Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: Neon Healthcare Ltd., 8 The Chase, John Tate Road, Hertford, SG13 7NN, United Kingdom
Hypnovel is a short-acting sleep-inducing drug that is indicated:
In adults:
In children:
Midazolam is a potent sedative agent that requires titration and slow administration. Titration is strongly recommended to safely obtain the desired level of sedation according to the clinical need, physical status, age and concomitant medication. In adults over 60 years, debilitated or chronically ill patients and paediatric patients, dose should be determined with caution and risk factors related to each patient should be taken into account. Standard dosages are provided in Table 1 and additional details are provided in the text following Table 1.
Table 1. Standard dosages of midazolam:
| Indication | Adults <60 y | Adults ≥60 y / debilitated or chronically ill | Children |
|---|---|---|---|
| Conscious sedation | i.v. Initial dose: 2 – 2.5 mg Titration doses: 1 mg Total dose: 3.5 – 7.5 mg | i.v Initial dose: 0.5 – 1 mg Titration doses: 0.5 – 1 mg Total dose: < 3.5 mg | i.v. in patients 6 months – 5 years Initial dose: 0.05 – 0.1 mg/kg Total dose: < 6 mg i.v. in patients 6 – 12 years Initial dose: 0.025 – 0.05 mg/kg Total dose: < 10 mg rectal > 6 months 0.3 – 0.5 mg/kg i.m. 1 – 15 years 0.05 – 0.15 mg/kg |
| Anaesthesia premedication | i.v. 1 – 2 mg repeated i.m. 0.07 – 0.1 mg/kg | i.v. Initial dose: 0.5 mg Slow uptitration as needed i.m. 0.025 – 0.05 mg/kg | rectal > 6 months 0.3 – 0.5 mg/kg i.m. 1 – 15 years 0.08 – 0.2 mg/kg |
| Anaesthesia induction | i.v. 0.15 – 0.2 mg/kg (0.3 – 0.35 without premedication) | i.v. 0.05 – 0.15 mg/kg (0.15 – 0.3 without premedication) | |
| Sedative component in combined anaesthesia | i.v. intermittent doses of 0.03 -0.1 mg/kg or continuous infusion of 0.03 – 0.1 mg/kg/h | i.v. lower doses than recommended for adults <60 years | |
| Sedation in ICU | i.v. Loading dose: 0.03 – 0.3mg/kg in increments of 1 – 2.5 mg Maintenance dose: 0.03 – 0.2 mg/kg/h | i.v. in neonates ≤ 32 weeks gestational age 0.03 mg/kg/h i.v. in neonates > 32 weeks and children up to 6 months 0.06 mg/kg/h i.v. in patients > 6 months of age Loading dose: 0.05 – 0.2 mg/kg Maintenance dose: 0.06 – 0.12 mg/kg/h | |
For conscious sedation prior to diagnostic or surgical intervention, midazolam is administered i.v. The dose must be individualised and titrated, and should not be administered by rapid or single bolus injection. The onset of sedation may vary individually depending on the physical status of the patient and the detailed circumstances of dosing (e.g. speed of administration, amount of dose). If necessary, subsequent doses may be administered according to the individual need. The onset of action is about 2 minutes after the injection. Maximum effect is obtained in about 5 to 10 minutes.
The i.v. injection of midazolam should be given slowly at a rate of approximately 1 mg in 30 seconds.
In adults below the age of 60 the initial dose is 2 to 2.5 mg given 5 to10 minutes before the beginning of the procedure. Further doses of 1 mg may be given as necessary. Mean total doses have been found to range from 3.5 to 7.5 mg. A total dose greater than 5 mg is usually not necessary.
In adults over 60 years of age, debilitated or chronically ill patients, the initial dose must be reduced to 0.5-1.0 mg and given 5-10 minutes before the beginning of the procedure. Further doses of 0.5 to 1 mg may be given as necessary. Since in these patients the peak effect may be reached less rapidly, additional midazolam should be titrated very slowly and carefully. A total dose greater than 3.5 mg is usually not necessary.
I.V. administration: midazolam should be titrated slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. One must wait an additional 2 to 5 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. Infants and young children less than 5 years of age may require substantially higher doses (mg/kg) than older children and adolescents.
Rectal administration: the total dose of midazolam usually ranges from 0.3 to 0.5 mg/kg. Rectal administration of the ampoule solution is performed by means of a plastic applicator fixed on the end of the syringe. If the volume to be administered is too small, water may be added up to a total volume of 10 ml. Total dose should be administered at once and repeated rectal administration avoided.
The use in children less than 6 months of age is not recommended, as available data in this population are limited.
I.M. administration: the doses used range between 0.05 and 0.15 mg/kg. A total dose greater than 10.0 mg is usually not necessary. This route should only be used in exceptional cases. Rectal administration should be preferred as i.m. injection is painful.
In children less than 15 kg of body weight, midazolam solutions with concentrations higher than 1 mg/ml are not recommended. Higher concentrations should be diluted to 1 mg/ml.
Premedication with midazolam given shortly before a procedure produces sedation (induction of sleepiness or drowsiness and relief of apprehension) and preoperative impairment of memory. Midazolam can also be administered in combination with anticholinergics. For this indication midazolam should be administered i.v. or i.m., deep into a large muscle mass 20 to 60 minutes before induction of anaesthesia, or preferably via the rectal route in children (see below). Close and continuous monitoring of the patients after administration of premedication is mandatory as interindividual sensitivity varies and symptoms of overdose may occur.
For preoperative sedation and to impair memory of preoperative events, the recommended dose for adults of ASA Physical Status I & II and below 60 years is 1-2 mg i.v. repeated as needed, or 0.07 to 0.1 mg/kg administered i.m. The dose must be reduced and individualised when midazolam is administered to adults over 60 years of age, debilitated or chronically ill patients. The recommended initial i.v. dose is 0.5 mg and should be slowly uptitrated as needed. A dose of 0.025 to 0.05 mg/kg administered i.m. is recommended. In case of concomitant administration of narcotics the midazolam dose should be reduced. The usual dose is 2 to 3 mg.
Neonates and children up to 6 months of age:
The use in children less than 6 months of age is not recommended as available data are limited.
Children over 6 months of age:
Rectal administration: The total dose of midazolam, usually ranging from 0.3 to 0.5 mg/kg should be administered 15 to 30 minutes before induction of anaesthesia.
Rectal administration of the ampoule solution is performed by means of a plastic applicator fixed on the end of the syringe. If the volume to be administered is too small, water may be added up to a total volume of 10 ml.
I.M. administration: As i.m. injection is painful, this route should only be used in exceptional cases. Rectal administration should be preferred. However, a dose range from 0.08 to 0.2 mg/kg of midazolam administered i.m. has been shown to be effective and safe. In children between ages 1 and 15 years, proportionally higher doses are required than in adults in relation to body-weight.
In children less than 15 kg of body weight, midazolam solutions with concentrations higher than 1 mg/ml are not recommended. Higher concentrations should be diluted to 1 mg/ml.
If midazolam is used for induction of anaesthesia before other anaesthetic agents have been administered, the individual response is variable. The dose should be titrated to the desired effect according to the patient’s age and clinical status. When midazolam is used before or in combination with other i.v. or inhalation agents for induction of anaesthesia, the initial dose of each agent should be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.
The desired level of anaesthesia is reached by stepwise titration. The i.v. induction dose of midazolam should be given slowly in increments. Each increment of not more than 5 mg should be injected over 20 to 30 seconds allowing 2 minutes between successive increments.
Midazolam can be given as a sedative component in combined anaesthesia by either further intermittent small i.v. doses (range between 0.03 and 0.1 mg/kg) or continuous infusion of i.v. midazolam (range between 0.03 and 0.1 mg/kg/h) typically in combination with analgesics. The dose and the intervals between doses vary according to the patient’s individual reaction.
In adults over 60 years of age, debilitated or chronically ill patients, lower maintenance doses will be required.
The desired level of sedation is reached by stepwise titration of midazolam followed by either continuous infusion or intermittent bolus, according to the clinical need, physical status, age and concomitant medication (see section 4.5).
I.V. loading dose: 0.03 to 0.3 mg/kg should be given slowly in increments. Each increment of 1 to 2.5 mg should be injected over 20 to 30 seconds allowing 2 minutes between successive increments. In hypovolaemic, vasoconstricted, or hypothermic patients the loading dose should be reduced or omitted. When midazolam is given with potent analgesics, the latter should be administered first so that the sedative effects of midazolam can be safely titrated on top of any sedation caused by the analgesic.
I.V. maintenance dose: doses can range from 0.03 to 0.2 mg/kg/h. In hypovolaemic, vasoconstricted, or hypothermic patients the maintenance dose should be reduced. The level of sedation should be assessed regularly. With long-term sedation, tolerance may develop and the dose may have to be increased.
Midazolam 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 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. Midazolam 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 midazolam can be administered to increase or maintain the desired effect.
When initiating an infusion with midazolam 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 midazolam and require careful monitoring of respiratory rate and oxygen saturation.
In premature infants, neonates and children less than 15 kg of body weight, midazolam solutions with concentrations higher than 1 mg/ml are not recommended. Higher concentrations should be diluted to 1 mg/ml.
In patients with severe renal impairment (creatinine clearance below 30 ml/min) midazolam may be accompanied by more pronounced and prolonged sedation possibly including clinically relevant respiratory and cardiovascular depression.
Midazolam should therefore be dosed carefully in this patient population and titrated for the desired effect (see section 4.4). In patients with renal failure (creatinine clearance < 10 ml/min) the pharmacokinetics of unbound midazolam following a single i.v. dose is similar to that reported in healthy volunteers. However, after prolonged infusion in intensive care unit (ICU) patients, the mean duration of the sedative effect in the renal failure population was considerably increased most likely due to accumulation of 1'-hydroxymidazolam glucuronide (see sections 4.4 and 5.2).
Hepatic impairment reduces the clearance of i.v. midazolam with a subsequent increase in terminal half-life. Therefore the clinical effects in patients with hepatic impairment may be stronger and prolonged. The required dose of midazolam may have to be reduced and proper monitoring of vital signs should be established (see section 4.4).
See above and section 4.4.
Like other benzodiazepines, midazolam commonly causes drowsiness, ataxia, dysarthria and nystagmus. Overdose of midazolam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardio-respiratory 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.
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 cardio-respiratory effects or central nervous system effects.
If taken orally further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure.
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.
60 months.
Keep ampoules in the outer carton.
Clear glass 2ml ampoules.
Hypnovel ampoule solution is stable, both physically and chemically, for up to 24 hours at room temperature when mixed with 500ml infusion fluids containing Dextrose 4% with Sodium Chloride 0.18%, Dextrose 5% or Sodium Chloride 0.9%.
There is no evidence of the adsorption of midazolam onto the plastic of infusion apparatus or syringes.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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