EMERADE Solution for injection in a pre-filled pen Ref.[27518] Active ingredients: Epinephrine

Circulating adrenaline is metabolized in the liver and other tissues by the enzymes COMT and MAO. Inactive metabolites are excreted in the urine.

The half-life of adrenaline in plasma is about 2 to 3 minutes. However, when adrenaline is injected subcutaneously or intramuscularly the absorption is retarded by local vasoconstriction and thus the effects can last longer than as predicted by half-life. Massage around the injection site is advised to accelerate absorption.

In a comparative PK/PD study in healthy subjects of Emerade 300 mcg with other marketed adrenaline auto-injectors in the same strength but with shorter needles and higher propulsive force, an influence of propulsive force upon plasma adrenaline concentrations was indicated. Despite high variability in plasma adrenaline concentrations, devices with shorter needles demonstrated a trend to superior adrenaline bioavailability in the time critical first 30 minutes following injection, compared with Emerade. Therefore, despite a longer needle, plasma adrenaline concentrations appear to be lower following Emerade compared with devices that have shorter needles but higher propulsive force. The trend to inferiority for Emerade was more apparent in subjects with higher skin to muscle depth (STMD). The reasons for this are not understood but it underlines the importance of carrying two Emerade devices at all times.

A within-product (Emerade) comparative analysis was also conducted in healthy subjects with different STMD. In Cohort 1 (STMD ≥10, <15 mm) mean adrenaline concentrations displayed two peaks. An initial early peak was observed in the first 5 minutes, and a second peak was observed between 40 and 60 minutes. Concentrations in the initial peak were generally lower than concentrations in the second peak. A similar early peak could be observed for adrenaline concentrations following Emerade 300 μg or Emerade 500 μg in Cohorts 2 (STMD ≥15, ≤20 mm) and 3, (STMD >20 mm) although the initial peak was not as pronounced as in the first cohort. After Emerade 500 μg injection, adrenaline concentrations in Cohort 2 rapidly increased to a plateau around 8 minutes. The concentrations remained at this value steadily up to about 30 minutes, and then decreased for the remainder of the measured timepoints.

Due to the high variability of adrenaline plasma concentration observed in the conducted PK/PD studies, robust conclusions cannot be drawn.

Adrenaline bioavailability in healthy subjects who have well perfused subcutaneous tissue cannot necessarily be extrapolated to patients in established anaphylactic shock in whom there may peripheral circulatory shutdown. This underlines the importance of early administration of adrenaline at the first signs of anaphylaxis, while the superficial tissues are still well perfused, in order to maximise adrenaline uptake into the systemic circulation.

Adrenaline has been extensively used in the emergency treatment of severe allergic reactions for many years. There is no further preclinical data relevant for prescribers besides those already described in this SmPC.