Dormitol

As intravenous sedative cover before and during minor medical, dental and surgical procedures such as gastroscopy, endoscopy, cystoscopy, bronchoscopy and cardiac catheterisation.

As an alternative intravenous agent for the induction of anaesthesia in high risk and elderly patients, especially where cardiovascular stability is of particular importance. Induction is more reliable when heavy opiate premedication has been administered or when Dormitol is given with a narcotic analgesic such as fentanyl.

As a sedative in intensive care units.

Treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to < 18 years).

Dormitol must only be used by parents/carers where the patient has been diagnosed to have epilepsy.

For infants between 3-6 months of age treatment should be in a hospital setting where monitoring is possible and resuscitation equipment is available.

Posology

Intravenous sedation: One or more intravenous administrations over a single operating session. Severe cardio respiratory events have been reported and are most likely to occur when injection is given too rapidly or when too high dose is used.

When initiating an infusion with Dormitol in haemodynamically compromised patients, the usual loading dose should be titrated in small increments and the patient monitored for haemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of Dormitol and require careful monitoring of respiratory rate and oxygen saturation.

Adults: An assessment should be made of the degree of sedation necessary for the planned procedure.

The dose should be titrated against the response of the patient. The desired titration end point will depend upon the procedure. Full sedation will be evident by drowsiness, slurred speech but response to commands will be maintained.

As a guide, it is recommended that 2ml of Dormitol 1mg/1ml solution (equivalent to 2mg Dormitol) be administered intravenously over 30 seconds. If after 2 minutes, sedation is not adequate, incremental doses of 0.5ml to 1ml of Dormitol 1mg/1ml solution (0.5 to 1mg Dormitol) should be given.

Usual dose range 2.5mg - 7.5mg total dose (equivalent to around 0.07mg/kg body weight).

Dosages greater than 5.0mg are not usually necessary.

Older people: OLDER PATIENTS ARE MORE SENSITIVE TO THE EFFECTS OF BENZODIAZEPINES. IN THESE PATIENTS DOSES GREATER THAN 3.5MG ARE NOT USUALLY NECESSARY AND LOW DOSES AS LITTLE AS 1MG - 2MG (1.0 -2ML) MAY BE ADEQUATE. THE INITIAL DOSE SHOULD NOT EXCEED 1 -1.5MG (1 - 1.5ML).

Paediatric population:

Children over 6 months of age

In intubated and ventilated paediatric patients, a loading dose of 0.05 to 0.2 mg/kg i.v. should be administered slowly over at least 2 to 3 minutes to establish the desired clinical effect. Dormitol should not be administered as a rapid intravenous dose. The loading dose is followed by a continuous i.v. infusion at 0.06 to 0.12 mg/kg/h (1 to 2 µg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental i.v. doses of Dormitol can be administered to increase or maintain the desired effect.

Neonates and children up to 6 months of age

Dormitol should be given as a continuous i.v. infusion, starting at 0.03 mg/kg/h (0.5 µg/kg/min) in neonates with a gestational age <32 weeks or 0.06 mg/kg/h (1 µg/kg/min) in neonates with a gestational age >32 weeks and children up to 6 months.

Intravenous loading doses is not recommended in premature infants, neonates and children up to 6 months, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation.

Careful monitoring of respiratory rate and oxygen saturation is required.

In premature infants, neonates and children less than 15 kg of body weight, Dormitol solutions with concentrations higher than 1 mg/ml are not recommended. Higher concentrations should be diluted to 1 mg/ml.

Method of Administration: For the administration of Dormitol Injection, the patient should be placed in a supine position and remain there throughout the procedure. Resuscitation facilities should always be available and a second person fully trained in the use of such equipment should always be present. It is recommended that patients should remain under medical supervision until at least 1 hour has elapsed from the time of injection. They should always be accompanied home by a responsible adult.

Patients who have received Dormitol Injection alone for IV sedation prior to minor procedures should be warned not to drive or operate machinery for 12 hours. Where Dormitol is used concurrently with other central nervous system depressants (e.g. potent analgesics) recovery may be prolonged. Patients should therefore be assessed carefully before being allowed to go home or resume normal activities.

Combination therapy

Intravenous bolus sedation: where analgesia is provided by a narcotic analgesic the latter should be administered first, the dose of Dormitol should be carefully titrated and low doses 1 - 2mg (1.0- 2.0ml) may be adequate.

Posology

Standard doses are indicated below:

Carers should only administer a single dose of midazolam. If the seizure has not stopped within 10 minutes after administration of midazolam, emergency medical assistance must be sought and the empty syringe given to the healthcare professional to provide information on the dose received by the patient.

A second or repeat dose when seizures re-occur after an initial response should not be given without prior medical advice.

Special populations

Renal impairment

No dose adjustment is required, however, Dormitol should be used with caution in patients with chronic renal failure as elimination of midazolam may be delayed and the effects prolonged.

Hepatic impairment

Hepatic impairment reduces the clearance of midazolam with a subsequent increase in terminal half-life. Therefore, the clinical effects may be stronger and prolonged, hence careful monitoring of the clinical effects and vital signs is recommended following administration of midazolam in patients with hepatic impairment.

Dormitol is contraindicated in patients with severe hepatic impairment.

Paediatric population

The safety and efficacy of midazolam in children aged 0 to 3 months has not been established. No data are available.

Method of administration

Dormitol is for oromucosal use. The full amount of solution should be inserted slowly into the space between the gum and the cheek. Laryngo-tracheal insertion should be avoided to prevent accidental aspiration of the solution. If necessary (for larger volumes and/or smaller patients), approximately half the dose should be given slowly into one side of the mouth, then the other half given slowly into the other side.

Precautions to be taken before handling or administering the medicinal product

No needle, intravenous tubing or any other device for parenteral administration should be attached to the oral syringe.

Dormitol is not for intravenous use.

The oral syringe cap should be removed before use to avoid risk of choking.

Use of this drug in patients with known hypersensitivity to benzodiazepines or to any excipient of the product

Use of this drug for conscious sedation in patients with severe respiratory failure, acute respiratory depression or unstable myasthenia gravis

Myasthenia gravis

Severe respiratory insufficiency

Sleep apnoea syndrome

Severe hepatic impairment

Dormitol should be administered only by experienced physicians in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by persons specifically trained in the recognition and management of expected adverse events including respiratory and cardiac resuscitation.

Severe cardiorespiratory adverse events have been reported. These have included respiratory depression, apnoea, respiratory arrest and/or cardiac arrest. Such life-threatening incidents are more likely to occur when the injection is given too rapidly or when a high dosage is administered.

Special caution is required for the indication of conscious sedation in patients with impaired respiratory function.

Paediatric patients less than 6 months:

In this population, Dormitol is indicated for sedation in ICU only. Paediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful respiratory rate and oxygen saturation monitoring are essential (see also section 'Preterm infants' below).

When Dormitol is used for premedication, adequate observation of the patient after administration is mandatory as inter-individual sensitivity varies and symptoms of overdose may occur.

Special caution should be exercised when administering Dormitol to high-risk patients:

− adults over 60 years of age

− chronically ill or debilitated patients, e.g.

− patients with chronic respiratory insufficiency

− patients with chronic renal failure, impaired hepatic function or with impaired cardiac function

− paediatric patients especially those with cardiovascular instability.

These high-risk patients require lower dosages and should be continuously monitored for early signs of alterations of vital functions.

As with any substance with CNS depressant and/or muscle-relaxant properties, particular care should be taken when administering Dormitol to a patient with myasthenia gravis.

Tolerance

Some loss of efficacy has been reported when Dormitol was used as long-term sedation in intensive care units (ICU).

Dependence

When Dormitol is used in long-term sedation in ICU, it should be borne in mind that physical dependence on Dormitol may develop. The risk of dependence increases with dose and duration of treatment it is also greater in patients with a medical history of alcohol and/or drug abuse.

Withdrawal symptoms

During prolonged treatment with Dormitol in ICU, physical dependence may develop. Therefore, abrupt termination of the treatment will be accompanied by withdrawal symptoms. The following symptoms may occur: headaches, muscle pain, anxiety, tension, restlessness, confusion, irritability, rebound insomnia, mood changes, hallucinations and convulsions. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, it is recommended to decrease doses gradually.

Amnesia

Dormitol causes anterograde amnesia (frequently this effect is very desirable in situations such as before and during surgical and diagnostic procedures), the duration of which is directly related to the administered dose. Prolonged amnesia can present problems in outpatients, who are scheduled for discharge following intervention. After receiving Dormitol parenterally, patients should be discharged from hospital or consulting room only if accompanied by an attendant.

Paradoxical reactions

Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic convulsions and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement and assault, have been reported to occur with Dormitol. These reactions may occur with high doses and/or when the injection is given rapidly. The highest incidence to such reactions has been reported among children and the elderly.

Altered elimination of Dormitol

Dormitol elimination may be altered in patients receiving compounds that inhibit or induce CYP3A4 and the dose of Dormitol may need to be adjusted accordingly

Dormitol elimination may also be delayed in patients with liver dysfunction, low cardiac output and in neonates

Preterm infants and neonates

Due to an increased risk of apnoea, extreme caution is advised when sedating pre-term and former pre-term non intubated patients. Careful monitoring of respiratory rate and oxygen saturation is required.

Rapid injection should be avoided in the neonatal population.

Neonates have reduced and/or immature organ function and are also vulnerable to profound and/or prolonged respiratory effects of Dormitol.

Adverse haemodynamic events have been reported in paediatric patients with cardiovascular instability; rapid intravenous administration should be avoided in this population.

Concomitant use of alcohol / CNS depressants

The concomitant use of Dormitol with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Dormitol possibly including severe sedation or clinically relevant respiratory depression.

Medical history of alcohol or drug abuse

Dormitol as other benzodiazepines should be avoided in patients with a medical history of alcohol or drug abuse.

Discharging criteria

After receiving Dormitol, patients should be discharged from hospital or consulting room only when recommended by treating physician and if accompanied by an attendant. It is recommended that the patient is accompanied when returning home after discharge.

This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially 'sodium- free'

Respiratory insufficiency

Midazolam should be used with caution in patients with chronic respiratory insufficiency because midazolam may further depress respiration.

Paediatric patients aged 3 to 6 months

Given the higher metabolite to parent drug ratio in younger children, a delayed respiratory depression as a result of high active metabolite concentrations in the 3-6 months age group cannot be excluded. Therefore, the use of Dormitol in the 3-6 month age group should be limited for use only under the supervision of a health care professional where resuscitation equipment is available and where respiratory function can be monitored and equipment for respiratory assistance, if needed, is available.

Altered elimination of midazolam

Midazolam should be used with caution in patients with chronic renal failure, impaired hepatic or cardiac function. Midazolam may accumulate in patients with chronic renal failure or impaired hepatic function whilst in patients with impaired cardiac function it may cause decreased clearance of midazolam.

Concomitant use with other benzodiazepines

Debilitated patients are more prone to the central nervous system (CNS) effects of benzodiazepines and, therefore, lower doses may be required.

Medical history of alcohol or drug abuse

Midazolam should be avoided in patients with a medical history of alcohol or drug abuse.

Amnesia

Midazolam may cause anterograde amnesia.

Sedation, amnesia, impaired attention and impaired muscular function may adversely affect the ability to drive or use machines.

Prior to receiving Dormitol, the patient should be warned not to drive a vehicle or operate a machine until completely recovered. The physician should decide when these activities may be resumed. It is recommended that the patient is accompanied when returning home after discharge.

Where Dormitol is used concurrently with other central nervous system depressants (e.g. potent analgesics) recovery may be prolonged. Patients should therefore be assessed carefully before being allowed to go home or resume normal activities.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

- However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

Midazolam has a major influence on the ability to drive and use machines.

Sedation, amnesia, impaired attention and impaired muscular function may adversely affect the ability to drive, ride a bicycle or use machines. After receiving midazolam, the patient should be warned not to drive a vehicle or operate a machine until completely recovered.

The following undesirable effects have been reported ( frequency not known, cannot be estimated from the available data) to occur when Dormitol is injected:

Frequency categories are as follows:

Very common: >1/10;

Common >1/100 to <1/10;

Uncommon >1/1,000 to <1/100

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

* Such paradoxical drug reactions have been reported particularly among children and the elderly.

** Anterograde amnesia may still be present at the end of the procedure and in isolated cases prolonged amnesia has been reported.

*** The risk of falls and fractures is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

Dependence: Use of Dormitol even in therapeutic doses may lead to the development of physical dependence. After prolonged IV administration, discontinuation, especially abrupt discontinuation of the product, may be accompanied by withdrawal symptoms including withdrawal convulsions. Cases of abuse have been reported.

Severe cardio-respiratory adverse events have occurred. Life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the MHRA Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard

Summary of the safety profile

Published clinical studies show that oromucosal midazolam was administered to approx 443 children with seizures. Respiratory depression occurs at a rate of up to 5%, although this is a known complication of convulsive seizures as well as being related to midazolam use. One episode of pruritus was possibly attributed to the use of buccal midazolam.

Tabulated list of adverse reactions

The table below lists the adverse reactions reported to occur when oromucosal midazolam was administered to children in clinical studies.

The frequency of adverse reactions is classified as follows:

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness:

**These adverse reactions have been reported to occur when midazolam is injected in children and/or adults, which may be of relevance to oromucosal administration.

Description of selected adverse reactions

An increased risk for falls and fractures has been recorded in elderly benzodiazepine users.

Life-threatening incidents are more likely to occur in those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when a high dosage is administered.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA - Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Symptoms

Like other benzodiazepines, Dormitol commonly causes drowsiness, ataxia, dysarthria and nystagmus. Overdose of Dormitol is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and in rare cases to coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease.

Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment

Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.

If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

The correct information for using Flumazenil can also be obtained from the UK National Poison Information Service by calling on the following telephone number.

Tel: 0844-892-0111 (directs caller to relevant local centre.)

Symptoms

Midazolam overdose can present a threat to life if the patient has pre-existing respiratory or cardiac insufficiency, or when combined with other CNS depressants (including alcohol).

Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy, in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

Management

In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.

Following overdose with oral midazolam, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in intensive care.

Flumazenil may be useful as an antidote.

Pharmacotherapeutic group:

Hypnotics and sedatives (benzodiazepine derivatives), ATC code: N05CD08.

Dormitol 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 Dormitol to form water- soluble salts with acids. These produce a stable and well tolerated injection solution.

The pharmacological action of Dormitol is characterised by short duration because of rapid metabolic transformation. Dormitol 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).

Pharmacotherapeutic group: Psycholeptics, benzodiazepine derivatives ATC code: N05CD08.

Mechanism of action

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 midazolam to form the hydrochloride salt with acids. These produce a stable solution suitable for oromucosal administration.

Pharmacodynamic effects

The pharmacological action of midazolam is characterized by short duration because of rapid metabolic transformation. Midazolam has an anticonvulsant effect. It also exerts a sedative and sleep-inducing effect of pronounced intensity, and an anxiolytic and a muscle-relaxant effect.

Clinical efficacy and safety

In 4 rectal diazepam controlled studies and one study versus intravenous diazepam, in a total of 688 children, cessation of visible signs of seizures within 10 minutes was observed in 65% to 78% of children receiving oromucosal midazolam. Additionally, in 2 of the studies, cessation of visible signs of seizures within 10 minutes without recurrence within 1 hour after administration was observed in 56% to 70% of children. The frequency and severity of adverse drug reactions reported for Oromucosal midazolam during published clinical trials were similar to the adverse drug reactions reported in the comparative group using rectal diazepam.

The European Medicines Agency has waived the obligation to submit the results of studies with Dormitol in the subset of the paediatric population < 3months old, on the grounds that the specific medicinal product does not represent a significant therapeutic benefit over existing treatments for these paediatric patients.

Absorption after i.m. injection

Absorption of Dormitol 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%.

Distribution

When Dormitol 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 Dormitol is bound to plasma proteins. The major fraction of plasma protein binding is due to albumin. There is a slow and insignificant passage of Dormitol into the cerebrospinal fluid. In humans, Dormitol has been shown to cross the placenta slowly and to enter foetal circulation. Small quantities of Dormitol are found in human milk.

Metabolism

Dormitol is almost entirely eliminated by biotransformation. The fraction of the dose extracted by the liver has been estimated to be 30 - 60%. Dormitol is hydroxylated by the cytochrome P4503A4 isozyme and the major urinary and plasma metabolite is alpha-hydroxyDormitol. Plasma concentrations of alpha-hydroxyDormitol are 12% of those of the parent compound. Alpha-hydroxyDormitol is pharmacologically active, but contributes only minimally (about 10%) to the effects of intravenous Dormitol.

Elimination

In healthy volunteers, the elimination half-life of Dormitol is between 1.5 - 2.5 hours. Plasma clearance is in the range of 300 - 500ml/min. Dormitol is excreted mainly by renal route (60 - 80% of the injected dose) and recovered as glucuroconjugated alpha-hydroxyDormitol. Less than 1% of the dose is recovered in urine as unchanged drug. The elimination half-life of alpha-hydroxy-Dormitol is shorter than 1 hour. When Dormitol is given by i.v. infusion, its elimination kinetics do not differ from those following bolus injection.

Pharmacokinetics in special populations

Elderly

In adults over 60 years of age, the elimination half-life may be prolonged up to four times.

Children

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.

Neonates

In neonates the elimination half-life is on average 6 - 12 hours, probably due to liver immaturity and the clearance is reduced.

Obese

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.

Patients with hepatic impairment

The elimination half-life in cirrhotic patients may be longer and the clearance smaller as compared to those in healthy volunteers.

Patients with renal impairment

The elimination half-life in patients with chronic renal failure is similar to that in healthy volunteers.

Critically ill patients

The elimination half-life of Dormitol is prolonged up to six times in the critically ill.

Patients with cardiac insufficiency

The elimination half-life is longer in patients with congestive heart failure compared with that in healthy subjects.

Simulated pharmacokinetic parameters for the recommended posology in children aged 3 months to less than 18 years, based on a population pharmacokinetic study are provided in tabulated format below:

Absorption

After oromucosal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes in children. The absolute bioavailability of oromucosal midazolam is about 75% in adults. The bioavailability of oromucosal midazolam has been estimated at 87% in children with severe malaria and convulsions.

Distribution

Midazolam is highly lipophilic and distributes extensively. The steady state volume of distribution following oromucosal administration is estimated to be 5.3 l/kg.

Approximately 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.

Biotransformation

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-hydroxy-midazolam. Following oromucosal administration in children the area under the curve ratio for alpha-hydroxy midazolam to midazolam is 0.46.

In a population pharmacokinetic study, the metabolite levels are shown to be higher in younger than older paediatric patients and thus likely to be of more importance in children than in adults.

Elimination

Plasma clearance of midazolam in children following oromucosal administration is 30 ml/kg/min. The initial and terminal elimination half-lives are 27 and 204 minutes, respectively. Midazolam is excreted mainly by the renal route (60-80% of the injected dose) and recovered as glucuroconjugated alpha-hydroxy-midazolam. Less than 1% of the dose is recovered in urine as unchanged medicinal product..

Pharmacokinetics in special populations

Obese

The mean half-life is greater in obese than in non-obese patients (5.9 versus 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.

Hepatic impairment

The elimination half-life in cirrhotic patients may be longer and the clearance lower as compared to those in healthy volunteers.

Renal impairment

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.

Cardiac insufficiency

The elimination half-life is longer in patients with congestive heart failure compared with that in healthy subjects.

Exposure following a second dose in the same seizure episode

Simulated exposure data show that the overall AUC approximately doubles when a second dose is administered at 10, 30 and 60 minutes following the first dose. A second dose at 10 minutes results in a significant increase in mean C_max of between 1.7 to 1.9 fold. At 30 and 60 minutes, significant elimination of midazolam has already occurred and therefore the increase in mean C_max is less pronounced; 1.3 to 1.6 and 1.2 to 1.5 fold respectively..

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

In a rat fertility study, animals dosed up to ten times the clinical dose, no adverse effects on fertility were observed.

There are no other preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

Dormitol Injection when mixed with 500ml infusion fluids containing dextrose 4% with sodium chloride 0.18%, dextrose 5% or sodium chloride 0.9% is chemically and physically stable for up to 24 hours at 25°C and up to 72 hours at 2 to 8°C. However, for pharmaceutical microbiological reasons, the product should be used immediately after dilution. When aseptically prepared, the diluted solution may be kept for not more than 24 hours if stored under refrigeration at a temperature between 2 - 8°C.

Admixture with Hartmann's solution is not recommended, as the potency of Dormitol decreases.

Not applicable

If only part used, discard the remaining solution.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Administration of Dormitol

Dormitol is not for intravenous use.

Step 1

Step 2

Step 3

Step 4

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.