INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
MIDACUM* 5 mg/1 mL solution for injection
MIDACUM* 15 mg/3 mL solution for injection

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

MIDACUM* 5 mg/1 mL solution for injection
MIDACUM* 15 mg/3 mL solution for injection

COMPOSITION
MIDACUM contains 5 mg or 15 mg midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a][1,4]benzodiazepine) as the hydrochloride, per 1 mL or 3 mL ampoule respectively.

PHARMACOLOGICAL CLASSIFICATION
A.2.2. Sedatives, hypnotics

PHARMACOLOGICAL ACTION
Pharmacodynamics:
The active ingredient, 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 the active substance of MIDACUM to form water-soluble salts with acids.
Midazolam possesses pronounced sleep-inducing and sedative properties. It also exerts a muscle-relaxant effect, anxiolytic and anticonvulsant effect.
After intramuscular or intravenous administration, anterograde amnesia of short duration may occur (the patient has no recollection of the events following the injection).
Pharmacokinetics:
Midazolam is rapidly and completely absorbed from the muscle tissue after IM injection. Maximum plasma concentrations are reached within 30 minutes. Bioavailability after IM injection is over 90%.
Distribution:
When midazolam is injected intravenously, the course of the plasma concentration shows a short distribution phase of 5-15 minutes, followed by an elimination phase. 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 %.
Metabolism:
Midazolam is completely metabolized and the primary metabolite is alpha-hydroxy-midazolam. The fraction extracted by the liver is 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 (refer to “Interactions”). Immediately after its formation, this active metabolite conjugates with glucuronic acid (inactivation) and is then eliminated by the kidneys more rapidly than midazolam.
Elimination:
The elimination half-life is between 1,5 and 2,5 hours. Plasma clearance is in the region of 300-400 mL per minute. When midazolam is given by IV infusion, its elimination kinetics do not differ from those following bolus injection. After 48 hours infusion elimination may be prolonged. About 50 to 70 % of midazolam is eliminated by the kidneys in the form of a conjugate of the alpha-hydroxy metabolite.
Pharmacokinetics in special situations:
The elimination half-life may be prolonged by up to 3 times in adults over 60 years of age. The elimination half-life may be prolonged by up to six times in some patients requiring intensive care when given midazolam by IV infusion for long-term sedation. In these patients, infusion at an unchanged rate results in higher plasma levels at steady-state. Consequently, the infusion rate should be adjusted according to the patient’s clinical response. The elimination half-life may be prolonged in patients with congestive heart failure, with chronic renal failure and with hepatic dysfunction.
The elimination half-life is between 1 and 1,5 hours, in children (3-10 years). In neonates the elimination half-life is prolonged with a mean of 6 hours (3-12 hours) due to liver immaturity.

INDICATIONS
Basal sedation before diagnostic or surgical interventions carried out under local anaesthesia.
Pre-medication before induction of anaesthesia.
Induction of anaesthesia. As an induction agent in inhalation anaesthesia or a sleep-inducing component in combined anaesthesia, including total intravenous anaesthesia (IV injection, IV infusion).
Maintenance of anaesthesia where subsequent ICU administration with ventilation is envisaged for the purpose of recovery and stabilization.
Long-term sedation in intensive care units (IV administration as bolus injection or continuous infusion).
Midazolam is only indicated when the disorder is severe, disabling or subjecting the individual to extreme stress.

CONTRA-INDICATIONS
Myasthenia gravis, hypersensitivity to benzodiazepines.
Safety in pregnancy has not been established. Midazolam has been shown to cross the placenta and to enter foetal circulation.
Midazolam passes into breast milk and should not be administered to breast-feeding mothers.

WARNINGS
Patients should not be discharged from hospital for at least four hours following the parenteral administration of midazolam. They must then be accompanied by a responsible person. Before receiving midazolam patients must be warned not to operate machinery or drive a vehicle for at least twelve hours thereafter.
When midazolam is given with potent analgesics, the latter should be administered first so that the sedative effects of midazolam can be safely titrated on top of any sedation caused by the analgesic.
Special caution should be exercised when midazolam is administered parenterally to patients representing a higher risk group: elderly (adults over 60 years), debilitated or chronically ill patients, patients with obstructive pulmonary disease, with chronic renal failure, impaired hepatic function or with congestive heart failure. These higher-risk patients require lower and individualized dosages and should be continuously monitored for early signs of alterations of vital functions.
Special care must be taken when benzodiazepines are used during labour and delivery, as high single doses may produce respiratory depression, irregularities in the foetal heart rate and hypotonia, poor sucking and hypothermia in the neonate.

DOSAGE AND DIRECTIONS FOR USE
Midazolam is a potent sedative agent, requiring slow administration and individualized dosing. 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 the case of elderly patients (adults over 60 years) with organic cerebral changes or impaired cardiac and respiratory function, debilitated or chronically ill patients, the dosage should be determined with caution, the special factors relating to each patient being taken into consideration.
Treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded.
1. Basal sedation:
Intravenous basal sedation:
Intravenous injections must be given slowly (approximately 1 mg in 30 seconds for sedation). The drug takes effect in about two minutes after the injection is given.
For basal sedation in diagnostic or surgical interventions carried out under local anaesthesia: In adults below the age of 60, the initial dose is 2,5 mg (0,04 mg/kg) 5-10 minutes before the beginning of the procedure. Further doses of 1 mg may be given as necessary. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.
In adults over 60 years, debilitated or chronically ill patients, the initial dose must be reduced to 1 to 1,5 mg and given 5-10 minutes before the beginning of the procedure. Further doses of 0,5 to 1,0 mg may be given as necessary. Total doses greater than 3,5 mg are not usually necessary.
2. Pre-medication before an operation:
Intramuscular administration:
Pre-medication with midazolam given shortly before a procedure produces sedation (induction of sleepiness or drowsiness and relief of apprehension), and pre-operative impairment of memory.
Adults below the age of 60:
0.07-0.1 mg/kg body weight IM according to general condition of the patient. Usual dose is about 5 mg.
Children:
(between ages 1 and 15) proportionately higher doses are required than in adults in relation to bodyweight. The dose range from 0.08 to 0.20 mg/kg body weight has been shown to be effective and safe. These doses should be administered into a large muscle mass about 30 to 60 minutes before induction of anaesthesia.
In adults over 60 years , debilitated and chronically ill patients:
0.025-0.05 mg / kg bodyweight IM. The usual dose is 2 to 3 mg.
3. Induction and maintenance of anaesthesia:
Intravenous injection:
Induction: intravenous injections must be given slowly (approximately 2,5 mg in 10 seconds for induction of anaesthesia).
The desired level of anaesthesia is reached by step-wise titration. The intravenous induction dose of midazolam should be given slowly in increments. Each increment of not more than 5 mg should be injected over 20 to 30 seconds, allowing 2 minutes between successive increments.
In pre-medicated adults below the age of 60 the dose can range from 10-15 mg IV (0.15 to 0.2 mg/kg). A total dose greater than 15 mg is usually not necessary. A sufficiently deep level of sleep is generally achieved after 2-3 minutes.
In non pre-medicated adults below the age of 60, the dose may be higher (0,3 to 0,35 mg/kg body weight), but a total dose greater than 20 mg is usually not necessary.
In adults over 60 years of age, debilitated and chronically ill patients, lower doses will be required.
Maintenance:
Intravenous continuous infusion:
The maintenance dose usually ranges from 0,03 to 0,1 mg/kg/hr when used in combination with narcotics or ketamine.
In high-risk surgical patients, adults over 60 years, debilitated and chronically ill patients lower maintenance doses will be required.
4. Sedation in intensive care units (ICU):
Intravenous sedation in ICU:
The desired level of sedation is reached by step-wise titration of midazolam followed by either continuous infusion or intermittent bolus.
For sedation in ICU, the dosage should be individualized and midazolam titrated to the desired state of sedation according to the clinical need, physical status, age and concomitant medication.
The intravenous loading dose should be given slowly in increments. Each increment of 1 to 2,5 mg should be injected over 20 to 30 seconds allowing 2 minutes between successive increments.
The intravenous loading dose can range from 0.03 to 0.3 mg/kg, but a total dose greater than 15 mg is usually not necessary.
The loading dose should be reduced or omitted in hypovolaemic, vasoconstricted or hypothermic patients.
The maintenance dose ranges from 0.03 to 0.2 mg/kg/hr. In hypovolaemic, vasoconstricted or hypothermic patients the maintenance dose should be reduced, at times to as low as 25 % of the usual dose.
The level of sedation should be assessed regularly if permitted by the patient’s condition.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The most commonly encountered side-effects include drowsiness and over-sedation.
Drowsiness is more common in elderly and debilitated patients and in patients receiving high doses. Less common are depression of mood and affect, disorientation or confusion, lethargy and ataxia.
Pain, tenderness and thrombophlebitis have occurred following the injection of midazolam.
The following adverse events have been observed: nausea, vomiting, headache, laryngospasm, hiccoughs, dyspnoea and hallucinations. Anterograde amnesia may still be present at the end of the procedure and in isolated cases prolonged amnesia has been reported.
Convulsions have been reported in premature infants and neonates.
Patients with chronic renal failure, impaired hepatic function and congestive heart failure may eliminate midazolam more slowly.
Generalized hypersensitivity –including anaphylactoid reactions and skin reactions have been reported. Local effects on veins (pain on injection and thrombophlebitis) can occur.
A reduction in arterial blood pressure, and changes, of pulse rate and breathing may occur. As a rule the systolic blood pressure falls by a maximum of 15% while the pulse rate simultaneously shows a corresponding rise. Apnoea may occur due to a depressant effect on the respiratory centre, and cardiovascular collapse may occur following intravenous administration.
Severe cardio-respiratory adverse events have occurred less frequently. These have included respiratory depression, apnoea, respiratory arrest and / or cardiac arrest.

WARNING

Midazolam ampoules should be used only when resuscitation facilities are available, as IV administration of midazolam may depress myocardial contractility and cause apnoea.

Routine intravenous midazolam induction is not recommended in children under 7 years of age.
Paradoxical reactions such as hyperactivity, agitation and combativeness have occurred; involuntary movements (including tonic/clonic convulsions and muscle tremor) have also been observed. Should such reactions occur, the response to each dose of midazolam should be evaluated before proceeding.
After prolonged IV administration of midazolam abrupt discontinuation of the product may be accompanied by withdrawal symptoms.
Therefore, a gradual reduction of midazolam is recommended.

DEPENDENCE
There is a potential for abuse and the development of physical and psychic dependence, especially with prolonged use and high doses. The risk of dependence 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: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

REBOUND EFFECTS
A transient syndrome whereby the symptoms that led to treatment with midazolam recur in an enhanced form may occur on withdrawal of 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.

INTERACTIONS
Enhancement of the central depressive effect may occur when midazolam is used concomitantly with:
antipsychotics
hypnotics
anxiolytics
antidepressants
narcotic analgesics
antiepileptic drugs
anaesthetics
sedative antihistamines
This potentiation of effect can in certain cases be of therapeutic advantage. Special attention must be paid to the possibility of potentiation in patients at particular risk.
The mutual potentiation of alcohol and midazolam can produce unforeseeable reactions (alcoholic beverages should not be consumed for at least 12 hours following parenteral administration of midazolam).
There is a potentially relevant interaction between midazolam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 IIIA). Data clearly indicate that these compounds influence the pharmacokinetics of midazolam and may lead to increased and prolonged sedation.
At present this reaction is known to occur with ranitidine, cimetidine, erythromycin, diltiazem, verapamil, itraconazole, ketoconazole and saquinavir but not with cyclosporin and nitrendipine.
Prescriptions of midazolam in patients receiving the above compounds or other compounds which inhibit P450 III A should thus be monitored carefully for the first few hours after administration of midazolam.
Studies involving healthy individuals suggest that a clinically important pharmacokinetic interaction between parenteral midazolam and ranitidine is unlikely to occur in clinical practice.
One study in vitro has shown the hydroxylation of midazolam to be inhibited by a number of other substances (e.g. amiodarone, neuroleptics); accordingly, interaction with a whole range of medicaments is theoretically possible. However, the clinical relevance of these findings is unknown.

INCOMPATIBILITIES
Do not dilute midazolam ampoule solutions with macrodex 6 % in dextrose. Do not mix midazolam ampoule solutions in alkaline injections. Midazolam precipitates in sodium bicarbonate.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
The symptoms of midazolam overdosage are primarily an intensification of the therapeutic effects (mental confusion, lethargy, sedation, muscle weakness, profound sleep) or paradoxical excitation.
In these cases only observation of vital functions is required.
Extreme overdosage may lead to coma, areflexia, cardio-respiratory depression and apnoea, requiring appropriate counter-measures (ventilation, cardiovascular support).
The effects of overdosage can be controlled with the benzodiazepine antagonist flumazenil.

IDENTIFICATION

Midacum 5 mg/mL solution for injection	Clear and slightly yellow (<G7), free from foreign particles
Midacum 15 mg/3 mL solution for injection	Clear and slightly yellow (<G7), free from foreign particles

PRESENTATION

Midacum 5 mg/mL solution for injection	1 mL clear glass ampoules (5 ampoules packed into a carton).
Midacum 15 mg/3 mL solution for injection	3 mL clear glass ampoules (5 ampoules packed into a carton).

STORAGE INSTRUCTIONS
Store at room temperature 25°C +2°C.
Protect the ampoules from light.
Keep the ampoules in the outer carton until required for use.
Keep out of reach of children.

REGISTRATION NUMBERS

Midacum 5 mg/mL solution for injection	35/2.2/0323
Midacum 15 mg/3 mL solution for injection	35/2.2/0324

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Hexal Pharma (SA) (PTY) Ltd
10 Fangio Road
Mahogany Ridge
Westmead
Pinetown

DATE OF PUBLICATION OF THIS PACKAGE INSERT
February 2002

MIDP1

* = Trademark

Updated on this site: January 2003
Source: Pharmaceutical Industry
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