Pharmacology Consult

Epinephrine auto-injectors: The expense behind potentially lifesaving medication

For children diagnosed with allergies to food, insect venom, drugs, or other allergenic substances, epinephrine auto-injectors can be lifesaving. Epinephrine auto-injectors have made the lay media headlines recently, because their significant price increases have sparked concerns among many families and health care professionals alike. Although the AAP and several professional allergy organizations have published treatment guidelines on anaphylaxis and the role of epinephrine, it is crucial for clinicians to extend that education to patients and their parents, including the appropriate use of epinephrine auto-injector devices currently on the market.

The role of epinephrine and antihistamines

Food, including peanuts and other nuts, eggs, milk, and fish (crustaceans, finned fish), are the most common causes of anaphylaxis in children. In addition, insect venom (ie, stings) and drugs (eg, antibiotics) are responsible for anaphylactic reactions in children. Diagnostic criteria for anaphylaxis include an acute onset of illness with involvement of the skin, mucosal tissue (or both), plus respiratory compromise or end-organ dysfunction; two or more of the following symptoms: skin involvement, respiratory compromise, hypotension or associated symptoms and persistent gastrointestinal symptoms; or reduced blood pressure.

Edward A. Bell

Considered the first-line treatment for the immediate treatment of anaphylaxis, epinephrine has been demonstrated to reduce or prevent hospitalization and reduce mortality, whereas delays in administering an epinephrine auto-injector (EAI) have been shown to increase hospitalization and risks of adverse outcomes, including death. Epinephrine has numerous beneficial physiologic effects, including countering anaphylaxis-induced vasodilation with vasoconstrictive effects, as well as the lessening of upper airway mucosal edema and respiratory compromise via its alpha-receptor and beta-receptor adrenergic agonist pharmacologic actions.

Although additional pharmacotherapies can be used to treat anaphylaxis symptoms, including H1 antihistamines (eg, loratadine and diphenhydramine) and H2 antihistamines (eg, ranitidine), their role is supportive only, and they should not be relied on as initial therapy or as a replacement for an EAI. No data directly support the use of antihistamines for the treatment of anaphylaxis.

Benefits of H1 antihistamine use, as indicated by their use in other allergic conditions, may relieve allergic skin symptoms — itching, urticaria and flushing — as well as gastrointestinal symptoms. However, it is important to realize that antihistamines do not treat the adverse respiratory and vasoactive components of anaphylaxis, and thus should not be considered as a first-line or initial substitutive therapy for an EAI device.

Because most episodes of anaphylaxis occur outside of a medical facility, availability of an EAI and familiarity with its use by children with serious allergies or their family members is paramount. A child or family member is more likely to accurately administer emergency epinephrine through an EAI than from an ampule or vial with a syringe, methods that are both time consuming and more difficult.

Intramuscular administration of epinephrine into the lateral thigh muscle (vastus lateralis), as recommended with all available EAI devices, has been shown to result in faster and higher plasma concentrations of epinephrine vs. subcutaneous administration or intramuscular administration into the deltoid muscle.

Devices and their prices

EAI devices are available in two doses — 0.15 mg and 0.3 mg. Weight-based dosing of epinephrine given intramuscularly is traditionally described as 0.01 mg/kg, although no data from dose-response studies or other direct evidence support this dosing regimen. This is important to keep in mind when determining a proper dose for younger children with lower weights. Dosing for intramuscular administration of EAI is often listed as 0.15 mg and 0.3 mg for infants and children with weights of 15 to 29 kg, and 30 kg or more, respectively.

Recently published guidelines from the AAP recommend prescribing the 0.15 mg EAI dose for infants and children weighing less than 30 kg, and the 0.3 mg EAI dose for children weighing 25 to 30 kg and greater. One or two additional doses may be repeated every 5 to 15 minutes if the child does not significantly improve after the initial dose. Although intramuscular administration of epinephrine is safe and effective for the treatment of anaphylaxis, as with all pharmacotherapies, adverse events can occur, including pallor, palpitations, tremor and anxiety.

EAI devices have attracted the attention of the lay media recently owing to significant pricing spikes — about 500% or more over the past several years. Three EAI trade products are currently available (Table), with varying prices. EpiPen products (Mylan) comprise the majority of the EAI market share, and they recently have become available as generic products, likely due to increasing public concerns over their dramatic price increases.

Although all available EAI devices are clinically effective, patient-specific product prescribing and choice depends on familiarity and comfort with use of the device by the child and family, in addition to pricing — which is contingent upon the family’s insurance availability and income. For example, the EAI devices differ by the manufacturer’s recommended length of time for administration (intramuscular needle insertion time), varying from 3 seconds for EpiPen, 5 seconds for Auvi-Q (Kaleo), and 10 seconds for Adrenaclick (Amedra Pharmaceuticals).

All EAI products are available as packages containing two auto-injectors, and it is recommended that children carry both devices, not just one, because a second dose may be necessary for emergency treatment. As noted in the Table, the actual price the patient pays for an EAI relies on many variables, including the availability of insurance and specific insurance co-pays and deductibles.

As discussed in the January column of Pharmacology Consult, determination of drug costs and pricing is complex. Prices charged to health insurers, private payers, governmental agencies, and a drug’s “list” price, significantly vary for all drugs. All EAI manufacturers provide various savings cards, co-pay coupons or other out-of-pocket cost-reduction programs. The exact price patients pay depends on these factors.

Prescribers can benefit patients through their familiarity with state Medicaid and health insurance preferred drug formularies. Additional information on specific manufacturer discount cards can be obtained on the EAI manufacturer’s website. Patient families may further benefit from discussion of cost concerns with their local pharmacy staff.

Disclosure: Bell reports no relevant financial disclosures.

For children diagnosed with allergies to food, insect venom, drugs, or other allergenic substances, epinephrine auto-injectors can be lifesaving. Epinephrine auto-injectors have made the lay media headlines recently, because their significant price increases have sparked concerns among many families and health care professionals alike. Although the AAP and several professional allergy organizations have published treatment guidelines on anaphylaxis and the role of epinephrine, it is crucial for clinicians to extend that education to patients and their parents, including the appropriate use of epinephrine auto-injector devices currently on the market.

The role of epinephrine and antihistamines

Food, including peanuts and other nuts, eggs, milk, and fish (crustaceans, finned fish), are the most common causes of anaphylaxis in children. In addition, insect venom (ie, stings) and drugs (eg, antibiotics) are responsible for anaphylactic reactions in children. Diagnostic criteria for anaphylaxis include an acute onset of illness with involvement of the skin, mucosal tissue (or both), plus respiratory compromise or end-organ dysfunction; two or more of the following symptoms: skin involvement, respiratory compromise, hypotension or associated symptoms and persistent gastrointestinal symptoms; or reduced blood pressure.

Edward A. Bell

Considered the first-line treatment for the immediate treatment of anaphylaxis, epinephrine has been demonstrated to reduce or prevent hospitalization and reduce mortality, whereas delays in administering an epinephrine auto-injector (EAI) have been shown to increase hospitalization and risks of adverse outcomes, including death. Epinephrine has numerous beneficial physiologic effects, including countering anaphylaxis-induced vasodilation with vasoconstrictive effects, as well as the lessening of upper airway mucosal edema and respiratory compromise via its alpha-receptor and beta-receptor adrenergic agonist pharmacologic actions.

Although additional pharmacotherapies can be used to treat anaphylaxis symptoms, including H1 antihistamines (eg, loratadine and diphenhydramine) and H2 antihistamines (eg, ranitidine), their role is supportive only, and they should not be relied on as initial therapy or as a replacement for an EAI. No data directly support the use of antihistamines for the treatment of anaphylaxis.

Benefits of H1 antihistamine use, as indicated by their use in other allergic conditions, may relieve allergic skin symptoms — itching, urticaria and flushing — as well as gastrointestinal symptoms. However, it is important to realize that antihistamines do not treat the adverse respiratory and vasoactive components of anaphylaxis, and thus should not be considered as a first-line or initial substitutive therapy for an EAI device.

Because most episodes of anaphylaxis occur outside of a medical facility, availability of an EAI and familiarity with its use by children with serious allergies or their family members is paramount. A child or family member is more likely to accurately administer emergency epinephrine through an EAI than from an ampule or vial with a syringe, methods that are both time consuming and more difficult.

Intramuscular administration of epinephrine into the lateral thigh muscle (vastus lateralis), as recommended with all available EAI devices, has been shown to result in faster and higher plasma concentrations of epinephrine vs. subcutaneous administration or intramuscular administration into the deltoid muscle.

Devices and their prices

EAI devices are available in two doses — 0.15 mg and 0.3 mg. Weight-based dosing of epinephrine given intramuscularly is traditionally described as 0.01 mg/kg, although no data from dose-response studies or other direct evidence support this dosing regimen. This is important to keep in mind when determining a proper dose for younger children with lower weights. Dosing for intramuscular administration of EAI is often listed as 0.15 mg and 0.3 mg for infants and children with weights of 15 to 29 kg, and 30 kg or more, respectively.

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Recently published guidelines from the AAP recommend prescribing the 0.15 mg EAI dose for infants and children weighing less than 30 kg, and the 0.3 mg EAI dose for children weighing 25 to 30 kg and greater. One or two additional doses may be repeated every 5 to 15 minutes if the child does not significantly improve after the initial dose. Although intramuscular administration of epinephrine is safe and effective for the treatment of anaphylaxis, as with all pharmacotherapies, adverse events can occur, including pallor, palpitations, tremor and anxiety.

EAI devices have attracted the attention of the lay media recently owing to significant pricing spikes — about 500% or more over the past several years. Three EAI trade products are currently available (Table), with varying prices. EpiPen products (Mylan) comprise the majority of the EAI market share, and they recently have become available as generic products, likely due to increasing public concerns over their dramatic price increases.

Although all available EAI devices are clinically effective, patient-specific product prescribing and choice depends on familiarity and comfort with use of the device by the child and family, in addition to pricing — which is contingent upon the family’s insurance availability and income. For example, the EAI devices differ by the manufacturer’s recommended length of time for administration (intramuscular needle insertion time), varying from 3 seconds for EpiPen, 5 seconds for Auvi-Q (Kaleo), and 10 seconds for Adrenaclick (Amedra Pharmaceuticals).

All EAI products are available as packages containing two auto-injectors, and it is recommended that children carry both devices, not just one, because a second dose may be necessary for emergency treatment. As noted in the Table, the actual price the patient pays for an EAI relies on many variables, including the availability of insurance and specific insurance co-pays and deductibles.

As discussed in the January column of Pharmacology Consult, determination of drug costs and pricing is complex. Prices charged to health insurers, private payers, governmental agencies, and a drug’s “list” price, significantly vary for all drugs. All EAI manufacturers provide various savings cards, co-pay coupons or other out-of-pocket cost-reduction programs. The exact price patients pay depends on these factors.

Prescribers can benefit patients through their familiarity with state Medicaid and health insurance preferred drug formularies. Additional information on specific manufacturer discount cards can be obtained on the EAI manufacturer’s website. Patient families may further benefit from discussion of cost concerns with their local pharmacy staff.

Disclosure: Bell reports no relevant financial disclosures.