Professional Information

Midazolam Hydrochloride

Pronunciation: (meh-DAZE-oh-lam HIGH-droe-KLOR-ide)
Class: General anesthetic

Trade Names:
Midazolam
- Syrup 2 mg/mL
- Injection 1 mg (as hydrochloride)/mL
- Injection 5 mg (as hydrochloride)/mL

Midazolam Injection (Canada)

Pharmacology

Depresses all levels of CNS, including limbic and reticular formation, probably through increased action of GABA, which is major inhibitory neurotransmitter in brain.

Pharmacokinetics

Absorption

Midazolam is rapidly absorbed. The oral AUC ratio of metabolite to midazolam is higher than IV. Mean T _max is 0.17 to 2.65 h and the absolute bioavailability is 36%.

Distribution

Midazolam exhibits linear pharmacokinetics (dose 0.25 to 1 mg/kg). Approximately 97% is protein bound (mainly to albumin). The mean steady-state Vd is 1.24 to 2.02 L/kg in children 6 mo to younger than 16 yr of age receiving 0.15 mg/kg IV.

Metabolism

Midazolam is subject to substantial intestinal and hepatic first-pass metabolism by CYP-450 3A4. Active metabolite is alpha-hydroxymidazolam.

Onset

Onset is 10 to 20 min.

Special Populations

Hepatic Function Impairment

Following oral administration (15 mg), C _max and bioavailability were 43% and 100% higher, respectively. Cl was reduced 40% and t _½ increased 90%. Doses should be titrated.

CHF

Following oral administration (7.5 mg), t _½ increased 43%.

Indications and Usage

Preoperative sedative; conscious sedation prior to diagnostic, therapeutic or endoscopic procedures; induction of general anesthesia; supplement to nitrous oxide and oxygen for short surgical procedures; infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in critical care setting.

Unlabeled Uses

Treatment of epileptic seizures; alternative for the termination of refractory status epilepticus.

Contraindications

Hypersensitivity to benzodiazepines; uncontrolled pain; existing CNS depression; shock; acute narrow-angle glaucoma; acute alcohol intoxication; coma.

Dosage and Administration

Preoperative Sedative
Adults

IM 0.07 to 0.08 mg/kg approximately 1 h before surgery.

Conscious Sedation
Adults

IV 1 to 2.5 mg as 1 mg/mL dilution over 2 min. Increase by small increments to total dose of no more than 5 mg in at least 2 min intervals; use less if patient is premedicated with other CNS depressants.

Children

IM 0.1 to 0.15mg/kg. Doses up to 0.5 mg/kg have been used for more anxious patients. Total dose usually does not exceed 10 mg.

Children (younger than 6 mo of age)

IV Titrate in small increments to clinical effect and monitor carefully.

Children (6 mo to 5 yr of age)

IV 0.05 to 0.1 mg/kg. Total dose up to 0.6 mg/kg may be necessary. Do not exceed 6 mg.

Children (6 to 12 yr of age)

IV 0.025 to 0.05 mg/kg. Total dose up to 0.4 mg/kg. Do not exceed 10 mg.

Children (12 to 16 yr of age)

IV Dose as adults.

Induction of General Anesthesia
Unpremedicated Adults

IV 0.3 to 0.35 mg/kg as 1 mg/mL dilution over 20 to 30 sec, allowing 2 min for effect; may use increments of approximately 25% of initial dose.

Premedicated Adults

IV 0.15 to 0.35 mg/kg over 20 to 30 sec.

Continuous Infusion
Adults Loading dose

0.01 to 0.05 mg/kg given slowly over several minutes. May be repeated at 10- to 15-min intervals until adequate sedation is achieved.

Maintenance

0.02 to 0.1 mg/kg/h (1 to 7 mg/h).

Children (non-neonatal)

IV 0.05 to 0.2 mg/kg over at least 2 to 3 min in patients whose trachea is intubated. Loading dose may be followed by continuous IV infusion at 0.06 to 0.12 mg/kg/h (1 to 2 mcg/kg/min). Increase or decrease approximately 25% of the initial infusion rate or subsequent infusion rate.

Intubated preterm and term newborns (younger than 32 wk of age)

0.03 mg/kg/h (0.5 mcg/kg/min).

Intubated preterm and term newborns (younger than 32 wk of age)

0.06 mg/kg/h (1 mcg/kg/min).

Maintenance Of Anesthesia

IV Increments of approximately 25% of induction dose in response to signs of lightening of anesthesia and repeat as necessary.

Storage/Stability

Store at room temperature (59° to 86°F).

Drug Interactions

Anesthetics, inhalation

Inhalation anesthetics may need to be reduced if midazolam is used as an induction agent. IV administration decreases minimum alveolar concentration of halothane required for general anesthesia.

Azole antifungal agents

Serum concentration of certain benzodiazepines may be increased and prolonged, producing enhanced CNS depression and prolonged effects.

Barbiturates, alcohol, other CNS depressants

May prolong effect and increase risk of underventilation or apnea.

Cimetidine

May increase midazolam levels.

Contraceptives, oral

Coadministration may result in prolongation of benzodiazepine t _½ .

Droperidol, narcotics, secobarbital

May accentuate hypnotic effect of midazolam.

Ethanol

Increased CNS effects with acute ethanol ingestion.

Fluvoxamine

Reduced clearance, prolonged t _½ and increased serum concentrations of certain benzodiazepines may occur. Sedation or ataxia may be increased.

Indinavir

Possibly severe sedation and respiratory depression.

Propofol

Pharmacologic effects of propofol may be increased.

Rifamycins

Pharmacokinetic parameters of benzodiazepines may be altered.

Ritonavir

Possibly severe sedation and respiratory depression.

Theophyllines

Sedative effects of benzodiazepines may be antagonized.

Thiopental

Moderate reduction in induction dosage requirements has been noted following use of IM midazolam for premedication.

Valproic acid

Pharmacokinetic parameters of benzodiazepines may be increased. Liver metabolism may be decreased.

Verapamil

Effects of certain benzodiazepines may be increased, producing increased CNS depression and prolonged effects.

Incompatibility

Dimenhydrinate, pentobarbital, perphenazine, prochlorperazine, ranitidine.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Bigeminy; hypotension; PVCs; tachycardia; cardiac arrest; vasovagal episode; bradycardia; nodal rhythm.

CNS

Headache; oversedation; retrograde amnesia; euphoria or dysphoria; confusion; argumentativeness; anxiety; emergence delirium and dreaming; nightmares; tonic/clonic movements; tremor; athetoid movements; ataxia; dizziness; slurred speech; paresthesia; weakness; loss of balance; drowsiness; nervousness; agitation; restlessness; prolonged emergence from anesthesia; insomnia; dysphonia.

Dermatologic

Hives; hive-like elevation at injection site; swelling or feeling of burning; warmth or coldness at injection site; rash; pruritus.

EENT

Vision disturbances; nystagmus; pinpoint pupils; cyclic eyelid movements; blocked ears; blurred vision; diplopia; difficulty focusing; loss of balance.

GI

Nausea; vomiting; acid taste; excessive salivation; retching.

Respiratory

Respiratory depression or arrest; decreased tidal volume, decreased respiratory rate; apnea, coughing; laryngospasm; bronchospasm; dyspnea; hyperventilation; wheezing; shallow respirations; airway obstruction; tachypnea.

Miscellaneous

Pain, tenderness and induration at injection site; yawning; chills; lethargy; weakness; toothache; faint feeling; hematoma; desaturation, apnea, hypotension, paradoxical reactions, hiccough, seizure-like activity, nystagmus (children).

Precautions

Warnings

Respiratory depression/arrest has been reported with use for sedation in noncritical care settings and occurs most often with concurrent CNS depressants. Midazolam should only be used in settings that can provide continuous monitoring for respiratory and cardiac function. Severe hypotension and seizures have been reported in neonates after rapid IV injection, particularly with concurrent fentanyl. Do not administer via rapid injection in this population.

Pregnancy

Category D .

Lactation

Midazolam is excreted in breast milk. Exercise caution when administering to a breast-feeding woman.

Children

As a group, children generally require higher dosages of midazolam (mg/kg) than do adults. Children (younger than 6 yr of age) may require higher dosages (mg/kg) than older children and may require closer monitoring. In obese children, calculate the dose based on ideal body weight.

Elderly

May need to decrease dosage. Titration should be more gradual.

Labor and Delivery

Drug not recommended because of transplacental transfer.

Renal Function

Patients with renal function impairment may have longer t _½ for midazolam, which may result in slower recovery.

Special Risk Patients

High-risk surgical patients require lower doses. Patients with COPD are unusually sensitive to respiratory depressant effects. In renal or heart failure patients, give less frequently. Exercise care when administering to patients with uncompensated acute illness (eg, severe fluid or electrolyte disturbances).

Hazardous Tasks

No patient should operate hazardous machinery or a motor vehicle until the adverse reactions of the drug have subsided or until the day after anesthesia and surgery, whichever is longer.

Abrupt withdrawal

Withdrawal symptoms (convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting, and sweating) may occur following abrupt discontinuation.

Benzyl alcohol

The midazolam injection contains benzyl alcohol, which has been associated with a fatal “gasping syndrome” in premature infants.

Debilitated patients

May need to decrease dosage. Titration should be more gradual.

Serious cardiorespiratory events

Have occurred, including respiratory depression, airway obstruction, desaturation, permanent neurologic injury, apnea, respiratory arrest or cardiac arrest, sometimes resulting in death.

Improper dosing

Reactions such as agitation, involuntary movements, hyperactivity, and combativeness have been reported.

Ophthalmic

Moderate lowering of IOP following induction with midazolam.

Intra-arterial injection

Unknown.

Intracranial pressure/circulatory side effects

Does not protect against the increase in intracranial pressure or circulatory effects associated with endotracheal intubation under light general anesthesia.

Overdosage

Symptoms

Sedation, impaired coordination and reflexes, hypotension, hypoventilation, somnolence, coma, confusion.

Patient Information

Inform patient and family pre-operatively about possibility of temporary postoperative amnesia.
Advise patient that drug may cause drowsiness and to use caution while driving or performing other tasks requiring mental alertness until drowsiness has subsided or until day after administration, whichever is longer.
Advise patient to avoid alcohol and other CNS depressants for 24 h following administration.
Patients receiving continuous infusion in critical care settings over an extended period of time may experience symptoms of withdrawal following abrupt discontinuation.