Adults
Conscious sedation before diagnostic or surgical interventions with or without local anaesthesia
(intravenous administration).
Premedication before the induction of anaesthesia (intramuscular administration).
Induction and maintenance of anaesthesia. As an induction agent in inhalation anaesthesia or
as a sedative component in balanced anaesthesia, including intravenous general anaesthesia
(intravenous injection, intravenous infusion).
Long-term sedation in intensive care units (i.v. administration as bolus injection or continuous
infusion).
Children
Conscious sedation before diagnostic or surgical interventions with or without local anaesthesia
(i.v., i.m. or rectal administration).
Premedication before induction of anaesthesia (i.m. or mainly rectal administration).
Ataralgesia in combination with ketamine in children (intramuscular administration).

Long-term sedation in intensive care units (intravenous injection as a bolus or continuous
infusion).
(Dosage recommendations for specific age groups: see section 4.2)

Standard dosage
Midazolam is a potent sedative that requires slow administration and an individualised dosage.
The dose must be adapted to each case. Dose titration is a mandatory recommendation to ensure
the safe induction of the desired degree of sedation according to clinical need, physical status,
age and comedication.
In patients over 60 years of age, critically ill patients, or patients belonging to a high-risk group,
and in paediatric patients, the dosage must be determined with caution and careful regard for
the specific characteristics of each patient. Intravenous injection must be given slowly
(approximately 2.5 mg in 10 seconds for the induction of anaesthesia and 1 mg in 30 seconds
for conscious sedation). Onset of effect is approximately 2 minutes after the start of injection.
Peak effect is achieved after approximately 5 to 10 minutes.
Standard dosages are provided in the table below. Additional details are provided in the text
following the table.
Table 1. Standard dosages

Conscious sedation
Dormicum is administered intravenously for conscious sedation before a diagnostic or surgical
procedure. The dose must be individualised and titrated; the drug must not be administered by
rapid or single bolus injection. The onset of sedation may vary between individuals depending
on the patient’s physical status and the exact administration conditions (e.g. rate of
administration, amount of dose). If necessary, subsequent doses may be administered according
to individual need.
Special care is mandatory in conscious sedation in patients with respiratory disorders (see
section 4.4).
Adults
Intravenous Dormicum injection must be given slowly – at a rate of approximately 1 mg in
30 seconds.
In adults below the age of 60 years, the initial dose is 2 to 2.5 mg; this is administered 5 to
10 minutes before the beginning of the procedure. Further doses of 1 mg may be given as
necessary. Mean total doses of 3.5 to 7.5 mg are generally administered. A total dose exceeding
5.0 mg is not generally necessary.
In adults over the age of 60 years, critically ill patients or high-risk patients, the initial dose
must be reduced to 0.5–1.0 mg and administered 5–10 minutes before the start of the procedure.
Further doses of 0.5–1 mg may be given as needed. Since maximum effect may be reached less
rapidly in these patients, additional doses of Dormicum should be titrated very slowly and
carefully.
A total dose exceeding 3.5 mg is not generally necessary.

Children
Intravenous administration
Dormicum should be administered with slow dose titration until the desired clinical effect is
achieved. The initial dose of Dormicum should be administered over 2 to 3 minutes. Waiting a
further 2–5 minutes is then recommended to allow careful assessment of the sedative effect
before beginning the procedure or administering a new dose. If further sedation appears
necessary, continue to titrate the dose with small increments until the desired level of sedation
is achieved. Under certain conditions, infants and children under 5 years of age require
markedly higher doses than older children or adolescents.
• Infants under 6 months of age: In infants under 6 months of age, the risk of upper
respiratory tract obstruction and hypoventilation is particularly high. For this reason, the
use of Dormicum is not recommended for conscious sedation in infants under 6 months
of age, except if the benefit outweighs the risks. In such cases, dose titration in small
increments and close supervision are essential until clinical effect is achieved.
• Children aged 6 months to 5 years: Initial dose: 0.05 to 0.1 mg/kg. A total dose up to
0.6 mg/kg may prove necessary to achieve the desired effect; however, the total dose
should not exceed 6 mg. Prolonged sedation and a risk of hypoventilation may occur
with the administration of higher doses (see section 4.4).
• Children aged 6 to 12 years: 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 prove necessary. Prolonged sedation and a
risk of hypoventilation may occur with the administration of higher doses (see section
4.4).
• Adolescents aged 13 to 16 years: The dose is identical to that in adults.
Rectal administration (in children >6 months)
The total dose of Dormicum ranges from 0.3 to 0.5 mg/kg.
The total dose should be administered at once; repeated rectal administration should be avoided.
Use in infants under 6 months of age is not recommended, as only limited data are available in
this group of patients.
Rectal administration of Dormicum: see sections 6 and 6.6.
Intramuscular administration (children aged 1 to 15 years)
The recommended dose ranges from 0.05 to 0.15 mg/kg and administration should be
performed 5–10 minutes before the start of the procedure. A total dose exceeding 10.0 mg is
not generally necessary. This route of administration should only be used in exceptional cases.
Rectal administration should be preferred as intramuscular injection can be painful.
Administration of midazolam solutions at concentrations exceeding 1 mg/ml in children whose
body weight is under 15 kg is not recommended. Higher concentrations should be diluted to
1 mg/ml.
Premedication before induction of anaesthesia
Premedication with Dormicum administered just before a procedure produces sedation (with
drowsiness and anxiolysis) and decreases preoperative memory capacity. Dormicum can also

be administered in combination with anticholinergics. For this indication, Dormicum should be
administered intravenously or intramuscularly (by deep injection into a large muscle mass 20 to
60 minutes before induction of anaesthesia) or in children preferably via the rectal route (see
below). Close patient monitoring is mandatory after administration as response varies between
individuals and symptoms of overdose may occur.
Adults
For preoperative sedation and to decrease memory of preoperative events, the recommended
dose for ASA I/II adults under 60 years of age is 1–2 mg intravenously (repeat administration
as required) or 0.07–0.1 mg/kg intramuscularly.
The dose must be reduced and individually adjusted when Dormicum is administered to adults
over 60 years of age, critically ill patients or those at high risk. The recommended initial
intravenous dose is 0.5 mg, which should be increased as required by slow dose titration. This
should be followed by 2–3 minutes’ wait to allow careful assessment of the effect of dose
augmentation. A dose of 0.025–0.05 mg/kg i.m. is recommended in the absence of narcotic
coadministration. The usual dose is 2–3 mg.
Children
Rectal administration (children >6 months):
The total dose of Dormicum is generally 0.4 mg/kg (range: 0.3–0.5 mg/kg), which should be
administered 20 to 30 minutes before induction of anaesthesia.
Rectal administration of Dormicum: see sections 6 and 6.6.
Use in infants under 6 months of age is not recommended, as only limited data are available in
this group of patients.
Intramuscular administration (children aged 1 to 15 years):
Since intramuscular injections can be painful, this route of administration should only be used
in exceptional cases. Rectal administration should be preferred. However, Dormicum doses
ranging from 0.08 to 0.2 mg/kg have proved effective and safe.
Children aged 1 to 15 years require proportionally higher doses relative to body weight than
adults. It is recommended that Dormicum be administered by deep injection into a large muscle
mass 30 to 60 minutes before induction of anaesthesia.
In children less than 15 kg of body weight, midazolam solutions at concentrations higher than
1 mg/ml are not recommended. Higher concentrations should be diluted to 1 mg/ml.
Induction of anaesthesia
Adults
When Dormicum is used to induce anaesthesia before the administration of other anaesthetics,
individual response is variable. The dose should be titrated to the desired effect according to
the patient’s age and clinical status. When Dormicum is used before or in combination with
other intravenous or inhalational agents for inducing anaesthesia, the initial dose of the various
drugs can be set much lower (25% of their initial dose may suffice).
The desired level of anaesthesia is reached by stepwise titration. The initial intravenous dose of
Dormicum must be administered slowly and in increments. Each dose increment, which must

not exceed 5 mg, must be injected over 20 to 30 seconds. A 2-minute pause should be observed
between injections to titrate the dose.
Adults under 60 years of age
• A dose of 0.2 mg/kg, administered intravenously over 20 to 30 seconds and followed
by a 2-minute pause to evaluate the effect, generally suffices.
• In non-premedicated patients, higher doses (0.3–0.35 mg/kg) may prove necessary;
these are administered intravenously over 20 to 30 seconds and are followed by a 2-
minute pause to evaluate the effect. If necessary, to complete the induction of
anaesthesia, the patients concerned can be given increments of approximately 25% of
the initial dose. To complete the induction of anaesthesia, inhalation of volatile liquid
anaesthetics can also be used as an alternative. In the event of inadequate patient
response, a total dose of up to 0.6 mg/kg can be used to induce anaesthesia; however,
doses as high as this may delay recovery.
Adults over 60 years of age and/or critically ill patients or those at high risk
• In non-premedicated patients, the lowest initial dose of 0.15–0.2 mg/kg is
recommended.
• In premedicated patients, a dose of 0.05–0.15 mg/kg, administered intravenously over
20–30 seconds and followed by a 2-minute pause to evaluate the effect, generally
suffices.
Children
The use of Dormicum to induce anaesthesia is reserved for adults, as experience is very limited
in children.
Sedative component in combined anaesthesia
Adults
When used as a sedative component in combined anaesthesia, Dormicum can be administered
as a series of intermittent low doses (ranging from 0.03 to 0.1 mg/kg) or as a continuous
intravenous infusion (range: 0.03–0.1 mg/kg/h), generally in combination with analgesics. Dose
and dose range depend on individual patient response.
Adults over 60 years of age, critically ill patients or those at high risk require lower maintenance
doses.
Children
The use of Dormicum as a sedative component in combined anaesthesia is reserved for adults
as experience in children is very limited.
Sedation in intensive care units
The desired level of sedation is reached by increasing the dose of Dormicum stepwise (dose
titration). Continuous infusion or intermittent bolus injection are then performed depending on
clinical need, physical status, age and comedication (see section 4.5).
Adults
Administration of the initial intravenous dose (0.03–0.3 mg/kg) should be given slowly in

increments. Each increment of 1–2.5 mg should be injected over 20 to 30 seconds. A 2-minute
pause for dose titration should be observed between injections.
The initial dose should be reduced or even withdrawn in patients with hypovolaemia,
vasoconstriction or hypothermia.
When Dormicum is combined with very potent analgesics, these should be administered first
in order to evaluate their sedative effect. The patient’s level of sedation can then be increased
without risk by titrating the dose of Dormicum.
Intravenous maintenance dose: The intravenous maintenance dose may range between 0.03 and
0.2 mg/kg/h. The maintenance dose should be reduced in patients with hypovolaemia,
vasoconstriction or hypothermia. If the patient’s condition allows, the level of sedation should
be regularly checked. In long-term sedation loss of effect may occur, requiring an increase in
dose.
Children
Administration of midazolam solutions in concentrations exceeding 1 mg/ml is not
recommended in neonates (whether pre- or full-term) or in children weighing less than 15 kg.
Higher concentrations should be diluted to 1 mg/ml.
Infants under 6 months of age
Dormicum should be administered as a continuous intravenous infusion.
• Preterm infants of gestational age <32 weeks: initial dose: 0.03 mg/kg/h
(0.5 μg/kg/min).
• Infants of gestational age >32 weeks to 6 months: initial dose: 0.06 mg/kg/h
(1 μg/kg/min).
Intravenous initial doses should not be administered. Instead the infusion rate can be increased
for the first few hours until therapeutic plasma concentrations are reached. The infusion rate
should be carefully monitored, in particular after the first 24 hours, to ensure that the lowest
possible effective dose is administered and that the risk of accumulation is kept as low as
possible.
Respiratory rate and oxygen saturation should be closely monitored.
Children aged >6 months
In intubated and ventilated patients, an initial dose of 0.05–0.2 mg/kg should be administered
slowly i.v. over at least 2–3 minutes to achieve the desired effect. Dormicum should not be
given by rapid intravenous administration. The initial dose is followed by a continuous
intravenous infusion of 0.06–0.12 mg/kg/h (1–2 μg/kg/min) Dormicum. The rate of infusion
can be increased or decreased (generally by 25% of the initial infusion rate or the rate chosen
immediately afterwards); supplemental doses of Dormicum can be administered intravenously
to augment or maintain the effect.
When initiating treatment with Dormicum infusion in patients with hemodynamic disorders,
the usual initial dose should be initiated by titrating the dose in small increments and the patient
should be monitored for hemodynamic instability (e.g. the development of hypotension). These
patients are also at risk of Dormicum-induced respiratory depression; their respiratory rate and

oxygen saturation must be closely monitored for that reason.
Special dosage instructions
Renal impairment
Patients with renal impairment are similar to healthy volunteers in the pharmacokinetics of free
midazolam.
However, α-hydroxymidazolam accumulation has been observed in patients with chronic renal
disease. The clinical effect of midazolam may therefore be augmented and lead to prolonged
sedation.

Hepatic impairment
Hepatic impairment delays the elimination of intravenously administered midazolam, leading
to an increase in terminal half-life. This may enhance and prolong the clinical effect. The dose
of midazolam required to achieve the desired effect may be lower and vital functions need to
be closely monitored (see sections 4.2 and 4.4).

Dormicum ampoules should only be used when the availability of resuscitation facilities
appropriate to the patient’s age and size can be guaranteed, as intravenous Dormicum
administration may depress myocardial contractility and cause apnoea. Severe cardiorespiratory
adverse events, such as respiratory depression, apnoea, and respiratory and/or cardiac arrest,
have been observed in rare cases. The probability of such life- threatening events occurring is
increased if the product is injected too rapidly or at too high a dose.
When conscious sedation is to be performed by a physician who is not an anaesthetist, the
mandatory recommendation is to check current guidelines concerning practice in this regard.
Premedication
When using midazolam for premedication, intensive patient monitoring is mandatory after

administration since response may vary between individuals and symptoms of overdosage may
occur.
High-risk patients
Caution is especially mandatory when administering Dormicum to patients in high-risk groups:
patients over 60 years of age
critically ill patients
 patients with organ dysfunction:
o respiratory impairment
o renal impairment
o hepatic impairment
o cardiac impairment.
These high-risk patients require lower dosages (see section 4.2) and should be continuously
monitored for early signs of alterations in vital functions.
Criteria for discharging patients from hospital
Patients who have received parenteral Dormicum should not leave hospital until at least 3 hours
after the last injection and must be accompanied. Their attention should be drawn to the fact
that they must not drive or operate machinery for at least 12 hours.
Tolerance
Some loss of efficacy has been observed when Dormicum has been used for long-term sedation
in intensive care units (ICU).
Withdrawal symptoms
Since abrupt treatment discontinuation increases the risk of withdrawal symptoms, in particular
after long-term sedation lasting ≥2–3 days, gradual dose reduction is recommended. The
following withdrawal symptoms may occur: headaches, muscle pains, anxiety, tension,
restlessness, confusion, irritability, rebound insomnia, mood swings, hallucinations and
convulsions.
Amnesia
Midazolam causes anterograde amnesia. Prolonged amnesia can present problems in
outpatients who are due to go home after their procedure.
Paradoxical reactions
Paradoxical reactions such as agitation, involuntary movements (e.g. tonic/clonic convulsions
and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal
excitement and assault, have been reported to occur with midazolam. These reactions may occur
after the administration of high doses and/or rapid injection. Low susceptibility to such
reactions has been reported in children and after high intravenous doses in the elderly.
Altered elimination of midazolam

Midazolam elimination may be altered in patients receiving drugs that inhibit or induce
CYP3A4. The dose of midazolam may need to be adjusted accordingly (see section 4.5).
Midazolam elimination may also be delayed in patients with hepatic impairment, low cardiac
output, and in neonates (see sections 5.2 and 5.2: Pharmacokinetics in special patient groups).
Preterm infants
Due to the increased risk of apnoea, extreme caution is mandatory when sedating preterm
infants of gestational age <36 weeks without an endotracheal tube in situ. Rapid injection must
always be avoided in preterm infants of gestational age <36 weeks. Respiratory rate and oxygen
saturation must be closely monitored.
Infants under 6 months of age
In infants under 6 months of age, the risks of airway obstruction and hypoventilation are
particularly high. Dose titration in small increments until clinical effect is achieved and careful
monitoring of respiratory rate and oxygen saturation are therefore essential (see also the Preterm
infants section above).
Concomitant use of alcohol/CNS depressants
The concomitant use of Dormicum and alcohol and/or CNS depressants should be avoided due
to the risk of potentiation of the clinical effect of Dormicum, possibly severe sedation and
clinically significant respiratory and/or cardiovascular depression (see section 4.5).
History of alcohol, drug or prescription drug abuse
Dormicum should not be used in patients with a history of alcohol or prescription drug abuse.
Miscellaneous
As with all substances having a central depressant and/or muscle relaxant effect, particular
caution is mandatory when administering Dormicum to patients with myasthenia gravis.
Dependence
Physical dependence on midazolam may develop when Dormicum is used for long-term
sedation. The risk of dependence increases with dose and treatment duration and is also
increased in patients with a history of alcohol or prescription drug abuse.

Pharmacokinetic drug interactions
Midazolam is almost exclusively metabolised by cytochrome P450 3A4 (CYP3A4). Inhibitors
and inducers of CYP3A may increase or decrease plasma concentrations and hence the
pharmacodynamic effects of midazolam. Apart from modulation of CYP3A activity, no other
mechanism capable of causing pharmacokinetic drug interactions with midazolam has been
demonstrated. Acute displacement from its plasma protein (albumin) binding sites may,
however, at least theoretically, cause drug interactions with drugs reaching high serum
concentrations, as for example has been suspected with valproic acid (see below). No change
due to midazolam is known in the pharmacokinetics of other drugs.
Close monitoring of clinical effects and vital signs is recommended when using midazolam,
taking into account the fact that midazolam may have a more marked and sustained clinical

effect if coadministered with a CYP3A inhibitor. Depending on the degree of CYP3A
inhibition, marked reduction of the dose of midazolam may sometimes be possible. Conversely,
when coadministering a CYP3A inducer, it may prove necessary to increased the dose of
midazolam to achieve the desired effect.
In CYP3A induction and irreversible inhibition (known as mechanism-based inhibition), the
effect of administering the CYP3A inhibitor on the pharmacokinetics of midazolam may last
for several days, or even several weeks. Drugs that may cause mechanism-based inhibition of
CYP3A include: antibacterials (e.g. clarithromycin, erythromycin, isoniazid), anti-HIV drugs
(e.g. HIV protease inhibitors), antihypertensives (e.g. verapamil, diltiazem), steroid sex
hormones and modulators of their receptors (e.g. gestoden, raloxifen) and various plant
components (e.g. the bergamottin contained in grapefruit). Unlike the other substances causing
mechanism-based inhibition (see the list below), use of ethinylestradiol/norgestrel for oral
contraception or grapefruit juice (200 ml) has caused no change of note in the plasma
concentrations of intravenously administered midazolam.
The intensity of drug-induced CYP3A inhibition or induction is very variable. The antimycotic
ketoconazole, a highly potent CYP3A inhibitor, multiplied the plasma concentrations of
intravenously administered midazolam approximately 5-fold. The tuberculostatic rifampicin is
one of the most potent CYP3A inducers. When coadministered with midazolam, it reduced the
plasma concentrations of intravenously administered midazolam by approximately 60%.
The route of midazolam administration also affects the degree of pharmacokinetic impact
caused by CYP3A modulation:
a) the impact on plasma concentrations should be slighter when midazolam is administered
intravenously rather than orally, since CYP3A modulation affects not only the systemic
clearance of midazolam but also its bioavailability after oral administration;
b) there are no studies on the effects of CYP3A modulation on the pharmacokinetics of rectally
or intramuscularly administered midazolam. Since the drug partially bypasses the liver
when administered rectally, and since CYP3A is more weakly expressed in the colon than
in the upper gastrointestinal tract, the impact of CYP3A modulation on plasma midazolam
concentrations is likely to be weaker after rectal than after oral administration. Since the
drug enters the systemic circulation directly after intramuscular injection, CYP3A
modulation is likely to have the same effect as after intravenously administered midazolam.
c) Consistent with pharmacokinetic principles, clinical studies have shown that following the
administration of a single intravenous dose of midazolam, the impact of CYP3A
modulation on maximum clinical effect is weaker, whereas the duration of effect may be
longer. However, after prolonged midazolam administration, both intensity and duration of
effect are increased in the presence of CYP3A inhibition.
The following list provides clinical examples of pharmacokinetic drug interactions with
intravenously administered midazolam. It is important to note that each drug capable of
modulating CYP3A in vitro or in vivo may in principle modify the plasma concentrations and
hence effect of midazolam. Where no information is available on midazolam coadministered
intravenously with another drug, the list incorporates data from clinical studies relating to drug
interactions with orally administered midazolam. As mentioned above, the impact on plasma
concentrations should be slighter when midazolam is administered intravenously than when it
is administered orally.

Drugs that inhibit CYP3A4
Azole antifungals
• Ketoconazole multiplied the plasma concentrations of intravenously administered
midazolam 5-fold while approximately tripling its terminal half-life.
• Parenteral midazolam should only be coadministered with ketoconazole, a potent CYP3
inhibitor, in an intensive care unit (ICU) or similar setting to ensure close clinical
monitoring in the event of respiratory depression and/or prolonged sedation. In particular,
incremental dosing and dose adjustment should be considered when administering more
than one intravenous dose of midazolam.
• Fluconazole and itraconazole both multiplied the plasma concentrations of intravenously
administered midazolam between two- and three-fold and prolonged the terminal half-life
2.4-fold (itraconazole) and 1.5-fold (fluconazole).
• Posaconazole approximately doubled the plasma concentrations of intravenously
administered midazolam.
Macrolide antibiotics
Erythromycin multiplied the plasma concentrations of intravenously administered midazolam
approximately 1.6-fold to 2-fold and simultaneously prolonged the terminal half-life of
midazolam 1.5-fold to 1.8-fold.
Clarithromycin multiplied the plasma concentrations of midazolam 2.5-fold while prolonging
the terminal half-life 1.5-fold to 2-fold.
Additional information for orally administered midazolam
• Roxithromycin: Roxithromycin has less impact on the pharmacokinetics of midazolam
than erythromycin or clarithromycin. It increased the plasma concentrations of orally
administered midazolam by approximately 50%, whereas erythromycin and clarithromycin
multiplied them 4.4-fold and 2.6-fold, respectively. The relatively slight prolongation of
the terminal half-life of midazolam, approximately 30%, indicates that roxithromycin may
have only a slight impact on intravenously administered midazolam.
HIV protease inhibitors
Saquinavir and other HIV protease inhibitors: when coadministered with ritonavir- boosted
lopinavir, the plasma concentrations of intravenously administered midazolam were multiplied
5.4-fold and the terminal half-life was correspondingly prolonged.
When coadministering midazolam with HIV protease inhibitors, treatment should comply with
the description given in the above paragraph on ketoconazole in the Azole antifungals section.
No study on the in vivo interactions of intravenously administered midazolam with other
protease inhibitors is available. However, saquinavir is generally a weaker CYP3A4 inhibitor
than the other HIV protease inhibitors and it has been shown that HIV protease inhibitors
increase exposure to orally administered midazolam and to other CYP3A substrates.
H2 histamine receptor antagonists
• Cimetidine increases plasma midazolam concentrations at steady state by 26%.

Calcium antagonists
• Diltiazem: A single dose of diltiazem increases the plasma concentrations of intravenously
administered midazolam by approximately 25% and the terminal half- life by
approximately 43%.
Additional information for orally administered midazolam
• Verapamil and diltiazem multiply the plasma concentrations of orally administered
midazolam 3-fold and 4-fold, respectively. They increase the terminal half-life of
midazolam by 41% and 49%, respectively.
Miscellaneous drugs/herbal medicines
• Atorvastatin multiplied the plasma concentrations of intravenously administered
midazolam approximately 1.4-fold versus the control group.
Additional information for orally administered midazolam
• Fluvoxamine caused a slight increase in the plasma concentrations of orally administered
midazolam (28%) and doubled its terminal half-life.
• Nefazodone multiplied the plasma concentrations of orally administered midazolam 4.6-
fold and its terminal half-life 1.6-fold.
• Aprepitant dose-dependently increased the concentrations of orally administered
midazolam (3.3-fold after a dose of 80 mg/day) this was associated with an approximate
doubling of the terminal half-life.
• Chlorzoxazone lowered the ratio between the CYP3A-generated metabolite,
-hydroxymidazolam, and midazolam, indicating that it has an inhibitory effect on
CYP3A.
• Bicalutamide had only a weak impact on orally administered midazolam (27% increase in
plasma concentrations).
• Curcuma rhizome extract lowered the ratio between the CYP3A-generated metabolite,
-hydroxymidazolam, and midazolam, by approximately 40%, indicating that it has an
inhibitory effect on CYP3A.
Drugs that induce CYP3A
• Rifampicin 600 mg/day for 7 days reduced the concentrations of intravenously
administered midazolam by approximately 60%. It decreased the terminal half-life by
50%–60%.
Additional information for orally administered midazolam
• Carbamazepine/phenytoin: Repeated doses of carbamazepine or phenytoin reduced the
plasma concentrations of orally administered midazolam by up to 90%; at the same time
they shortened its terminal half-life by approximately 60%.
• Efavirenz: Five-fold multiplication of the ratio between the CYP3A-generated metabolite,
-hydroxymidazolam, and midazolam, confirmed this drug’s CYP3A- inducing activity.

Herbal medicines and food
• Echinacea purpurea root extract reduced the plasma concentrations of intravenously
administered midazolam by 20% and its half-life by approximately 42%.
• St John’s wort reduced the plasma concentrations of midazolam by 20%–40%; it also
shortened its terminal half-life by 15%–17%.
Acute displacement from plasma protein binding sites
• Valproic acid: One publication has discussed the displacement of midazolam from its
plasma protein binding sites by valproic acid as a possible mechanism of drug interaction.
However, for methodological reasons the clinical significance of this study has been
considered very limited. Given that the therapeutic plasma concentration of valproic acid
is high, however, displacement of midazolam from its plasma protein binding sites by the
administration of acute doses cannot be excluded, resulting in a more marked clinical effect
of midazolam.
Pharmacodynamic drug interactions
Coadministration of midazolam with other sedatives/hypnotics (including alcohol) is likely to
have an enhanced sedative or sleep-inducing effect. Examples of such substances include:
opiates/opioids (used as analgesics, antitussives or replacement treatments), neuroleptics, other
benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate,
sedative antidepressants, antihistamines and centrally-acting antihypertensives. Midazolam
decreases the minimum alveolar concentration of inhalational anaesthetics.
A more marked effect on sedation, respiration and haemodynamics may occur when
coadministering midazolam with centrally-acting antidepressants, including alcohol.
Appropriate monitoring of vital functions should be performed for this reason. Alcohol must
not be used in any form after midazolam administration (see section 4.9).
It has been shown that spinal anaesthesia may enhance the sedative effect of intravenously
administered midazolam. In such cases the dose of midazolam can be reduced. Intramuscular
administration of lidocaine and bupivacaine also reduces the dose of intravenously administered
midazolam required for sedation.
Drugs that enhance attention and memory, such as physostigmine, an acetylcholinesterase
inhibitor, suppress the sleep-inducing effect of midazolam. Similarly, 250 mg caffeine also
partially inhibits the sedative effect of midazolam.
Paediatric population
Interaction studies have only been performed in adults.

Pregnancy
There is clear evidence of risk to the human foetus from benzodiazepine administration during
pregnancy.
Dormicum must therefore not be used during pregnancy, except if absolutely necessary.
Caution is mandatory when administering benzodiazepines in late pregnancy and during labour,

given that irregularities in the heart rate and hypotension may occur in the foetus, while a
reduced desire to suck, respiratory depression, reduced activity, floppy infant syndrome,
withdrawal symptoms and hypothermia may occur in the neonate.
Lactation
Midazolam passes in low quantities into breast milk. Nursing mothers should be advised to
discontinue breastfeeding for 24 hours following administration of midazolam.
Fertility
The effects of midazolam on fertility have not been established.

Sedation, amnesia, concentration difficulties and muscle dysfunction impair the ability to drive
and use machines. Before receiving Dormicum, patients should be warned not to drive or use
machines until the effect of the drug has fully worn off, but in no case less than 12 hours after
the last injection. The physician should decide when the patient may resume these activities.

The following undesirable effects have been observed in very rare cases after midazolam
injection and are presented according to the MedDRA system organ classification.
Tabulated list of adverse reactions
Frequency categories are as follows:

Symptoms
Benzodiazepines generally cause confusion, ataxia, dysarthria and nystagmus. Dormicum
overdose 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. If coma occurs, it
generally lasts a few hours but it may be prolonged and cyclical in elderly patients.
Benzodiazepine respiratory depressant effects are more serious in patients with respiratory
disease.
Benzodiazepines potentiate the effect of CNS 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 taken orally, further absorption should be prevented using appropriate methods, such as
treatment within 1–2 hours with activated charcoal. If activated charcoal is used, the airway
must be protected in drowsy patients. Gastric lavage should be considered in the event of mixed
intoxication, but not as a routine measure.

The use of Anexate® (active substance flumazenil), a benzodiazepine antagonist, should be
considered if central nervous system depression is severe. It should only be administered under
closely monitored conditions. Since it has a short half-life (about 1 hour), patients receiving
flumazenil must be monitored when its effect wears off. Flumazenil is to be used with extreme
caution in conjunction with drugs that reduce the seizure threshold (e.g. tricyclic
antidepressants). Refer to the prescribing information for Anexate® (flumazenil) for further
information on the correct use of this drug.

Pharmacotherapeutic group: Hypnotics and sedatives (benzodiazepine derivatives), ATC code:
N05CD08.
Midazolam, the active substance in Dormicum, is an imidazobenzodiazepine. The free base is
lipophilic and weakly water-soluble.
Thanks to the basic nitrogen in position 2 of the imidazobenzodiazepine ring system, the active
substance in Dormicum is able to form water-soluble salts with acids that produce a stable
injectable solution.
The pharmacological characteristics of Dormicum are rapid onset of effect and, thanks to rapid
metabolic transformation, short duration of effect. The low toxicity of Dormicum confers a
wide therapeutic safety margin.
Dormicum has a very rapid sedative and sleep-inducing effect. It also has an anxiolytic,
anticonvulsant and muscle-relaxant effect.
Short-lasting anterograde amnesia (patients do not remember events that occur during the phase
of maximum drug activity) follows intramuscular or intravenous administration.
Clinical efficacy
Clinical studies conducted in patients confirm the indications for intravenous and rectal
Dormicum administration mentioned in Indications and uses.

Absorption
Absorption after intramuscular injection
Midazolam absorption from muscle tissue is rapid and complete. Peak plasma concentrations
are reached within 30 minutes. Absolute bioavailability exceeds 90%.
Absorption after rectal administration
Midazolam absorption after rectal administration is rapid. Peak plasma concentrations are
reached within approximately 30 minutes. Absolute bioavailability is approximately 50%.
Distribution
When Dormicum is administered intravenously, 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. Midazolam is 96%–98% bound to plasma protein. Protein binding is due mainly to

albumin. Midazolam passes slowly but in insignificant amounts into cerebrospinal fluid.
In humans, midazolam has been shown to cross the placental barrier slowly and to enter the
foetal circulation. Half to one hour after oral dosing with 15 mg, the ratio between the foetal
serum concentration (cord blood) and maternal serum concentration was 0.6–1.0. The
elimination half-life of midazolam and its main metabolites in neonates is approximately
6.3 hours. In humans, small quantities of midazolam have also been demonstrated in breast
milk.
Biotransformation
Midazolam is almost entirely eliminated by biotransformation. Less than 1% of the dose is
recovered in urine as unchanged drug. Midazolam is hydroxylated by the cytochrome P450 3A4
isoenzyme. The major urinary and plasma metabolite is α-hydroxymidazolam. Plasma
concentrations of α-hydroxymidazolam are 12% those of the parent compound. The fraction of
the dose extracted by the liver has been estimated to be 30%–60%. The elimination half-life of
the metabolite is less than 1 hour; α-hydroxymidazolam is pharmacologically active, but
contributes minimally (approximately 10%) to the effect of intravenously administered
midazolam. There is no evidence of genetic polymorphism in oxidative midazolam metabolism
(see section 4.5).
Elimination
In healthy volunteers, the elimination half-life is 1.5–3.5 hours. Plasma clearance is in the range
300–500 ml/min; 60%–80% of the dose is eliminated in the urine as the α-hydroxymidazolam
glucuronide conjugate. Less than 1% of the dose is recovered in urine as unchanged drug. The
elimination half-life of the metabolite is under 1 hour. When midazolam is given by intravenous
infusion, its elimination kinetics do not differ from those observed following bolus injection.
Pharmacokinetics in special patient groups
Elderly patients
In persons over 60 years of age, the elimination half-life may be quadrupled.
Children
In children, the rate of midazolam absorption after rectal administration is similar to that in
adults, but bioavailability is lower (5%–18%). However, the elimination half-life (t½) after
intravenous and rectal administration in children aged 3–10 years is shorter than in adults (1.0–
1.5 h). The difference is consistent with increased metabolic clearance in children.
Neonates
In preterm infants and neonates, the average elimination half-life is 6–12 h, probably due to
liver immaturity; clearance is reduced (see section 4.4).
Overweight patients
Mean half-life is longer in overweight than in normal-weight patients (8.4 vs 2.7 h). This is due
to an increase of approximately 50% in the volume of distribution corrected for total body
weight. Clearance does not differ significantly in overweight compared to normal-weight
patients.
Patients with hepatic impairment
In cirrhotic patients, the elimination half-life may be longer and clearance lower than in healthy

subjects (see section 4.4).
Patients with renal impairment
In patients with chronic renal failure, the elimination half-life is similar to that in healthy
subjects. It has, however, been shown that -hydroxymidazolam accumulates and could enhance
the clinical effect of midazolam, which could result in prolonged sedation (see sections 4.2 and
4.4).
Critically ill patients
The elimination half-life of midazolam is prolonged in critically ill patients.
Patients with heart failure
In patients with heart failure, the elimination half-life is longer than in healthy subjects (see
section 4.4).

Mutagenic and carcinogenic potential
Liver and thyroid tumours were observed in long-term studies in mice and rats. The consensus
view is that these data cannot be extrapolated to humans.
The results of in vitro and in vivo genotoxicity studies show that mutagenic, clastogenic and
aneugenic effects are unlikely with the use of midazolam.
Reproductive toxicology
Like all benzodiazepines, midazolam crosses the placental barrier.
Teratogenicity
Studies of midazolam in rats and mice revealed no evidence of teratogenicity.
However, signs of behavioural disturbance were observed in the offspring of females exposed
to benzodiazepines.

Sodium chloride, hydrochloric acid, sodium hydroxide, water for injection.

Midazolam precipitates in sodium bicarbonate.
This medicinal product must not be mixed with other medicinal products except those
mentioned under section 6.6.

Do not store above 30°C.

1 ml ampoules containing 5 mg              10
3 ml ampoules containing 15 mg              5
5 ml ampoules containing 5 mg              10
10 ml ampoules containing 50 mg            5
Rectal applicators                                       50
Not all pack sizes/ strengths are marketed

Compatibility with infusion solutions: Dormicum solution can be diluted in 0.9% sodium
chloride, 5% and 10% glucose, 5% levulose, Ringer’s solution and Hartmann’s solution in a
ratio of 15 mg midazolam per 100–1,000 ml infusion solution. These solutions remain
physically and chemically stable for 24 hours at room temperature (or for 3 days at 5°C).
Dormicum solution must not be diluted in glucose solution with 6% macrodex nor mixed with
alkaline solutions for injection.
Dormicum ampoules are for single use only. Discard all unused residual product. Inspect the
solution before use. Only use clear solutions devoid of particulate matter.
Rectal administration
For rectal administration of the ampoule solution, a plastic applicator (rectal applicator) is fitted
onto the syringe tip. If the administration volume is too low, water can be added to a total
volume of 10 ml.