An epinephrine autoinjector (or adrenaline autoinjector, also known by the trademark EpiPen) 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. The first epinephrine autoinjector was brought to market in 1983.
Medical uses
Epinephrine autoinjectors are hand-held devices carried by those who have severe allergies; the epinephrine delivered by the device is an emergency treatment for anaphylaxis.
When anaphylaxis is suspected, epinephrine solution should be given as soon as possible as an intramuscular injection, in the middle of the outer side of the thigh, which corresponds to the location of the vastus lateralis muscle. Last revised 03/15/2017 The injection may be repeated every 5 to 15 minutes if there is insufficient response. A second dose is needed in 16–35% of episodes with more than two doses rarely required; in around 80% of the cases where a second dose is administered, it is by a medical professional. It is not clear which are the people who might need a second injection at the outset. The intramuscular route is preferred over subcutaneous administration because the latter may have delayed absorption. Minor adverse effects from epinephrine include tremors, anxiety, headaches, and palpitations.
The epinephrine in autoinjectors expires after one year. A study in rabbits showed that intramuscular epinephrine has decreased effectiveness after it expires; that study also recommended that if the drug in an expired device has not started to precipitate (if the solution is not cloudy and has no particles in it) using the expired device is better than no injection at all in an emergency situation.
Design
The devices contain a fixed dose of epinephrine and a spring-loaded needle (or, in the case of AuviQ, a CO2-driven needle) that exits the tip or edge of the device and penetrates the recipient's skin, to deliver the medication via intramuscular injection.
People to whom epinephrine autoinjectors are prescribed need to be trained how to use the specific device prescribed. The rate of unintentional injections using these devices is unknown but a 2009 review found that the rate is increasing. Unintentional injections are delivered to a finger or thumb around 90% of the time; they cause intense pain locally but usually completely resolve. The cause of unintentional injections has been attributed to design flaws, where the device is mistaken for a pen or the user mistakes which end of the device contains the needle.
The European Medicines Agency conducted a review of the safety of devices then on the market and found several factors that determine whether the devices successfully deliver drug into muscle, including "needle length, the thickness of fat under the skin, the way the auto-injector works (e.g., if it is spring loaded or not), the angle at which the device is placed on the skin and the force used to activate the device as well as how well the user follows the instructions for injection." It found that how well the user was trained was the most important factor determining successful delivery, and requested companies to develop better training materials for doctors and people to whom the devices are prescribed.
In 2013, emergency physician Seth C. Hawkins and coauthors published a technique for obtaining multiple additional doses of epinephrine from used, single dose autoinjectors EpiPen and Adrenaclick. It was emphasized this was an emergency adaptation of the intended design for austere environments when no additional epinephrine was available. In 2016, Robinson and Lareau published a similar technique adapted to used AuviQ autoinjectors.
History Product introduction Autoinjectors were originally developed for the rapid administration of nerve gas antidotes in kits like the Mark I NAAK. The first modern epinephrine autoinjector, the EpiPen, was invented in the mid-1970s at Survival Technology in Bethesda, Maryland, US by Sheldon KaplanNational Inventors Hall of Fame Kaplan Sheldon and was first approved for marketing by the FDA in 1987.FDA Approval history for NDA 019430 - EpiPen Page accessed Aug 30, 2016
One of the people who helped in making the EpiPen was Richard B. Toren. He had the idea to use this technology for allergic reactions because his daughter was allergic to bees and had to carry around a complex kit if she was ever stung. He then helped to slightly alter the technology in order to create EpiPen's current design.
In 1996, Survival Technology merged with a company called Brunswick Biomedical and the new company was called Meridian Medical Technologies.Meridian Medical Technologies 10-K Filing For the fiscal year ended July 31, 1997 In 1997, Dey, a subsidiary of Merck KGaA, acquired the exclusive right to market and distribute the EpiPen.Dey, Inc. Amendment No. 3 to Form S-1 Registration Statement under The Securities Act Of 1933. Filed April 30, 1999King Pharmaceuticals Oct 21, 2002. Press Release: King Pharmaceuticals to Acquire Meridian Medical Technologies In 1998 there was a recall of one million EpiPens, the second such recall in a year.
In 2001 Meridian and Dey 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.Meridian Medical Technologies, Merck KGaA. April 03, 2001 Press Release: Meridian Announces Launch Of New EpiPen 2-Pak In 2002 King Pharmaceuticals acquired Meridian for $247.8 million in cash; the deal was completed in January 2003.King Pharmaceuticals Form 11K filed For the fiscal year ended December 31, 2003. 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.Jennifer Sudick for the Spokane Spokesman-Review. July 20, 2005 Spokane firm sells rights to auto-injectorFDA Twinject Approval PackageFDA Approval History NDA 020800 - Twinject and Adrenaclick Page accessed August 25, 2016 In 2005, it sold the product to Verus Pharmaceuticals, which launched the product the same year. In March 2008, Sciele Pharma acquired Twinject from VerusSciele Pharma. March 13, 2008. Press Release: Sciele Pharma Acquires Twinject® Epinephrine Auto-Injector from Verus Pharmaceuticals and later that year, Sciele was acquired by Shionogi.Z+Kazuhiro Shimamua for The Wall Street Journal. Sept. 1, 2008 Shionogi to Buy Sciele Pharma
In 2007, Mylan acquired the right to market the EpiPen from Merck KGaA as part of a larger transaction.Tara Parker-Pope and Rachel Rabkin Peachman for the New York Times. Aug 22, 2016 EpiPen Price Rise Sparks Concern for Allergy Sufferers At that time annual sales were around $200 million and the EpiPen had about 90% of the market.
In 2009, Mylan and King started marketing a new version of EpiPen with the same basic mechanism but a stronger spring, better safety features, and clearer markings and instructions; an expert for NBC News estimated that the cost to redesign the device and packaging may have been "several million dollars" and the cost to retool the manufacturing process may have "run into the double-digit millions."
Market development
In 2009, Teva Pharmaceuticals filed an ANDA to market a generic EpiPen in collaboration with Antares Pharma Inc, a maker of injection systems; Pfizer and 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.Phil Milford for Bloomberg News April 26, 2012 Mylan, Pfizer Reach Epinephrine-Pen Settlement With Teva
In 2009, Intelliject, a US startup developing a new epinephrine autoinjector, licensed their product to Sanofi.Katie Thomas for the New York Times. Feb 1, 2013 Brothers Develop New Device to Halt Allergy Attacks
King was acquired by Pfizer in 2010 for $3.6 billion in cash.
In 2010, Sciele/Shionogi faced a recall of Twinject devicesRecalls.org December 2010 and launched Adrenaclick, a modified version of the Twinject that could deliver only one dose.Staff, Monthly Prescribing Reference. January 07, 2010 Adrenaclick Auto-injector launched for anaphylaxisFDA/Shionogi Adrenaclick original label 2009
In 2010, European regulators approved Twinject,Shionogi. August 31, 2010 Press Release: Shionogi Announces Positive Outcome to the Decentralized Procedure For The European Approval Of Twinject (Epinephrine Auto-Injector) 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.
Also in 2010, Shionogi authorized Greenstone, the authorized generics division of Pfizer, to begin selling an authorized generic of Adrenaclick. The media noted that Pfizer, through Greenstone, was marketing a generic epinephrine autoinjector when Pfizer acquired King later that year. At that time, King and Mylan's EpiPen had 91% of the global market share for epinephrine autoinjectors and 96% of the US market.
In 2010, Pfizer and King sued Novartis' Sandoz generic unit for patent infringement after Sandoz submitted an ANDA to sell a generic EpiPen.Julie Zeveloff for Law360. July 16, 2010. King Pharma Sues Sandoz Over Generic EpiPen In response, Sandoz challenged the validity of the patents, and as of July 2016 this litigation was ongoing.Pfizer Quarterly Report (Form 10-Q) for the quarterly period ended July 3, 2016
In 2011, Pfizer and King sued Intelliject and Sanofi after the companies filed a 505(b)(2)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 New Drug Application for the product, then known as "e-cue";Sherri Oslick for PatentDocs. Court Report January 23, 2011 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.Mylan. Feb 16, 2012 Press Release: Mylan and Pfizer Announce Epinephrine Auto-injector Settlement Agreement In August 2012, the FDA approved the autoinjector, called "Auvi-Q" after the FDA required a name change from "e-cue".John Reid Blackwell for the Richmond Times-Dispatch. August 14, 2012 FDA approves Intelliject's life-saving device for allergy sufferers The device is equipped with a sound chip to provide electronic voice instructions to guide the user in the proper use of the device.Sanofi August 13, 2012 Press Release: Sanofi Announces FDA Approval for Auvi-Q
In 2012, Mylan launched a program called EpiPen4Schools to sell EpiPens in bulk and with discounts to schools; to participate in the program schools had to agree not to buy epinephrine autoinjectors from any other company for a year.