midazolam

Therapeutic Classification: antianxiety agents, anticonvulsants, sedative/hypnotics

Pharmacologic Classification: benzodiazepines

IM:

BEERS REMS, High Alert

PO: Preprocedural sedation and anxiolysis in pediatric patients.
IV: Preoperative sedation/anxiolysis/amnesia:
- Status epilepticus.
IV: Provides sedation/anxiolysis/amnesia during therapeutic, diagnostic, or radiographic procedures (conscious sedation).
- Aids in the induction of anesthesia and as part of balanced anesthesia.
- As a continuous infusion, provides sedation of mechanically ventilated patients during anesthesia or in a critical care setting.
Acute treatment of intermittent, stereotypic episodes of frequent seizure activity (e.g., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy.

Acts at many levels of the CNS to produce generalized CNS depression.
Effects may be mediated by GABA, an inhibitory neurotransmitter.

Therapeutic effects:

Short-term sedation.
Postoperative amnesia.
Termination of seizure activity.

Absorption: Rapidly absorbed following oral and nasal administration; undergoes substantial intestinal and first-pass hepatic metabolism. Well absorbed following IM administration; IV administration results in complete bioavailability.

Distribution: Crosses the blood-brain barrier.

Protein Binding: 97%.

Metabolism/Excretion: Almost exclusively metabolized by the liver by the CYP3A4 isoenzyme, resulting in conversion to hydroxymidazolam, an active metabolite, and 2 other inactive metabolites; metabolites are excreted in urine.

Half-Life: Preterm neonates: 2.6–17.7 hr; Neonates: 4–12 hr; Children: 3–7 hr; Adults: 2–6 hr (↑ in renal impairment, HF, or cirrhosis).

(sedation)

ROUTE	ONSET	PEAK	DURATION
IN	5 min	10 min	30–60 min
IM	15 min	30–60 min	2–6 hr
IV	1.5–5 min	rapid	2–6 hr

Contraindicated in:

Hypersensitivity;
Cross-sensitivity with other benzodiazepines may occur;
Shock;
Comatose patients or those with pre-existing CNS depression;
Uncontrolled severe pain;
Acute angle-closure glaucoma;
Pedi: Products containing benzyl alcohol should not be used in neonates.

Use Cautiously in:

All patients (may ↑ risk of suicidal thoughts/behaviors);
Pulmonary disease;
HF;
Renal impairment;
Severe hepatic impairment;
Open-angle glaucoma;
OB: Use late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, feeding difficulties) in neonates;
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
Pedi: Obese pediatric patients (calculate dose on the basis of ideal body weight);
Pedi: Rapid injection in neonates has caused severe hypotension and seizures, especially when used with fentanyl; may affect brain development in children <3 yr; safety and effectiveness of nasal spray has not been established in children <12 yr;
Geri: Appears on Beers list. ↑ risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults. If possible, avoid use in older adults.

CV: arrhythmias, CARDIAC ARREST

Derm: rash

EENT: blurred vision

GI: hiccups, nausea, vomiting

Local: phlebitis at IV site, pain at IM site

Neuro: agitation, drowsiness, excess sedation, headache, SUICIDAL THOUGHTS

Resp: APNEA, bronchospasm, cough, LARYNGOSPASM, RESPIRATORY DEPRESSION

Misc:

physical dependence

psychological dependence

, tolerance

Drug-drug:

Use with opioids or other CNS depressants, including other benzodiazepines, nonbenzodiazepine sedative/hypnotics, anxiolytics, general anesthetics, muscle relaxants, antipsychotics, and alcohol, may cause profound sedation, respiratory depression, coma, and death; reserve concurrent use for when alternative treatment options are inadequate.
↑risk of hypotension with antihypertensives, opioid analgesics, acute ingestion of alcohol, or nitrates.
Moderate CYP3A4 inhibitors and strong CYP3A4 inhibitors, including clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, and verapamil, may ↑ levels and risk of toxicity; avoid concurrent use.
Strong CYP3A4 inducers, including carbamazepine, phenobarbital, phenytoin, rifampin, and rifabutin, may ↓ levels and effectiveness.

Drug-Natural Products:

Kava-kava, valerian, or chamomile can ↑ risk of CNS depression.
Long-term use of St. John's wort may significantly ↓ levels and effectiveness.

Drug-Food:

Grapefruit juice may ↑ levels and risk of toxicity.

Preoperative Sedation/Anxiolysis/Amnesia

PO (Children 6 mo–16 yr): 0.25–0.5 mg/kg; may require up to 1 mg/kg (dose should not exceed 20 mg); Patients with cardiac/respiratory compromise or concurrent CNS depressants: 0.25 mg/kg.
IM (Adults <60 yr, otherwise healthy ): 0.07–0.08 mg/kg 1 hr before surgery (usual dose 5 mg).
IM (Adults ≥60 yr, debilitated, or chronically ill): 0.02–0.03 mg/kg 1 hr before surgery (usual dose 1–3 mg).
IM (Children ): 0.1–0.15 mg/kg up to 0.5 mg/kg 30–60 min prior to procedure; not to exceed 10 mg/dose.

Conscious Sedation for Short Procedures

IV (Adults and Children >12 yr and <60 yr, otherwise healthy): 1–2.5 mg initially; dosage may be ↑ further as needed. Total doses >5 mg are rarely needed (↓ dose by 50% if other CNS depressants are used). Maintenance doses of 25% of the dose required for initial sedation may be given as necessary.
IV (Children 6–12 yr): 0.025–0.05 mg/kg initially; then titrate dose carefully; may need up to 0.4 mg/kg total; maximum dose 10 mg.
IV (Children 6 mo–5 yr): 0.05 mg/kg initially; then titrate dose carefully; may need up to 0.6 mg/kg total; maximum dose 6 mg.
IV Geriatric Patients ≥60 yr, debilitated, or chronically ill): 1–1.5 mg initially; dose may be ↑ further as needed. Total doses >3.5 mg are rarely needed (↓ dose by 30% if other CNS depressants are used). Maintenance doses of 25% of the dose required for initial sedation may be given as necessary.
(Children ): 0.2–0.3 mg/kg, may repeat in 5–15 min.

Status Epilepticus

IM (Adults ): 10 mg single dose.
IV (Children >2 mo): 0.15 mg/kg load followed by a continuous infusion of 1 mcg/kg/min. Titrate dose upward every 5 min until seizure controlled, range: 1–18 mcg/kg/min.

Seizure Clusters

(Adults and Children ≥12 yr): One spray (5 mg) into one nostril initially; if inadequate response after 10 min, administer one spray (5 mg) into other nostril. Not to exceed 2 doses for a single seizure episode. Should not be used to treat more than one episode every 3 days and no more than 5 episodes per mo.

Induction of Anesthesia (Adjunct)

IV (Adults <55 yr, otherwise healthy): 300–350 mcg/kg initially (up to 600 mcg/kg total). May give additional dose of 25% of initial dose if needed. If patient is premedicated, initial dose should be further ↓.
IV Geriatric Patients >55 yr): 150–300 mcg/kg as initial dose. May give additional dose of 25% of initial dose if needed. If patient is premedicated, initial dose should be further ↓.
IV (Adults , debilitated): 150–250 mcg/kg initial dose. May give additional dose of 25% of initial dose if needed. If patient is premedicated, initial dose should be further ↓.

Sedation in Critical Care Settings

IV (Adults ): 0.01–0.05 mg/kg (0.5–4 mg in most adults) initially if a loading dose is required; may repeat every 10–15 min until desired effect is obtained; may be followed by infusion at 0.02–0.1 mg/kg/hr (1–7 mg/hr in most adults).
IV (Children ): Intubated patients only: 0.05–0.2 mg/kg initially as a loading dose; follow with infusion at 0.06–0.12 mg/kg/hr (1–2 mcg/kg/min); titrate to effect, range: 0.4–6 mcg/kg/min.
IV (Neonates >32 wk): Intubated patients only: 0.06 mg/kg/hr (1 mcg/kg/min).
IV (Neonates <32 wk): Intubated patients only: 0.03 mg/kg/hr (0.5 mcg/kg/min).

(Generic available)

Oral syrup cherry flavor: 2 mg/mL
Nasal spray (Nayzilam): 5 mg/0.1 mL single-dose unit
Premixed infusion: 100 mg/100 mL 0.8% NaCl; 50 mg/50 mL 0.9% NaCl; 100 mg/100 mL 0.9% NaCl
Solution for injection: 1 mg/mL; 5 mg/mL

Assess level of sedation and level of consciousness during and for 2–6 hr following administration.
Monitor BP, HR, and respiratory rate continuously during administration, especially if coadministering opioid analgesics. Oxygen and resuscitative equipment should be immediately available during IV administration.
Assess risk for addiction, abuse, or misuse before starting and periodically during therapy.
Prolonged high-dose therapy may lead to psychological or physical dependence. Restrict the amount of drug available to patient. Assess regularly for continued need for treatment.

Toxicity and Overdose:

If overdose occurs, monitor BP, HR, and respiratory rate continuously. Maintain patent airway and assist ventilation as needed. If hypotension occurs, treatment includes IV fluids, repositioning, and vasopressors.
- The effects of midazolam can be reversed with flumazenil.

High Alert: Accidental overdose of oral midazolam syrup in children has resulted in serious harm or death. Do not accept orders prescribed by volume (5 mL or 1 teaspoon); instead, request dose be expressed in milligrams. Have second practitioner independently check original order and dose calculations. Midazolam syrup should only be administered by health care providers authorized to administer conscious sedation.
Supervise ambulation and transfer of patients after administration. Two side rails should be raised and call bell within reach at all times.
Gradually taper to discontinue or ↓ dose to reduce risk of withdrawal reactions, seizure frequency, and status epilepticus. If a patient develops withdrawal reactions, consider pausing taper or ↑ dose to previous tapered dose level. Subsequently ↓ dose more slowly. Some patients may require longer tapering period (weeks to >12 mo).
PO: To use the Press-in Bottle Adaptor, remove the cap and push bottle adaptor into neck of bottle. Close bottle tightly with cap. Solution is a clear red to purplish-red cherry-flavored syrup. Then remove cap and insert tip of oral dispenser in bottle adaptor. Push the plunger completely down toward tip of oral dispenser and insert firmly into bottle adaptor. Turn entire unit (bottle and oral dispenser) upside down. Pull plunger out slowly until desired amount of medication is withdrawn into oral dispenser. Turn entire unit right side up and slowly remove oral dispenser from the bottle. Tip of dispenser may be covered with tip of cap until time of use. Close bottle with cap after each use.
- Dispense directly into mouth. Do not mix with any liquid prior to dispensing.
Administer 1 spray into one nostril. If no response to initial dose after 10 min, may administer 1 spray into other nostril.
IM: Administer IM doses deep into mid-outer thigh (vastus lateralis muscle), maximum concentration 1 mg/mL. Solution is clear, colorless to light yellow. Do not administer solutions that are discolored or contain particulate matter.

IV Administration:

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
IV Push: Diluent: Administer undiluted or diluted with D5W or 0.9% NaCl. Concentration: Undiluted: 1 mg/mL or 5 mg/mL. Diluted: 0.03–3 mg/mL.
Rate:
Administer slowly over at least 2–5 min. Titrate dose to patient response. Rapid injection, especially in neonates, has caused severe hypotension.
Continuous Infusion: Diluent: Dilute with 0.9% NaCl or D5W. Concentration: 0.5–1 mg/mL.
Rate: Based on patient's weight (see Route/Dosage section). Titrate to desired level of sedation. Assess sedation at regular intervals and adjust rate up or down by 25–50% as needed. Dose should also be ↓ by 10–25% every few hours to find minimum effective infusion rate, which prevents accumulation of midazolam and provides more rapid recovery upon termination.
Y-Site Compatibility:
- acetaminophen
- alemtuzumab
- alprostadil
- amikacin
- amiodarone
- anidulafungin
- argatroban
- arsenic trioxide
- atracurium
- atropine
- aztreonam
- benztropine
- bivalirudin
- bleomycin
- buprenorphine
- caffeine citrate
- calcium chloride
- calcium gluconate
- carboplatin
- carmustine
- caspofungin
- cefazolin
- cefiderocol
- cefotaxime
- cefoxitin
- ceftaroline
- ceftolozane/tazobactam
- ceftriaxone
- chlorpromazine
- ciprofloxacin
- cisatracurium
- cisplatin
- cyanocobalamin
- cyclophosphamide
- cyclosporine
- cytarabine
- dacarbazine
- dactinomycin
- daptomycin
- daunorubicin
- dexmedetomidine
- dexrazoxane
- digoxin
- diltiazem
- diphenhydramine
- docetaxel
- dopamine
- doxorubicin hydrochloride
- doxorubicin liposomal
- doxycycline
- enalaprilat
- ephedrine
- epinephrine
- epirubicin
- eptifibatide
- eravacycline
- erythromycin
- esmolol
- etomidate
- etoposide
- etoposide phosphate
- famotidine
- fentanyl
- fluconazole
- fludarabine
- folic acid
- gemcitabine
- gentamicin
- glycopyrrolate
- granisetron
- hetastarch
- hydromorphone
- idarubicin
- ifosfamide
- imipenem/cilastatin/relebactam
- irinotecan
- isavuconazonium
- isoproterenol
- ketamine
- labetalol
- LR
- leucovorin
- levofloxacin
- lidocaine
- linezolid
- lorazepam
- magnesium sulfate
- mannitol
- meperidine
- mesna
- methadone
- metoclopramide
- metoprolol
- metronidazole
- milrinone
- minocycline
- mitoxantrone
- morphine
- multivitamins
- mycophenolate
- nalbuphine
- naloxone
- nicardipine
- nitroglycerin
- nitroprusside
- norepinephrine
- octreotide
- ondansetron
- oritavancin
- oxacillin
- oxaliplatin
- oxytocin
- paclitaxel
- palonosetron
- pamidronate
- papaverine
- pemetrexed
- penicillin G
- pentamidine
- phentolamine
- phenylephrine
- phytonadione
- plazomicin
- potassium chloride
- potassium phosphates
- procainamide
- promethazine
- propranolol
- protamine
- pyridoxine
- remifentanil
- remimazolam
- rifampin
- rocuronium
- sildenafil
- succinylcholine
- sufentanil
- sulbactam/durlobactam
- tacrolimus
- tedizolid
- theophylline
- thiotepa
- tigecycline
- tirofiban
- tobramycin
- topotecan
- vancomycin
- vasopressin
- vecuronium
- verapamil
- vinblastine
- vincristine
- vinorelbine
- voriconazole
- zoledronic acid
Y-Site Incompatibility:
- acyclovir
- albumin, human
- aminocaproic acid
- aminophylline
- amphotericin B deoxycholate
- amphotericin B lipid complex
- amphotericin B liposomal
- ampicillin
- ampicillin/sulbactam
- ascorbic acid
- azathioprine
- azithromycin
- blinatumomab
- cefepime
- ceftazidime
- cefuroxime
- chloramphenicol
- dantrolene
- dexamethasone
- diazepam
- diazoxide
- epoetin alfa
- ertapenem
- esomeprazole
- fluorouracil
- foscarnet
- fosphenytoin
- ganciclovir
- gemtuzumab ozogamicin
- ibuprofen lysine
- indomethacin
- ketorolac
- letermovir
- meropenem
- meropenem/vaborbactam
- methotrexate
- micafungin
- mitomycin
- pentobarbital
- phenobarbital
- phenytoin
- piperacillin/tazobactam
- potassium acetate
- prochlorperazine
- sodium bicarbonate
- trimethoprim/sulfamethoxazole

Inform patient that this medication will ↓ mental recall of the procedure.
Advise patient to avoid grapefruit juice during therapy.
May cause drowsiness or dizziness. Advise patient to request assistance prior to ambulation and transfer and to avoid driving or other activities requiring alertness for 24 hr following administration.
Caution patient not to stop taking midazolam without consulting health care provider. Abrupt withdrawal may cause sweating, vomiting, muscle cramps, tremors, and seizures; may be life-threatening.
Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking any Rx, OTC, or herbal products, especially blood pressure medicine, antibiotics, and St. John's wort.
Advise patient that midazolam is a drug with known abuse potential. Protect it from theft, and never give to anyone other than the individual for whom it was prescribed. Store out of sight and reach of children, and in a location not accessible by others.
Advise patient to avoid the use of alcohol or other CNS depressants, including opioids, concurrently with midazolam; may cause respiratory depression and overdose. Instruct patient to consult health care provider before taking Rx, OTC, or herbal products concurrently with this medication.
Advise patient and family to notify health care provider if thoughts about suicide or dying, attempts to commit suicide, new or worse depression, new or worse anxiety, feeling very agitated or restless, panic attacks, trouble sleeping, new or worse irritability, acting aggressive, being angry or violent, acting on dangerous impulses, an extreme increase in activity and talking, other unusual changes in behavior or mood, or skin rash occur.
Rep: May cause fetal harm. Advise patient to notify health care provider if pregnancy is planned or suspected or if breastfeeding. Use in late pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, feeding difficulties) in the neonate. Monitor neonates exposed to midazolam during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam during pregnancy for signs of withdrawal. Monitor infants exposed to midazolam through breast milk for sedation, poor feeding, and poor weight gain. Encourage women who take midazolam during pregnancy to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org to monitor pregnancy outcomes in women exposed to antiepileptic drugs.
Nayzilam: Instruct individual administering Nayzilam on how to identify seizure clusters and use product appropriately. Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy and with each Rx refill. Discuss safe use, risks, and proper storage and disposal with patients and caregivers.

Sedation during and amnesia following surgical, diagnostic, and radiologic procedures.
Sedation and amnesia for mechanically ventilated patients in a critical care setting.
Termination of seizure activity.

Nayzilam, Seizalam, ~~Versed~~

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆ ⬇

Contr. Subst. Schedule ⬆