Use Caution/Monitor. midazolam and topiramate both increase sedation. Modify Therapy/Monitor Closely.tramadolMonitor Closely (1)midazolam and tramadol both increase sedation. Use Caution/Monitor.trazodoneMonitor Closely (1)midazolam and trazodone both increase sedation. Use Caution/Monitor.triazolamMonitor Closely (1)midazolam and triazolam both increase sedation. Use Caution/Monitor.triclofosMonitor Closely (1)midazolam and triclofos both increase sedation. Use Caution/Monitor.trifluoperazineMonitor Closely (1)midazolam and trifluoperazine both increase sedation. Use Caution/Monitor.trimipramineMonitor Closely (1)midazolam and trimipramine both increase sedation. Use Caution/Monitor.triprolidineMonitor Closely (1)triprolidine and midazolam both increase sedation. Use Caution/Monitor.trofinetideMonitor Closely (1)trofinetide will increase the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor CYP3A4 substrates for which a small increase in plasma concentration may lead to serious toxicities if coadministered with trofinetide (a weak CYP3A4 inhibitor).tucatinibSerious - Use Alternative (1)tucatinib will increase the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.turmericMonitor Closely (1)turmeric will increase the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.ustekinumabMonitor Closely (1)ustekinumab, midazolam. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, normalizing the formation of CYP450 enzymes. Upon initiation or discontinuation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.valerianSerious - Use Alternative (1)valerian and midazolam both increase sedation. Avoid or Use Alternate Drug.verapamilMonitor Closely (1)verapamil will increase the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.vinpocetineMinor (1)midazolam increases effects of vinpocetine by unspecified interaction mechanism. Minor/Significance Unknown. Desirable interaction enhanced memory improvement (based on preliminary trial).voriconazoleMonitor Closely (1)voriconazole will increase the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.voxelotorSerious - Use Alternative (1)voxelotor will increase the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.xylometazolineMonitor Closely (1)midazolam increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.yohimbineMonitor Closely (1)midazolam increases and yohimbine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.zafirlukastMonitor Closely (1)zafirlukast will increase the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.ziconotideMonitor Closely (1)midazolam and ziconotide both increase sedation. Use Caution/Monitor.ziprasidoneMonitor Closely (1)midazolam and ziprasidone both increase sedation. Use Caution/Monitor.zolpidemMinor (1)zolpidem, midazolam. Either increases effects of the other by pharmacodynamic synergism. Minor/Significance Unknown. Additive CNS depression.zotepineMonitor Closely (1)midazolam and zotepine both increase sedation. Use Caution/Monitor. >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 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 riskContraindications 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 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 suckingPregnancy 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. 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%) 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,