Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: PRIMEX PHARMACEUTICALS OY, Mariankatu 21 C, 00170 Helsinki, Finland
Pharmacotherapeutic group: benzodiazepines
ATC code: N05CD08
Midazolam is a derivative of the imidazobenzodiazepine group. The pharmacological effects of benzodiazepines result from reversible interactions with the γ-amino butyric acid (GABA) receptor of the benzodiazepines in the central nervous system, the principal inhibitory neurotransmitter in the central nervous system.
The pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepines, include sedative, anxiolytic, amnesic (anterograde amnesia), hypnotic, muscle relaxant and anticonvulsant effects.
The pharmacological action of midazolam is characterised by a short duration of action due to rapid metabolic transformation. The action of midazolam is easily reversed by the benzodiazepine receptor antagonist: flumazenil.
The data from published reports of studies in paediatric patients clearly demonstrate that oral midazolam acts as a sedative and an anxiolytic prior to a surgical procedure requiring anaesthesia as well as in other medical procedures requiring sedation without anaesthesia.
Several studies have been conducted involving hundreds of children requiring moderate sedation before anaesthetic premedication or medical procedure. These children received a single dose of oral midazolam (without combining another central nervous system depressant drug). Maximum sedation was generally reached within 30 to 45 minutes following administration of midazolam for a dose of midazolam between 0.25 and 1.0 mg/kg. Similar data were obtained for the anxiolytic effect. The sedative effects were obtained for plasma midazolam concentrations between 30 and 160 ng/ml and an EC50 ranging between 18 and 171 ng/ml depending on the method used to evaluate sedation (paediatric and adult data).
A study involving Ozalin has been conducted in paediatric patients aged between 6 months and 17 years of age requiring anaesthetic premedication. The findings from this study are consistent with those of the literature. Sedative and anxiolytic effects were observed within 30 minutes following oral administration of a single dose of Ozalin of 0.269 mg/kg on average and a plasma midazolam concentration between 15 and 65 ng/ml. An EC50 of 53.82 ng/ml was observed following oral administration of Ozalin at a dose of 15 mg (0.245 mg/kg on average) in healthy adult subjects. There are no data in non-fasted children from 6 months to 17 years old receiving a single oral dose of Ozalin.
Midazolam is absorbed rapidly and completely following oral administration.
The peak plasma concentration (Cmax) is achieved in 30 to 60 minutes (Tmax) following oral administration of midazolam. A Cmax between 70 and 154 ng/ml has been reported after administration of a dose of 15 mg in healthy adults. A Cmax ranging from 30 to 200 ng/ml has been reported according to the dose administered (from 0.25 to 1.0 mg/kg) and to the age of the child (from 6 months to 17 years of age).
Bioavailability varies between 30 and 50% depending on the study and the oral formulation used.
After administration of a single dose of Ozalin orally, Cmax was achieved in 35 to 45 minutes (median Tmax) in adult and adolescent subjects, respectively. From the population pharmacokinetics (Pop-PK) analysis including adults and paediatric data, most midazolam is absorbed within 30 minutes of administering Ozalin.
Following a 15 mg (0.245 mg/kg on average) oral dose of Ozalin, a Cmax of 113 ng/ml was obtained in healthy adult subjects. With an Ozalin dose of 0.12 to 0.30 mg/kg, a mean Cmax of 40.8 ng/ml was reached in children.
The absolute bioavailability of orally administered midazolam is 39.4% in adults who received one 15 mg dose of Ozalin.
Tissue distribution of oral midazolam is very rapid and, in most cases, the distribution phase is not apparent or is essentially completed within 1 to 2 hours of oral administration. Midazolam is very lipophilic and extensively distributed. Midazolam is highly bound to plasma proteins (in the region of 96-98%), and primarily to albumin.
The passage of midazolam into the cerebrospinal fluid is slow and insignificant. In humans, midazolam crosses the placental barrier and slowly enters foetal circulation. Small amounts of midazolam are found in breast milk.
The volume of distribution at steady state is between 1.0 and 2.5 l/kg and up to 6.6 l/kg.
The volume of distribution of midazolam is 4.7 l/kg in healthy adult subjects.
From the Pop PK analysis, the central volume of distribution and the peripheral volume of distribution were estimated at 27.9 l at 413 l, respectively, for a typical subject of 34 kg.
Midazolam is almost completely eliminated by biotransformation. Midazolam is hydroxylated by the CYP3A4 enzyme and the main urinary and plasma metabolite is α-hydroxymidazolam. Plasma concentrations of α-hydroxymidazolam are 30 to 50% of those of the parent molecule. Alpha-hydroxymidazolam is pharmacologically active, and contributes significantly (about 34%) to the effects of oral midazolam.
After oral administration, hepatic first-pass metabolism is estimated at around 30 to 60%.
Following oral administration in children, the ratio of the area under the curve (AUC) of α-hydroxymidazolam to midazolam varies from 0.38 to 0.75.
About 40% of α-hydroxymidazolam exposure is due to the hepatic first-pass effect.
The metabolic ratio is 0.504, 0.364 and 0.313 in children, adolescents and adults respectively.
In healthy adult subjects, plasma clearance is between 300 and 500 ml/min (or between 4 and 13 ml/min/kg). Midazolam is eliminated primarily by renal excretion; 60 to 80% of the administered dose is excreted within 24 hours of administration and is recovered in the form of glucuronidated α-hydroxymidazolam. Less than 1% of the administered dose is recovered unchanged in urine. The elimination half-life of midazolam is about 3 hours, and that of α-hydroxymidazolam is approximately 2 hours.
In children, half-life can vary greatly, from 0.5 to 7 hours depending on the study, regardless of the age of the child and the dose of midazolam. Plasma clearance has been estimated at between 1.5 and 3.6 l/h/kg.
Half-life has been estimated at 3.6 hours in adolescents. From, the Pop-PK analysis, the midazolam clearance has been estimated at 34.7 l/h and α-hydroxymidazolam clearance at 40.6 l/h, for a typical subject of 34 kg.
Ozalin has not been studied in paediatric patients under 6 months of age.
The mean half-life of midazolam is higher in obese patients than in non-obese patients (5.9 hours versus 2.3 hours). This is due to an increase of about 50% in the volume of distribution corrected for total body weight. There is no significant difference in plasma clearance between obese and non-obese subjects. Longer monitoring of obese patients following the procedure may be required.
In patients with cirrhosis, the elimination half-life may be longer and clearance lower than those observed in healthy subjects, due to the risk of α-hydroxymidazolam accumulation (see Sections 4.2 and 4.3).
The elimination half-life in patients with chronic renal failure is similar to that in healthy subjects. However, oral midazolam should be used with caution in patients with impaired renal function.
The elimination half-life is longer in patients with congestive heart failure than in healthy subjects (see Section 4.4).
In a rat fertility study, during which the animals received up to ten times the clinical dose, no adverse effects on fertility were observed.
There are no preclinical data of relevance to the prescriber other than those already included in other sections of the SmPC.
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