An epinephrine autoinjector is a medical device for injecting a measured dose or doses of epinephrine (adrenaline) by means of autoinjector technology. It is most often used for the treatment of anaphylaxis. One autoinjector, the EpiPen, is derived from the Mark I NAAK ComboPen, which was developed for the U.S. military for treating exposure to nerve agents in the course of chemical warfare.
Units that have exceeded their expiration date can still be used in an emergency if an unexpired unit is unavailable and the solution is neither discoloured nor contains precipitates.
The devices contain a fixed dose of epinephrine and a spring-loaded needle that exits the tip or edge of the device and penetrates the recipient's skin, to deliver the medication via intramuscular injection.
The first modern epinephrine autoinjector, the EpiPen, was invented in the mid-1970s at Survival Technology in Bethesda, Maryland by Sheldon Kaplan. In 1996 Survival Technology merged with a company called Brunswick Biomedical and the new company was called Meridian Medical Technologies Inc.. The EpiPen was marketed and distributed for Medical Technologies by Dey LP, a subsidiary of Merck KGaA.
In 2001 Meridian introduced a two-pack version of the EpiPen; at that time the device had $23.9 million in annual sales and accounted for 75% of the market in the United States. In 2002 King Pharmaceuticals acquired Meridian for $247.8 million in cash; the deal was completed in January 2003. (King was later acquired by Pfizer in 2010 for $3.6 billion in cash.) Kaplan continued to improve his designs over the years, filing for example US Patent 6,767,336 in 2003.
In 2003 Hollister-Stier received approval from the FDA to market an epinephrine autoinjector called Twinject that could deliver two shots of epinephrine, which it had spent ten years developing. In 2005 it sold the product to Verus Pharmaceuticals, which launched the product the same year. In March 2008 Sciele Pharma acquired Twinject from Verus and later that year, Sciele was acquired by Shionogi.
In 2009 Teva Pharmaceuticals filed an ANDA to market a generic EpiPen in collaboration with Antares Pharma Inc, a maker of injection systems; King sued them for infringing US Patent 7,449,012 that was due to expire in 2025; Pfizer, Mylan, and Teva settled in April 2012 in a deal that allowed Teva to start selling the device in mid-2015, pending FDA approval.
In the 2009 Intelliject, a US startup developing a new epinephrine autoinjector, licensed their product to Sanofi. In 2011 King sued Intelliject and Sanofi after the companies filed a 505(b)(2) New Drug Application for the product, then known as "e-cue"; Pfizer, Mylan and Sanofi settled in 2012 under a deal that allowed the device to enter the market no earlier than November 2012, pending FDA approval. On August 13, 2012, the FDA approved the autoinjector, called "Auvi-Q" after the FDA required a name change from "e-cue". The device is equipped with a sound chip to provide electronic voice instructions to guide the user in the proper use of the device.
In 2010, European regulators approved Twinject, and also approved a new epinephrine autoinjector made by ALK and sold under the brand name Jext. Jext was launched in the European Union in September 2011.
In 2012, Shionogi, the manufacturer of Adrenaclick and Twinject, announced it would stop making them; it had sold the rights to the NDA to a company called Amedra Pharmaceuticals. In June 2013 Amedra relaunched Adrenaclick.
After successful lobbying from Mylan, in 2013 the "School Access to Emergency Epinephrine Act" became law after passing Congress with broad and bipartisan support; it protected anyone from liability if they administered epinephrine to a child in a school (previously, only trained professionals or the affected person were allowed to administer the drug, and were open to liability), and it provided some financial incentives for schools that didn’t already stock epinephrine autoinjector to start stocking them.
Also in 2013, Lineage Therapeutics launched a generic version of Adrenaclick.
In March 2015 Impax Laboratories acquired the parent company of Amedra and placed Amedra and the Adrenaclick in its Impax Specialty Pharma division; at the same time it acquired Lineage, which it placed, along with its generic version of Adrenaclick, in its Impax Generics division.
In October 2015 Auvi-Q devices were voluntarily recalled by Sanofi in North America. The reason stated by Sanofi was that the products had been found to potentially have inaccurate dosage delivery, which may include failure to deliver drug.
In March 2016 Teva's ANDA for a generic EpiPen, which had already faced several delays, was rejected by the FDA.
Society and culture
Mylan acquired the right to market the EpiPen line of epinephrine autoinjector devices from Merck KGaA as part of their 2007 deal. The devices deliver about $1 worth of drug. At that time annual sales were around $200M. Heather Bresch, Mylan's CEO, saw an opportunity to increase sales in the US through marketing and advocacy, and the company launched a marketing campaign to increase awareness of the dangers of anaphylaxis for people with severe allergies that made the "EpiPen" brand as identified with epinephrine autoinjectors as "Kleenex" is for facial tissue; the company also successfully lobbied the FDA to broaden the label to include risk of anaphylaxis and in parallel, successfully lobbied Congress to generate legislation making EpiPens available in public places like defibrillators are, and hired the same people that Medtronic had worked with on defibrillator legislation to do so.
Mylan's efforts to gain market dominance were aided when Sanofi's competing product was recalled in November 2015 and further when Teva's generic competitor was rejected by the FDA in March 2016. By the first half of 2015, Mylan had an 85% market share of such devices in the US and in that year sales reached around $1.5B and accounted for 40% of Mylan's profit. Those profits were also due in part to Mylan's continually raising the price of EpiPens starting in 2009; in 2007 the wholesale price of two EpiPens was about $100, the price was about the same in 2009, by July 2013 the price about $265, in May 2015 it was around $461, and in May 2016 the price rose again to around $609, around a 500% jump from the price in 2009. The last price increase sparked widespread outrage.
In response to criticism, Mylan increased financial assistance available for some patients to purchase EpiPens, a gesture that was called a "classic public relations move" by Harvard Medical School professor Aaron Kesselheim. The up to $300 saving cards can only be used by a small number of people who need the drug, and no one on Medicaid. They do nothing about the high price which is still being paid by insurers, who ultimately pass the cost onto consumers.
As of 2015, the following epinephrine autoinjectors were available in various parts of Europe: Adrenalina WZF, Adrenaline (epinephrine) 1 in 1000 solution for injection BP auto-injector, Altellus, Anapen, Emerade, EpiPen, Fastjekt, FastPen, and Jext.
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- National Inventors Hall of Fame Kaplan Sheldon
- Meridian Medical Technologies 10-K Filing For the fiscal year ended July 31, 1997
- King Pharmaceuticals Oct 21, 2002. Press Release: King Pharmaceuticals to Acquire Meridian Medical Technologies
- Meridian Medical Technologies, Merck KGaA. April 03, 2001 Press Release: Meridian Announces Launch Of New EpiPen 2-Pak
- King Pharmaceuticals Oct 21, 2002. Press Release: King Pharmaceuticals to Acquire Meridian Medical Technologies
- King Pharmaceuticals Form 11K filed For the fiscal year ended December 31, 2003.
- "Pfizer Completes Acquisition Of King Pharmaceuticals, Inc.; Pfizer and King begin joint operations on March 1, 2011" (press release). Pfizer. March 1, 2011.
- US Patent 6,767,336, cited in Steve Brachmann for IPWatchdog June 28, 2016 EpiPen gives doses of life-saving epinephrine for nearly 50 years
- Jennifer Sudick for the Spokane Spokesman-Review. July 20, 2005 Spokane firm sells rights to auto-injector
- FDA Twinject Approval Package
- FDA Approval History NDA 020800 - Twinject and Adrenaclick Page accessed August 25, 2016
- "Verus Pharmaceuticals Announces U.S. Launch of Twinject for Anaphylaxis". veruspharm.com.
- Sciele Pharma. March 13, 2008. Press Release: Sciele Pharma Acquires Twinject® Epinephrine Auto-Injector from Verus Pharmaceuticals
- Z+Kazuhiro Shimamua for The Wall Street Journal. Sept. 1, 2008 Shionogi to Buy Sciele Pharma
- Tara Parker-Pope and Rachel Rabkin Peachman for the New York Times. Aug 22, 2016 EpiPen Price Rise Sparks Concern for Allergy Sufferers
- Cynthia Koons and Robert Langreth for Bloomberg Businessweek. September 23, 2015 How Marketing Turned the EpiPen Into a Billion-Dollar Business
- US Patent 7,449,012, cited in PatentDoc's September 07, 2009 Court Report
- Phil Milford for Bloomberg News April 26, 2012 Mylan, Pfizer Reach Epinephrine-Pen Settlement With Teva
- Recalls.org December 2010
- Staff, Monthly Prescribing Reference. January 07, 2010 Adrenaclick Auto-injector launched for anaphylaxis
- FDA/Shionogi Adrenaclick original label 2009
- Julie Zeveloff for Law360. July 16, 2010. King Pharma Sues Sandoz Over Generic EpiPen
- Katie Thomas for the New York Times. Feb 1, 2013 Brothers Develop New Device to Halt Allergy Attacks
- Note - a "505(b)(2)" is a kind of new drug application that allows the applicant to rely in part on someone else's drug approval data - this pathway is used for example to get approval for an existing drug for a new indication. The information about the drug itself is someone else's, but the applicant has to generate the data showing the drug works for the new indication. In the case of Intelliject, it is the generic drug in a new device. For an explanation see Kenneth V. Phelps for Drug Discovery & Development Magazine. Aug 9, 2012 Taking the 505(b)(2) Route
- Sherri Oslick for PatentDocs. Court Report January 23, 2011
- Mylan. Feb 16, 2012 Press Release: Mylan and Pfizer Announce Epinephrine Auto-injector Settlement Agreement
- John Reid Blackwell for the Richmond Times-Dispatch. August 14, 2012 FDA approves Intelliject's life-saving device for allergy sufferers
- "Auvi-Q Fact Sheet" (PDF). Retrieved 18 August 2012.
- Sanofi August 13, 2012 Press Release: Sanofi Announces FDA Approval for Auvi-Q
- Shionogi. August 31, 2010 Press Release: Shionogi Announces Positive Outcome to the Decentralized Procedure For The European Approval Of Twinject (Epinephrine Auto-Injector)
- "ALK media release (07 October 2010)". Retrieved 2014-04-08.
- "ALK media release (13 October 2010)". Retrieved 2014-04-08.
- "ALK media release (06 September 2011)". Retrieved 2014-04-08.
- National Council for Prescription Drug Programs May 2013 QUIC FORM 201313 Adrenaclick Auto-Injector, NDC 59630-0803-02 And 59630-0804-02 Resolution. Indexed here
- Shionogi FY2011 Financial Results: Supplement See note in the margin of page 6
- Amedra Pharmaceutical June 14th, 2013 Press Release: Amedra Pharmaceuticals Markets Adrenaclick Auto-Injector
- Novak, Matt (August 23, 2016). "How Congress, the FDA, and Sarah Jessica Parker Helped EpiPen Become a $1 Billion Business". Gizmodo.
- Lineage Therapeutics. Jun 14, 2013 Press Release: Lineage Therapeutics Markets Authorized Generic Epinephrine Auto-Injector
- "Impax 2014 Annual Report" (PDF).
- Impax March 10, 2015 Press Release: Impax Completes Acquisition Of Tower Holdings, Inc. And Lineage Therapeutics Inc.
- Tammie Smith (October 29, 2015). "Auvi-Q auto injector being recalled". Richmond Times-Dispatch.
- Associated Press (30 October 2015). "Allerject epinephrine auto-injectors recalled by drugmaker Sanofi". Canadian Broadcasting Company.
- "UPDATED: Sanofi US Issues Voluntary Nationwide Recall of All Auvi-Q® Due to Potential Inaccurate Dosage Delivery".
- Staff, The Pharma Letter. March 3, 2016 Teva suffers setback over EpiPen generic
- Bartolotta, Devin (18 August 2016). "Cost Jumps Nearly 500-Percent For Life-Saving EpiPens". CBS Baltimore. Retrieved 19 August 2016.
- Carly Helfand for FiercePharma Mar 1, 2016 FDA swats down Teva's EpiPen copy, putting Mylan in cruise control
- Emma Court for MarketWatch. Aug 18, 2016 Mylan’s EpiPen price increases are Valeant-like in size, Shkreli-like in approach
- Goldberg, Kenny. "People With Food Allergies Say Life-Saving Drug Too Expensive". KPBS Public Media. Retrieved 8 June 2016.
- "Mylan to provide EpiPen cost assistance as CEO is asked to testify on price hike | Business | The Guardian".
- Carolyn Y. Johnson (August 25, 2016). "Why Mylan's 'savings card' won't make EpiPen cheaper for all patients". Washington Post. Washington Post.
- Ginger Skinner (August 11, 2016). "Can You Get A Cheaper EpiPen?".
- Lack of competition leads to EpiPen pricing woes, Adam Rubenfire, Modern Healthcare, March 28, 2016
- EMA. Annex I: List of the names, pharmaceutical form(s), strength(s) of the medicinal product(s), route(s) of administration, marketing authorisation holder(s) in the Member States. Published April 25, 2014; Updated August 26, 2015. See Index page for EMA Review of Adrenaline auto-injectors