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Teodolinda Mattson
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.
The epinephrine in autoinjectors expires after one year.[2] 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.[6]
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.[2]
People to whom epinephrine autoinjectors are prescribed need to be trained how to use the specific device prescribed.[1][4] The rate of unintentional injections using these devices is unknown but a 2009 review found that the rate is increasing.[7] Unintentional injections are delivered to a finger or thumb around 90% of the time; they cause intense pain locally but usually completely resolve.[7] 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.[7]
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."[8] 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.[8]
Another design of epinephrine autoinjectors was created by two identical twin brothers (Eric and Evan Edwards) who were also users of epinephrine autoinjectors. They realized the inconveniences of carrying bulky autoinjectors and decided to come up with a new device to address the problems while they were in college. The brothers split to study different fields with a shared goal to create a new device. One brother took an engineering major and the other took a pre-medical track and earned a doctorate degree in pharmaceutical sciences. Eventually, they came up with a design that has the shape and size of a smartphone which can be put into a pocket. The new device also has retractable needle and automated voice instructions to assist the users on how to correctly use the autoinjectors. The Company they created was called Intelliject and was later named kaleo. The product was launched with the brand name "Auvi-Q" in the United States and "Allerject" in Canada.[9][10]
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.[11] In 2016, Robinson and Lareau published a similar technique adapted to used AuviQ autoinjectors.[12]
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[13][14] and was first approved for marketing by the FDA in 1987.[15]
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.[16]
In 1996, Survival Technology merged with a company called Brunswick Biomedical and the new company was called Meridian Medical Technologies.[17] In 1997, Dey, a subsidiary of Merck KGaA, acquired the exclusive right to market and distribute the EpiPen.[18][19] In 1998 there was a recall of one million EpiPens, the second such recall in a year.[20]
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.[21] In 2002 King Pharmaceuticals acquired Meridian for $247.8 million in cash;[19] the deal was completed in January 2003.[22] Kaplan continued to improve his designs over the years, filing for example US Patent 6,767,336 in 2003.[23]
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.[24][25][26] In 2005, it sold the product to Verus Pharmaceuticals,[24] which launched the product the same year.[27] In March 2008, Sciele Pharma acquired Twinject from Verus[28] and later that year, Sciele was acquired by Shionogi.[29]
In 2007, Mylan acquired the right to market the EpiPen from Merck KGaA as part of a larger transaction.[30] At that time annual sales were around $200 million[31] and the EpiPen had about 90% of the market.[32]
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."[33]
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;[34] 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.[35]
In 2010, European regulators approved Twinject,[41] and also approved a new epinephrine autoinjector made by ALK and sold under the brand name Jext.[42][43] Jext was launched in the European Union in September 2011.[44][45]
Also in 2010, Shionogi authorized Greenstone, the authorized generics division of Pfizer,[46][47] to begin selling an authorized generic of Adrenaclick.[48][49] The media noted that Pfizer, through Greenstone, was marketing a generic epinephrine autoinjector when Pfizer acquired King later that year.[50] At that time, King and Mylan's EpiPen had 91% of the global market share for epinephrine autoinjectors and 96% of the US market.[50]
In 2010, Pfizer and King sued Novartis' Sandoz generic unit for patent infringement after Sandoz submitted an ANDA to sell a generic EpiPen.[51] In response, Sandoz challenged the validity of the patents, and as of July 2016 this litigation was ongoing.[52]
In 2011, Pfizer and King sued Intelliject and Sanofi after the companies filed a 505(b)(2)[53] New Drug Application for the product, then known as "e-cue";[54] 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.[55] In August 2012, the FDA approved the autoinjector, called "Auvi-Q" after the FDA required a name change from "e-cue".[56] The device is equipped with a sound chip to provide electronic voice instructions to guide the user in the proper use of the device.[57][58]
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.[59]
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.[60]
In June 2013, Amedra relaunched Adrenaclick.[63] and at the same time, Lineage Therapeutics launched its authorized generic version of Adrenaclick.[64] Lineage was a wholly owned subsidiary of Amedra that had acquired the rights to the Adrenaclick authorized generic from Greenstone/Pfizer.[65]
After successful lobbying from Mylan,[31] 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.[66] Joe Manchin, the father of Mylan's CEO, was a senator at that time.[60]
In January 2015 Mylan filed a citizen petition with the FDA raising concerns about TEVA's ANDA application to market a generic EpiPen and filed an additional supplement later in May; the FDA rejected the petition in June.[67][68]
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