Epinephrine for Anaphylaxis: Doses, Devices and What the Guidelines Say

Epinephrine, also called adrenaline, is the drug that allergy guidelines name first for anaphylaxis, the fast, whole-body allergic reaction that can close the airway and drop blood pressure. The 2020 United States anaphylaxis practice parameter states that epinephrine is the first-line drug treatment for anaphylaxis, both for a single reaction and for a reaction that comes back. The United States labels list the drug's first approval in the country as 1939, and they list no contraindications for its emergency use in allergic reactions.

This page reports what the labels and the research say about how epinephrine works, why it goes into the outer thigh muscle, the doses the labels give by body weight, the kinds of devices that deliver it, how often a second dose is needed, what the 2020 and 2023 practice parameters changed, the side effects the labels list, where the drug came from, and what is still not known. Devices are described by type only. The condition itself is covered on the Anaphylaxis page, and the step-by-step emergency plan used by people with alpha-gal syndrome is on the Alpha-Gal Anaphylaxis Emergency Plan page.

Table of Contents

  1. How Epinephrine Works: Alpha and Beta Receptors
  2. Why the Outer Thigh Muscle
  3. Doses by Body Weight on the US Labels
  4. The Kinds of Devices
  5. How Often a Second Dose Is Given
  6. Biphasic Reactions
  7. What the 2020 and 2023 Practice Parameters Say
  8. Emergency Services and Observation Time
  9. Side Effects and Cautions on the Labels
  10. Where Epinephrine Came From
  11. What Is Not Known
  12. Key Research Papers
  13. Connections
  14. Featured Videos

How Epinephrine Works: Alpha and Beta Receptors

Epinephrine is a catecholamine, the same family of chemical messengers the body itself uses in the fight-or-flight response. The labels describe it as acting on both alpha-adrenergic and beta-adrenergic receptors. These are two families of "docking sites" on cells. When epinephrine attaches to them, the cell changes what it is doing.

During anaphylaxis, immune cells release a flood of chemicals that make small blood vessels widen and leak. Fluid leaves the bloodstream, and blood pressure falls. At the same time, the muscles around the airways tighten. The labels explain what epinephrine does against each of these problems:

The labels state that when epinephrine is given under the skin or into a muscle, it acts quickly and its effect is short. In a 1998 study of children with a history of anaphylaxis, the average elimination half-life of injected epinephrine was 43 minutes (Simons 1998). This short action is one reason the labels describe epinephrine as emergency supportive therapy, not a substitute for medical care.

The same receptors explain some of the drug interactions on the labels. Beta-blocker drugs, such as propranolol, work against epinephrine's heart-stimulating and airway-opening effects. Alpha-blocker drugs, such as phentolamine, work against its blood-vessel-tightening and blood-pressure-raising effects. An interactive model of these effects is on the anaphylaxis and epinephrine animation page.

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Why the Outer Thigh Muscle

Epinephrine can be injected just under the skin (subcutaneously) or into a muscle (intramuscularly). Two small studies by a group at the University of Manitoba measured how quickly the drug reaches the blood by each route. The 1998 authors wrote that the recommendations for injection under the skin in children were based on anecdotal experience.

Children (1998). In a randomized, blinded study of 17 children with a history of anaphylaxis, nine received epinephrine under the skin and eight received 0.3 mg into the muscle from an auto-injector. In the under-the-skin group, the highest blood level came at an average of 34 minutes, with a range from 5 to 120 minutes, and only two of the nine children reached their peak by 5 minutes. In the muscle group, the peak came at an average of 8 minutes, and six of the eight children reached it by 5 minutes. No serious adverse effects were seen in any child. The authors wrote that the intramuscular route is preferable (Simons 1998).

Adults (2001). In a randomized, blinded, placebo-controlled crossover study in young men, peak blood epinephrine levels were significantly higher after an injection into the thigh muscle than after an injection into the muscle of the upper arm or under the skin of the upper arm. The authors named the thigh muscle as the preferred route and site for the first treatment of anaphylaxis (Simons 2001).

The current labels follow this. The auto-injector labels give the front-and-outer part of the thigh (the anterolateral thigh) as the injection site and state that the injection can be given through clothing. They warn against injecting into a vein, into the buttock, or into fingers, toes, hands or feet, and they give the reasons:

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Doses by Body Weight on the US Labels

Ready-to-use epinephrine devices hold a fixed dose, so the labels assign each strength to a weight band rather than calculating a dose for each person. The figures below are what the United States labels give.

Injected epinephrine (auto-injectors)

Each auto-injector is a single dose for a single use. The generic auto-injector label notes that because the doses are fixed, other forms of injectable epinephrine are the option when a dose lower than 0.15 mg is judged necessary; the voice-guided label says the same for doses below 0.1 mg. The generic label also explains that the device holds 2 mL of solution and that about 1.7 mL stays inside after it fires. That leftover liquid is not available as a second dose.

Epinephrine nasal spray

The nasal spray label, revised in March 2026, states that the spray's safety and effectiveness have not been established in children who weigh less than 15 kg. The original 2024 approval of the spray, which covered people of at least 30 kg, is described on the FDA approval of the first needle-free epinephrine page.

Second doses and the limit of two

The voice-guided auto-injector label and the nasal spray label both state that if there is no improvement, or if symptoms get worse, a second dose may be given with a new device starting 5 minutes after the first. For the nasal spray, the second spray goes into the same nostril. The generic auto-injector label states that repeat injections may be necessary with severe, persistent anaphylaxis. All three labels state that more than two doses in a row are given only under direct medical supervision.

How the weight bands compare with weight-based dosing

In hospitals, injected epinephrine is often dosed by weight. A 2022 review by Dreborg and colleagues notes that a dose of 0.01 mg per kilogram of body weight has been "arbitrarily recommended," and that for ethical reasons there have been no dose-response studies or double-blind studies in people having anaphylaxis. The review reports that auto-injectors exist worldwide in four strengths (0.1, 0.15, 0.3 and 0.5 mg), but that in many countries only the 0.15 mg and 0.3 mg strengths are sold. As a result, the authors write, many heavy adults are prescribed 0.3 mg, which may give them only one-fifth to one-third of the weight-based dose. They propose weight-based prescribing, with possible exceptions such as heart disease (Dreborg 2022).

Guidelines also differ on where to draw the lines. A 2024 review of 12 pediatric anaphylaxis guidelines from several countries found that 6 gave weight-based auto-injector dosing and 5 gave age-based dosing, and that the weight cutoffs for the 0.15 mg and 0.3 mg devices differed between guidelines (Athanasopoulou 2024).

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The Kinds of Devices

Several kinds of products deliver epinephrine outside a hospital. They are described here by type only.

What the nasal spray label adds

The nasal spray label states that its studies included people with a history of hay fever, but not people with structural nasal problems such as nasal polyps, past nasal fractures or injuries, or past nasal surgery. It states that absorption may be affected in those people and that products given by other routes are an option for them. The label also states that the spray may change the lining of the nose for up to 2 weeks after use, which may increase how much of any nasal product, including another dose of the spray, is absorbed.

A separate, higher-dose nasal spray has also been studied. A 2024 pooled analysis of four early-phase studies in healthy adults compared a 13.2 mg nasal spray, which the authors describe as under development, with a 0.3 mg auto-injector. The median time to the highest blood level was 25.1 minutes with sprays in opposite nostrils, 20.1 minutes with sprays in the same nostril, and 20.0 minutes with the auto-injector. Total exposure over 6 hours was higher with the spray, and the effects on heart rate and blood pressure were similar in pattern and size (Greenhawt 2024). This 13.2 mg spray is a different product from the 1 mg and 2 mg sprays on the United States label.

Storage on the labels

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How Often a Second Dose Is Given

For years, people at risk of anaphylaxis have been told to carry two epinephrine devices. A 2021 systematic review and meta-analysis by Patel and colleagues asked how often a second dose is actually used. It pooled 86 studies covering 36,557 anaphylaxis events caused by food or insect venom, published from 1946 to January 2020. Twenty of the studies were prospective, and 64 reported reactions in the community.

The review notes a split in advice: regulatory bodies recommend that everyone at risk be prescribed two auto-injectors to carry at all times, while some guidelines do not (Patel 2021).

A 2024 review by Shaker, Anagnostou and Greenhawt adds a timing point. Based on how epinephrine is absorbed and how the body responds to it, the authors report that the peak response is more likely to come closer to 15 minutes than before 5 minutes, and that few patients need a second dose because most stabilize within 15 minutes. They write that earlier food-allergy guidance to give a second dose if there was no response within 5 minutes, and the rule that everyone carry two auto-injectors at all times, have lacked evidence of better outcomes (Shaker 2024). The voice-guided auto-injector and nasal spray labels, for their part, still allow a second dose starting at 5 minutes, and the labels still describe having two devices at hand at all times. The two sources differ, and both positions are reported here.

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Biphasic Reactions

A biphasic reaction is a return of anaphylaxis symptoms hours after the first reaction settled, without any new contact with the trigger. It is one of the reasons emergency departments watch people after treatment.

A 2015 systematic review and meta-analysis by Lee and colleagues pooled 27 observational studies that enrolled 4,114 people with anaphylaxis, among whom 192 had a biphasic reaction. The second wave began a median of 11 hours after the first reaction, with a range from 0.2 to 72 hours. The review found:

The authors concluded that observation periods are best matched to each person's features (Lee 2015).

The 2020 practice parameter names severe anaphylaxis and the need for repeated doses of epinephrine as risk factors for a biphasic reaction. It states that antihistamines and steroid drugs (glucocorticoids) are not reliable ways to prevent a biphasic reaction, and that epinephrine is the first-line drug treatment for the second wave as well as the first (Shaker 2020).

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What the 2020 and 2023 Practice Parameters Say

In the United States, the main anaphylaxis guidance comes from practice parameters prepared through the Joint Task Force on Practice Parameters. Two recent editions matter most for epinephrine.

The 2020 practice parameter

The 2020 update combined a systematic review with GRADE (Grading of Recommendations, Assessment, Development and Evaluation) analysis. Its summary statements include these points (Shaker 2020):

The 2023 practice parameter

The 2023 update focused on seven areas with new evidence and new recommendations (Golden 2023). Among them:

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Emergency Services and Observation Time

The 2023 change on calling emergency services was explained in a 2024 review by Shaker, Anagnostou and Greenhawt on whether patients can treat their anaphylaxis at home. The review describes what had been standard practice and why it changed (Shaker 2024):

The authors conclude that immediate activation of emergency services is no longer required every time self-injected epinephrine is used outside a hospital. The device labels take a different line. The generic auto-injector label describes the device as emergency supportive therapy that is not a substitute for immediate medical care and states that the patient seeks immediate medical or hospital care along with using it. The nasal spray and voice-guided labels describe advising patients on when to seek emergency help for close monitoring and further treatment. Both positions are part of the current record.

The auto-injector label lists the signs of an anaphylactic reaction as flushing, apprehension, fainting, a fast heartbeat, a weak or absent pulse with a fall in blood pressure, seizures, vomiting, diarrhea and stomach cramps, loss of bladder control, wheezing, shortness of breath from a spasm of the voice box, itching, rashes, hives and deep swelling. Symptoms that do not improve, or that get worse, after the first dose are the point at which the labels describe a second dose. The six-step plan used by people with alpha-gal syndrome, including how emergency calls are described in written action plans, is set out on the Alpha-Gal Anaphylaxis Emergency Plan page.

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Side Effects and Cautions on the Labels

Common effects

The auto-injector label lists the common effects of epinephrine in the body as anxiety, apprehension, restlessness, tremor, weakness, dizziness, sweating, a pounding heartbeat (palpitations), paleness, nausea and vomiting, headache and breathing difficulty. It states that these occur in some people at normal doses and are more likely in people with high blood pressure or an overactive thyroid. The label also states that because there are no randomized, controlled trials of epinephrine for anaphylaxis, the true rate of side effects is hard to know; the effects listed come from observational studies, case reports and other studies.

The nasal spray label gives figures from its four studies in 175 adults without anaphylaxis. After one 2 mg dose, the most common effects were nasal discomfort (10%), headache (6%), and runny nose, dizziness and nausea (3% each). After two doses given 10 minutes apart, throat irritation (19%), headache (18%), nasal discomfort (13%), feeling jittery (11%) and tremor (8%) were among the most common.

Serious effects the labels report

The nasal spray label states that an overdose of epinephrine can raise blood pressure to extreme levels, which may cause bleeding in the brain, particularly in older people, and can also cause fluid in the lungs.

Conditions the labels name

The labels describe giving epinephrine with caution to people with heart disease, including abnormal heart rhythms, coronary artery disease or high blood pressure, and state that in these people it may bring on or worsen angina and cause dangerous heart rhythms. They also name an overactive thyroid, diabetes, older age and pregnancy, and state that people with Parkinson's disease may notice a temporary worsening of symptoms; the nasal spray label adds kidney impairment. The labels then state that none of these conditions is a contraindication to epinephrine in an acute, life-threatening situation.

The labels also state that the sulfite preservative in epinephrine products is not a reason to withhold the drug in a serious allergic emergency, even for a person sensitive to sulfites, because the alternatives to epinephrine in a life-threatening situation may not be satisfactory.

Drug interactions on the labels

Pregnancy

The nasal spray label states that several decades of published experience with epinephrine in pregnant women have not identified a drug-related risk of major birth defects, miscarriage or poor outcomes for mother or baby. It states that anaphylaxis in pregnancy can be catastrophic, leading to brain injury from lack of oxygen or death in the mother and, more commonly, in the fetus or newborn.

How a safety review weighs it

A 2025 narrative review by Bernstein and colleagues set out to describe the safety of epinephrine given for anaphylaxis. It reports that heart and blood vessel side effects are the greatest safety concern, and that these events and overdoses are significantly more likely after an accidental injection straight into a vein than after an injection into muscle. Serious side effects have been reported with injections into muscle, and some people carry risk factors for heart events, but the review finds no absolute contraindication in a life-threatening situation. It describes epinephrine for anaphylaxis as underused, and links some of the hesitancy to fear of injection and to a common unsupported belief that the drug is dangerous. The authors conclude that the potential harm of delaying or withholding epinephrine in anaphylaxis far outweighs the potential risk of side effects (Bernstein 2025).

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Where Epinephrine Came From

Epinephrine is described as the first hormone isolated in the twentieth century. Its story involves an American pharmacologist, a Japanese chemist working in the United States, and an assistant whose part was long overlooked.

Writing on the hormone's centenary in 1999, the physiologist Max Bennett described the active principle of adrenal gland extract, the part that raises blood pressure, as isolated "by the joint research of John Abel in 1899 and Jokichi Takamine in 1901." Within three years, he writes, Elliott, working in Langley's laboratory, suggested that this substance was released from sympathetic nerve endings to act on smooth muscle. Bennett notes that it was not until 1946 that von Euler showed that the nerve messenger is in fact the closely related noradrenaline (Bennett 1999).

A 2003 biography of Takamine (1854 to 1922) states that he crystallized the hormone from the inner part of the adrenal gland, the adrenal medulla, in the summer of 1900, and calls it the first hormone isolated in the twentieth century (Yamashima 2003).

A 2020 study by Mieda and colleagues gives credit to a third person. Keizo Uenaka, Takamine's assistant, kept a handwritten memorandum titled "On Adrenaline, Memorandum, July to December, 1900," now held in a Buddhist temple in Japan. The authors compared it with Takamine's published reports in the American Journal of Pharmacy (1901) and the Journal of Physiology (1901), and with a Japanese version published in 1903. They concluded that Uenaka's precise procedures were carried over into the published papers, and that he was the main scientist who did the actual purification work (Mieda 2020).

Abel's long effort to isolate the hormone, and how its discovery is credited, is told in detail on the Epinephrine and Crystalline Insulin: John Jacob Abel's Hunt for Pure Hormones page. The physiologist who named the reaction anaphylaxis is described on the Charles Richet page.

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What Is Not Known

Decisions about epinephrine prescriptions, device choice and action plans belong with a clinician who knows the person's history.

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Key Research Papers

  1. Shaker MS, Wallace DV, Golden DBK, Oppenheimer J, Bernstein JA, Campbell RL, Dinakar C, Ellis A, Greenhawt M, Khan DA, Lang DM, Lang ES, Lieberman JA, Portnoy J, Rank MA, Stukus DR, Wang J, et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. The Journal of Allergy and Clinical Immunology. 2020;145(4):1082-1123. — PubMed PMID: 32001253
  2. Golden DBK, Wang J, Waserman S, Akin C, Campbell RL, Ellis AK, Greenhawt M, Lang DM, Ledford DK, Lieberman J, Oppenheimer J, Shaker MS, Wallace DV, Abrams EM, Bernstein JA, Chu DK, Horner CC, Rank MA, Stukus DR, et al. Anaphylaxis: A 2023 practice parameter update. Annals of Allergy, Asthma & Immunology. 2024;132(2):124-176. — PubMed PMID: 38108678
  3. Shaker MS, Anagnostou A, Greenhawt M. To the ER? Can Patients Treat Their Anaphylaxis at Home? Current Allergy and Asthma Reports. 2024;24(11):623-629. — PubMed PMID: 39222197
  4. Patel N, Chong KW, Yip AYG, Ierodiakonou D, Bartra J, Boyle RJ, Turner PJ. Use of multiple epinephrine doses in anaphylaxis: A systematic review and meta-analysis. The Journal of Allergy and Clinical Immunology. 2021;148(5):1307-1315. — PubMed PMID: 33862009
  5. Lee S, Bellolio MF, Hess EP, Erwin P, Murad MH, Campbell RL. Time of Onset and Predictors of Biphasic Anaphylactic Reactions: A Systematic Review and Meta-analysis. The Journal of Allergy and Clinical Immunology: In Practice. 2015;3(3):408-16.e1-2. — PubMed PMID: 25680923
  6. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. The Journal of Allergy and Clinical Immunology. 1998;101(1 Pt 1):33-7. — PubMed PMID: 9449498
  7. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. The Journal of Allergy and Clinical Immunology. 2001;108(5):871-3. — PubMed PMID: 11692118
  8. Dreborg S, Walter G, Kim H. International recommendations on epinephrine auto-injector doses often differ from standard weight-based guidance: a review and clinical proposals. Allergy, Asthma, and Clinical Immunology. 2022;18(1):102. — PubMed PMID: 36471385
  9. Athanasopoulou SG, Leeds S, Auerbach M. Variation in the Guidelines for the Acute Management of Anaphylaxis in Pediatric Patients: An International Narrative Review. Pediatric Emergency Care. 2024;40(3):233-238. — PubMed PMID: 37358800
  10. Greenhawt M, Lieberman J, Blaiss M, Bernstein DI, Oppenheimer J, DuBuske L, Fleischer D, Dworaczyk DA. Pharmacokinetic and Pharmacodynamic Profile of Epinephrine Nasal Spray Versus Intramuscular Epinephrine Autoinjector in Healthy Adults. The Journal of Allergy and Clinical Immunology: In Practice. 2024;12(12):3274-3282.e2. — PubMed PMID: 39395775
  11. Bernstein DI, Blaiss M, Dellon ES, Rance K. Benefits of Epinephrine for Anaphylaxis Outweigh Potential Harm-A Safety Review. The Journal of Allergy and Clinical Immunology: In Practice. 2025;13(12):3188-3194. — PubMed PMID: 40254271
  12. Bennett MR. One hundred years of adrenaline: the discovery of autoreceptors. Clinical Autonomic Research. 1999;9(3):145-59. — PubMed PMID: 10454061
  13. Yamashima T. Jokichi Takamine (1854-1922), the samurai chemist, and his work on adrenalin. Journal of Medical Biography. 2003;11(2):95-102. — PubMed PMID: 12717538
  14. Mieda R, Aso C, Hiroki T, Kanamoto M, Suto T, Tobe M, Saito S. Comparison of four documents describing adrenaline purification, and the work of three important scientists, Keizo Uenaka, Nagai Nagayoshi and Jokichi Takamine. Journal of Anesthesia History. 2020;6(2):42-48. — PubMed PMID: 32593376

Label sources: United States prescribing information on DailyMed (National Library of Medicine) for the generic epinephrine injection auto-injector (0.3 mg and 0.15 mg), for a voice-guided epinephrine auto-injector (0.3 mg, 0.15 mg and 0.1 mg), and for epinephrine nasal spray (2 mg and 1 mg; revised March 2026). — DailyMed: epinephrine labels

PubMed Topic Searches

  1. PubMed: intramuscular epinephrine in the thigh for anaphylaxis
  2. PubMed: epinephrine auto-injector dose and body weight
  3. PubMed: second and multiple epinephrine doses in anaphylaxis
  4. PubMed: biphasic anaphylaxis and observation time
  5. PubMed: epinephrine nasal spray

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Connections

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