Posology : מינונים

4.2   Posology and method of administration
STANDARD DOSAGE
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

Adults ≥ 60 y /
Indication           Adults < 60 y              debilitated or                     Children chronically ill i.v.                       i.v.                         i.v. in patients 6 months – Initial dose: 2 - 2.5 mg   Initial dose: 0.5 - 1 mg     5 years
Titration doses: 1 mg      Titration doses:             Initial dose: 0.05 - 0.1 mg/kg Total dose: 3.5 - 7.5 mg   0.5 - 1 mg                   Total dose: < 6 mg Total dose: < 3.5 mg         i.v. in patients 6 - 12 years
Conscious
Initial dose: 0.025 - 0.05 sedation mg/kg
Total dose: <10 mg
 i.m. 1 - 15 years
0.05 - 0.15 mg/kg i.v.                       i.v.                         i.m. 1 - 15 years 1 - 2 mg repeated          Initial dose: 0.5 mg         0.08 - 0.2 mg/kg Slow uptitration as
Anaesthesia i.m.                       needed premedication
0.07 - 0.1 mg/kg i.m.
0.025 - 0.05 mg/kg i.v.                       i.v.
Anaesthesia      0.15 - 0.2 mg/kg (0.3 -    0.05 - 0.15 mg/kg (0.15 - induction        0.35 without               0.3 without premedication)             premedication)
Sedative         i.v.                       i.v.
component in     intermittent doses of      lower doses than
combined           0.03 - 0.1 mg/kg or       recommended for adults anaesthesia        continuous infusion of    <60 years
0.03 - 0.1 mg/kg/h i.v.                                                    i.v. in neonates ≤32 weeks Loading dose: 0.03 - 0.3 mg/kg in increments of         gestational age 1 - 2.5 mg                                              0.03 mg/kg/h
Maintenance dose: 0.03 - 0.2 mg/kg/h                    i.v. in neonates >32 weeks and children up to 6 months
Sedation in                                                                0.06 mg/kg/h ICU                                                                        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

CONSCIOUS SEDATION DOSAGE
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 to10 minutes.

Adults
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.

Children
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.

•         Paediatric patients less than 6 months of age: paediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation. For this reason, the use in conscious sedation in children less than 6 months of age is not recommended.
•         Paediatric patients 6 months to 5 years of age: initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint, but the total dose should not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.
•         Paediatric patients 6 to 12 years of age: initial dose 0.025 to 0.05 mg/kg. A total dose of up to 0.4 mg/kg to a maximum of 10 mg may be necessary. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.
•     Paediatric patients 12 to 16 years of age: should be dosed as adults.

I.M. administration: the doses used range between 0.05 and 0.15 mg/kg. A total dose greater than 10 mg is usually not necessary. This route should only be used in exceptional cases.
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.

ANAESTHESIA DOSAGE
Premedication
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.
Close and continuous monitoring of the patients after administration of premedication is mandatory as interindividual sensitivity varies and symptoms of overdose may occur.

Adults
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.

Paediatric Patients
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
I.M. administration: As i.m. injection is painful, this route should only be used in exceptional cases. 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 ages1 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.

Induction
Adults
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.

•     In premedicated adults below the age of 60 years an i.v. dose of 0.15 to 0.2 mg/kg will usually suffice.
•     In non-premedicated adults below the age of 60 the dose may be higher (0.3 to 0.35 mg/kg i.v.). If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used. Induction may instead be completed with inhalational anaesthetics. In resistant cases, a total dose of up to 0.6 mg/kg may be used for induction, but such larger doses may prolong recovery.
•     In premedicated adults over 60 years of age, debilitated or chronically ill patients the dose should significantly be reduced, e.g. down to 0.05-0.15 mg/kg administered i.v. over 20-30 seconds and allowing 2 minutes for effect.
•     Non-premedicated adults over 60 years of age usually require more midazolam for induction; an initial dose of 0.15 to 0.3 mg/kg is recommended. Non-premedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.15 to 0.25 mg/kg will usually suffice.

Sedative component in combined anaesthesia
Adults
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.

SEDATION IN INTENSIVE CARE UNITS
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).

Adults
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.

Neonates and children up to 6 months of age
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.

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.
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.

Use in Special Populations
Renal Impairment
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
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).

Paediatric population
See above and section 4.4.

Method of administration
For intravenous and intramuscular use.
For instructions on dilution of the medicinal product before administration, see section 6.6.