Pharmacokinetics in children

Oral: effect after 30-45 min
Rectal: effect after 10-20 min
Intravenous: effect after 3 min
Duration of effect after a single dose is 1-2 hours.

The following kinetic parameters have been observed after oromucosal administration [SmPC for Buccolam]:

Dose (mg)	2.5	5	7.5	10
Age	3-11 months	1-4 years	5-9 years	10-18 years
Cmax (ng/ml)	104	148	140	87

Cl: 30 ml/kg/min
t½: 204 min

After intravenous or rectal administration, the t½ in healthy children aged 3-10 years is 1-1.5 hours. In neonates is this 6-12 hours [SmPC for Dormicum]. In severely sick children (1-17 years), the following kinetic parameters were found for intravenously administered midazolam [De Wildt 2003]:
Cl: 5.0 ± 3.9 ml/kg/min
t½: 5.5 ± 3.5 hours
Vd: 1.7 ± 1.1 l/kg

After nasal administration, the following parameters were found in children aged 1.75-4 years (n=6) [Rey 1991]:
Cl/F: 1.44 l/kg/hour
t½: 2.22 hours
tmax: 0.19 hours
Cmax: 104 µg/l

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Premedication before the induction of anaesthesia

Oral 1 month up to 18 years [1] [8] [57] [60] 0.25 - 0.5 mg/kg/dose, once only. Max: 20 mg/dose. Administration under medical supervision by professional expert. Rectal 1 month up to 18 years [1] [14] [64] [69] 0.25 - 0.5 mg/kg/dose, once only. Max: 15 mg/dose. Directions for administration: The liquid for injection can be used rectally. Administration under medical supervision by professional expert, Intravenous 1 month up to 18 years [1] 0.05 mg/kg/dose, once only. Max single dose: 10 mg/dose. Nasal 1 month up to 18 years [6] [9] [10] [71] 0.25 - 0.5 mg/kg/dose, once only. Max: 10 mg/dose. Administration under medical supervision of professional expert. Sublingual 1 month up to 18 years [58] [59] [64] 0.25 - 0.5 mg/kg/dose, once only. Max: 10 mg/dose. Administration under medical supervision by professional expert.

Procedural sedation

Oromucosal 1 month up to 18 years [11] [74] 0.2 - 0.5 mg/kg/dose, once only. Max: 10 mg/dose. Rectal 1 month up to 18 years [5] 0.2 - 0.5 mg/kg/dose, once only. Max: 15 mg/dose. Directions for administration: The liquid for injection can be used rectally Intravenous 1 month up to 18 years [72] [73] [75] [78] [79] 0.05 - 0.2 mg/kg/dose Repeat if this does not have enough effect. Max: 10 mg/dose. Administer with monitoring. Nasal 1 month up to 18 years [7] [10] [62] [66] [70] [73] [74] [76] [80] 0.2 - 0.5 mg/kg/dose, once only. Max: 10 mg/dose. Oral 1 month up to 18 years [63] [70] [72] [74] [76] [77] 0.2 - 0.5 mg/kg/dose, once only. Max: 20 mg/dose.

Sedation on the IC ward

Intravenous Premature infants Gestational age < 32 weeks [18] [19] [20] [21] Initial dose: THIS DOSE IS APPLICABLE UP TO A POSTNATAL AGE OF 8 WEEKS 0.05 mg/kg/dose, bolus in half an hour. If a direct sedative effect is needed, the risk of hypotension should be weighed against a faster effect. . Maintenance dose: 0.03 - 0.1 mg/kg/hour, continuous infusion. If there is insufficient effect, increase the dose depending on sedation and side effects. Before increasing the continuous infusion dose, administer a new starting dose (0.05 mg/kg).. Administer with monitoring. Premature infants Gestational age 32 weeks up to 37 weeks [18] [19] [20] [21] Initial dose: THIS DOSE IS APPLICABLE UP TO A POSTNATAL AGE OF 4 WEEKS 0.05 mg/kg/dose, bolus. Maintenance dose: 0.05 - 0.2 mg/kg/hour, continuous infusion. If there is insufficient effect, increase the dose depending on sedation and side effects. Before increasing the continuous infusion dose, administer a new starting dose (0.05 mg/kg).. Administer with monitoring.  Term neonate [18] [19] [20] [21] Initial dose: 0.05 - 0.1 mg/kg/dose, bolus. Maintenance dose: 0.05 - 0.3 mg/kg/hour, continuous infusion. If there is insufficient effect, increase the dose depending on sedation and side effects. Before increasing the continuous infusion dose, administer a new starting dose (0.05-0.1 mg/kg).. Administer with monitoring 1 month up to 18 years and < 40 kg [18] [19] [20] [21] Initial dose: 0.05 - 0.2 mg/kg/dose, bolus. Maintenance dose: 0.05 - 0.3 mg/kg/hour, continuous infusion. Max: 1 mg/kg/hour. If there is insufficient effect, increase the dose depending on sedation and side effects. Before increasing the continuous infusion dose, administer a new starting dose (0.05-0.2 mg/kg).. Administer with monitoring. Increasing to above 0.4 mg/kg/hour is often not effective, in which case adding another opioid or other sedative should be considered.  1 month up to 18 years and ≥ 40 kg [18] [19] [20] [21] Initial dose: 0.05 - 0.2 mg/kg/dose, bolus. Maintenance dose: 0.05 - 0.2 mg/kg/hour, continuous infusion. If there is insufficient effect, increase the dose depending on sedation and side effects. Before increasing the continuous infusion dose, administer a new starting dose (0.05-0.2 mg/kg).. Administer with monitoring

Status epilepticus

Intravenous Premature infants Gestational age < 36 weeks [4] [82] [83] Initial dose: THIS DOSE IS APPLICABLE UP TO A POSTNATAL AGE OF 8 WEEKS Loading dose: 0.05 mg/kg/dose, bolus. Maintenance dose: 0.05 - 0.3 mg/kg/hour, continuous infusion. Increase the maintenance dose in steps of 0.05 mg/kg/hour. Give an extra loading dose before an increase.. If seizures have stopped: phase back by 0.05 mg/kg/hour every 24 hours In premature infants, the clearance is reduced and there may possibly be a high risk of hypotension and reduced cerebral perfusion. Neonates Gestational age ≥ 36 weeks [4] [82] [83] [84] Neonaten WITH hypothermia Loading dose:  0,05 mg/kg/dose bolus injection Maintenance dose:   0,05-0,1 mg/kg/hour continuous infusion during max. 24 hours. Administer a loading dose prior to every dose increment.  Neonaten WITHOUT hypothermia Loading dose:  0,1 mg/kg/dose blous injections Maintenance dose:  0,1-0,3 mg/kg/hour continuous infusion.  Increase maintenance dose with dose increments of  0,1 mg/kg/hour. Administer a loading dose prior to every dose increment. If seizures have stopped: decrease dose by 0,1 mg/kg/hour every 24 hours 1 month up to 18 years [2] [15] [47] 0.1 - 0.2 mg/kg/dose, once only. Max: 5 mg/dose. Repeat if necessary once after 5 minutes.. If the status persists (30-90 minutes): loading dose 0.1 mg/kg IV followed by a continuous infusion of 0.1 mg/kg/hour. Increase the rate of administration by 0.1 mg/kg/hour every 5 minutes until the status is under control; maximum 1 mg/kg/hour. For each dose increase, give another bolus dose of 0.1 mg/kg. Intramuscular 1 month up to 18 years [2] [45] [47] [50] [51] [52] [53] 0.2 mg/kg/dose, once only. Max: 10 mg/dose. Repeat if necessary once after 5 minutes. . Do not exceed the maximum dose of 0,5 mg/kg or 10 mg/dose without access to monitoring of vital functions (Emergency department or Intensive care unit) Oromucosal 1 month up to 3 months [2] [32] [33] [42] [43] [44] [47] [48] [49] In the hospital: 0.2 mg/kg/dose, once only. Repeat  once if necessary after 5 minutes. . 3 months up to 6 months [32] [33] [42] [43] [44] [47] [48] [49] In the hospital: 2.5 mg/dose, once only. Repeat once if necessary after 5 minutes. 6 months up to 1 year [32] [33] [42] [43] [44] [47] [48] [49] 2.5 mg/dose, once only Repeat once if necessary after 5 minutes. 1 year up to 5 years [32] [33] [42] [43] [44] [47] [48] [49] 5 mg/dose, once only. Repeat once if necessary after 5 minutes. 5 years up to 10 years [32] [33] [42] [43] [44] [47] [48] [49] 7.5 mg/dose, once only. Repeat once if necessary after 5 minutes.. 10 years up to 18 years [32] [33] [42] [43] [44] [47] [48] [49] 10 mg/dose, once only. Repeat once if necessary after 5 minutes. Nasal 1 month up to 18 years [2] [6] [34] [35] [36] [37] [38] [39] [40] [41] 0.2 mg/kg/dose, once only. Max: 10 mg/dose. Repeat if necessary once after 5 minutes. Equivalent to: > 2.5-5 kg:                      0.5 mg (1 spray, 0.5 mg/spray) > 5-7.5 kg:                      1 mg (2 sprays, 0.5 mg/spray) > 7.5-10 kg:                    1.5 mg (3 sprays, 0.5 mg/spray) > 10-12.5 kg:                2 mg (4 sprays, 0.5 mg/spray) > 12.5-25 kg:            2.5 mg (1 spray, 2.5 mg/spray) > 25-37.5 kg:                5 mg (2 sprays, 2.5 mg/spray) > 37.5-50 kg:                7.5 mg (3 sprays, 2.5 mg/spray) > 50 kg:                            10 mg (4 sprays 2.5 mg/spray)

Palliative sedation

Intravenous 0 months up to 6 months [22] Initial dose: 0.1 mg/kg/dose, bolus in 30 minutes. Maintenance dose: 0.02 - 0.05 mg/kg/hour, continuous infusion.  . If necessary, increase the maintenance dose every 2-4 hours by 0.05 mg/kg/hour. Give a starting dose (0.1 mg/kg) once again before each increase. When a dose of 0.3 mg/kg/hour is reached, consider adding levomepromazine. 6 months up to 6 years [22] [23] Initial dose: 0.1 mg/kg/dose, bolus. Maintenance dose: 0.1 mg/kg/hour, continuous infusion.  . If necessary, increase the maintenance dose every 2 hours by 0.05-0.1 mg/kg/hour. Give a starting dose (0.1 mg/kg) once again before each increase. A more rapid rate of increase may be needed. When a dose of 0.3 mg/kg/hour is reached, consider adding levomepromazine. 6 years up to 18 years and < 50 kg [22] [23] Initial dose: 0.1 mg/kg/dose, bolus. Maintenance dose: 0.05 mg/kg/hour, continuous infusion.  . If necessary, increase the maintenance dose every 2 hours by 0.05 mg/kg/hour. Give a starting dose (0.1 mg/kg) once again before each increase. When a dose of 0.3 mg/kg/hour is reached, consider adding levomepromazine. 6 years up to 18 years and ≥ 50 kg [22] Initial dose: 10 mg/dose, bolus. Maintenance dose: 1.5 - 2.5 mg/hour, continuous infusion.  . If necessary, increase the maintenance dose every 4 hours by 50%. Give a new bolus (5 mg) before each increase. When a dose of 20 mg is reached, consider adding levomepromazine. Subcutaneous 0 months up to 6 months [22] Initial dose: 0.1 mg/kg/dose, bolus in 30 minutes. Maintenance dose: 0.02 - 0.05 mg/kg/hour, continuous infusion.  . If necessary, increase the maintenance dose every 2-4 hours by 0.05 mg/kg/hour. Give a starting dose (0.1 mg/kg) once again before each increase. When a dose of 0.3 mg/kg/hour is reached, consider adding levomepromazine. 6 months up to 6 years [22] [23] Initial dose: 0.1 mg/kg/dose, bolus. Maintenance dose: 0.1 mg/kg/hour, continuous infusion.  . If necessary, increase the maintenance dose every 2 hours by 0.05-0.1 mg/kg/hour. Give a starting dose (0.1 mg/kg) once again before each increase. A more rapid rate of increase may be needed. When a dose of 0.3 mg/kg/hour is reached, consider adding levomepromazine. 6 years up to 18 years and < 50 kg [22] [23] Initial dose: 0.1 mg/kg/dose, bolus. Maintenance dose: 0.05 mg/kg/hour, continuous infusion.  . If necessary, increase the maintenance dose every 2 hours by 0.05 mg/kg/hour. Give a starting dose (0.1 mg/kg) once again before each increase. When a dose of 0.3 mg/kg/hour is reached, consider adding levomepromazine. 6 years up to 18 years and ≥ 50 kg [22] Initial dose: 10 mg/dose, bolus. Maintenance dose: 1.5 - 2 mg/hour, continuous infusion.  . If necessary, increase the maintenance dose every 4 hours by 50%. Give a new bolus (5 mg) before each increase. When a dose of 20 mg is reached, consider adding levomepromazine. Nasal 1 month up to 18 years 0.2 - 0.5 mg/kg/dose, as required. Oral 1 month up to 18 years 0.2 - 0.5 mg/kg/dose, as required.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Adjustment not necessary.

GFR 30-50 ml/min/1.73 m2

Adjustment not necessary.

GFR 10-30 ml/min/1.73 m2

Dose depending on the effect and the side-effects. Watch out for accumulation of the active metabolite.

GFR < 10 ml/min/1.73 m2

No generalized dose recommendations are given

Clinical consequences

In mild intoxication sleepiness and confusion occur; in severe cases, ataxia, hypotonia, hypotension, respiratory depression and coma can also occur. These symptoms disappear over the course of a couple of days.

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Paradoxical reactions such as restlessness, anxiety, nervousness, agitation, irritability, excitement, hyperactivity, aggression, hostility, behavioral abnormalities, abnormal dreams, hallucinations, delusions, psychosis, involuntary movements (such as tonic-clonic movements, tremors). Convulsions in preterm and neonates. [SmPC]

Midazolam can cause hypotension in both preterm and term neonates and reduced cerebral blood flow in preterm infants [Kumar 2010].

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Administer under monitoring.
The antagonist flumazenil (Anexate) must be available: 0.01 mg/kg, repeat if necessary after 1 min.
Be aware of the possibility of respiratory depression, asthma, respiratory obstruction, combination with opiates.
For outpatient/day treatment use: only let the child go home when properly well awake.
Avoid rapid intravenous administration in children with an unstable cardiovascular status.
In neonates and pre-term born infants who have not been intubated, caution should be exercised in sedation due to an increased risk of apnoea. Do not use benzodiazepines in children for treating sleep disorders.
Midazolam nasal spray can be felt to be painful, so consider a lidocaine nasal spray beforehand. The nasal spray has a nasty taste; give a lollipop if necessary.

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

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