Skip to Content

Midazolam

Pronunciation

Pronunciation

(MID aye zoe lam)

Index Terms

  • Midazolam HCl
  • Midazolam Hydrochloride
  • Versed

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Generic: 2 mg/2 mL (2 mL); 5 mg/5 mL (5 mL); 10 mg/10 mL (10 mL); 5 mg/mL (1 mL); 10 mg/2 mL (2 mL); 25 mg/5 mL (5 mL); 50 mg/10 mL (10 mL)

Solution, Injection [preservative free]:

Generic: 2 mg/2 mL (2 mL); 5 mg/5 mL (5 mL); 5 mg/mL (1 mL); 10 mg/2 mL (2 mL)

Syrup, Oral:

Generic: 2 mg/mL (118 mL)

Pharmacologic Category

  • Benzodiazepine

Pharmacology

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. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors.

Absorption

IM: Rapid, complete; Oral, Intranasal: Rapid

Distribution

Widely distributed in body including CSF; Vd:

Preterm infants (n=24; GA: 26 to 34 weeks; PNA: 3 to 11 days): Median: 1.1 L/kg (range: 0.4 to 4.2 L/kg)

Infants and Children 6 months to 16 years: 1.24 to 2.02 L/kg

Adults: 1 to 3.1 L/kg; increased in CHF, chronic renal failure, females, elderly, and obesity

Metabolism

Extensively hepatic CYP3A4; 60% to 70% of biotransformed midazolam is the active metabolite 1-hydroxy-midazolam (or alpha-hydroxymidazolam)

Excretion

IV: Urine (primarily as glucuronide conjugates of the hydroxylated metabolites); Oral: Urine (~90% within 24 hours; primarily [60% to 70%] as glucuronide conjugates of the hydroxylated metabolites; <0.03% as unchanged drug); feces (~2% to 10% over 5 days) (Kanto 1985; Smith 1981)

Clearance:

Preterm infants (n=24; GA: 26 to 34 weeks; PNA: 3 to 11 days): Median: 1.8 mL/minute/kg (range: 0.7 to 6.7 mL/minute/kg)

Neonates <39 weeks GA: 1.17 mL/minute/kg

Neonates >39 weeks GA: 1.84 mL/minute/kg

Seriously ill neonates: 1.2 to 2 mL/minute/kg

Infants >3 months: 9.1 mL/minute/kg

Children >1 year: 3.2 to 13.3 mL/minute/kg

Healthy adults: 4.2 to 9 mL/minute/kg

Adults with acute renal failure: 1.9 mL/minute/kg

Onset of Action

Onset of action: IM: Sedation: Children: Within 5 minutes; Adults: ~15 minutes; IV: 1 to 5 minutes; Oral: 10 to 20 minutes; Intranasal: Children: 4 to 8 minutes (Lee-Kim 2004); Adults: Within 5 minutes

Peak effect: IM: Children: 15 to 30 minutes; Adults: 30 to 60 minutes; IV: 5 to 7 minutes; Intranasal: 10 minutes

Time to Peak

IM: 0.5 to 1 hour; Oral: 0.2 to 3 hours

Duration of Action

IM: Up to 6 hours; Mean: 2 hours; Intranasal: Children: 18 to 41 minutes (Lee-Kim 2004); IV: Single dose: <2 hours (dose-dependent) (Fragen 1997); Cirrhosis: Up to 6 hours (MacGilcrhist 1986)

Half-Life Elimination

Preterm infants (n=24; GA: 26 to 34 weeks; PNA: 3 to 11 days): Median: 6.3 hours (range: 2.6 to 17.7 hours)

Neonates: 4 to 12 hours; seriously ill neonates: 6.5 to 12 hours

Children: IV: 2.9 to 4.5 hours; Syrup: 2.2 to 6.8 hours

Adults: 3 hours (range: 1.8 to 6.4 hours)

Prolonged in cirrhosis, congestive heart failure, obesity, renal failure, and elderly. Note: In patients with renal failure, reduced elimination of active hydroxylated metabolites leads to drug accumulation and prolonged sedation.

Protein Binding

~97%; in patients with cirrhosis, protein binding is reduced with a free fraction of ~5% (Trouvin 1988)

Special Populations: Hepatic Function Impairment

Following oral administration (15 mg), Cmax and bioavailability were 43% and 100% higher, respectively. Clearance was reduced 40% and half-life increased 90%. Doses should be titrated.

Special Populations Note

CHF: Following oral administration (7.5 mg), half-life increased 43%.

Use: Labeled Indications

Anesthesia: IV: Induction of general anesthesia before administration of other anesthetic agents and maintenance of anesthesia as a component of balanced anesthesia

Sedation/anxiolysis/amnesia (preoperative/procedural):

IM: Preoperative sedation, anxiolysis, and amnesia.

IV: Sedation, anxiolysis, and amnesia prior to or during diagnostic, therapeutic, or endoscopic procedures, or prior to surgery.

Oral: Sedation, anxiolysis, and amnesia in children prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Sedation for mechanically-ventilated patients: IV: Sedation of intubated and mechanically-ventilated patients as a component of anesthesia or during treatment in a critical care setting by continuous IV infusion.

Use: Unlabeled

Anxiety, status epilepticus, conscious sedation (intranasal route)

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)

Per respective protease inhibitor manufacturer's labeling: Concurrent use of oral midazolam with amprenavir, atazanavir, darunavir, indinavir, lopinavir-ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir and concurrent use of oral or injectable midazolam with fosamprenavir

Dosing: Adult

Note: The dose of midazolam needs to be individualized based on the patient's age, underlying diseases, and concurrent medications. Consider reducing dose by 20% to 50% in elderly, chronically ill, or debilitated patients and those receiving opioids or other CNS depressants.

Anesthesia: IV:

Induction: Adults <55 years:

Unpremedicated patients: 0.3 to 0.35 mg/kg over 20 to 30 seconds; after 2 minutes, may repeat if necessary at 25% of initial dose every 2 minutes, up to a total dose of 0.6 mg/kg in resistant cases

Premedicated patients: Usual dosage range: 0.05 to 0.2 mg/kg (Barash 2009; Miller 2010). Use of 0.2 mg/kg administered over 5 to 10 seconds has been shown to safely produce anesthesia within 30 seconds (Samuelson, 1981) and is recommended for ASA physical status P1 and P2 patients. When used with other anesthetic drugs (ie, co-induction), the dose is <0.1 mg/kg (Miller 2010).

ASA physical status >P3 or debilitation: Reduce dose by at least 20% (Miller 2010).

Maintenance: 0.05 mg/kg as needed (Miller 2010), or continuous infusion 0.015 to 0.06 mg/kg/hour (0.25 to 1 mcg/kg/minute) (Barash 2009; Miller 2010)

Sedation/anxiolysis/amnesia (preoperative/procedural):

Manufacturer's labeling:

Healthy adults <60 years:

IM: 0.07 to 0.08 mg/kg 30 to 60 minutes prior to surgery/procedure; usual dose: 5 mg

IV:

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 geriatric dosing.

Alternate recommendations:

Intranasal (off-label route): 0.1 mg/kg; administer 15 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.

IV: American Society for Gastrointestinal Endoscopy (off-label dosing): Initial: 0.5 to 2 mg administered over at least 2 minutes; slowly titrate to effect by repeating doses every 2 to 3 minutes if needed; usual total dose: 2.5 to 5 mg (ASGE [Waring 2003])

Sedation in mechanically-ventilated patients (off-label dosing): IV: Initial dose: 0.01 to 0.05 mg/kg (~0.5 to 4 mg); may repeat at 5- to 15-minute intervals until adequate sedation achieved; maintenance infusion: 0.02 to 0.1 mg/kg/hour (0.3 to 1.7 mcg/kg/minute). Titrate to reach desired level of sedation. Titration to maintain a light rather than a deep level of sedation is recommended unless clinically contraindicated (Barr 2013). May consider a trial of daily awakening; if agitated after discontinuation of drip, then restart at 50% of the previous dose (Kress 2000).

Status epilepticus (off-label use): Note: Administered when convulsions last >5 minutes or if convulsions are occurring after having intermittent seizures without regaining consciousness for >5 minutes. IM: 10 mg once (Silbergleit 2012) or 0.2 mg/kg once (maximum dose: 10 mg) (NCS [Brophy 2012])

Status epilepticus, refractory (off-label use): IV: Note: Mechanical ventilation and cardiovascular monitoring required; titrate dose to cessation of electrographic seizures or burst suppression (NCS [Brophy 2012]).

Neurocritical Care Society recommendations (NCS [Brophy 2012]):

Loading dose: 0.2 mg/kg followed by a continuous infusion.

Continuous infusion: 0.05 to 2 mg/kg/hour (0.83 to 33.2 mcg/kg/minute) titrated to cessation of electrographic seizures or burst suppression. If patient experiences breakthrough status epilepticus while on the continuous infusion, administer a bolus of 0.1 to 0.2 mg/kg and increase infusion rate by 0.05 to 0.1 mg/kg/hour (0.83 to 1.66 mcg/kg/minute) every 3 to 4 hours. Note: A period of at least 24 to 48 hours of electrographic control is recommended prior to withdrawing the continuous infusion; withdraw gradually to prevent recurrent status epilepticus.

Dosing: Geriatric

The dose of midazolam needs to be individualized based on the patient's age, underlying diseases, and concurrent medications. Consider reducing dose by 20% to 50% in elderly, chronically ill, or debilitated patients and those receiving opioids or other CNS depressants.

Anesthesia: IV:

Induction: Adults ≥55 years:

Unpremedicated patients: Initial dose: 0.3 mg/kg

Premedicated patients: Reduce dose by at least 20% (Miller 2010).

Maintenance: Refer to adult dosing.

Sedation/Anxiolysis/Amnesia (preoperative/procedural):

Manufacturer's labeling:

IM: 2 to 3 mg (or 0.02 to 0.05 mg/kg) 30 to 60 minutes prior to surgery/procedure; some may only require 1 mg if anticipated intensity and duration of sedation is less critical.

IV:

Initial: Some patients respond to doses as low as 1 mg; 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

Maintenance: 25% of dose used to reach sedative effect

Alternate recommendations: IV: American Society for Gastrointestinal Endoscopy (off-label dosing): Initial: 0.5 to 2 mg administered over at least 2 minutes (smaller doses may be used in the elderly); slowly titrate to effect by repeating doses every 2 to 3 minutes if needed; usual total dose: 2.5 to 5 mg (ASGE [Waring 2003])

Dosing: Pediatric

Note: 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 <6 years may require higher doses and closer monitoring than older children; in children with obesity, calculate dose based on ideal body weight.

Sedation/Anxiolysis/Amnesia (preoperative/procedural): Infants ≥ 6 months, Children, and Adolescents ≤16 years:

Oral: 0.25 to 0.5 mg/kg (maximum: 20 mg) as a single dose 20 to 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 to 16 years of age or for cooperative patients. Doses of 0.5 to 0.75 mg/kg administered 20 to 30 minutes prior to procedure have also been suggested; however, doses above 0.5 mg/kg typically do not improve the sedative and anxiolytic effects but increase side effects during recovery (Bozkurt 2007).

IM: 0.1 to 0.15 mg/kg 30 to 60 minutes before surgery or procedure; range: 0.05 to 0.15 mg/kg; doses up to 0.5 mg/kg have been used in more anxious patients; maximum total dose: 10 mg

Intranasal (off-label route): 0.2 to 0.5 mg/kg (maximum total dose: 10 mg or 5 mg per nare); may be administered 10 to 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.

IV:

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 to 0.1 mg/kg; total dose of 0.6 mg/kg may be required; maximum total dose: 6 mg

Children 6 to 12 years: Initial: 0.025 to 0.05 mg/kg; total doses of 0.4 mg/kg may be required; maximum total dose: 10 mg

Children 12 to 16 years: Dose as adults; maximum total dose: 10 mg

Rectal (off-label route): 0.5 to 0.75 mg/kg (maximum: 20 mg) as a single dose 20 to 30 minutes prior to procedure (Bozkurt 2007).

Sedation in mechanically-ventilated patients (off-label dosing): Infants, Children and Adolescents: IV: Loading dose: 0.05 to 0.2 mg/kg, followed by initial continuous infusion: 0.06 to 0.12 mg/kg/hour (1 to 2 mcg/kg/minute); range in clinical trials: 0.024 to 0.564 mg/kg/hour (0.4 to 9.4 mcg/kg/minute) (Hartman 2009)

Seizures (off-label use): Children and Adolescents: IM: 0.2 mg/kg (maximum dose: 6 mg); may repeat every 10 to 15 minutes (AAP [Hegenbarth 2008]; Chamberlain, 1997)

Status epilepticus (off-label use): Children and Adolescents: Note: Administered when convulsions last >5 minutes or if convulsions are occurring after having intermittent seizures without regaining consciousness for >5 minutes (Silbergleit 2012).

IM (NCS [Brophy 2012]; Silbergleit 2012):

<13 kg: Not evaluated

13 to 40 kg: 5 mg once

>40 kg: 10 mg once

Intranasal: 0.2 mg/kg (NCS [Brophy 2012]) Note: Use 5 mg/mL injectable concentrated solution to deliver dose (Ljungman 2000). Due to the low pH of the solution, burning upon administration is likely to occur (Bozkurt 2007).

Buccal: 0.5 mg/kg (NCS [Brophy 2012])

Status epilepticus, refractory (off-label use): Infants, Children, and Adolescents: IV: Note: Mechanical ventilation and cardiovascular monitoring required; titrate dose to cessation of electrographic seizures or burst suppression (NCS [Brophy 2012])

Neurocritical Care Society recommendations (NCS [Brophy 2012]):

Loading dose: 0.2 mg/kg followed by a continuous infusion.

Continuous infusion: 0.05 to 2 mg/kg/hour (0.83 to 33.2 mcg/kg/minute) titrated to cessation of electrographic seizures or burst suppression. If patient experiences breakthrough status epilepticus while on the continuous infusion, administer a bolus of 0.1 to 0.2 mg/kg and increase infusion rate by 0.05 to 0.1 mg/kg/hour (0.83 to 1.66 mcg/kg/minute) every 3 to 4 hours. Note: A period of at least 24 to 48 hours of electrographic control is recommended prior to withdrawing the continuous infusion; withdraw gradually to prevent recurrent status epilepticus.

American Academy of Pediatrics recommendations (AAP [Hegenbarth 2008]):

Loading dose: 0.15 to 0.2 mg/kg followed by a continuous infusion.

Continuous infusion: 1 mcg/kg/minute titrated every 15 minutes by increments of 1 mcg/kg/minute until the cessation of seizures (maximum: 5 mcg/kg/minute)

Dosing: Renal Impairment

There are no dosage adjustments provided in manufacturer's labeling; however, patients with renal failure receiving a continuous infusion cannot adequately eliminate the active hydroxylated metabolites (eg, 1-hydroxymidazolam) contributing to prolonged sedation sometimes for days after discontinuation (Spina 2007).

Intermittent hemodialysis: Supplemental dose is not necessary.

Continuous venovenous hemofiltration (CVVH): Unconjugated 1-hydroxymidazolam not effectively removed; 1-hydroxymidazolamglucuronide effectively removed; sieving coefficient = 0.45 (Swart 2005).

Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics.

Dosing: Hepatic Impairment

Severe hepatic impairment (eg, cirrhosis): Note: Use with caution in patients with any degree of hepatic impairment; patients with hepatic encephalopathy likely to be more sensitive to midazolam.

Single dose (eg, induction): No dosage adjustment recommended; patients with hepatic impairment may be more sensitive compared to patients without hepatic impairment; anticipate longer duration of action (MacGilchrist, 1986; Trouvin, 1988).

Multiple dosing or continuous infusion: Expect longer duration of action and accumulation; based on patient response, dosage reduction likely to be necessary (Trouvin, 1988).

Administration

Intranasal (off-label route): 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 per nare is 1 mL.

Using the 5 mg/mL injectable solution, draw up desired dose with a 1 to 3 mL needleless syringe; may attach a nasal mucosal atomization device prior to delivering dose. Deliver half of the total dose volume (of the 5 mg/mL concentration) 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.

Oral: Do not mix with any liquid (such as grapefruit juice) prior to administration

Parenteral:

IM: Administer deep IM into large muscle.

IV: Administer by slow IV injection over at least 2 to 5 minutes at a concentration of 1 to 5 mg/mL or by IV infusion. For induction of anesthesia, administer IV bolus over 5 to 30 seconds. Continuous infusions should be administered via an infusion pump.

Dietary Considerations

Avoid grapefruit juice with oral syrup.

Compatibility

Stable in D5NS, D5W, NS; incompatible with LR.

Y-site administration: Incompatible with 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.

Compatibility in syringe: Incompatible with dimenhydrinate, heparin, pantoprazole, pentobarbital, prochlorperazine edisylate, ranitidine.

Storage

Oral: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Injection: Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). 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 (McMullin, 1995). Admixtures do not require protection from light for short-term storage.

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Antihepaciviral Combination Products: May increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with antihepaciviral combination products. When used with intravenous midazolam, monitor for increased midazolam effects (eg, sedation, respiratory depression) and consider using a reduced midazolam dose. Avoid combination

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

AtorvaSTATin: May increase the serum concentration of Midazolam. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Boceprevir: May increase the serum concentration of Midazolam. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. 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. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Cobicistat: May increase the serum concentration of Midazolam. Management: Oral midazolam use is contraindicated with cobicistat-containing products. IV midazolam should be used with caution, close monitoring, and consideration of lower IV midazolam doses. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dimethindene (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ginkgo Biloba: May decrease the serum concentration of Midazolam. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Itraconazole: May increase the serum concentration of Midazolam. Management: Oral midazolam is contraindicated. Use intravenous midazolam with great caution in patients receiving itraconazole, employing reduced initial doses whenever possible and monitoring closely for enhanced and prolonged effects. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Midazolam. Avoid combination

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Midazolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Avoid combination

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. 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. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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. Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Propofol: Midazolam may increase the serum concentration of Propofol. Propofol may increase the serum concentration of Midazolam. 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. Avoid combination

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Roxithromycin: May increase the serum concentration of Midazolam. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. 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. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of Midazolam. Monitor therapy

Sodium Oxybate: Benzodiazepines may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Teduglutide: May increase the serum concentration of Benzodiazepines. 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. Avoid combination

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofisopam: May increase the serum concentration of Midazolam. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

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% IM, 5% IV; 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% (Limited to important or life-threatening): Agitation, amnesia, bigeminy, bronchospasm, emergence delirium, euphoria, hallucinations, laryngospasm, rash

ALERT: U.S. Boxed Warning

Respiratory depression:

Midazolam oral and injection have been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings.

Midazolam syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other CNS depressants (eg, opioids). Midazolam syrup should be used only in hospital or ambulatory care settings, including physicians' and dentists' offices, that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubation, and personnel trained in their use and skilled in airway management should be ensured. Patients should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea (ie, pulse oximetry). Hypoventilation, airway obstruction, and apnea can lead to hypoxia or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Special populations:

The initial dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other CNS depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam hydrochloride for sedation/anxiolysis/amnesia is age, procedure, and route dependent.

Neonates (injection):

Midazolam hydrochloride should not be administered by rapid injection in the neonatal population. Rapid injection should be avoided in the neonatal population. Midazolam hydrochloride administered rapidly as an IV injection (less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid IV injection of fentanyl. Seizures have been reported in several neonates following rapid IV administration.

Warnings/Precautions

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; may consider treatment with flumazenil (Massanari, 1997).

• Respiratory depression: [US 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 opioids) 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.

• CYP3A4 Inhibitors: Use with caution in patients receiving CYP3A4 inhibitors; may result in more intense and prolonged sedation; consider reducing midazolam dose and anticipate potential for prolongation and intensity of effect. The concurrent use of all protease inhibitors is contraindicated with oral midazolam per their respective manufacturer’s labeling. The concurrent use of fosamprenavir is contraindicated with both oral and parenteral forms of midazolam. Of note, a sixfold higher incidence of severe prolonged sedation has been noted in HIV-positive patients receiving IV midazolam for sedation during inpatient bronchoscopy as compared to those not receiving antiretroviral agents (Hsu 2012).

Special populations:

• Debilitated patients: [US Boxed Warning]: Initial doses in debilitated patients should be conservative; start at the lower end of dosing range.

• Elderly: [US 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: [US Boxed Warning]: Do not administer by rapid IV injection in neonates; severe hypotension and seizures have been reported; risk may be increased with concomitant fentanyl use.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

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.

• Tolerance: 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 and anticonvulsant effects. It does not develop to the anxiolytic effects (Vinkers 2012).

• 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.

Monitoring Parameters

Respiratory and cardiovascular status, blood pressure, blood pressure monitor required during IV administration

Critically-ill patients: Monitor depth of sedation with either the Richmond Agitation-Sedation Scale (RASS) or Sedation-Agitation Scale (SAS) (Barr 2013)

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were not observed in animal reproduction 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 (Bergman, 1992; Iqbal 2002; Wikner 2007).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, loss of strength and energy, or memory impairment. Have patient report immediately to prescriber difficulty breathing, slow breathing, shallow breathing, angina, tremors, twitching, severe nausea, vomiting, seizures, or severe dizziness (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Hide