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30-50% of the active ingredient is metabolized dur-

ing the first passage through the liver.


Elimination
The metabolites formed are rapidly conjugated with
glucuronic acid and are eliminated as glucuronides
via the kidneys.
The half-life of midazolam is 1.5 to 3.5 hours and
that of alpha-hydroxymidazolam 0.8 to 1 hour. The
plasma concentration decreases in two phases with
half-lives of 10 minutes (distribution phase) and 1.5
to 3.5 hours (elimination phase), respectively.
Pharmacokinetics in Special Clinical Situations
The elimination half-life of midazolam can be pro-
longed in elderly subjects.
Indications
Dormicum is used for the short-term treatment of sleep
disturbances. Like all hypnotics, it should be used only
for sleep disturbances of clinically significant severity.
Disturbances of sleep pattern, difficulty in getting
to sleep, and difficulty in getting back to sleep after
premature waking.
Sedation in premedication before surgical or diag-
nostic procedures.
Contraindications
Hypersensitivity to benzodiazepines; patients who
have a history of alcohol and/or drug abuse or
dependency or who currently abuse drugs and/or
alcohol; severe respiratory failure; insomnia in chil-
dren; severe impairment of liver function; myasthe-
nia gravis; sleep apnea syndrome.
Dormicum should not be used alone to treat insom-
nia associated with psychosis or depression (risk of
suicide in these conditions). In such cases priority
should be given to treatment of the basic disease.
Side Effects
Tiredness, daytime drowsiness, reduced alertness,
confusion, headache, dizziness, muscle weakness,
ataxia.
Composition
Active ingredient: midazolam as the maleate. Tablets
(scored) of 7.5 mg. Tablets (scored) of 15 mg.
Excipients: Tablets of 15 mg: color: E132 (indigo car-
mine).
Properties
Dormicum is a rapidly acting hypnotic with a short
biological half-life. In controlled trials and in the
sleep laboratory Dormicum was shown to reduce
sleep onset time and to prolong sleep without quan-
titatively impairing REM sleep. Waking phases are
reduced and sleep efficiency is improved.
Onset of sleep generally occurs within 20 minutes
of ingestion of Dormicum and the duration of sleep
generally becomes normal for the age of the patient.
After a suitable dose and duration of sleep there is
generally no impairment of performance or reactive
capacity.
Midazolam, the active ingredient of Dormicum, also
has anticonvulsant, anxiolytic, sedative and muscle-
relaxant properties.
Pharmacokinetics
Absorption
After oral administration of Dormicum the active
ingredient midazolam is absorbed rapidly and com-
pletely.
After a single dose of 15 mg of midazolam a maxi-
mum plasma concentration of 15451 ng/mI is
reached after 0.5 to 1.5 hours.
Distribution
Midazolam is strongly (96-98%) bound to plasma
proteins. The volume of distribution of midazolam
after I.V. administration ranges from 0.7 to 1.2 I/kg.
Metabolism
Midazolam is rapidly and completely metabolized
via cytochrome P-450 3 A.
The pharmacologically active principal metabolite is
alpha-hydroxymidazolam.
DORMICUM TABLETS
Roche
should be cautious in patients wit organic brain con-
ditions, patients in respiratory failure, and patients in
poor general condition (increased drug sensitivity).
Alertness, Reactive Capacity
Because of the properties of Dormicum, the abil-
ity to drive a motor vehicle or operate dangerous
machines may be impaired (see Side Effects).
Patients should therefore be warned against driv-
ing motor vehicles or operating dangerous machines
unless normal alertness and reactive capacity can
be ensured. Such activities should be avoided dur-
ing the first seven to eight hours after ingestion of
the medication.
Dependence
Use of benzodiazepines can lead to dependence.
This risk increases with dose and duration of treat-
ment and is higher in predisposed patients.
Withdrawal phenomena occur especially after
abrupt discontinuation and in milder cases are lim-
ited to tremor, restlessness, insomnia, anxiety,
headache and impairment of concentration, though
symptoms such as sweating, muscle pain, abdomi-
nal pain, disturbances of perception, and in rare
cases delirium and convulsions may occur.
Depending on the duration of action of the sub-
stance concerned, withdrawal phenomena com-
mence a few hours to a week or more after discon-
tinuation of treatment.
In order to minimize the risk of dependence, benzodi-
azepines should be prescribed only after a careful con-
sideration of the indication and should be taken for as
short a period as possible (generally no longer than
two weeks when used as a hypnotic, for example). The
need for continuation of treatment should be reviewed
regularly. The risk-benefit relationship of more pro-
longed treatment is less clear, hence it is indicated only
in certain patients (e.g. those with panic attacks).
In order to avoid withdrawal phenomena the drug
should be discontinued by tapering off the dose in
all patients. Should withdrawal phenomena occur,
close medical monitoring and support of the patients
is required.
These effects occur predominantly at the start of
treatment and generally disappear with dose reduc-
tion or continuation of treatment.
Paradoxical reactions such as restlessness, excit-
ability, agitation, aggressiveness, hallucinations and
behavioral disturbances are known to occur with
the use of benzodiazepines. They occur more com-
monly in older patients and call for discontinuation of
treatment and appropriate monitoring and support of
the patient.
Allergic reaction (e.g. skin rashes) occur very rarely.
As with all hypnotics, sedatives and tranquilizers,
prolonged treatment can lead to drug dependence in
predisposed patients.
Previously unrecognized depression may be
unmasked by treatment with Dormicum.
Anterograde amnesia: Rarely, patients who are pre-
vented from going to sleep or who are woken within
a few hours of taking Dormicum suffer amnesia with
regard to daily activities performed in the waking phas-
es. This anterograde amnesia may be accompanied by
unusual behavior. Such episodes are known to occur
more commonly in patients under unusual mental
stress. Such patients should not take Dormicum.
Precautions
Where treatment is given concomitantly with CNS
depressant medications or in general with substanc-
es such as erythromycin, azoletype antimycotics,
and cimetidine that interfere with the metabolism
of midazolam by cytochrome P-450 3 A, attention
should be paid to the Drug interactions section.
The patient should be warned against simultane-
ous consumption of alcohol, as the combination can
potentiate the undesirable effects of both substances.
As interactions between Dormicum and alcohol
or other centrally acting medications can result in
unusual or disturbed behavior, previous or simulta-
neous consumption of alcohol should be avoided.
Administration of Dormicum concomitantly with other
centrally acting medications should be avoided.
Relative Restrictions on Use
As in the case of other sedating medications, dosing
Even after short-term use, discontinuation of the
product may be followed by temporary recurrence of
the sleep disturbance for a few nights. This can gen-
erally be avoided by stepwise dose reduction.
Pregnancy and Lactation
There is clear evidence that the use of benzodiaze-
pines during pregnancy endangers the human fetus.
Therefore, Dormicum should not be taken during
pregnancy, especially the first trimester, unless there
is a compelling indication for its use and no safer
therapeutic alternative is available.
Use of benzodiazepines during late pregnancy or
confinement can have undesirable effects on the
neonate such as respiratory depression, hypother-
mia, hypotension and delayed appearance of with-
drawal phenomena.
Midazolam is excreted in breast milk and can there-
fore cause drowsiness and poor feeding in the
infant. Therefore, Dormicum should not be taken by
nursing mothers.
Overdosage
The following effects can occur after overdosage:
tiredness, ataxia, deep sleep, amnesia, respiratory
depression. Such cases call for general supportive
measures and gastric lavage, if this can be per-
formed shortly after ingestion. If the patient is con-
scious, activated charcoal can be given. Specific
therapy is available in the form of Anexate (active
ingredient: flumazenil).
As with overdosage of other sedatives and hypnot-
ics, it is important to keep the airways free and to
monitor vital functions.
Special Remarks
This medicine should not be used after the expiry
date (EXP) shown on the pack.
Drug Interactions
Caution is required when Dormicum is taken con-
comitantly with CNS depressant medications and/or
alcohol, as mutual potentiation of effects occurs.
Such medications include neuroleptics, tranquilizers,
antidepressants, hypnotics, narcotics, antiepilep-
tics, centrally acting analgesics and antihistamines.
In the case of narcotics the euphoria and hence the
risk of psychologic dependence may be increased.
The plasma concentration of midazolam after oral
administration is demonstrably increased (C
max
and t


more than doubled) when the substance is taken in
combination with erythromycin. This results in potenti-
ation of the sedative effect of midazolam. In vitro data
show that the hydroxylation of midazolam is inhibited
by many other substances that specifically inhibit the
isozyme cytochrome P-450 3 A. Clinically relevant
potentiation of the effect of midazolam has been dem-
onstrated with erythromycin, diltiazem, verapamil,
ketoconazole, itraconazole, cimetidine and ranitidine,
but not with cyclosporin or nitrendipine.
When Dormicum is used concomitantly with erythro-
mycin or cimetidine its oral dose should be reduced,
in the case of erythromycin to a half to a quarter,
and in that of cimetidine to about two thirds, of the
usual dose.
A much smaller change in plasma concentration,
but no potentiation of the sedative effect, has been
observed after I.V. administration of midazolam.
Nevertheless, caution is advised.
With concomitant intake of other CNS depressant
medications (e.g. neuroleptics, narcotics) or alcohol
there is a risk of life-threatening respiratory depres-
sion.
During the clinical trials Dormicum was given togeth-
er with various medications including oral antidia-
betics and anticoagulants. No interactions were
observed.
Dosage and Administration
In general the lowest effective dose should be given
for as short a time as possible.
Standard Dosage
The standard dose for adults is 7.5 to 15 mg.
Because of its rapid onset of action, Dormicum
should be swallowed whole with fluid immediately
before retiring. An uninterrupted period of at least six
hours of sleep must be available thereafter. The risk
of anterograde amnesia should be borne in mind
(see Side Effects).
Special Dosage Instructions
The standard dose for elderly or frail patients is
7.5 mg.
This dose may also be suitable for patients with mild
impairment of liver and/or renal function. Where
appropriate, treatment can be initiated with half a
7.5 mg tablet. A dose of 7.5 mg is generally also suf-
ficient for situational sleep disturbances. The above
doses may be increased to a maximum of 15 mg if
treatment with the recommended dose and other
measures such as improved sleep hygiene and
treatment of sleep-disturbing underlying disease are
unsuccessful.
For premedication of adults, 7.5 to 15 mg of
Dormicum should be administered orally 30 to 60
minutes before the procedure, unless the parenteral
route is preferred (see Dormicum Ampoules).
The duration of treatment should generally not
exceed two weeks. In some cases a shorter period
of treatment may be adequate; in other cases a lon-
ger period of treatment may be necessary, but this
requires a careful re-evaluation.
At the end of treatment the dose of Dormicum
should be tapered off. The tapering-off process
should be tailored to the individual.