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Dormicum

Dormicum Tablet is a sleep-inducing agent belonging to the benzodiazepines.

 

Composition

Active ingredient: midazolam as the maleate.

Tablets containing midazolam maleate equivalent to 7.5 mg and 15 mg of midazolam.

The 7.5 mg tablet is oval, cylindrical, biconvex and of a white to almost white colour; the 15 mg tablet is oblong and of a grey-blue color

 

Excipients: described as per local requirements (Dormicum tablets contain anhydrous lactose. For warning related to lactose monohydrate, see General (Warnings and Precautions)).

 

Properties and effects

Dormicum is a sleep-inducing agent characterized by a rapid onset and short duration of action, It also exerts anxiolytic, hypnotic, anticonvulsant and muscle-relaxant effects. Dormicum impairs psychomotor function after single and/or multiple doses but causes minimal haemodynamic changes.

 

As for other benzodiazepines, it is believed that the effects of Dormicum are mainly mediated via agonistic binding to gamma-aminobutyric acid receptors (GABAA) in the CNS. The hypothesis is that benzodiazepines do not directly activate GABAA receptors, but require the endogenous ligand. i.e. GABA, to exert the effects.

 

Pharmacokinetics

Absorption

Midazolam is absorbed rapidly and completely after oral administration.

After a single administration of a Dormicum 15 mg tablet, maximum plasma concentrations of 70-120 ng/ml are reached within one hour. Food prolongs the time to peak plasma concentration by around one hour, pointing to a reduced absorption rate of midazolam. The absorption half-life is 5-20 minutes.

 

Due to the substantial first-pass effect, the absolute bioavailability of oral midazolam ranges between is 30-70%. The pharmacokinetics of midazolam is linear in the 7.5-20mg oral dose range.

 

Distribution

The tissue distribution of midazolam is very rapid and in most cases a distribution phase is not apparent or is essentially finished within 1-2 hours after oral administration. The volume of distribution at steady state is 0.7-1.21/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 cerebrospinal fluid In humans, midazolam has been shown to cross the placenta slowly and to enter fetal circulation. Small quantities of midazolam are found in human milk.

 

Metabolism

Midazolam is almost entirely eliminated by biotransformation. Less than 1% of the dose is recovered in urine as unchanged drug. Midazolam is hydroxylated by cytochrome P450, CYP3A4 isozymes. Both isozymes, CYP3A4 and also CYP3A5 are actively involved in the hepatic oxidative metabolism of midazolam

 

There are two main oxidized metabolites 1'-hydroxymidazolam (also named α-hydroxymidazolam) and 4-hydroxymidazolam. 1'-{-hydroxymidazolam is the major urinary and plasma metabolite. 60-80% of the dose is glucuronidated and excreted in the urine in form of 1'-hydroxymidazolam conjugate. Plasma concentrations of 1'{-hydroxymidazolam may reach 30-50% those of the parent compound. 1'{-hydroxymidazolam is pharmacologically active and contributes significantly (about 34%) to the effects of oral midazolam.

 

Previous investigation did not show a clinically relevant genetic polymorphism in the oxidative metabolism of midazolam.

 

Elimination

In young healthy volunteers, the elimination half-life of midazolam range between 1.5 to 2.5 hours. Midazolam is a non-accumulating drug when given once daily. Repeated administrations of midazolam do not induce drug-metabolizing enzymes.

 

The elimination half-life of 1'-hydroxymidazolam is shorter than 1 hour

 

Pharmcokinetics in special populations

Elderly

In elderly male subjects over 60 years of age, the elimination half-life of midazolam was significantly prolonged by a factor 2.5 as compared with younger male subjects. Total midazolam clearance was significantly reduced in male elderly subjects and the bioavailability of the oral tablet was significantly increased. However no significant differences were observed in elderly female compared to younger subjects.

 

Patient with hepatic impairment

The pharmacokinetics of midazolam were significantly modified in patients with chronic liver disease including advanced liver cirrhosis. In particular, as a consequence of a decreased liver clearance. the elimination half-life was prolonged and the absolute bioavailability of oral midazolam was significantly increased in cirrhotic patients compared to control.

 

Patients with renal impairment

The pharmacokinetics of midazolam are not altered in patients with chronic renal failure. However the major midazolam metabolite, 1'-hydroxymidazolam glucuronide, which is excreted through the kidney, accumulates in patients with severe chronic renal failure. This accumulation produces a prolonged sedation. Oral midazolam should therefore be administered carefully in patients with renal impairment.

 

Obese patients

In obese patients the volume of distribution of midazolam is increased. As a consequence, the mean elimination half-life of midazolam is longer in obese than in non-obese patients (5.9 hours vs 2.3 hours). The oral bioavailability of the midazolam tablet was not different in obese patients compared to non-obese patients.

 

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