Adrenalin-Autoinjektor

An old version of a 0.3 mg EpiPen autoinjector

A current version of a 0.3 mg EpiPen autoinjector

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. The first epinephrine autoinjector was brought to market in the 1970s.

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 anaphylactic reaction.

When anaphylaxis is suspected, epinephrine solution should be injected into the thigh muscle as soon as possible. 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 what people might need a second injection ahead of time. 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.

Design

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. 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.

History

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 2007, Mylan acquired the right to market the EpiPen from Merck KGaA as part of a larger transaction. At that time annual sales were around $200 million.

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.

In 2009 Intelliject, a US startup developing a new epinephrine autoinjector, licensed their product to Sanofi.

In 2010 Sciele/Shionogi faced a recall of Twinject devices and launched Adrenaclick, a modified version of the Twinject that could deliver only one dose.

In 2010, Pfizer and King sued Novartis' Sandoz generic unit for patent infringement after Sandoz submitted an ANDA to sell a generic EpiPen. In response, Sandoz challenged the validity of the patents, and as of July 2016 this litigation was ongoing.

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 2011 Pfizer and 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. In August 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 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

US prices

In the United States, one brand of autoinjector, the EpiPen, manufactured by Mylan, dominates the market. Mylan raised the price from around $100 for a package of two EpiPens in 2007 to around $600 in 2016.

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. There were widespread social media messages about acquiring the device at a lower cost ($120) from New Zealand.

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 August 2016, the authorized generic of a different device called Adrenaclick, which supplies the same drug, costs $142 at retail stores.

Brands

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. As of 2014, three branded products were available in the US: Adrenaclick, Auvi-Q, and EpiPen.