Adult: Conscious sedation for procedures; for dental and minor surgical procedures: Initially, 2-2.5 mg given at a rate of 2 mg/minute 5-10 minutes before procedure, with increments of 0.5-1 mg at intervals of at least 2 minutes if required until the desired endpoint is achieved. Child: 6 months to 5 years Initially, 0.05-0.1 mg/kg, up to 0.6 mg/kg if necessary. Max: 6 mg; 6-12 years Initially, 0.025-0.05 mg/kg, up to 0.4 mg/kg if necessary. Max: 10 mg. >12 years Same as adult dose. Initial doses are given over 2-3 minutes, 5-10 minutes before procedure, with an additional interval of 2-5 minutes before giving further doses. Elderly: Initially, 0.5-1 mg at a max rate of 2 mg/minute, 5-10 minutes before procedure, with increments of 0.5-1 mg if required. Max total dose: 3.5 mg or until the desired endpoint is achieved.
Intravenous Sedation in critical care
Adult: Loading dose: 0.03-0.3 mg/kg, may be given in increments of 1-2.5 mg, injected slowly over 20-30 seconds, allowing 2 minutes between each dose. Maintenance: 0.03-0.2 mg/kg/hour. Patient with hypovolaemia, vasoconstriction or hypothermia: Reduce or omit loading dose and reduce maintenance dose. Child: Neonates <32 weeks to 6 months 0.06 mg/kg/hour via continuous infusion, adjust dose after 1st 24 hours to lowest possible effective dose. >6 months Loading dose: 0.05-0.2 mg/kg given slow inj over at least 2-3 minutes to establish desired clinical effect. Maintenance dose: 0.06-0.12 mg/kg/hour given as continuous infusion. Elderly: Dose reduction may be necessary.
Intravenous Induction of anaesthesia
Adult: Premedicated patient: 0.15-0.2 mg/kg via slow IV inj. Non-premedicated patient: 0.3-0.35 mg/kg via slow IV inj. For resistant cases, a total dose up to 0.6 mg/kg may be given. For sedation in combined anaesthesia: 0.03-0.1 mg/kg by inj repeated as required or by infusion in a dose of 0.03-0.1 mg/kg/hour. Elderly: >60 years Premedicated patient: 0.05-0.15 mg/kg. Non-premedicated patient: 0.15-0.3 mg/kg.
Oral Seizures
Child: 3-6 months Hospital setting: 2.5 mg; >6 months to <1 year 2.5 mg; 1->5 years 5 mg; 5->10 years 7.5 mg; 10->18 years 10 mg. Doses are given as single dose.
Oral Preoperative sedation
Child: 6 months to 16 years 0.25-1 mg/kg as single dose 15-30 minutes prior to procedure, depending on patient status and desired effect. Max: 20 mg.
Oral Short-term management of insomnia
Adult: 7.5-15 mg at night. Max: 15 mg. Elderly: 7.5 mg at night.
Parenteral Premedication in surgery
Adult: 0.07-0.1 mg/kg (approx 5 mg) via IM inj, given 20-60 minutes before surgery. Alternatively, 1-2 mg via IV inj, repeated if necessary, given 5-30 minutes before surgery. Child: 1-15 years 0.08-0.2 mg/kg via IM inj given 15-30 minutes before surgery. Elderly: 0.025-0.05 mg/kg given approx 20-60 minutes before surgery via IM inj. Alternatively, 0.5 mg given IV 5-30 minutes before procedure, repeated slowly if required.
Renal Impairment
Oral: Short-term management of insomnia:
Dose reduction may be necessary.
Hepatic Impairment
Oral: Preoperative sedation; Short-term management of insomnia; Seizures:
Severe: Contraindicated.
Intravenous: Sedation; Induction of anaesthesia; Sedation in critical care:
Dose reduction may be necessary.
Parenteral: Premedication in surgery:
Dose reduction may be necessary.
Administration
May be taken with or without food.
Incompatibility
IV: Visual incompatibility by immediate formation of white precipitate with dimenhydrinate, pentobarbital Na, perphenazine, prochlorperazine edisilate, ranitidine hydrochloride, furosemide, thiopental and parenteral nutrition solutions.
Contraindications
Acute narrow-angle glaucoma, severe respiratory insufficiency, severe respiratory failure, acute respiratory depression, myasthenia gravis, sleep apnoea syndrome; severe hepatic impairment (oral). Concomitant use with CYP3A4 inhibitors.
Special Precautions
Patient with uncompensated acute illnesses (e.g. severe fluid or electrolyte disturbances), CV disease (e.g. heart failure), respiratory disease (e.g. COPD), history of alcohol or drug abuse; at risk of falls; obese, debilitated. Avoid abrupt withdrawal. Renal and hepatic impairment. Elderly and children. Pregnancy and lactation.
Adverse Reactions
Significant: Anterograde amnesia, CNS depression, hypotension, paradoxical reactions (e.g. hyperactive or aggressive behaviour), suicidal ideation, withdrawal symptoms. Cardiac disorders: Bradycardia, tachycardia. Gastrointestinal disorders: Nausea, vomiting, constipation, dry mouth, hiccups. General disorders and administration site conditions: Fatigue, inj site reactions (e.g. erythema, pain, phlebitis, thrombosis). Injury, poisoning and procedural complications: Falls, fractures. Musculoskeletal and connective tissue disorders: Muscle weakness. Nervous system disorders: Sedation (prolonged and post-operative), decreased alertness, somnolence, headache, dizziness, drowsiness, ataxia. Psychiatric disorders: Confusion, euphoric mood, depression, hallucinations, physical drug dependence, withdrawal syndrome. Respiratory, thoracic and mediastinal disorders: Dyspnoea, laryngospasm, bronchospasm, cough. Skin and subcutaneous tissue disorders: Rash, urticaria, pruritus. Potentially Fatal: Cardiorespiratory effects (e.g. respiratory depression, respiratory arrest, apnoea, cardiac arrest).
This drug may cause sedation, amnesia, impaired concentration and muscular function, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor the level of sedation, respiratory rate, heart rate, blood pressure, oxygen saturation (e.g. pulse oximetry), vital signs.
Overdosage
Symptoms: Sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma and deleterious effects on vital signs. Management: Symptomatic and supportive treatment. Monitor respiration, pulse rate, blood pressure and hepatic function. Maintain adequate airway and support of ventilation, including administration of oxygen. IV fluid therapy, repositioning, judicious use of appropriate vasopressors may be done in case of hypotension. Gastrointestinal decontamination (e.g. lavage, activated charcoal) may be considered within 1-2 hours after ingestion or once the patient’s airway is secured. Flumazenil may be given as an antidote.
Drug Interactions
Decreased plasma concentration with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin). Potentiate the action of antipsychotics, barbiturates, propofol, ketamine, sedative antidepressants, antihistamines and centrally acting antihypertensive drugs. Potentially Fatal: Increased plasma concentrations with CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, boceprevir, nefazodone). Increased risk of profound sedation, respiratory depression, coma and death with opioids (e.g. morphine, meperidine, fentanyl).
Food Interaction
Enhanced CNS depressant effects of alcohol. Decreased plasma concentration with St. John’s wort. Increased plasma concentration with grapefruit juice.
Action
Description: Midazolam binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at various sites within the CNS, including limbic system and reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to Cl ions, which results in hyperpolarisation and stabilisation. Onset: Approx 15 minutes; 3-5 minutes (IV); 10-20 minutes (oral). Duration: Up to 6 hours (IM); <2 hours (IV: single dose). Pharmacokinetics: Absorption: Rapidly absorbed. Bioavailability: 40-50% (oral); >90% (IM). Time to peak plasma concentration: 0.5-1 hour (IM); 0.17-2.65 hours (oral). Distribution: Widely distributed in the body, including CSF. Crosses the placenta and enters the breastmilk. Volume of distribution: 1-3.1 L/kg, increased in females, elderly and obesity. Plasma protein binding: Approx 97%, mainly albumin. Metabolism: Extensively metabolised in the liver by CYP3A isoenzyme; 60-70% of biotransformed midazolam is 1-hyrdoxy-midazolam or α-hydroxymidazolam (active metabolite). Excretion: Oral: Via urine (approx 90% within 24 hours; mainly as glucuronide conjugates [60-70%]; <3% as unchanged drug); faeces (approx 2-10% over 5 days). Elimination half-life: 3 hours; 4.2±1.87 hours (IM); <1 hour (active metabolite).
Chemical Structure
Midazolam Source: National Center for Biotechnology Information. PubChem Database. Midazolam, CID=4192, https://pubchem.ncbi.nlm.nih.gov/compound/Midazolam (accessed on Jan. 22, 2020)
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