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midazolam (Versed)

 

Classes: Antianxiety Agents; Anxiolytics, Benzodiazepines

Dosing and uses of Versed (midazolam)

 

Adult dosage forms and strengths

oral syrup: Schedule IV

  • 2mg/mL

injectable solution: Schedule IV

  • 1mg/mL
  • 5mg/mL

 

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

 

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

 

Status Epilepticus (Off-label)

Administer when convulsion >5 min or if convusions occur after having intermittent seizures without regaining consciousness for >5 mi

Administer 10 mg IM once or 0.2 mg/kg IM once; not to exceed 10 mg Im

 

Refractory Status Epilepticus (Off-label)

Alternatively, 0.2 mg/kg bolus followed by continuous infusion of 0.05-2 mg/kg/hr; titrate to cessation of electrographic seizures or burst of suppression; if breakthrough of status epilepticus occurs while on continuous infusion, administer bolus of 0.1-0.2 mg/kg and increase infusion rate by 0.05-0.1 mg/kg/hr (0.83-1.66 mcg/kg/min q3-4hr; may withdraw infusion after at least 24-48 hr of electrographic control; withdraw gradually to prevent recurrent status epilepticus

 

Status Epilepticus (Orphan)

Orphan designation for treatment of status epilepticus

Sponsor

  • Meridian Medical Technologies, Inc., A Pfizer Company; 6350 Stevens Forest Road; Columbia, Maryland 21046

 

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

 

Seizure Clusters (Orphan)

Rescue treatment of seizures in patients on stable AED regimens who require control of intermittent bouts of increased seizure activity (eg, acute repetitive seizures, seizure clusters)

Administered by intranasal route

Orphan indication sponsors

  • Upsher-Smith Laboratories, Inc. 6701 Evenstad Drive Maple Grove, MN 55369-6026
  • Schwarz Biosciences, Inc. 8010 Arco Corporate Drive Raleigh, NC 27617

 

Geriatric Dosing

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

  • 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

 

Pediatric dosage forms and strengths

syrup: Schedule IV

  • 2mg/mL

injectable solution: Schedule IV

  • 1mg/mL
  • 5mg/mL

 

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
  • 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

Continuous infusion: 0.5 mcg/kg/min IV infusion

 

Versed (midazolam) adverse (side) 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)

Respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, particularly when used with concomitant CNS depressants (eg, opioids), have been reported

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

 

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

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 and lactation

Pregnancy category: d

Lactation: Distributed in breast milk, use caution

Minor tranquilizers should be avoided in first trimester of pregnancy due to increased risk of congenital malformations

Maternal use shortly before delivery is associated with floppy infant syndrome (good and consistent evidence)

Prenatal benzodiazepine exposure was found to slightly increase oral cleft risk (limited or inconsistent evidence)

 

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 of Versed (midazolam)

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(?), floxacillin, 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/IM Administration

Im

  • Deep into large muscle mass

IV

  • 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

IV monitoring

  • Monitor for irritation and infiltration
  • Extravasation can cause tissue damage and necrosis