The U.S. Food and Drug Administration told EpiPen's maker, Pfizer Inc., this week that it failed to properly investigate reports of malfunctioning auto-injectors, including incidents associated with patient deaths and severe illnesses.
The FDA's Sept. 5 warning letter to Pfizer's Meridian Medical Technologies unit includes new details surrounding a global recall of EpiPen and EpiPen Jr. in March.
Tens of thousands of EpiPens, sold by Mylan NV, were recalled worldwide in March after two reports of the life-saving shot failing to work in emergencies.
"Your own data show that you received hundreds of complaints that your EpiPen products failed to operate during life-threatening emergencies, including some situations in which patients subsequently died," the U.S. regulator wrote.
The letter outlines the FDA's inspection of Meridian's manufacturing facility in Brentwood, Mo.
Christina Antoniou, senior manager of corporate affairs for Pfizer Canada, said the manufacturing facility supplies all EpiPens.
The FDA letter says the company failed to investigate problems with the devices, recall batches and act on problems, including expanding its internal investigation after two customer complaints of EpiPen failures were traced to a deformed component.
Pfizer makes EpiPens for Mylan, which has come under fire for hiking the price of the device in the U.S.
"Between 2015 and now, we have shipped more than 30 million EpiPen Auto-Injectors globally. It's not unusual to receive product complaints, especially when the product is frequently administered by non-medically trained individuals," Pfizer said in an emailed statement.
"We currently have no information to indicate that there was any causal connection between these product complaints and any patient deaths."
In an interview with CBC News, Antoniou said all necessary actions were taken to remediate the component, which she called a "low-level defect."
There is currently no recall.
Carry 1 pen minimum
Antoniou said the complaints were from outside Canada and the U.S.
The Institute for Safe Medication Practices Canada, an independent, not-for-profit organization committed to medication safety, said it hasn't received any reports of malfunctioning devices.
Since such reports to the institute and regulators such as Health Canada are voluntary, it's impossible to say what percentage of incidents relate to failed activations, said Dr. Michael Hamilton, physician lead at ISMP Canada.
"If you particularly rely on this medication and it doesn't work, that can certainly lead to catastrophe. We'd encourage users of these devices to maybe be aware of the potential for a failed deployment or failed activation," said Hamilton, a family physician who has treated anaphylaxis in the emergency room.
Hamilton said a backup plan can include calling 911 as the injector is applied and alerting a caregiver.
Anaphylaxis is a cascade of events that can involve everything from skin rashes to vomiting to gastrointestinal problems, with trouble swallowing, speaking or breathing and even a reduced level of consciousness, said Dr. Elana Lavine, a pediatric allergist and clinical immunologist at Humber River Hospital in Toronto.
Administering epinephrine as quickly as possible can avert and reduce the severity of the reaction.
"At a minimum we want everyone to carry one unexpired pen that contains the appropriate dose of epinephrine for their weight," Lavine said.
No specific details
Anaphylaxis may cause deaths even with the best treatment available, Lavine noted.
"The language [in the letter] is so opaque, in terms of it doesn't mention any specific details, it doesn't mention a time frame, I think it would be tragic if it made people less likely to carry the No. 1, meaning first-line treatment in the form of ephinephrine auto-injector."
In an emailed statement, Mylan said: "Pfizer's recall several months ago of certain lots of EpiPen Auto-Injector was taken as a proactive and precautionary measure with FDA in relation to these issues."
Both Mylan and Pfizer said they are confident in the safety and efficacy of EpiPen products being produced at the site.
Mylan said it does not currently anticipate any supply issues as a result of the warning letter.
In an email to CBC News, the FDA said it will "work to ensure that the company's corrections are adequate."
The FDA has given Pfizer 15 working days to detail what it's done to correct and to prevent further violations.
The EpiPen is used to treat allergic reactions to certain foods and stings from bees, wasps and hornets.