Dormicum

Midazolam.

Dormicum tablet contains midazolam maleate while the ampoule contains midazolam HCl.
Each ampoule also contains sodium chloride, hydrochloric acid, sodium hydroxide and water for injection as excipients.
Midazolam is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4] benzodiazepine.

Short-acting benzodiazepine for premedication, sedation, induction and maintenance of anesthesia.
Tablet: Sleep-inducing agent.
Pharmacology: Midazolam has a very rapid sedative and sleep-inducing action of pronounced intensity. It also exerts an anxiolytic, an anticonvulsant and a muscle-relaxant effect.
Ampoule: Midazolam is a derivative of the imidazobenzodiazepine group. The free base is a lipophilic substance with low solubility in water.
The basic nitrogen in position 2 of the imidazobenzodiazepine ring system enables midazolam to form water-soluble salts with acids. These produce a stable and well-tolerated injection solution.
The pharmacological action of midazolam is characterized by rapid onset, and because of rapid metabolic transformation, short duration. Because of its low toxicity, midazolam has a wide therapeutic range.
After parenteral administration, anterograde amnesia of short duration occurs (the patient does not recall events that occurred during the peak of activity of the compound).
Pharmacokinetics: Tablet: Absorption: Dormicum is absorbed rapidly and completely after oral administration. Due to the first-pass effect, bioavailability is approximately 40%.
With a dose of 15 mg, a C_max of 70-120 ng/mL is reached at T_max 0.5-1.5 hrs.
Distribution: The concentrations in the plasma decrease in 2 phases with half-lives of 0.3-0.5 hrs (distribution phase) and 1.5-3.5 hrs (elimination phase). 96-98% of midazolam becomes bound to plasma proteins. The volume of distribution ranges from 0.7-1.2 L/kg.
Metabolism: Midazolam is rapidly and completely metabolized. 30-50% of the active ingredient is already metabolized in the course of the first passage through the liver.
The main pharmacologically active metabolite is α-hydroxy midazolam, the elimination half-life of which is shorter than that of the parent substance.
There is no accumulation of midazolam or its active metabolites on prolonged once-daily administration.
Elimination: Midazolam is eliminated via metabolism. The metabolites formed undergo conjugation with glucuronic acid and are eliminated as glucuronides via the kidneys.
Ampoule: Absorption After IM Injection: Absorption of midazolam from the muscle tissue is rapid and complete. Maximum plasma concentrations are reached within 30 min. Bioavailability is over 90%.
Distribution: When midazolam is injected IV, the plasma concentration-time curve shows 2 distinct phases of distribution. The volume of distribution calculated under steady-state conditions is 0.7-1.2 L/kg body weight. Studies show a protein-binding of 96-98%.
In animals and humans, midazolam has been shown to cross the placenta and to enter fetal circulation. Small quantities of midazolam are found in human milk.
Metabolism: Midazolam is metabolized rapidly and completely. The primary metabolite is a α-hydroxy-midazolam. The fraction of the dose extracted by liver has been estimated at 40-50%. Many medicaments have been found to inhibit the production of this metabolite in vitro. For some of these drugs, this has been confirmed in vivo (see Interactions).
Elimination: In healthy volunteers, the elimination half-life is between 1.5 and 2.5 hrs. Plasma clearance is in the range of 300-400 mL/min. When midazolam is given by IV infusion, its elimination kinetics do not differ from those following bolus injection. The elimination half-life of the main metabolite, α-hydroxy-midazolam, is shorther than that of the parent substance. It is conjugated with glucuronic acid (inactivation). The metabolites are renally excreted.
Pharmacokinetics in Special Clinical Situations: In adults >60 years, the elimination half-life may be prolonged up to 3 times and in some intensive-care patients requiring midazolam by IV infusion for long-term sedation, up to 6 times. In these patients, infusion at an unchanged rate results in higher plasma levels at steady state.
The elimination half-life may also be prolonged in patients with congestive heart failure and with reduced hepatic function.
In children (3-10 years), the elimination half-life is between 1 and 1.5 hrs.
In neonates, the half-life of elimination is prolonged with a mean of 6 hrs (3-12 hrs) due to liver immaturity.

Tablet: Short-term treatment of insomnia. Benzodiazepines are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress. Sedation in premedication before surgical or diagnostic procedures.
Ampoule: Conscious sedation before diagnostic or therapeutic procedures with or without local anesthesia (IV administration).
Premedication before induction of anesthesia (IM or rectal administration in children).
Induction and Maintenance of Anesthesia: As an induction agent in inhalation anesthesia or a sedative component in combined anesthesia, including total IV anesthesia (IV injection, IV infusion).
Ataralgesia in combination with ketamine in children (IM administration).
Long-term sedation in intensive care units (IV administration as bolus injection or continuous infusion).

Tablet: Treatment should be as short as possible. Generally, the duration of treatment varies from a few days to a maximum of 2 weeks. The tapering off process should be tailored to the individual.
In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status. Dormicum should be taken just before going to bed, and swallowed whole with fluid.
Standard Dosage: Adults: Dosage Range: 7.5-15 mg.
Elderly and Debilitated Patients: Recommended Dose: 7.5 mg.
Treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded because of the increased risk of unacceptable CNS adverse effects.
Special Dosage Instructions: Patients with Impaired Liver Function: Recommended Dose: 7.5 mg. Dormicum can be taken at any time of the day, provided the patient is subsequently assured of at least 7-8 hrs undisturbed sleep.
If the patient concomitantly receives cimetidine, erythromycin, diltiazem, verapamil, ketoconazole and itraconazole, see Special Dosing Instructions under Interactions.
Premedication: In premedication, Dormicum tablet should be given 30-60 min before the procedure, unless the parenteral route is preferred.
Ampoule: Midazolam is a potent sedative agent which requires slow administration and individualization of dosage.
The dose should be individualized and titrated to the desired state of sedation according to the clinical need, physical status, age and concomitant medication.
In adults >60 years, debilitated or chronically ill patients, the dose should be determined with caution, the special factors relating to each patient being taken into consideration.
IV Conscious Sedation: The IV injection of Dormicum should be given slowly at a rate of approximately 1 mg in 30 sec. The drug takes effect in about 2 min after the injection has been given.
In adults <60 years, the initial dose is 2.5 mg given 5-10 min before the beginning of the procedure.
Further doses of 1 mg may be given as necessary.
A total dose >5 mg is usually not necessary. In adults >60 years, debilitated or chronically ill patients, the initial dose must be reduced to 1-1.5 mg and given 5-10 min before the beginning of the procedure.
Further doses of 0.5-1 mg may be given as necessary. A total dose >3.5 mg is usually not necessary.
Anesthesia: Premedication: Premedication with Dormicum given shortly before a procedure does produce sedation (induction of sleepiness or drowsiness and relief of apprehension) and preoperative impairment of memory.
Dormicum can also be administered in combination with anticholinergics.
The premedication is usually administered 20-60 min before induction of anesthesia.
IM Administration: In adults <60 years, the dose of Dormicum ranges from 0.07-0.1 mg/kg according to the general condition of the patient.
The usual dose is 5 mg.
In adults >60 years, debilitated or chronically ill, the dose range is from 0.025-0.05 mg/kg.
The usual dose is 2-3 mg.
In children between 1 and 15 years, proportionally higher doses are required than in adults in relation to body weight. The dose range from 0.08-0.2 mg/kg body weight has been shown to be effective and safe.
Dormicum should be administered deep into a large muscle mass 30-60 min prior to the induction of anesthesia.
Induction: The desired level of anesthesia is reached by stepwise titration.
The IV induction dose of Dormicum should be given slowly in increments.
Each increment of not more than 5 mg should be injected over 20-30 sec allowing 2 min between successive increments.
In premedicated adults <60 years, the dose can range from 0.15-0.2 mg/kg but a total dose >15 mg is usually not necessary.
In non-premedicated adults <60 years, the dose may be higher (0.3-0.35 mg/kg body weight), but a total dose >20 mg is usually not necessary.
In adults >60 years, debilitated or chronically ill patients, lower doses will be required.
Maintenance: The maintenance of the desired level of unconsciousness can be achieved by either further intermittent doses or continuous infusion of IV Dormicum typically in combination with analgesics.
The maintenance dose usually ranges from 0.03-0.1 mg/kg/hr when used in combination with narcotics or ketamine.
In adults >60 years, debilitated or chronically ill patients, lower maintenance doses will be required.
In children receiving ketamine for anesthesia (ataralgesia), an IM dose of Dormicum of 0.15-0.2 mg/kg is recommended.
A sufficiently deep level of sleep is generally achieved after 2-3 min.
IV Sedation in the Intensive Care Unit: The desired level of sedation is reached by stepwise titration of Dormicum followed by either continuous infusion or intermittent bolus.
The IV loading dose should be given in increments.
Each increments of 1-2.5 mg should be injected over 20-30 sec allowing 2 min between successive increments.
The IV loading dose can range from 0.03-0.3 mg/kg but a total dose >15 mg is usually not necessary.
In hypovolemic, vasoconstricted or hypothermic patients, the loading dose should be reduced or omitted.
The maintenance dose can range from 0.03-0.2 mg/kg/hr. The level of sedation should be assessed regularly if permitted by the patient's condition.
In hypovolemic, vasoconstricted or hypothermic patients, the maintenance dose should be reduced, at times to as low as 25% of the usual dose.
When Dormicum is given with potent analgesics, the latter should be administered first so that the sedative effects of Dormicum can be safely titrated on top of any sedation caused by the analgesic.
Special Dosage Instructions: Compatibility with Infusion Solutions: Dormicum solution can be diluted with sodium chloride 0.9%, dextrose 5% and 10%, levulose 5%, Ringer's solution and Hartmann's solution in a mixing ratio of 15 mg midazolam per 100-1000 mL infusion solution. These solutions remain physically and chemically stable for 24 hrs at room temperature, or 3 days at 5°C.
Dormicum solution should not be diluted with Macrodex 6% in dextrose or mixed with alkaline injections.

Tablet: As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol).
In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.
Following overdose with oral benzodiazepines, vomiting should be induced (within 1 hr) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in intensive care. Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy; in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression; rarely coma and very rarely death.
The specific benzodiazepine antagonist flumazenil may be useful for reversing the severe effects of overdose caused by benzodiazepines.
Ampoule: The symptoms of overdose are mainly an intesification of the pharmacological effects; central depression (from oversedation to coma), mental confusion, lethargy and muscle relaxation or paradoxical excitation. In most cases, only observation of vital functions is required.
Extreme overdosage may lead to coma, areflexia, cardiorespiratory depression and apnea, requiring appropriate countermeasures (ventilation, cardiovascular support). The effects of overdosage can be controlled with the benzodiazepine antagonist Anexate (flumazenil).

Known hypersensitivity to benzodiazepines.
Tablet: Patients with severe respiratory (due to risk of respiratory depression) and hepatic (as they may precipitate encephalopathy) insufficiency; sleep apnoea syndrome and myasthenia gravis.
Use in children: Tablet: Dormicum is contraindicated in children.

Tablet: Tolerance: Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines may develop after repeated use for a few weeks.
Dependence: Use of benzodiazepines and benzodiazepine-like agents may lead to the development of physical and psychological dependence upon these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: Derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.
Rebound Insomnia: A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine or benzodiazepine-like agent recur in an enhanced form, may occur on withdrawal of hypnotic treatment. It may be accompanied by other reactions including mood changes, anxiety and restlessness.
Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.
Duration of Treatment: The duration of treatment with benzodiazepine hypnotics should be as short as possible (see Dosage & Administration), but it should not exceed 2 weeks. The tapering off process should be tailored to the individual. Extension beyond this period should not take place without re-evaluation of the situation.
It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover, it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.
There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can be manifested within the dosage interval, especially when the dosage is high.
Amnesia: Benzodiazepines may induce anterograde amnesia. The condition occurs most frequently within the first few hours after ingesting the product and therefore to reduce the risk, patients should ensure that they are able to have an uninterrupted sleep of 7-8 hrs (see Side Effects).
Psychiatric and Paradoxical Reactions: Reactions ie, restlessness, agitation, irritability, aggressiveness, and more rarely, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of midazolam should be discontinued.
They are more likely to occur in the elderly.
Benzodiazepines are not recommended for the primary treatment of psychotic illness. These should not be used alone to treat depression or anxiety associated with depression as suicide may occur in such patients.
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
Hypersensitivity reactions may occur in susceptible individuals.
Ampoule: Special caution should be exercised when administering Dormicum parenterally to patients representing a higher risk group: Adults >60 years, debilitated or chronically ill, patients with obstructive pulmonary disease, with chronic renal failure, impaired hepatic function or with congestive heart failure. These higher-risk patients require lower dosages (see Dosage & Administration) and should be continuously monitored for early signs of alterations of vital functions. As with any substance with CNS depressant and/or muscle-relaxant properties, particular care should be taken when administering Dormicum to a patient with myasthenia gravis, owing to preexisting muscle weakness.
In rare cases, paradoxical reactions eg, agitation,hyperactivity and aggressivity have occurred; involuntary movements (including tonic/clonic convulsions and muscle tremor) have also been observed. Should such symptoms suggestive of a paradoxical reaction occur, the response to Dormicum should be evaluated before proceeding.
Convulsions have been reported in premature infants and neonates.
Dormicum should be used only when resuscitation facilities are available, as IV administration of Dormicum may depress myocardial contractility and cause apnea.
After receiving Dormicum parenterally, patients should not be discharged from hospital or consulting room for at least 3 hrs and then only if accompanied by an attendant.
After prolonged IV administration of Dormicum, abrupt discontinuation of the product may be accompanied by withdrawal symptoms. Therefore, a gradual reduction of Dormicum is recommended.
Effects on the Ability to Drive or Operate Machinery: Tablet: Sedation, amnesia and impaired concentration and muscular function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see Interactions).
Ampoule: Prior to receiving Dormicum, the patient should be warned not to drive a vehicle or operate a machine for at least 12 hrs.
Use in pregnancy: Tablet: If exceptionally it is considered by a physician that administration of the medicinal product during the last 3 months of pregnancy or during labour is essential, effects on the neonate eg, hypothermia, hypotonia, moderate respiratory depression can be expected due to the pharmacological action of Dormicum.
Insufficient data are available on midazolam to assess its safety during pregnancy and lactation. A woman of childbearing potential must be warned to contact a physician regarding discontinuance of the Dormicum if the patient intends to become or suspects that she is pregnant.
Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.
Ampoule: Dormicum should not be given during pregnancy. Special care must be taken when benzodiazepines are used during labour and delivery, as high single doses may produce respiratory depression, hypotonia, hypothermia and poor sucking in the neonate.
Use in lactation: Since benzodiazepines are found in the breast milk, midazolam should not be administered to breastfeeding mothers.
Use in the elderly: Tablet: See Dosage & Administration.

Use in pregnancy: Tablet: If exceptionally it is considered by a physician that administration of the medicinal product during the last 3 months of pregnancy or during labour is essential, effects on the neonate eg, hypothermia, hypotonia, moderate respiratory depression can be expected due to the pharmacological action of Dormicum.
Insufficient data are available on midazolam to assess its safety during pregnancy and lactation. A woman of childbearing potential must be warned to contact a physician regarding discontinuance of the Dormicum if the patient intends to become or suspects that she is pregnant.
Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.
Ampoule: Dormicum should not be given during pregnancy. Special care must be taken when benzodiazepines are used during labour and delivery, as high single doses may produce respiratory depression, hypotonia, hypothermia and poor sucking in the neonate.
Use in lactation: Since benzodiazepines are found in the breast milk, midazolam should not be administered to breastfeeding mothers.

Ampoule: Dormicum is well tolerated. Slight decrease in arterial blood pressure and slight changes of heart rate and respiration are fairly common.
Severe cardiorespiratory adverse events have occurred on rare occasions. These have included respiratory depression, apnea, respiratory arrest and/or cardiac arrest.
Such life-threatening incidents are more likely to occur in adults >60 years and those with preexisting respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered. Dormicum should be used only when resuscitation facilities are available.
The following adverse events have also been observed: Nausea, vomiting, headache, hiccups, laryngospasm, dyspnea, hallucination, oversedation, drowsiness and ataxia. Anterograde amnesia may still be present at the end of the procedure and in isolated cases, prolonged amnesia has been reported.
In rare cases, paradoxical reactions eg, agitation, hyperactivity and aggressiveness have occurred; involuntary movements (including tonic/clonic convulsions and muscle tremor) have also been observed.
Local effects on veins (pain on injection and thrombophlebitis) can occur.
In isolated cases, generalized hypersensitivity, from skin reactions to anaphylactoid reactions, have been reported. Convulsions have been reported in premature infants and neonates.
After prolonged IV administration of Dormicum, abrupt discontinuation of the product may be accompanied by withdrawal symptoms.
After rectal administration, a slight euphoria has been observed.

Tablet: Drowsiness during the day, numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia or double vision. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration.
Other side effects ie, gastrointestinal disturbances, changes in libido or skin reactions have been reported occasionally.
When used as premedication, Dormicum may contribute to postoperative sedation.
Amnesia: Anterograde amnesia may occur using therapeutic doses, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see Precautions).
Depression: Preexisting depression may be unmasked during benzodiazepine use.
Psychiatric and Paradoxical Reactions: See Precautions.
Dependence: Use (even at therapeutic doses) may lead to the development of physical dependence. Discontinuation of the therapy may result in withdrawal or rebound phenomena (see Precautions). Psychological dependence may occur. Abuse has been reported in poly-drug abusers.

Enhancement of the central depressive effect may occur when Dormicum is used concomitantly with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressants, narcotic analgesics, antiepileptic drugs, anesthetics and sedative antihistamines.
There is a potentially relevant interaction between midazolam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P-450 IIIA). Data clearly indicate that these compounds influence the pharmacokinetics of midazolam and that this may lead to prolonged sedation. At present, this reaction is known to occur in vivo with ketoconazole, itraconazole, erythromycin, diltiazem, verapamil, cimetidine and ranitidine (tablet), but not with cyclosporin (ampoule) and nitrendipine (ampoule).
Therefore, patients receiving the previously mentioned compounds or others which inhibit P-450 IIIA together with midazolam IV should be monitored carefully for the first few hours after administration of midazolam. (Studies have shown that ranitidine has no significant effect on the pharmacokinetics of IV given midazolam.) In tablets, prescription of midazolam should be avoided whenever possible. Otherwise, the dose of Dormicum tablet should be reduced.
Tablet: Not Recommended: Concomitant intake with alcohol.
The sedative effect may be enhanced when Dormicum is used in combination with alcohol. This affects the ability to drive or use machines (see Precautions).
Take into Account: Combination with CNS depressants.
In the case of narcotic analgesics, enhancement of the euphoria may also occur leading to an increase in psychological dependence.
Compounds which inhibit certain hepatic enzymes (particularly cytochrome P-450) may enhance the activity of benzodiazepines and benzodiazepine-like agents.
With regard to concomitant intake of Dormicum and erythromycin, the dose of Dormicum should be reduced by 50-75%. In such cases, the patient should be kept under careful surveillance.
Ampoule: One in vitro study has shown the hydroxylation of midazolam to be inhibited by a number of other substances (eg, amiodarone, neuroleptics); accordingly, interaction with a whole range of medicaments is theoretically possible. However, there is no evidence that these results are of clinical relevance.
Alcohol may enhance the sedative effect of midazolam.
Incompatibilities: Do not dilute Dormicum solutions with Macrodex 6% in dextrose.
Do not mix Dormicum solutions in alkaline injections. Midazolam precipitates in sodium bicarbonate.

Ampoule: Dormicum should not be frozen because they can burst. Furthermore, precipitation can occur which dissolves on shaking at room temperature.

Hypnotics & Sedatives

N05CD08 - midazolam ; Belongs to the class of benzodiazepine derivatives. Used as hypnotics and sedatives.

DD, P₁S₁S₃