Epinephrine autoinjector

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. The injection may be repeated every 5 to 15 minutes if there is insufficient response. 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==

solution. 5. Outer body. When retracted upward (left) exposes the needle and triggers the latch mechanism. Later springs back to cover the needle after use. 6. Needle exits through a protective barrier when this is pressed against the skin. 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. The rate of unintentional injections using these devices is unknown but a 2009 review found that the rate is increasing. 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 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 Kaplan and was first approved for marketing by the FDA in 1987. 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. In 1997, Dey, a subsidiary of Merck KGaA, acquired the exclusive right to market and distribute the EpiPen. 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. In 2002 King Pharmaceuticals acquired Meridian for $247.8 million 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, 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, 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. In 2009, Intelliject, a US startup developing a new epinephrine autoinjector, licensed their product to Sanofi. King was acquired by Pfizer in 2010 for $3.6 billion in cash. 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, 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. 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 response, Sandoz challenged the validity of the patents, and as of July 2016 this litigation was ongoing. 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, 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. In December 2012, the National Association of State Boards of Education launched a policy initiative designed to "help state boards of education as they develop student health policies regarding anaphylaxis and epinephrine auto-injector access and use", and advocated for state laws protecting school from legal liability for stocking and using epinephrine autoinjectors. Gayle Conelly Manchin, mother of Mylan's CEO, Heather Bresch, had become president of the association in 2010, and shortly after had discussed donations from her "daughter's company" to the association. Manchin had been appointed to the West Virginia state school board by her husband Joe Manchin, then-governor of the state, in 2012. In 2012, Shionogi, the manufacturer of Adrenaclick and Twinject, announced it would stop making them; In June 2013, Amedra relaunched Adrenaclick. and at the same time, Lineage Therapeutics launched its authorized generic version of Adrenaclick. Lineage was a wholly owned subsidiary of Amedra that had acquired the rights to the Adrenaclick authorized generic from Greenstone/Pfizer. After successful lobbying from Mylan, Joe Manchin, the father of Mylan's CEO, was a senator at that time. In March 2015, Impax Laboratories acquired the parent company of Amedra and Lineage, 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 May 2015, the Emerade epinephrine autoinjector developed by the Swedish company Medeca was approved in Sweden and Germany; it had been approved in the UK in 2013. Also in 2015 Valeant, which had licensed the rights from Medeca, abandoned its efforts to get Emerade approved in the US. In October 2015, Auvi-Q and Allerject 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 February 2016, Sanofi terminated its license to manufacture and market the Auvi-Q, leaving Kaléo (Intelliject was renamed) to consider how and whether to re-introduce the device. The EpiPen had 89% of the market for epinephrine autoinjectors in 2015; In 2015 Mylan had about $1.5 billion in sales of EpiPens, which accounted for 40% of Mylan's profit. and the West Virginia State Attorney General opened an investigation into whether Mylan had given the state the correct discount under the Medicaid Drug Rebate Program and subpoenaed the company when it refused to provide the documentation the state requested. In October 2016, Mylan announced a $465M settlement with the US Department of Justice over rebates paid by Mylan to states under the Medicaid Drug Rebate Program. On 16 August 2018 the FDA approved the first generic EpiPen from Teva Pharmaceuticals. In an effort to address the supply shortage of EpiPens, on August 21, 2018 the FDA approved extending the expiration dates on some products by four months. The Sandoz division of Novartis announced on 9 July 2019 the availability of Symjepi, a manual epinephrine injection as an alternative to autoinjectors, in 0.3 mg and 0.15 mg versions. ==Society and culture==

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 2018, three branded products were available in the United States: Adrenaclick, Auvi-Q, and EpiPen. , EpiPen is the only epinephrine autoinjector available in Canada. One generic autoinjector has been approved by Health Canada but is not marketed. From 2015 to 2020, a previous period where EpiPen was the only autoinjector marketed in Canada, production issues led to supply shortages. During a 2018 shortage of EpiPens, Health Canada temporarily permitted the importation of Auvi-Q autoinjectors from the United States. As of 2005, epinephrine autoinjectors were not available in most of the developing world. , two Jext autoinjectors cost users about £8.50 (US$) in Britain, and the National Health Service pays around £48 (US$) in order to make them available; that price was about 17 percent less than 2013. United States In October 2016 the CEO of Mylan testified to Congress that Pfizer/King charged Mylan about $34.50 for one EpiPen. In September 2016, a Silicon Valley engineering consultancy performed a teardown analysis of the EpiPen and estimated the manufacturing and packaging costs at about $10 for a two-pack. The EpiPen, manufactured by Meridian Medical Technologies, and marketed by Mylan, has dominated the market. In the United Kingdom, an EpiPen costs £26.45 as of 2015. In Canada they are about 120 CAD each. Mylan acquired the right to market the EpiPen line of epinephrine autoinjector devices from Merck KGaA as part of their 2007 deal. By the first half of 2015, sales of EpiPen accounted for 40% of Mylan's profit. Some Americans responded to the high price by buying EpiPens online from pharmacies outside the US, forgoing new EpiPens and relying on their expired EpiPen, 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 be used only 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 on to consumers. Questions had been raised by Congress and others about why EpiPen had been classified as a generic rather a proprietary product in the program since 1997; generic drugs have lower rebates (13%) than proprietary drugs (23%), and price hikes for generic drugs cannot be passed onto states, and a common form of pharmaceutical fraud involves misclassifying proprietary drugs as generic under the program. Under the agreement, Mylan agreed to pay a $465 million payment and to a sign a corporate integrity agreement requiring it to perform better in the future; , the authorized generic of Adrenaclick cost $142 at retail stores. In September 2016, a group of hackers called the Four Thieves Vinegar published a video and documents describing what they call an EpiPencil, an autoinjector which can be built using off-the-shelf parts, for a claimed price tag of about $30. This device has not been subject to any validation by regulatory agencies. ==References==