FasEpi® - Oral Epinephrine Fast Dissolving Tablet
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By Edward J. Petrus, MD

Background:

The time between exposure and onset of severe allergic symptoms is usually less than 30 minutes in cases of fatal anaphylaxis (hypersensitivity resulting from sensitization following prior contact with the causative agent).  Dr. Paul Greenberger, of Northwestern University, Fineberg School of Medicine, Chicago, and colleagues examined 25 cases as reported in the Annals of Allergy, Asthma, and Immunology 2007;98:252-257.  Of the 25 cases of anaphylactic deaths, 7 were reactions to medications, 6 were from radiocontrast media, 6 from Hymenoptera stings, 4 from food, and 2 from reactions to insect repellent and hair coloring products.  The anaphylactic reaction began within 30 minutes of allergen exposure in 21 cases.  Thirteen of the cases died within 60 minutes, 4 died between 1 and 6 hours and 4 died between 24 and 96 hours after exposure.  Dr. Greenberger noted that “patients should be taught how and when to self-administer epinephrine.”

About 0.5% of the general population, or 1 in 200 persons, is severely allergic to the venom of insects of the Hymenoptera order, whose members include; honeybees, bumblebees, yellow jackets, white-faced and yellow hornets, paper wasps, and fire ants.  Adults who’ve had a systemic reaction have a 30-50% risk of having another systemic reaction if stung again, in the future.  The authors noted that epinephrine will halt swelling and itching much faster than antihistamines.  Patient Care, June 15, 1998, pg. 38-59.

Epinephrine acts quickly to improve breathing, stimulate the heart and reverse hives and swelling around the face and lips.  This medication is used in emergencies to treat potentially dangerous allergic reactions to insect stings or bites, foods, drugs or other substances.  Prompt administration of epinephrine is by intramuscular injection, such as EpiPen (0.33 mg epinephrine) and EpiPenJr (0.15 mg epinephrine) auto-injectors.  EpiPen is now only available in 2-packs because more than one may be needed, approximate cost $200. 

Epinephrine is also available as Primatine Mist, a nonprescription inhalation aerosol that delivers 0.22 mg of epinephrine, and Bronchial Mist (Walgreens).  While some of the epinephrine reaches the bronchial tree, much is absorbed by the oral mucosa.  Epinephrine restores breathing by relaxing the muscles around the airways in the lungs, but the effect lasts only 20 to 30 minutes to overcome the bronchoconstriction.

It is not practical to administer epinephrine by means of a swallowed tablet because it is rapidly inactivated, conjugated and oxidized by catechol-O-methyltransferase in the wall of the gastrointestinal tract.  However, epinephrine is well absorbed and rapidly absorbed by the buccal mucosa when in the form of an orally disintegrating tablet (ODT).  In one study a sublingual epinephrine tablet reached peak effectiveness at 20.8 minutes and peak effectiveness at 15.8 minutes with an IM injection (Biopharm Drug Dispos. 2003;23:213-216).  In a recent clinical study, aspirin in the form of an ODT was detected in the blood stream in 5 minutes (J of Clin Res Ltrs, 2012;3(2):41-45).  It normally takes 20-30 minutes to detect aspirin in the plasma after swallowing a tablet (Am J Cardiol 1999;84:404-409).

Due to high buccal vascularity, bucally-delivered drugs can gain direct access to the systemic circulation and are not subject to first-pass hepatic metabolism.  In addition, therapeutic agents administered via the oral buccal route are not exposed to the acidic environment of the gastrointestinal tract (Encyclopedia of Pharm Tech, 2002;2081-2095).  Further, the buccal mucosa has low enzymatic activity relative to the nasal and rectal routes.  Thus, the potential for drug inactivation due to biochemical degradation is less rapid and extensive than other administration routes (Crit Rev Ther Drug Carr Syst 1991;8:271-303).

Feasibility studies in humans and animals have shown that epinephrine can be absorbed sublingually.  Epinephrine bitartrate was used in the study because it was readily available in the pharmacologically active form (AAPs Pharm Sci Tech 2006;7(2):E1-E7).  In a communication with the author, it was disclosed that 40 mg of epinephrine bitartrate in a sublingual tablet was equivalent to the amount of epinephrine obtained with an EpiPen (0.33 mg).

Side effects of epinephrine include; nervousness, increased heart rate, sweating, nausea, dizziness and headache, but wear off after 10 to 20 minutes.  In a study of the cardiovascular effects of epinephrine on hypertensive dental patients there was a small nonsignificant increase in systolic and diastolic blood pressure but no adverse outcomes (Oral Surg Oral Med Pathol Oral Radiol Endod 2002;93(6):647-53).

The U.S. House of Representatives voted on July 30, 2013 to approve, the School Access to Emergency Epinephrine Act (H.R. 2094) legislation championed by Food Allergy Research & Education (FARE) that will help protect students with food allergies.  The bill, introduced by Rep. Phil Roe, M.D. (R-TN) and Rep. Steny Hoyer (D-MD) encourages states to adopt laws requiring achools to have on hand “stock” epinephrine, not prescribed by a specific student to be used for any student or staff member in an anaphylactic emergency. 

In Canada, Motion 230, brought by the Canadian Anaphylaxis Initiative was debated on April 19, 2013 before Canada’s House of Commons.  The Anaphylaxis Survival Act would require private companies, schools, government offices, fitness facilities, arenas, dental offices, group homes, correctional service facilities, hotels, transportation centers, air carriers, and restaurants to have Epinephrine Kits on site and to train all employees in anaphylaxis first aid.  Epinephrine is available without a prescription in Canada.

Dr. Sandra Fryhofer, an internist and chair of the American Medical Association’s Council on Science and Public Health, said that the FDA is proposing increasing over-the-counter (OTC) access to medications such as epinephrine for allergic reactions.

Conclusion:

Availability of epinephrine and speed of administration are key to preventing deaths due to anaphylaxis.  If everyone with difficulty breathing due to an insect bite, asthmatic attack, food or drug allergy is required to be treated in an emergency room, the ER’s would be overwhelmed.  From 1993 to 2003 the US population grew by 12%, but ER visits grew by 27%.  During the same period, 425 ER departments closed along with about 700 hospitals and nearly 200,000 beds.  FasEpi® a fast-dissolving oral tablet of epinephrine, with the bioequivalent or near bioequivalent pharmacokinetic properties to EpiPen® would certainly present a viable option for people in need for a convenient, handy, quick and economic treatment of anaphylaxis.