midazolam hydrochloride
Versed

Available forms
Available by prescription only
Injection: 1 mg/ml in 2-ml, 5-ml, and 10-ml vials; 5 mg/ml in 1-ml, 2-ml, 5-ml, and 10-ml vials; 5 mg/ml in 2-ml disposable syringe
Syrup: 2 mg/ml in 118-ml bottle

Indications and dosages
 Preoperative sedation (to induce sleepiness or drowsiness and relieve apprehension). Adults younger than age 60: 0.07 to 0.08 mg/kg I.M. about 1/2 to 1 hour before surgery. May be administered with atropine or scopolamine and reduced doses of narcotics.
≡ Dosage adjustment. Reduce dosage in patients older than age 60, those with COPD, those considered to be high-risk surgical patients, and those who have received concomitant narcotics or other depressants.
 Conscious sedation. Adults younger than age 60: Initially, 1 to 2.5 mg I.V. administered over at least 2 minutes; repeat in 2 minutes, if needed, in small increments of initial dose over at least 2 minutes to achieve desired effect. Total dose up to 5 mg may be used. Additional doses to maintain desired level of sedation may be given by slow titration in increments of 25% of dose used to reach the sedation endpoint.
Adults age 60 and older: 1.5 mg or less over at least 2 minutes. If additional titration is needed, give at a rate not exceeding 1 mg over 2 minutes. Total doses exceeding 3.5 mg aren’t usually needed.
 Induction of general anesthesia. Adults younger than age 55: 0.3 to 0.35 mg/kg I.V. over 20 to 30 seconds if patient hasn’t received preanesthesia medication, or 0.15 to 0.35 mg/kg (usually 0.25 mg/kg) I.V. over 20 to 30 seconds if patient has received preanesthesia medication. Additional increments of 25% of the initial dose may be needed to complete induction.
Adults age 55 and older: Initially, 0.3 mg/kg. For debilitated patients, initial dose is 0.15 to 0.25 mg/kg. For premedicated patients, 0.15 mg/kg may be sufficient.
 Continuous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting. Adults: If a loading dose is needed to rapidly start sedation, give 0.01 to 0.05 mg/kg slowly or infused over several minutes, with dose repeated at 10- to 15-minute intervals until adequate sedation is achieved. For maintenance of sedation, usual infusion rate is 0.02 to 0.1 mg/kg/ hour (1 to 7 mg/hour). Titrate infusion rate to the desired amount of sedation. Drug can be titrated up or down by 25% to 50% of the initial infusion rate to achieve optimal sedation without oversedation.
Children: After a loading dose of 0.05 to 0.2 mg/kg over 2 to 3 minutes in intubated patients, an infusion may be started at 0.06 to 0.12 mg/kg/hour (1 to 2 mcg/kg/minute). Dose may be titrated up or down by 25% of initial or subsequent infusion rate to obtain optimal sedation.
Neonates: Use only on intubated neonates. No loading dose is used. Neonates under 32 weeks’ gestation receive infusion rates of 0.03 mg/kg/hour (0.5 mcg/kg/minute). In neonates over 32 weeks’ gestation, infusion rates are 0.06 mg/kg/hour (1 mcg/kg/minute). Infusion may be run more rapidly in the first few hours to obtain a therapeutic blood level. Rate of infusion should be frequently and carefully reassessed to administer the lowest possible amount of drug.
 Sedation, anxiolysis, and amnesia before diagnostic, therapeutic, or endoscopic procedures or before induction of anesthesia. Children ages 6 months to 16 years: 0.25 to 0.5 mg/kg P.O. up to 20 mg or up to 1 mg/kg. Lower doses may provide adequate therapeutic effect for children ages 6 months to 16 years or cooperative patients. Or, 0.1 to 0.15 mg/kg I.M. (up to 0.5 mg/kg may be needed) not to exceed 10 mg.
Children ages 13 to 16: 0.07 to 0.08 mg/kg I.M. 1/2 to 1 hour before surgery; for conscious sedation, 1 to 2.5 mg I.V. over at least 2 minutes.
Children ages 6 to 12: 0.025 to 0.05 mg/kg I.V. up to 0.4 mg/kg (usual dose doesn’t exceed 10 mg).
Children ages 6 months to 5 years: Initially 0.05 to 0.1 mg/kg I.V. up to 0.6 mg/kg (usual dose doesn’t exceed 6 mg).

Pharmacodynamics
Sedative and anesthetic actions: Although exact mechanism is unknown, midazolam, like other benzodiazepines, is thought to facilitate the action of gamma-aminobutyric acid to provide a short-acting CNS depressant action.
Amnesic action: Mechanism of action by which midazolam causes amnesia isn’t known.

Pharmacokinetics
Absorption: Absorption after I.M. administration appears to be 80% to 100% and after oral administration 40% to 50%.
Distribution: Drug has a large volume of distribution and is about 97% protein-bound. Drug crosses the placental barrier and enters fetal circulation.
Metabolism: Metabolized in the liver.
Excretion: Metabolites are excreted in urine. Half-life of drug is 1 1/4 to 12 1/3 hours. Half-life is prolonged in obese patients, the elderly, and seriously ill neonates.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug, in those with acute angle-closure glaucoma, and in those experiencing shock, coma, or acute alcohol intoxication. Use cautiously in patients with uncompensated acute illnesses, in geriatric or debilitated patients, in patients with myasthenia gravis or neuromuscular disorders and pulmonary disease.

Interactions
Drug-drug. Antidepressants, antihistamines, barbiturates, narcotics, tranquilizers, and other CNS and respiratory depressants: Potentiates effects. Use together cautiously.
Azole antifungals: May prolong CNS depressant effects of midazolam. Use together cautiously.
Cytochrome P450 3A4 inhibitors, saquinavir, verapamil: Decreases metabolism of midazolam and increases serum levels, leading to prolonged effects. Monitor patient closely.
Droperidol, fentanyl, narcotics: Potentiates hypnotic effect of midazolam and increases risk of hypotension. Monitor patient carefully.
Erythromycin: May decrease plasma clearance of midazolam. Monitor patient for adverse effects.
Inhaled anesthetics: May decrease the needed dose of inhaled anesthetics by depressing respiratory drive. Anesthesia dosage may require adjustment.
Isoniazid: May decrease metabolism of midazolam. Monitor patient closely.
Rifampin: Decreases midazolam levels. Monitor patient for effect.
Drug-herb. Catnip, kava, lady’s slipper, lemon balm, passionflower, sassafras, skullcap, valerian: May enhance sedative effects. Discourage use together.
Drug-food. Grapefruit juice: Increases bioavailability of oral syrup form of drug. Discourage use together.
Drug-lifestyle. Alcohol use: Potentiates effects of alcohol. Discourage alcohol use.

Adverse reactions
CNS: headache, oversedation, drowsiness, amnesia, pain.
CV: hypotension, irregular pulse, cardiac arrest.
GI: nausea, vomiting.
Respiratory: hiccups, decreased respiratory rate, APNEA, respiratory arrest, cough.
Skin: tenderness at injection site.

Effects on lab test results
None reported.

Overdose and treatment
Signs and symptoms of overdose include confusion, impaired coordination and reflexes, stupor, coma, respiratory depression, and hypotension.
 Treatment is supportive. Maintain patent airway, and ensure adequate ventilation with mechanical support, if needed. Monitor vital signs. Use I.V. fluids or ephedrine to treat hypotension. Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for complete or partial reversal of the sedative effects.

Special considerations
• Individualized dosages are advised, using the smallest effective dose possible. Use with extreme caution and reduce dosage in geriatric and debilitated patients.
• Medical personnel who administer midazolam should be familiar with airway management. Close monitoring of cardiopulmonary function is required. Continuously monitor patients who have received midazolam to detect potentially life-threatening respiratory depression.
• Laryngospasm and bronchospasm may occur rarely; countermeasures should be available.
• Midazolam can be mixed in the same syringe with morphine, meperidine, atropine, and scopolamine. Solution is stable for 30 minutes.
• Syrup form must be given only to patients visually monitored by health care professionals.
• Solutions compatible with midazolam include D₅W, normal saline solution, and lactated Ringer’s solution.
• Before I.V. administration, ensure the immediate availability of oxygen and resuscitation equipment. Apnea and death have been reported with rapid I.V. administration. Avoid intra-arterial injection because the hazards of this route are unknown. Avoid extravasation. Administer I.V. dose slowly to prevent respiratory depression.
• Benzyl alcohol in injectable forms creates an increased risk of adverse effects, such as hypotension, metabolic acidosis, and kernicterus, in neonates. Take into account the amount of benzyl alcohol when giving high doses of midazolam or other drugs that contain this preservative.
• Give I.M. dose deep into a large muscle mass to prevent tissue injury.
• Don’t use solution that’s discolored or that contains a precipitate.
Patient monitoring
• Hypotension is more likely in patients premedicated with narcotics. Monitor vital signs.
Breast-feeding patients
• Drug appears in breast milk. Use cautiously in breast-feeding women.
Pediatric patients
• Safety and efficacy of oral solution in children younger than age 6 months haven’t been established. Monitor the amount of benzyl alcohol when used in neonates.
Geriatric patients
• Geriatric or debilitated patients, especially those with COPD, are at significantly increased risk for respiratory depression and hypotension. Lower doses are indicated. Use cautiously.
• Oral forms aren’t recommended.

Patient education
• Advise patient to postpone tasks that require mental alertness or physical coordination until the effects of the drug have worn off.
• Instruct patient as necessary in safety measures, such as supervised walking and gradual position changes, to prevent injury.
• Advise patient to obtain medical approval before taking OTC drugs.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use