Branded Medicine

 

IV/IM INJECTION

 

 

Composition:

SEDACUM 1 mg/ml

Each ml contains:

Midazolam HCl 1 mg

 

SEDACUM 5 mg/ml

Each ml contains:

Midazolam HCl 5 mg

 

Pharmacology:

Pharmacodynamic: Midazolam is an imidazo benzodiazepine with properties very similar to those of other benzodiazepines. Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant. It binds to benzodiazepine receptors in various regions of the brain such as the spinal cord, brain stem, cerebellum, limbic system and the cerebral cortex. Midazolam blocks EEG arousal from stimulation of the brain stem reticular formation. Midazolam acts as a CNS depressant on CNS reflexes via the brain stem reticular formation. When midazolam injection is given IV as an anesthetic induction agent, induction of anesthesia occurs in approximately 1.5 minutes following previous narcotic premedication, and in 2 to 2.5 minutes without narcotic premedication. Midazolam injection, does not delay awakening from general anesthesia in adults. Gross tests of recovery after awakening usually indicate recovery within 2 hours but recovery may take up to 6 hours in some cases. Recovery from anesthesia or sedation for procedures in pediatric patients depends on the dose of midazolam administered, coadministration of other medications causing CNS depression and duration of the procedure. The usual recommended IM premedicating doses of midazolam injection do not depress the ventilatory response to carbon dioxide stimulation to a clinically significant extent in adults. Induction dose of midazolam IV depress the ventilatory response to carbon dioxide stimulation for 15 minutes or more beyond the duration of ventilatory depression following administration of thiopental in adults. Sedation with midazolam IV does not adversely affect the mechanics of respiration. IV induction of general anesthesia with midazolam injection was associated with a slight to moderate decrease in mean arterial pressure, cardiac output, stroke volume and systemic vascular resistance.

Pharmacokinetics: Midazolam's activity is primarily due to the parent drug. Elimination of the parent drug takes place via hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the urine. Elimination half life: 1.8 to 6.4 hours, total clearence: 0.25 to 0.54 l/hr/kg. Absorption of midazolam hydrochloride from IM injection sites is rapid and nearly complete (mean absolute bioavailability is greater than 90%). The mean peak concentration (Cmax) and time to peak (Tmax) following the IM dose was 90 ng/ml and 0.5 hour. Cmax for the 1-hydroxy metabolite following the IM dose was 8 ng/ml (Tmax=1.0 hour). Following IM administration, Cmax for midazolam and its metabolte is were approximately one-half of those achieved after intravenous injection. In adult and pediatric older than 1 year, midazolam is approximately 94-97% bound to plasma protein, principally albumin. The biotransformation of midazolam is mediated by cytochrome P450 3A4. The amount of midazolam excreted unchanged in the urine after a single IV dose is less than 0.5%. The pharmacokinetic profile of midazolam following continuous infusion has been shown to be similar to that following single-dose administration, but midazolam can accumulate in peripheral tissue with continuous infusion. Onset time of sedative effects after IM administration of midazolam in adults is 15 minutes, with peak sedation occuring 30-60 minutes following injection. Sedation in adults and pediatric patients is achieved within 3 to 5 minutes after IV injection, the time of will increase in obese, elderly, alcoholic patients, patients with renal impairment and, congestive heart failure. Pediatrics and Neonates: In pediatric patients 1 year the pharmacokinetic properties are similar to those in adults.

 

Indications:

Injectable SEDACUM is indicated for:

  • Premedication before induction of anesthesia (IM)

  • Basal sedation before diagnostic or surgical interventions carried out under local anesthesia (IV)

  • Induction and maintenance of anaesthesia. As an induction agent in inhalation anesthesia or a sleep-inducing component in combined anesthesia including total intravenous anesthesia (IV)

 

Contraindications:

Known benzodiazepine sensitivity, cross-sensitivity occurs with other benzodiazepines, respiratory insufficiency, acute narrow-angle glaucoma.

 

Dosage and administration:

Midazolam is a potent sedative agent which requires slow administration and individualization of dosage according to clinical need physical status, age and concomitant medication.

The intravenous injection must be given slowly (approximately 2.5 mg every 10 second for induction of anesthesia, and 1 mg per 30 seconds for premedication) the onset of effect takes place after approximately 2 minutes.

  • Pre-medication before an operation:

Intramuscular administration: in patients suffering from pain before an intervention. Administration alone or in combination with anticholinergics and possible analgesics:

  • Adults: 0.07 - 0.1 mg/kg bodyweight IM according to age and general condition of the patient. Usual dosage about 5 mg

  • Elderly and debilitated patients: 0.025 - 0.05 mg/kg bodyweight (IM).

These dose should be administered about 30 minutes before induction of anesthesia

  • Intravenous basal sedation:

For basal sedation in diagnostic or surgical interventions carried out under local anesthesia

      • Adults.

The initial dose should not exceed 2.5 mg IV 5 - 10 minutes before the beginning of the operation.

If necessary, further doses of 1 mg IV can be administered at 2 minutes intervals. However, total dosage should in general not exceed 5 mg IV, in case of concomitant use of other CNS depressants, the dose of midazolam has to be reduced.

      • Elderly and seriously ill patients:

The initial dose must be reduced to 1 - 1.5 mg IV.

The total dose should in general not exceed 3.5 mg IV.

The injection must be administered slowly (1 mg in 30 seconds).

  • Induction and maintenance of anesthesia. Intravenous injection:

    • Induction: The dose is 10 mg IV. A sufficiently deep level of sleep is generally achieved after 2 - 3 minutes. Dose should be reduced in elderly patients (above 55 years).

    • Maintenance dose: for maintenance of the desired level of unconsciousness, further small doses should be injected IV. The dose and the intervals between doses vary according to the individual patient's reactions.

These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation. 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 analgesics.

 

Warnings and Precautions:

  • Midazolam is a potent sedative and requires slow administration and individualized titration of dosage.

  • Intravenous midazolam has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical-care settings.

  • Midazolam injection should be administered by IM or IV only in hospital or ambulatory-care settings, in which continuous monitoring of respiratory and cardiac function is possible.

  • Patients receiving midazolam should be monitored continuously for early sign of underventilation or apnea since hypoxia and/or cardiac arrest can occur unless effective countermeasures are undertaken immediately. Monitoring of vital sign also should continue during the recovery period.

  • Precautions against unintended intra-arterial injection should be taken, and drugs extravasation should be avoided.

  • The newborn, particulary if premature, are very susceptible to the central depressant effects of benzodiazepines and they also have a reduced capacity for the elimination of these drugs and their metabolites. Particular care should be taken to ensure safe ambulation of pediatric patients following sedation with midazolam.

  • For deeply sedated pediatric patients, a dedicated individual, other than the clinician performing the procedure, should monitor the patient throughout the procedure.

  • Mutagenicity and carcinogenicity: In vitro and in vivo microbial and mammalian test systems using midazolam have not revealed evidence of mutagenicity. No evidence of carcinogenic potential was seen in experimental animals.

  • Pregnancy, fertility, and lactation: Midazolam can cause fetal toxicity when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risk to the fetus. Midazolam has been shown to cross the placenta in humans. It is not known wheter midazolam affects fertility in humans. Caution should be exercised when midazolam is administered to a nursing woman.

 

Adverse reactions:

Potentially life-threatening effects: Midazolam can cause respiratory and cardiovascular depression, ventricular irritability and a change in baroreflex control of heart rate.

Severe or irreversible adverse effects: Apart from dose-related central nervous system depression, no irreversible effects have been reported.

Symptomatic adverse effects: Systemic (<1%): agitation, involuntary movement, confusion, slurred speech, blurred vision, lethargy, and dizziness. ; Local: following IV injection: pain on injection (rare), thrombophlebitis and thrombosis (<1%); following IM injection: pain at site of injection (4%), local erythema, induration, muscle stiffness (<1%).

Other effects: Midazolam is not known to cause any modification of body biochemistry per se, although like other anesthetics it is known to depress renal blood flow and renal function and also liver blood flow in experimental animals.

Interference with clinical pathology test: Midazolam is not known to interfere with any clinical pathological measurements.

 

Drug Interactions:

  • Alcohol: Midazolam will potentiate the central nervous depressant effects of alcohol.

  • Opioids, barbiturates, sedative and anaesthetics: Midazolam will also potentiate the central depressant effects of opioid, barbiturates and other sedatives and anaesthetics. Profound and prolonged respiratory depression might results.

  • Cimetidine: Plasma midazolam concentrations were increased by about 30% following oral administration of cimetidine.

  • Ketamine: Midazolam will attenuate the increase in heart rate and arterial blood pressure produced by anaesthetic doses of ketamin, and will also reduce the psychotic sequelae following ketamin anesthesia.

 

  • Overdosage

  • The manifestations of midazolam overdosage reported are similar to those observed with other benzodiazepines, including sedation, somnolence, confusion, impaired coordination, diminish reflexes, coma and untoward effects of vital signs. No evidence of specific organ toxicity from midazolam overdosage has been reported.

  • Treatment of injectable midazolam overdosage is the same as that followed for overdosage with other benzodiazepines.

Flumazeline, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situation when an overdose with a benzodiazepines is known or suspected. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Flumazenile will only reverse benzodiazepine-induced effects but will not reverse the effects of other concomitant medications.

 

Package and registration number:

SEDACUM 5 mg/ml box, 5 ampoules @ 3 ml; DPL0505038843B1

SEDACUM 1 mg/ml box, 10 ampoules @ 5 ml; DPL0505038843A1

 

ON MEDICAL PRESCRIPTION ONLY.

 

STORE AT TEMPERATURE BELOW 30oC.

PROTECT FROM LIGHT.