EPIPEN (Page 2 of 5)

6 ADVERSE REACTIONS

Due to the lack of randomized, controlled clinical trials of epinephrine for the treatment of anaphylaxis, the true incidence of adverse reactions associated with the systemic use of epinephrine is difficult to determine. Adverse reactions reported in observational trials, case reports, and studies are listed below.

Common adverse reactions to systemically administered epinephrine include anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism [see Warnings and Precautions (5.5) ].

Cardiovascular Reactions

Arrhythmias, including fatal ventricular fibrillation, have been reported, particularly in patients with underlying cardiac disease or those receiving certain drugs [see Warnings and Precautions (5.5) and Drug Interactions (7)].
Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease [see Warnings and Precautions (5.5) ].
Angina may occur in patients with coronary artery disease [see Warnings and Precautions (5.5) ].
Rare cases of stress cardiomyopathy have been reported in patients treated with epinephrine.

Reactions from Accidental Injection and/or Improper Technique

Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area [see Warnings and Precautions (5.2) ].
Adverse reactions experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury.
Lacerations, bent needles, and embedded needles have been reported when EpiPen has been injected into the thigh of young children who are uncooperative and kick or move during the injection [see Warning and Precautions (5.2) ].
Injection into the buttock has resulted in cases of gas gangrene [see Warnings and Precautions (5.2) ].

Skin and Soft Tissue Infections

Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported following epinephrine injection, including EpiPen, in the thigh [see Warnings and Precautions (5.3) ].

7 DRUG INTERACTIONS

Cardiac Glycosides, Diuretics, and Anti-arrhythmics

Patients who receive epinephrine while concomitantly taking cardiac glycosides, diuretics, or anti-arrhythmics should be observed carefully for the development of cardiac arrhythmias [see Warnings and Precautions (5.5)].

Antidepressants, Monoamine Oxidase Inhibitors, Levothyroxine, and Antihistamines

The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine.

Beta-Adrenergic Blockers

The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta- adrenergic blocking drugs, such as propranolol.

Alpha-Adrenergic Blockers

The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha- adrenergic blocking drugs, such as phentolamine.

Ergot Alkaloids

Ergot alkaloids may also reverse the pressor effects of epinephrine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well controlled studies of the acute effect of epinephrine in pregnant women. In animal reproductive studies, epinephrine administered by the subcutaneous route to rabbits, mice, and hamsters during the period of organogenesis was teratogenic at doses 7 times and higher than the maximum recommended human intramuscular and subcutaneous dose on a mg/m2 basis. Epinephrine is the first-line medication of choice for the treatment of anaphylaxis during pregnancy in humans. Epinephrine should be used for treatment of anaphylaxis during pregnancy in the same manner as it is used in non-pregnant patients.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

During pregnancy, anaphylaxis can be catastrophic and can lead to hypoxic-ischemic encephalopathy and permanent central nervous system damage or death in the mother and, more commonly, in the fetus or neonate. The prevalence of anaphylaxis occurring during pregnancy is reported to be approximately 3 cases per 100,000 deliveries.

Management of anaphylaxis during pregnancy is similar to management in the general population. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in pregnant and non-pregnant patients. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care.

Data

Animal Data

In an embryofetal development study with rabbits dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including gastroschisis and embryonic lethality) at doses approximately 40 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous dose of 1.2 mg/kg/day for two to three days).

In an embryofetal development study with mice dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including embryonic lethality) at doses approximately 8 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at maternal subcutaneous dose of 1 mg/kg/day for 10 days). These effects were not seen in mice at approximately 4 times the maximum recommended daily intramuscular or subcutaneous dose (on a mg/m2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days).

In an embryofetal development study with hamsters dosed during the period of organogenesis from gestation days 7 to 10, epinephrine was shown to be teratogenic at doses approximately 7 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day).

8.2 Lactation

Risk Summary

There is no information on the presence of epinephrine in human milk, the effects on breastfed infants, or the effects on milk production. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in breastfeeding and non-breastfeeding patients.

8.4 Pediatric Use

EpiPen or EpiPen Jr may be administered to pediatric patients at a dosage appropriate to body weight [see Dosage and Administration (2.1) ]. Clinical experience with the use of epinephrine suggests that the adverse reactions seen in children are similar in nature and extent to those both expected and reported in adults. Since the doses of epinephrine delivered from EpiPen and EpiPen Jr are fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary.

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