Doctor Pharmacy

DORMICUM TABLETS:

Roche
 
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 154±51 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.
 
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.

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 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.
 
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 (Cmax and t½ 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.