for the uses for which the device is intended. The EZ Breathe Atomizer is also misbranded under section 502(o) the Act [21 U.S.C. § 352(o)], because your firm introduced or delivered for introduction into interstate commerce for commercial distribution this device, intended for a use different from the intended use of a legally marketed device in the generic type of device described under 21 CFR 868.5640 (Medicinal nonventilatory nebulizer (atomizer)), without submitting a premarket notification to FDA as required by section 510(k) of the Act [21 U.S.C. § 360(k)] and 21 CFR 868.9(a).
Devices classified under 21 CFR 868.5640 (Medicinal nonventilatory nebulizer (atomizer)) are exempt from premarket notification unless they exceed the limitations on exemption at 21 CFR 868.9. Generic devices of this type are “intended to spray liquid medication in aerosol form into the air that a patient will breathe.” They are not intended to spray liquid medication directly to a patient, nor are they intended to be combination products labeled or packaged for use with an unapproved new drug. Nevertheless, your firm has introduced the EZ Breathe Atomizer into commercial distribution with these intended uses.
Evidence of these different intended uses includes but is not limited to, the following statements and facts from the websites identified earlier:
- Product is packaged and marketed in the Asthmanefrin Starter Kit
- At the FAQ page: “Can I use other solution medications in the EZ Breathe Atomizer? The EZ Breather Atomizer has been provided for use with Asthmanefrin™.”
- Accessories are available with the product (mouth piece and masks) to deliver the aerosol directly to the patient.
Because the EZ Breathe Atomizer is intended for uses that are different from those of legally marketed devices classified under 21 CFR 868.5640, it exceeds the limitations described in 21 CFR 868.9(a) and is not exempt from premarket notification.
For a device requiring premarket approval, the notification required by section 510(k) of the Act, 21 U.S.C. § 360(k), is deemed satisfied when a PMA is pending before the agency. See 21 CFR 807.81(b). The kind of information that your firm needs to submit in order to obtain approval or clearance for the device is described on the Internet at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/default.htm. The FDA will evaluate the information that your firm submits and decide whether the product may be legally marketed.
In addition to the above violations, the Asthmanefrin Starter Kit and Asthmanefrin Refill are also misbranded under Section 502(a) of the Act [21 U.S.C § 352(a)] because the Principal Display Panels (PDP) claim “Alternative to Primatene Mist CFC Inhaler.” This claim is false or misleading because Asthmanefrin is an unapproved new drug that has not been proven by substantial evidence to be comparable to Primatene Mist CFC Inhaler, an OTC metered-dose inhalation drug product which is no longer marketed.
We are very concerned about the safety of Asthmanefrin as labeled for OTC use with an atomizer such as the EZ Breathe Atomizer. Since the Asthmanefrin Starter Kit and Asthmanefrin Refill products were introduced to the market in September 2012, there have been numerous FDA Adverse Event Reports that include reports of chest pain, nausea/vomiting, increased blood pressure, increased heart rate, and possible hemoptysis associated with the use of Asthmanefrin. Additionally, FDA is also aware that your firm recently initiated a nationwide recall of certain lots of Asthmanefrin Starter Kits containing faulty EZ Breathe Atomizers that could result in a choking hazard.
Given the available information, it is unclear how much active ingredient would be delivered to a patient when using Asthmanefrin, even if the conditions of use as set forth in the product labeling are strictly followed. Moreover, given that the EZ Breathe Atomizer is a continuous atomizer, FDA believes that there is a significant risk that patients will either over- or under-dose themselves when using Asthmanefrin, which could lead to serious and possibly fatal adverse outcomes. Because Asthmanefrin is intended to be used to relieve acute symptoms of asthma, if the dose of racepinephrine delivered via the EZ Breathe Atomizer is not effective, patients may be at risk for serious or potentially fatal asthma exacerbation. At the other extreme, if the dose of racepinephrine is too high, patients may be at increased risk for potentially serious adverse reactions. Cardiovascular adverse reactions may be of particular concern given that racepinephrine is a non-selective adrenergic agonist.
The violations cited in this letter are not intended to be an all-inclusive list of deficiencies regarding your products. Please be aware that you are responsible for investigating and determining the causes of these violations and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. Your reply should be addressed to Carla Norris, Compliance Officer, Food and Drug Administration, 555 Winderley Place, Suite 200, Maitland, FL 32751.
Emma R. Singleton
Director, Florida District
 The EZ Breathe Atomizer is a hand held battery powered atomizer that produces a continuous vapor that patients are to inhale. Consumers are instructed to add the contents of an Asthmanefrin vial to the EZ Breathe Atomizer and the atomizer produces a continuous vapor until the contents of the Asthmanefrin vial is depleted.