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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(MID aye zoe lam)
Generic Available (U.S.)
Yes
Index Terms
Controlled Substance
C-IV
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Preoperative sedation; moderate sedation prior to diagnostic or radiographic procedures; ICU sedation (continuous infusion); induction and maintenance of general anesthesia
Use: Dental
Sedation component in I.V. conscious sedation in oral surgery patients; syrup formulation is used for children to help alleviate anxiety before a dental procedure
Use: Unlabeled
Anxiety, status epilepticus, conscious sedation (intranasal route)
Pregnancy Risk Factor
D
Pregnancy Considerations
Adverse events were not observed in animal teratology studies. Midazolam has been found to cross the human placenta and can be detected in the serum of the umbilical vein and artery, as well as the amniotic fluid. Teratogenic effects have been observed with some benzodiazepines; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) have been reported with some benzodiazepines.
Lactation
Enters breast milk/use caution (AAP rates “of concern”; AAP 2001 update pending)
Breast-Feeding Considerations
Midazolam and hydroxymidazolam can be detected in breast milk. Based on information from two women, 2-3 months postpartum, the half-life of midazolam in breast milk is ~1 hour. Milk concentrations were below the limit of detection (<5 nmol/L) 4 hours after a single maternal dose of midazolam 15 mg. Drowsiness, lethargy, or weight loss in nursing infants have been observed in case reports following maternal use of some benzodiazepines.
Contraindications
Hypersensitivity to midazolam or any component of the formulation; intrathecal or epidural injection of parenteral forms containing preservatives (ie, benzyl alcohol); acute narrow-angle glaucoma; concurrent use of potent inhibitors of CYP3A4 (amprenavir, atazanavir, or ritonavir)
Warnings/Precautions
Boxed warnings:
• Debilitated patients: See “Special populations” below.
• Elderly: See “Special populations” below.
• Neonates: See “Special populations” below.
• Respiratory depression: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). A minimum of 1 day should elapse after midazolam administration before attempting these tasks.
• Hypotension: May cause hypotension; hemodynamic events are more common in pediatric patients or patients with hemodynamic instability. Hypotension may occur more frequently in patients who have received opioid analgesics.
• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients.
• Respiratory depression: [U.S. Boxed Warning]: May cause severe respiratory depression, respiratory arrest, or apnea. Use with extreme caution, particularly in noncritical care settings. Appropriate resuscitative equipment and qualified personnel must be available for administration and monitoring. Initial dosing must be cautiously titrated and individualized, particularly in elderly or debilitated patients, patients with hepatic impairment (including alcoholics), or in renal impairment, particularly if other CNS depressants (including opiates) are used concurrently.
Disease-related concerns:
• Heart failure (HF): Use with caution in patients with HF.
• Impaired gag reflex: Use with caution in patients with an impaired gag reflex.
• Renal impairment: Use with caution in patients with renal impairment; half-life of midazolam and metabolites may be prolonged.
• Respiratory disease: Use with caution in patients with respiratory disease.
Concurrent drug therapy issues:
• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated.
Special populations:
• Debilitated patients: [U.S. Boxed Warning]: Initial doses in debilitated patients should be conservative; start at the lower end of dosing range.
• Elderly: [U.S. Boxed Warning]: Initial doses in elderly should be conservative; start at the lower end of dosing range.
• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.
• Obese patients: Use with caution in obese patients; may have prolonged action when discontinued.
• Neonates: [U.S. Boxed Warning]: Do not administer by rapid I.V. injection in neonates; severe hypotension and seizures have been reported; risk may be increased with concomitant fentanyl use.
Dosage form specific issues:
• Benzyl alcohol: Some parenteral dosage forms may contain benzyl alcohol which has been associated with “gasping syndrome” in neonates.
Other warnings/precautions:
• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Does not protect against increases in heart rate or blood pressure during intubation. Should not be used in shock, coma, or acute alcohol intoxication. Avoid intra-arterial administration or extravasation of parenteral formulation. Use during upper airway procedures may increase risk of hypoventilation. Prolonged responses have been noted following extended administration by continuous infusion (possibly due to metabolite accumulation) or in the presence of drugs which inhibit midazolam metabolism.
• Cherry flavoring: Some formulations may contain cherry flavoring.
• Withdrawal: Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
Adverse Reactions
As reported in adults unless otherwise noted:
>10%: Respiratory: Decreased tidal volume and/or respiratory rate decrease, apnea (3% children)
1% to 10%:
Cardiovascular: Hypotension (3% children)
Central nervous system: Drowsiness (1%), oversedation, headache (1%), seizure-like activity (1% children)
Gastrointestinal: Nausea (3%), vomiting (3%)
Local: Pain and local reactions at injection site (4% I.M., 5% I.V.; severity less than diazepam)
Neuromuscular & skeletal: Myoclonic jerks (preterm infants)
Ocular: Nystagmus (1% children)
Respiratory: Cough (1%)
Miscellaneous: Physical and psychological dependence with prolonged use, hiccups (4%, 1% children), paradoxical reaction (2% children)
<1%: Acid taste, agitation, amnesia, bigeminy, bradycardia, bronchospasm, confusion, dyspnea, emergence delirium, euphoria, excessive salivation, hallucinations, hyperventilation, laryngospasm, PVC, rash, tachycardia, wheezing
Metabolism/Transport Effects
Substrate of CYP2B6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C8 (weak), CYP2C9 (weak), CYP3A4 (weak)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Management: The following combinations are specifically contraindicated: itraconazole with alprazolam, estazolam, oral midazolam, or triazolam; ketoconazole with alprazolam, estazolam, or triazolam. Consider initial dose reductions of other benzodiazepines. Risk D: Consider therapy modification
Aprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole systemic exposure/affects with concomitant use of a weak CYP3A4 inhibitor. Decrease aripiprazole dose to 25% of the usual dose in patients receiving both a CYP3A4 and a CYP2D6 inhibitor (regardless of potencies). Risk C: Monitor therapy
Atorvastatin: May increase the serum concentration of Midazolam. Risk C: Monitor therapy
Boceprevir: May increase the serum concentration of Midazolam. Risk X: Avoid combination
Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Bepridil [Off Market]. Risk D: Consider therapy modification
CarBAMazepine: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Cimetidine: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
Contraceptives (Estrogens): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Contraceptives (Progestins): May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Efavirenz: May increase the serum concentration of Midazolam. Risk X: Avoid combination
Fosaprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Specifically, the active metabolite aprepitant is likely responsible for this effect. Risk C: Monitor therapy
Fosphenytoin: Benzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Risk C: Monitor therapy
Ginkgo Biloba: May decrease the serum concentration of Midazolam. Risk C: Monitor therapy
Grapefruit Juice: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Isoniazid: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Macrolide Antibiotics: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin; Spiramycin. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Risk X: Avoid combination
Phenytoin: Benzodiazepines may increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Risk C: Monitor therapy
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Propofol: Midazolam may increase the serum concentration of Propofol. Propofol may increase the serum concentration of Midazolam. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with all protease inhibitors. IV midazolam contraindicated with fosamprenavir and nelfinavir; other protease inhibitors recommend caution, close monitoring, and consideration of lower IV midazolam doses with concurrent use. Risk X: Avoid combination
Proton Pump Inhibitors: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Exceptions: Lansoprazole; Pantoprazole; RABEprazole. Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Citalopram; Escitalopram; PARoxetine; Sertraline. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
St Johns Wort: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Telaprevir: May increase the serum concentration of Midazolam. Management: Use of oral midazolam with telaprevir is contraindicated. IV midazolam use may pose a lower risk, but dose reductions should be considered and patients should be monitored closely for signs/symptoms of toxicity. Risk X: Avoid combination
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Ethanol may increase CNS depression. Management: Avoid ethanol.
Food: Grapefruit juice may increase serum concentrations of midazolam. Management: Avoid concurrent use of grapefruit juice with oral midazolam.
Herb/Nutraceutical: St John's wort may decrease midazolam levels and increase CNS depression; valerian, kava kava, and gotu kola may increase CNS depression. Management: Avoid concurrent use with St John's wort, valerian, kava kava, and gotu kola.
Storage
The manufacturer states that midazolam, at a final concentration of 0.5 mg/mL, is stable for up to 24 hours when diluted with D5W or NS. A final concentration of 1 mg/mL in NS has been documented to be stable for up to 10 days (McMullen, 1995). Admixtures do not require protection from light for short-term storage.
Compatibility
Stable in D5NS, D5W, NS; incompatible with LR.
Y-site administration: Compatible: Abciximab, amikacin, amiodarone, anidulafungin, argatroban, atracurium, bivalirudin, calcium gluconate, caspofungin, cefazolin, cimetidine, ciprofloxacin, cisatracurium, clindamycin, digoxin, diltiazem, doripenem, epinephrine, eptifibatide, erythromycin lactobionate, esmolol, etomidate, famotidine, fenoldopam, fentanyl, fluconazole, gentamicin, heparin, hetastarch in lactate electrolyte injection (Hextend®), hydromorphone, insulin (regular), labetalol, linezolid, lorazepam, methadone, metronidazole, milrinone, morphine, nicardipine, nitroglycerin, nitroprusside, norepinephrine, palonosetron, pancuronium, piperacillin, ranitidine, remifentanil, sufentanil, theophylline, tirofiban, tobramycin, vancomycin, vecuronium. Incompatible: Albumin, amphotericin B cholesteryl sulfate complex, ampicillin, bumetanide, butorphanol, cefepime, ceftazidime, cefuroxime, dexamethasone sodium succinate, drotrecogin alfa, foscarnet, fosphenytoin, furosemide, hydrocortisone sodium succinate, imipenem/cilastatin, methotrexate, micafungin, nafcillin, sodium bicarbonate, thiopental, trimethoprim/sulfamethoxazole. Variable (consult detailed reference): Cefotaxime, clonidine, dobutamine, haloperidol, methylprednisolone sodium succinate, metoclopramide, pantoprazole, potassium chloride, propofol.
Compatibility in syringe: Compatible: Alfentanil, atracurium, atropine, buprenorphine, butorphanol, chlorpromazine, cimetidine, diphenhydramine, dopamine, droperidol, fentanyl, glycopyrrolate, hydromorphone, hydroxyzine, ketamine, meperidine, metoclopramide, morphine, nalbuphine, ondansetron, promethazine, rocuronium, scopolamine, sufentanil, trimethobenzamide. Incompatible: Dimenhydrinate, heparin, pantoprazole, pentobarbital, prochlorperazine edisylate, ranitidine. Variable (consult detailed reference): Dexamethasone sodium phosphate, methylprednisolone sodium succinate.
Mechanism of Action
Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization.
Pharmacodynamics/Kinetics
Onset of action: I.M.: Sedation: ~15 minutes; I.V.: 3-5 minutes; Oral: 10-20 minutes; Intranasal: Children: 4-8 minutes (Lee-Kim, 2004)
Peak effect: I.M.: 0.5-1 hour
Duration: I.M.: Up to 6 hours; Mean: 2 hours; Intranasal: Children: 18-41 minutes (Lee-Kim, 2004)
Absorption: Oral: Rapid
Distribution: Vd: 1-3.1 L/kg; increased in females, elderly, and obesity
Protein binding: ~97%
Metabolism: Extensively hepatic via CYP3A4
Bioavailability: 36% (oral, children); >90% (I.M.)
Half-life elimination: 2-6 hours; prolonged in cirrhosis, congestive heart failure, obesity, and elderly
Excretion: Urine (as glucuronide conjugated metabolites); feces (~2% to 10%)
Dosage
The dose of midazolam needs to be individualized based on the patient's age, underlying diseases, and concurrent medications. Decrease dose (by ~30%) if opioids or other CNS depressants are administered concomitantly.
Children: Note: Children <6 years may require higher doses and closer monitoring than older children; calculate dose based on ideal body weight.
Conscious sedation for procedures or preoperative sedation:
Oral, rectal: Children: 0.5-0.75 mg/kg as a single dose preprocedure (maximum: 20 mg); administer 20-30 minutes prior to procedure. Children <6 years or less cooperative patients may require as much as 1 mg/kg as a single dose; 0.25 mg/kg may suffice for children 6-16 years of age (Bozkurt, 2007).
Intranasal (unlabeled route): Children: 0.2-0.5 mg/kg (maximum total dose: 10 mg or 5 mg per nare); may be administered 10-20 minutes prior to procedure (Bozkurt, 2007; Chiaretti, 2011). Note: Use 5 mg/mL injectable concentrated solution to deliver dose. Due to the low pH of the solution, burning upon administration is likely to occur.
I.M.: Children: 0.1-0.15 mg/kg 30-60 minutes before surgery or procedure; range: 0.05-0.15 mg/kg; maximum total dose: 10 mg
I.V.:
Infants <6 months: Limited information is available in nonintubated infants; dosing recommendations not clear; infants <6 months are at higher risk for airway obstruction and hypoventilation; titrate dose in small increments to desired effect
Infants 6 months to Children 5 years: Initial: 0.05-0.1 mg/kg; total dose of 0.6 mg/kg may be required; maximum total dose: 6 mg
Children 6-12 years: Initial: 0.025-0.05 mg/kg; total doses of 0.4 mg/kg may be required; maximum total dose: 10 mg
Children 12-16 years: Dose as adults; maximum total dose: 10 mg
Conscious sedation during mechanical ventilation: Children: Loading dose: 0.05-0.2 mg/kg, followed by initial continuous infusion: 0.06-0.12 mg/kg/hour (1-2 mcg/kg/minute); usual range: 0.4-6 mcg/kg/minute
Status epilepticus refractory to standard therapy (unlabeled use): Note: Intubation required; adjust dose based on hemodynamics, seizure activity, and EEG. Infants >2 months and Children: Loading dose: 0.15 mg/kg followed by a continuous infusion of 0.06 mg/kg/hour (1 mcg/kg/minute); titrate dose upward every 5 minutes until clinical seizure activity is controlled; mean infusion rate required in 24 children was 0.14 mg/kg/hour (2.3 mcg/kg/minute) with a range of 0.06-1.1 mg/kg/hour (1-18.3 mcg/kg/minute) (Rivera, 1993).
A more aggressive approach has been demonstrated to provide control of status epilepticus within 30 minutes of initiation: Loading dose: 0.5 mg/kg followed by 0.12 mg/kg/hour (2 mcg/kg/minute). If seizures persist or recur, administer 0.5 mg/kg bolus with an increase in the infusion rate to 0.24 mg/kg/hour (4 mcg/kg/minute); if seizures continue to persist/recur, administer 0.1 mg/kg bolus and increase infusion to 0.48 mg/kg/hour (8 mcg/kg/minute); continue to repeat this last incremental increase until seizure control or a maximum dose of 1.44 mg/kg/hour (24 mcg/kg/minute) is reached; do not allow >5 minutes to elapse between each dose increment while seizures persist (dose range within clinical trial: 0.12-1.92 mg/kg/hour or 2-32 mcg/kg/minute) (Morrison, 2006).
Status epilepticus, prehospital treatment (unlabeled use; Silbergleit, 2012): Note: Administered by paramedics when convulsions last >5 minutes or if convulsions are occurring after having intermittent seizures without regaining consciousness for >5 minutes. I.M.: Children and Adolescents:
13-40 kg: 5 mg once
>40 kg: Refer to adult dosing
Adults: Note: Consider reducing dose by 30% to 50% in elderly or debilitated patients and those receiving opioids or other CNS depressants.
Preoperative sedation:
I.M.: 0.07-0.08 mg/kg 30-60 minutes prior to surgery/procedure; usual dose: 5 mg
I.V.: 0.02-0.04 mg/kg; repeat every 5 minutes as needed to desired effect or up to 0.1-0.2 mg/kg
Intranasal (unlabeled route): 0.1 mg/kg; administer 10-20 minutes prior to surgery/procedure (Uygur-Bayramiçli, 2002). Note: Use 5 mg/mL injectable solution to deliver dose. Due to the low pH of the solution, burning upon administration is likely to occur.
Conscious sedation: I.V.: Initial: 0.5-2 mg slow I.V. over at least 2 minutes; slowly titrate to effect by repeating doses every 2-3 minutes if needed; usual total dose: 2.5-5 mg
Healthy adults <60 years:
Initial: Some patients respond to doses as low as 1 mg; no more than 2.5 mg should be administered over a period of 2 minutes. Additional doses of midazolam may be administered after a 2-minute waiting period and evaluation of sedation after each dose increment. A total dose >5 mg is generally not needed.
Maintenance: 25% of dose used to reach sedative effect
Adults ≥60 years, debilitated, or chronically ill: Refer to elderly dosing.
Anesthesia: I.V.:
Induction:
Unpremedicated patients: 0.3-0.35 mg/kg (up to 0.6 mg/kg in resistant cases)
Premedicated patients: 0.15-0.35 mg/kg
Maintenance: 0.05-0.3 mg/kg as needed, or continuous infusion 0.25-1.5 mcg/kg/minute
Sedation in mechanically ventilated patients: Per the manufacturer: I.V.: Initial dose: 0.01-0.05 mg/kg (~0.5-4 mg); may repeat at 5- to 15-minute intervals until adequate sedation achieved; maintenance infusion: 0.02-0.1 mg/kg/hour. Titrate to reach desired level of sedation.
or
I.V.: Initial dose: 0.02-0.08 mg/kg (~1-5 mg in 70 kg adult); may repeat at 5- to 15-minute intervals until adequate sedation achieved; maintenance infusion: 0.04-0.2 mg/kg/hour. Titrate to reach desired level of sedation (Jacobi, 2002).
Status epilepticus refractory to standard therapy (unlabeled use): Note: Intubation required; adjust dose based on hemodynamics, seizure activity, and EEG. I.V.: 0.15-0.3 mg/kg (usual dose: 5-15 mg); may repeat every 10-15 minutes as needed or 0.2 mg/kg bolus followed by a continuous infusion of 0.05-0.6 mg/kg/hour (Lowenstein, 2005; Meierkord, 2010)
Status epilepticus, prehospital treatment (unlabeled use; Silbergleit, 2012): Note: Administered by paramedics when convulsions last >5 minutes or if convulsions are occurring after having intermittent seizures without regaining consciousness for >5 minutes. I.M.: 10 mg once
Elderly: I.V.: Conscious sedation: Initial: 0.5 mg slow I.V.; give no more than 1.5 mg in a 2-minute period; if additional titration is needed, give no more than 1 mg over 2 minutes, waiting another 2 or more minutes to evaluate sedative effect; a total dose of >3.5 mg is rarely necessary
Dosage adjustment in renal impairment: There are no dosage adjustments provided in manufacturer's labeling; use with caution.
Hemodialysis: Supplemental dose is not necessary.
Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics.
Dosage adjustment in hepatic impairment: Severe hepatic impairment: Reduce dose by 50%.
Dental Usual Dosing
Adults:
Preoperative sedation:
I.M.: 0.07-0.08 mg/kg 30-60 minutes prior to surgery/procedure; usual dose: 5 mg; Note: Reduce dose in patients with COPD, high-risk patients, patients ≥60 years of age, and patients receiving other narcotics or CNS depressants
I.V.: 0.02-0.04 mg/kg; repeat every 5 minutes as needed to desired effect or up to 0.1-0.2 mg/kg
Intranasal (not an approved route): 0.2 mg/kg (up to 0.4 mg/kg in some studies); administer 30-45 minutes prior to surgery/procedure
Conscious sedation: I.V.: Initial: 0.5-2 mg slow I.V. over at least 2 minutes; slowly titrate to effect by repeating doses every 2-3 minutes if needed; usual total dose: 2.5-5 mg; use decreased doses in elderly.
Healthy Adults <60 years: Initial: Some patients respond to doses as low as 1 mg; no more than 2.5 mg should be administered over a period of 2 minutes. Additional doses of midazolam may be administered after a 2-minute waiting period and evaluation of sedation after each dose increment. A total dose >5 mg is generally not needed. If narcotics or other CNS depressants are administered concomitantly, the midazolam dose should be reduced by 30%.
Administration: Oral
Do not mix with any liquid (such as grapefruit juice) prior to administration.
Administration: I.M.
Give deep I.M. into large muscle.
Administration: I.V.
Administer by slow I.V. injection over at least 2-5 minutes at a concentration of 1-5 mg/mL or by I.V. infusion. Continuous infusions should be administered via an infusion pump.
Administration: Other
Intranasal: Note: Due to the low pH of the solution, burning upon administration is likely to occur. Use of an atomizer, such as the MAD 300 Mucosal Atomizer which attaches to a tuberculin syringe, can reduce irritation. If possible, based upon dose to be administered, use higher concentration injectable solution to minimize volume administered intranasal. Smaller volume will reduce irritation and swallowing of administered dose. The maximum recommended dose volume (of the 5 mg/mL concentration) per nare is 1 mL.
Using the 5 mg/mL injectable solution, draw up desired dose with a 1-3 mL needleless syringe; may attach a nasal mucosal atomization device prior to delivering dose. Deliver half of the total dose volume into the first nare using the atomizer device or by dripping slowly into nostril, then deliver the other half of the dose into the second nare.
Administration: I.V. Detail
pH: 3 (adjusted)
Monitoring Parameters
Respiratory and cardiovascular status, blood pressure, blood pressure monitor required during I.V. administration
Dietary Considerations
Avoid grapefruit juice with oral syrup.
Patient Education
Avoid use of alcohol.
Geriatric Considerations
In the elderly if concomitant CNS depressant medications are used, the midazolam dose will be at least 50% less than doses used in healthy, young, unpremedicated patients.
Additional Information
Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms. For neonates, since both concentrations of the injection contain 1% benzyl alcohol, use the 5 mg/mL injection and dilute to 0.5 mg/mL with SWI without preservatives to decrease the amount of benzyl alcohol delivered to the neonate; with continuous infusion, midazolam may accumulate in peripheral tissues; use lowest effective infusion rate to reduce accumulation effects; midazolam is 3-4 times as potent as diazepam; paradoxical reactions associated with midazolam use in children (eg, agitation, restlessness, combativeness) have been successfully treated with flumazenil (Massanari, 1997).
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: Midazolam may accumulate in patients who are obese or in patients with hypoalbuminemia or renal failure. Concurrent use of CYP3A4 inhibitors may inhibit metabolism of midazolam and prolong its sedative effects.
In healthy volunteers, the combination of midazolam (0.05 mg/kg) with fentanyl (2 mcg/kg) produces synergistic respiratory depression (92% incidence of hypoxemia (SaO2 <90%) and 50% incidence of apnea (Bailey, 1990).
Intranasal Administration: Midazolam injectable solution has a pH of 3. Because of this, nasal burning is likely to occur upon administration. In one study, lidocaine (Ecocain 10 g/100 mL spray [Molteni Dental, Scandicci, Italy]) was sprayed into each nare 30 seconds prior to intranasal administration of midazolam. As a result, none of the patients experienced burning with intranasal midazolam administration. This study demonstrated that lidocaine spray prior to intranasal midazolam administration is safe and effective (Chiaretti, 2011). Note: The product used in this study is not currently available in the United States.
Evidence-Based Information: Agitation in the ICU Patient: Diazepam or midazolam is recommended for rapid sedation of the acutely-agitated patient. The 2002 ACCM/SCCM task force does not recommend midazolam use for ongoing sedation in the critically ill adult. Midazolam is 3-4 times as potent as diazepam. Paradoxical reactions associated with midazolam use in children (eg, agitation, restlessness, combativeness) have been successfully treated with flumazenil.
Cardiovascular Considerations
Hypotension may result in orthostatic lightheadedness or syncope. Benzodiazepines, as a class, may depress respiration. These medications may often be prescribed for difficulty in sleeping but may exacerbate sleep-disordered breathing.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
Compared to oral sedation, intranasal (IN) sedation resulted in greater irritability during the first 10-15 minutes after administration, but a faster onset and shorter duration of sedation with improved behavior following onset of sedation. (Johnson, 2010; Lee-Kim, 2004). Monitor oxygen saturation with midazolam. If desaturation occurs, reposition airway (head tilt, chin lift).
Mental Health: Comment
In 2007, the FDA requested that all manufacturers of sedative-hypnotic drug products revise labeling to include a greater emphasis on the risks of adverse effects. These risks include severe allergic reactions (anaphylaxis, angioedema) and complex sleep-related behaviors, which may include sleep-driving (driving while not fully awake and with no memory of the event), making phone calls, and preparing and eating food while asleep.
There are two subtypes of GABA receptors (GABA-A and GABA-B) and three different benzodiazepine receptors (Bz1, Bz2, and Bz3). Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors. The role of GABA-B receptors is unclear. Benzodiazepines have no specificity for benzodiazepine receptor subtypes.
Midazolam is a short half-life benzodiazepine and may be of benefit in patients where a rapidly and short-acting agent is desired (acute agitation). Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the sedative, hypnotic, and anticonvulsant effects. It does not develop to the anxiolytic or skeletal muscle relaxing effects. Psychological and physical dependence may occur with prolonged use of benzodiazepines. The onset of withdrawal symptoms is usually seen on the first day without drug and lasts 5-7 days in patients receiving short half-life benzodiazepines, whereas, the onset occurs after 5 days with a duration of 10-14 days after abrupt discontinuance of long half-life benzodiazepines. Risk factors for abuse include personal or family history of substance abuse and personality disorder.
Midazolam is rapidly and completely absorbed after I.M. injection.
Nursing: Physical Assessment/Monitoring
For inpatient use, institute safety measures. I.V.: Monitor cardiac and respiratory status continuously. Monitor I.V. infusion site carefully for extravasation. I.V./I.M.: Monitor closely following administration. Bedrest and assistance with ambulation necessary for several hours.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution: 1 mg/mL (2 mL, 5 mL, 10 mL); 5 mg/mL (1 mL, 2 mL, 5 mL, 10 mL)
Injection, solution [preservative free]: 1 mg/mL (2 mL, 5 mL); 5 mg/mL (1 mL, 2 mL)
Syrup, oral: 2 mg/mL (118 mL)
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International Brand Names
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Last full review/revision March 2012
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