Dosing & Uses
Dosage Forms & Strengths
oral syrup: Schedule IV
- 2mg/mL (generic)
injectable solution: Schedule IV
- 1mg/mL (generic)
- 5mg/mL (generic, Seizalam)
Preoperative Sedation/Anxiolysis With Anterograde Amnesia
IM
- 70-80 mcg/kg (dose range ~5 mg) 30-60 minutes before surgery (reduce 50% for chronically ill or geriatric patients)
IV
- Initial: Usually 0.5-1 mg given over 2 minutes (not to exceed 2.5 mg/dose); wait 2-3 minutes to evaluate sedative effect after each dose adjustment; total dose >5 mg usually not necessary to reach desired sedation; use 30% less midazolam if patient premedicated with narcotics or other CNS depressants
- Debilitated or chronically ill patients: 1.5 mg IV initially; may repeat with 1 mg/dose IV q2-3 min PRN; not to exceed cumulative dose of 3.5 mg; peak effect may be delayed in elderly, so increments should be smaller and rate of injection slower
- Maintenance: 25% of initial effective dose PRN by slow titration; reduce 30% if premedicated with opiate (50% in elderly/chronically ill)
Anesthesia
Induction
- <55 years without premedication: 300-350 mcg/kg IV injection over 20-30 seconds; wait 2-3 minutes to evaluate sedative effect after each dose adjustment; may use increments of 25% of initial dose PRN to complete induction; may use up to 0.6 mg/kg total dose in resistant cases, but such dosing may prolong recovery
- >55 years without premedication and with no systemic disease, in a patient who is not weak: 300 mcg/kg over 20-30 seconds initially; wait 2-3 minutes to evaluate sedative effect after each dose adjustment
- >55 years without premedication but presence of systemic disease or weak patient: 200-250 mcg/kg over 20-30 seconds usually enough; 0.15 mg/kg enough in some cases; wait 2-3 minutes to evaluate sedative effect after each dose adjustment
- >55 years with premedication: 150-350 mcg/kg IV injection over 20-30 seconds; wait 2-3 minutes to evaluate sedative effect after each dose adjustment; a dose of 250 mcg/kg usually enough to achieve desired effect
Maintenance
- May administer increments of 25% of induction dose PRN when there are signs that anesthetic effects are lightening
Sedation of Intubated/Ventilated Patients
Load: 10-50 mcg/kg (dose range 0.5-4 mg) slow IV injection or infusion over several minutes; repeat q5-15min PRN
Maintenance: Initial, 20-100 mcg/kg/hr infusion; titrate up or down 25-50% PRN
Status Epilepticus
Seizalam: Indicated for treatment of status epilepticus in adults
10 mg IM
Dosing Considerations
Because it is water soluble, takes approximately 3 times longer than diazepam to peak EEG effects; thus, clinician must wait 2-3 minutes to fully evaluate sedative effects before initiating procedure or repeating dose
Has twice the affinity for benzodiazepine receptors that diazepam has
May be administered IM if unable to obtain vascular access
Anesthesia: Typical adult induction and maintenance doses may need to be decreased in some elderly patients by 20-50%, because the elderly overall are more susceptible to CNS depressants than is the general population
Organophophorous Poisoning (Orphan)
Orphan designation for treatment of seizures induced by organophosphorous insecticide poisoning
Sponsor
- Meridian Medical Technologies, Inc., A Pfizer Company; 6350 Stevens Forest Road; Columbia, Maryland 21046
Dosage Forms & Strengths
syrup: Schedule IV
- 2mg/mL (generic)
injectable solution: Schedule IV
- 1mg/mL (generic)
- 5mg/mL (generic)
Sedation
500-750 mcg/kg PO once diluted by juice 20-30 minutes prior to procedure; not to exceed 20 mg
100-150 mcg/kg IM; up to 500 mcg/kg used; not to exceed 10 mg
IV
- <6 months: Initial, 50 mcg/kg IV over 2-3 minutes; titrate with small increments to clinical effect; monitor closely; data are limited in nonintubated infants
- 6 months-6 years: Initial, 50-100 mcg/kg IV over 2-3 minutes; repeat q2-3min PRN; may require up to 600 mcg/kg total dose; not to exceed 6 mg total dose
- 6-12 years: Initial, 25-50 mcg/kg IV over 2-3 minutes; repeat q2-3min PRN; may require up to 400 mcg/kg; not to exceed 10 mg total dose
Anesthesia (Non-neonatal)
Loading dose: 50-150 mcg/kg IV over 2-3 minutes PRN to achieve desired effect
Continuous infusion: 1-2 mcg/kg/min IV infusion
Anesthesia (Neonatal)
IV loading dose should not be used in neonates
Preoperative Sedation/Anxiolysis with Anterograde Amnesia
IM: 2-3 mg (~20-50 mcg/kg) 30-60 minutes before surgery; some elderly patients may respond to as little as 1 mg; onset is 15 minutes (peaking at 30-60 min)
IV (>60 years): 1-1.5 mg initially; not to exceed >1.5 mg in 2 min period; may repeat with 1 mg/dose q2-3min PRN; not to exceed cumulative dose of 3.5 mg; peak effect may be delayed in elderly, so increments should be smaller and rate of injection slower
IV maintenance: 25% of initial effective dose PRN by slow titration
Dosing Considerations
Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of midazolam are recommended
IV and IM doses of midazolam should be decreased for elderly and for debilitated patients, and patients aged ≥70 yr may be particularly sensitive
Anesthesia: Typical adult induction and maintenance doses may need to be decreased in some geriatric patients by 20-50%, because they are more susceptible to CNS depressants than is the general population
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Decreased respiratory rate (23%)
Apnea (15%)
1-10%
Drowsiness (1-5%)
Seizure-like activity (1%)
Nausea/vomiting (3%)
Cough (1%)
Pain at injection site (4-5%)
Frequency Not Defined
Headache
Sedation
Hiccoughs
Delirium
Euphoria
Pediatric
- Desaturation
- Hypotension
- Seizurelike activity
- Nystagmus
- Paradoxical reactions
- Hiccoughs
- Apnea
Warnings
Black Box Warnings
Respiratory depression/arrest has been associated with use, especially when used for sedation in noncritical care settings
Use lower end of dosing range in debilitated patients, including the elderly
Do not administer by rapid IV injection in neonates (hypotension and seizures reported, especially when used concomitantly with fentanyl)
Should be used only in settings (eg, hospital, ambulatory care settings, including physicians' or dentists' offices) that can provide continuous monitoring of respiratory and cardiac function; immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubations, as well as personnel trained in their use and skilled in airway management, should be ensured
For deeply sedated patients, a dedicated individual other than the practitioner performing the procedure should monitor the patient throughout the procedure
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
Adult dosing
- The initial IV dose for sedation in adult patients may be as little as 1 mg but should not exceed 2.5 mg in a normal, healthy adult; lower doses are necessary for older (>60 years) or debilitated patients and for 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
Pediatric dosing
- 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 for sedation/anxiolysis/amnesia is age, procedure, and route dependent.
Neonates
- Midazolam should not be administered by rapid injection in the neonatal population; severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl
General anesthetics and sedation drugs in young children and pregnant women
-
Brain development
- Prolonged or repeated exposure may result in negative effects on fetal or young children’s brain development
- Caution with use during surgeries or procedures in children younger than 3 yr or in pregnant women during their third trimester
- Assess the risk:benefit ratio in these populations, especially for prolonged procedures (ie, >3 hr) or multiple procedures
Risks from concomitant use with opioids
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate
Limit dosages and durations to the minimum required
Follow patients for signs and symptoms of respiratory depression and sedation
Inform patients and caregivers that potentially fatal additive effects may occur if drug is used with opioids and that such drugs should not be used concomitantly unless supervised by a health care provider
Prescribers should advise caregivers that they expect to be informed immediately if a patient develops any new findings which are not typical of the patient’s characteristic seizure episode
Addiction, abuse, and misuse
On September 2020, FDA addressed serious risks of benzodiazepine addiction, abuse, and misuse, which can lead to overdose and death
Physical dependence can occur when taken steadily for several days to weeks, even as prescribed
Stopping abruptly or reducing dosage too quickly can result in withdrawal reactions, including seizures, which can be life-threatening
Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes; before prescribing and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction
Assess each patient’s risk prior to prescribing and monitor regularly for the development of these conditions
Risks of dependence and withdrawal increase with longer treatment duration and higher daily dose; although injection is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction may precipitate acute withdrawal reactions, including seizures, which can be life-threatening; use gradual taper when discontinuing therapy to reduce withdrawal reactions risk
Contraindications
Documented hypersensitivity
Acute alcohol intoxication
Acute narrow angle glaucoma
Intrathecal/epidural use (formulations containing preservatives, such as, benzyl alcohol)
Potent inhibitors of CYP3A4 including amprenavir, atazanavir, darunavir, indinavir, lopinavir, ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir or oral or injectable midazolam with fosamprenavir
Cautions
Use caution in COPD, sleep apnea, renal/hepatic disease, open-angle glaucoma (questionable), depression, suicidal ideation, impaired gag reflex, heart failure, patients at risk of falls, or obese patients
Anterograde amnesia reported with benzodiazepines
Use caution in myasthenia gravis (allowable in limited circumstances)
Use in narrow-angle glaucoma questionable
May cause hypotension; may occur more frequently in patients receiving opioid analgesics
Use caution in patient receiving other CNS depressants or psychoactive medications
IV use in shock, coma, depressed respiration, patients who recently received other respiratory depressants not recommended
Paradoxical reactions, including hyperactive or aggressive behavior reported
Avoid extravasation of arterial formulation
Does not protect against increases in heart rate or blood pressure
May cause CNS depression and impair ability to perform hazardous tasks
Not for use as antidepressant, analgesic, or antipsychotic agent
Not for use in acute alcohol intoxication, shock, or coma
Use of drug, particularly in patients at elevated risk of abuse, necessitates counseling about risks and proper use of drug along with monitoring for signs and symptoms of abuse, misuse, and addiction; do not exceed recommended dosing frequency
Avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (eg, opioid analgesics, stimulants); advise patients on proper disposal of unused drug; if a substance use disorder is suspected, evaluate patient and institute (or refer them for) early treatment, as appropriate
For patients treated more frequently than recommended, use a gradual taper to discontinue therapy (a patient-specific plan should be used to taper the dose), to reduce risk of withdrawal reactions
Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use
In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months
Do not inject by rapid bolus to neonates or for sedation
IV
- Associated with risk of potentially fatal respiratory depression and arrest
- Wait 2-3 min to evaluate sedation before repeating dose
- Monitor respiratory and cardiac function
- Have resuscitative drugs and equipment available; must monitor respiratory and cardiovascular status while administering the drug IV
Pregnancy & Lactation
Pregnancy
There are no adequate and well-controlled studies of midazolam intranasal in pregnant women
Available data suggest benzodiazepines are not associated with marked increases in risk for congenital anomalies
Clinical considerations
- Exposure to benzodiazepines during the second and third trimesters of pregnancy or immediately prior to or during childbirth may increase risk for decreased fetal movement and/or fetal heart rate variability, floppy infant syndrome, dependence, and withdrawal
- Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting
Pregnancy registry
- Encourage women prescribed midazolam intranasal during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or register at http://www.aedpregnancyregistry.org/
Animal studies
- Administration of midazolam to rats and rabbits during the period of organogenesis or to rats during late pregnancy and throughout lactation at doses greater than those used clinically did not result in any apparent adverse effects on development
- However, published data for benzodiazepines suggest potential of neuronal cell death and long-term effects on neurobehavioral and immunological function in animals following prenatal or early postnatal exposure at clinically relevant doses
Lactation
Midazolam is excreted in human milk
Studies assessing effects in the breastfed infant or on milk production/excretion have not been performed
Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines may experience lethargy, somnolence, and poor sucking
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Binds receptors at several sites within the CNS, including the limbic system and reticular formation; effects may be mediated through GABA receptor system; increase in neuronal membrane permeability to chloride ions enhances the inhibitory effects of GABA; the shift in chloride ions causes hyperpolarization (less excitability) and stabilization of the neuronal membrane
Absorption
Bioavailability: 36% (children); 40-50% (PO); >90% (IM)
Onset: 15-20 min (IM, PO); 3-5 min (IV)
Duration: 1-6 hr (IM)
Duration of anterograde amnesia: 1 hr (IM); 20-40 min (IV)
Peak plasma concentration: 90 ng/mL (IM)
Peak effect: 0.5 hr (IM)
Peak sedation: 30-60 min
Distribution
Protein bound: 97%
Vd: 1.0-3.1 L/kg
Metabolism
Metabolized by liver via CYP3A4
Metabolites: 1-hydroxymethylmidazolam
Elimination
Half-life: 2-6 hr
Total body clearance: 0.25-0.54 L/hr/kg
Excretion: Urine (90%); feces (2%)
Administration
IV Incompatibilities
Additive: Aminophylline(?), amoxicillin
Syringe: Dimenhydrinate, heparin, pentobarbital, perphenazine, prochlorperazine, ranitidine
Y-site: Albumin, amoxicillin, amphotericin B cholSO4, ampicillin, bumetanide, butorphanol, ceftazidime, cefuroxime, clonidine, dexamethasone, dobutamine(?), foscarnet, fosphenytoin, furosemide, hydrocortisone, imipenem-cilastatin, methotrexate, nafcillin, omeprazole, Na-bicarbonate, thiopental, TMP-SMX
IV Compatibilities
Solution: D5W, D5/NS, NS
Additive: Cefuroxime, cimetidine, ciprofloxacin, furosemide, gentamicin, hydrocortisone, hydromorphone, metronidazole, ranitidine
Syringe: Alfentanil, atracurium, atropine, buprenorphine, butorphanol, chlorpromazine, cimetidine, diamorphine, diphenhydramine, droperidol, fentanyl, glycopyrrolate, hydromorphone, hydroxyzine, meperidine, metoclopramide, morphine, nalbuphine, ondansetron, promazine, promethazine, scopolamine, sufentanil, thiethylperazine, trimethobenzamide
Y-site: Abciximab, amikacin, amiodarone, argatroban, atracurium, bivalirudin, Ca-gluconate, cefazolin, cefotaxime, cimetidine, ciprofloxacin, cisatracurium, clindamycin, digoxin, diltiazem, dopamine, epinephrine, erythromycin, esmolol, etomidate, famotidine, fenoldopam, fentanyl, fluconazole, gatifloxacin, gentamicin, haloperidol, heparin, hetastarch, hydromorphone, insulin, labetalol, linezolid, lorazepam, methadone, methylprednisolone, metronidazole, milrinone, morphine, nicardipine, nitroglycerin, norepinephrine, pancuronium, piperacillin, KCl, propofol, ranitidine, remifentanil, sodium nitroprusside, sufentanil, theophylline, tirofiban, tobramycin, vancomycin, vecuronium
IV Preparation
Solution: 100 mg in 250 mL D5W or NS
IV Administration
Administered via infusion pump
Give slowly over at least 2 min
And wait at least 2 min when adjusting doses to desired effect
Excessive dose or too rapid infusion may cause respiratory arrest
Have resuscitation equipment available and monitor patient closely until effects of IV administration are known
May dilute 1 mg/mL or 5 mg/mL in D5W or NS to facilitate slow injection
IVP: Administer through side port of free-flowing IV
Pediatric patients
- As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults
- Younger (age <6 yr) may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring
- Obese pediatric patients: Calculate dose based on ideal body weight
Neonates
- Do not administer by rapid injection; severe hypotension and seizures reported, particularly with concomitant fentanyl use
IV monitoring
- Monitor for irritation and infiltration
- Extravasation can cause tissue damage and necrosis
IM Administration
Deep into large muscle mass
Seizalam: For IM injection only; inject in mid-outer thigh (vastus lateralis muscle)
Storage
Unopened vials: Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
Images
Patient Handout
Formulary
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Adding plans allows you to:
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