Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Mercury Pharmaceuticals Ltd, Capital House, 85 King William Street, London EC4N 7BL, UK
Pharmacotherapeutic group: Hypnotics and sedatives (benzodiazepine derivatives)
ATC code: N05CD08
Midazolam is a derivative of the imidazobenzodiazepine group. The free base is a lipophilic substance with low solubility in water.
The basic nitrogen in position 2 of the imidazobenzodiazepine ring system enables the active ingredient of midazolam to form water-soluble salts with acids. These produce a stable and well tolerated injection solution.
The pharmacological action of midazolam is characterised by short duration because of rapid metabolic transformation. Midazolam has a sedative and sleep-inducing effect of pronounced intensity. It also exerts an anxiolytic, an anticonvulsant and a muscle-relaxant effect.
After i.m. or i.v. administration anterograde amnesia of short duration occurs (the patient does not remember events that occurred during the maximal activity of the compound).
Absorption of midazolam from the muscle tissue is rapid and complete. Maximum plasma concentrations are reached within 30 minutes. The absolute bioavailability after i.m. injection is over 90%.
When midazolam is injected i.v., the plasma concentration-time curve shows one or two distinct phases of distribution. The volume of distribution at steady state is 0.7 – 1.2 l/kg. 96 – 98% of midazolam is bound to plasma proteins. The major fraction of plasma protein binding is due to albumin. There is a slow and insignificant passage of midazolam into the cerebrospinal fluid. In humans, midazolam has been shown to cross the placenta slowly and to enter foetal circulation. Small quantities of midazolam are found in human milk.
Midazolam is almost entirely eliminated by biotransformation. The fraction of the dose extracted by the liver has been estimated to be 30 – 60%. Midazolam is hydroxylated by the cytochrome P4503A4 isozyme and the major urinary and plasma metabolite is alpha-hydroxymidazolam. Plasma concentrations of alpha-hydroxymidazolam are 12% of those of the parent compound. Alpha-hydroxymidazolam is pharmacologically active, but contributes only minimally (about 10%) to the effects of intravenous midazolam.
In healthy volunteers, the elimination half-life of midazolam is between 1.5 – 2.5 hours. Plasma clearance is in the range of 300 – 500ml/min. Midazolam is excreted mainly by renal route (60 – 80% of the injected dose) and recovered as glucuroconjugated alpha-hydroxymidazolam. Less than 1% of the dose is recovered in urine as unchanged drug. The elimination half-life of alpha-hydroxy-midazolam is shorter than 1 hour. When midazolam is given by i.v. infusion, its elimination kinetics do not differ from those following bolus injection.
In adults over 60 years of age, the elimination half-life may be prolonged up to four times.
The elimination half-life after i.v. administration is shorter in children 3 – 10 years old (1 – 1.5 hours) as compared with that in adults. The difference is consistent with an increased metabolic clearance in children.
In neonates the elimination half-life is on average 6 – 12 hours, probably due to liver immaturity and the clearance is reduced (see section 4.4).
The mean half-life is greater in obese than in non-obese patients (5.9 vs 2.3 hours). This is due to an increase of approximately 50% in the volume of distribution corrected for total body weight. The clearance is not significantly different in obese and non-obese patients.
The elimination half-life in cirrhotic patients may be longer and the clearance smaller as compared to those in healthy volunteers (see section 4.4).
The elimination half-life in patients with chronic renal failure is similar to that in healthy volunteers.
The elimination half-life of midazolam is prolonged up to six times in the critically ill.
The elimination half-life is longer in patients with congestive heart failure compared with that in healthy subjects (see section 4.4).
There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
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