Midazolam (Dormicum) is a benzodiazepine drug that is used to treat patients with anxiety, insomnia, aggression, and as an anesthetic (before a procedure). It is also used in mechanically ventilated patients and for the acute treatment of seizures and status epilepticus.

Midazolam (Dormicum) Uses:

• Anesthesia:

  • Intravenous: As a part of balanced anaesthesia, it is advised for the induction of general anaesthesia as well as for maintaining  anaesthesia.

• Sedation, anxiolysis, and amnesia (preoperative/procedural):

  • IM:  It is used as a sedative before surgery, as an anxiolytic, and amnesia.
  • IV: As Sedative, anxiolytic, and for amnesia before or during endoscopic procedures or before surgery.
  • Oral: Before endoscopic procedures or the induction of anaesthesia, as a sedative, anxiolytic, and for amnesia in youngsters.

• Sedation for mechanically-ventilated patients:

  • IV: As a component of anesthesia in intubated patients or can be used as a continuous infusion in the critical care setting.

• Acute intermittent treatment of seizures:

  • Intranasal: It is prescribed for patients with epilepsy under the age of 12 who are experiencing acute treatment seizure clusters,  which are acute repeated seizures that differ from typical seizure patterns.

• Off Label Use of Midazolam in Adults:

  • Status epilepticus
  • Refractory Status epilepticus
  • Palliative sedation

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Midazolam Dose in Adults:

Note: Individualised doses according to age, underlying diseases, and concurrent medications should be given. Reduce the dose by 20% - 50% in elderly, chronically ill, or debilitated patients and patient who is using opioids or other CNS depressants

Midazolam (Dormicum) Dose as an anesthetic: IV:

• Induction: Adults <55 years of age:

  • Unpremeditated patients: I
    • Initial dose: 0.3 - 0.35 mg/kg over 20 - 30 seconds
    • In resistant situations, the dose may be repeated after 2 minutes and thereafter as needed at a rate of 25% of the  initial dose (every 2 minutes), up to a maximum total dose of 0.6 mg/kg.
  • Premedicated patients:

    • The typical dose range is 0.05 to 0.2 mg/kg. For patients with ASA physical status P1 and P2, the use of 0.2 mg/kg  delivered over 5 to 10 seconds has been demonstrated to safely generate anaesthesia within 30 seconds.

    • The dosage is 0.1 mg/kg when combined with other anaesthetic medications (coinduction).

      • ASA physical status >P3 or debilitation: Reduce dose by at least 20%.
  • Maintenance: .05 mg/kg as needed, or continuous infusion 0.015 to 0.06 mg/kg/hour (0.25 - 1 mcg/kg/minute).

Midazolam (Dormicum) Dose in the Palliative sedation (off-label):

Note: A skilled palliative care professional should be consulted closely before using midazolam for this purpose. Make sure flumazenil is accessible in case  of an accidental overdose.

• 4. SubQ: perpetual infusion: Initial: 0.5 to 1 mg/hour; may be increased based on need.

• Usual dosing range: 1 to 20 mg/hour; additional intermittent 1 to 5 mg throughout infusion may be given as needed.

• Some experts advise starting with a bolus dose of 5 to 10 milligrammes (size of dose depending on patient weight, age, and degree of debility).

Midazolam (Dormicum) Dose for  procedural or pre-operative sedation, anxiolysis, and amnesia:

• Healthy adults <60 years of age:

  • 15 minutes prior to surgery or a procedure, administer 0.1 mg/kg of an intranasal (solution, injection) medication.

Note: Give the dose using an injectable solution containing 5 mg/mL.

• IM: 0.07 - 0.08 mg/kg, 30 - 60 minutes before the surgery/procedure; usual dose: 5 mg.
• IV: Initial: 0.5 - 2 mg over at least 2 minutes; titrate and repeating dose every 2 - 3 minutes if required; usual total dose: 2.5 - 5 mg
• Authenticator's labelling: Current clinical practise might not be reflected in the dosing in the prescribed information.
  • Initial: Some patients respond to doses as low as 1 mg; no more than 2.5 mg should be administered over a period of at least 2 minutes. A total dose >5 mg is generally not needed.
    • Premedicated patients: Reduce initial dose by 30%.
    • Maintenance: 25% of dose used to reach sedative effect.
• Adults ≥60 years of age, debilitated, or chronically ill:
  • Refer to geriatric dosing.

Midazolam (Dormicum) Dose for Sedation in mechanically ventilated ICU patients:

Note: Nonbenzodiazepine sedation may be preferred.

• IV: Initial: 0.01 - 0.05 mg/kg (~0.5 - 4 mg); may repeat at 10 - 15 minute intervals until adequate sedation achieved; maintenance infusion: 0.02 - 0.1 mg/kg/hour (0.3 - 1.7 mcg/kg/minute).
• To maintain light rather than deep sedation, titrate to the desired level of sedation.
• Consider testing daily awakening; if you become agitated after stopping the drip, start it again at 50% of the previous dose.

Midazolam (Dormicum) Dose in the acute intermittent treatment of Seizures:

• Intranasal (nasal spray): Depending on reaction and tolerance, a repeat dose of 5 mg (one spray) in a different nostril after 10 minutes may be  given  (do not repeat if the patient is having trouble breathing or excessive sedation).
• Maximum dose: 10 mg (2 sprays) per single episode.
• Maximum treatment frequency: Treatment of 5 episodes in a month, at a rate of 1 episode every 3 days.

Midazolam (Dormicum) Dose in the treatment of Status epilepticus (off-label):

• IM: 10 mg once or 0.2 mg/kg once (maximum dose: 10 mg).
  • IM is the preferred without IV access.
  • Although the buccal and intranasal routes have also been employed, they are off-label and have received less research.
  • Prehospital status epilepticus: IM: Paramedics use 10 mg once if intermittent convulsions linger more  than five minutes or if the patient  is not regaining consciousness.
• Intranasal (solution, injection): 0.2 mg/kg
  • Note: Use 5 mg/mL injectable concentrated solution to deliver the dose.
• Buccal: 0.5 mg/kg.

Midazolam (Dormicum) Dose in the treatment of refractory Status epilepticus (off-label): IV:

Note: It is necessary to use mechanical breathing and cardiovascular monitoring; titrate the dose until electrographic seizures or burst suppression stop.

• Neurocritical Care Society recommendations:

  • Loading dose: 0.2 mg/kg
  • Continuous infusion: 0.05 - 2 mg/kg/hour (0.83 - 33.2 mcg/kg/minute)
    • If status epilepticus refractory emerges while receiving the continuous infusion,
      • Bolus of 0.1 - 0.2 mg/kg can be given
      • Increase rate by 0.05 - 0.1 mg/kg/hour (0.83 - 1.66 mcg/kg/minute) every 3 - 4 hours
      • Doses up to 2.9 mg/kg/hour has been studied

Note: To avoid a repeat, remove the continuous infusion gradually while continuing electrographic control for at least 24 to 48 hours.

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Midazolam (Dormicum) Dose in Children:

• Individualized dosage must take the patient's age, underlying conditions, current drugs, and desired effect into consideration.
• If opioids or other CNS depressants are also being provided, reduce the dose (by 30%).
• Allow 3 to 5 minutes between doses to reduce the risk of oversedation. Use a number of tiny doses and titrate to the desired sedative effect.
• The parenteral solution for injection can be used for lesser intranasal dosages; the nasal spray formulation gives a set dose of 5 mg and shouldn't be used universally for all paediatric patients.
• Ensure you are using the right product selection and administration method.

Midazolam (Dormicum) Dose for Sedation, anxiolysis, and amnesia prior to a procedure or before induction of anesthesia:

IM:

• Infants, Children, and Adolescents:

  • Usual: 0.1 - 0.15 mg/kg 30 - 60 minutes before surgery or procedure(range: 0.05 - 0.15 mg/kg)
  • Doses up to 0.5 mg/kg have been used in more anxious patients;
  • Maximum total dose: 10 mg.

IV:

• Infants 1 to 5 months: 

  • Limited data available in non-intubated infants; infants <6 months are at higher risk for airway obstruction and hypoventilation
  • Monitor carefully.

• Infants 6 months to Children 5 years:

  • Initial: 0.05 - 0.1 mg/kg; titrate dose carefully; total dose of 0.6 mg/kg may be required; usual total dose maximum: 6 mg.

• Children 6 to 12 years:

  • Initial: 0.025 - 0.05 mg/kg; titrate dose carefully; total doses of 0.4 mg/kg may be required; usual total dose maximum: 10 mg.

• Children 12 to 16 years:

  • Dose as adults; usual total dose maximum: 10 mg.

Intranasal (parenteral solution for injection product): Limited data available:

Note: To lessen discomfort and ensuing agitation, some researchers advise premedication with intranasal lidocaine.

• Infants 1 to 5 months:

  • 2 mg/kg (single dose).

• Infants ≥6 months, Children, and Adolescents:

  • 0.2 - 0.3 mg/kg (maximum single dose: 10 mg)
  • Can be repeated in 5 -15 minutes to a maximum of 0.5 mg/kg (maximum total dose: 10 mg).

Oral:

• Infants >6 months, Children, and Adolescents <16 years:

  • Single-dose:
    • 0.25 - 0.5 mg/kg once, according to patient condition and desired effect,
    • Usual: 0.5 mg/kg
    • Maximum dose: 20 mg

Note: While lower initial doses (0.25 mg/kg) can be used in older patients (6 to 16 years old), patients with cardiac or respiratory compromise, concomitant  CNS depressant, or high-risk surgical patients, higher doses (up to 1 mg/kg) may be needed in younger patients (6 months to 6 years old) and those  who are less cooperative.

Rectal: Limited data available:

• Infants >6 months and Children:

  • Usual: 0.25 - 0.5 mg/kg once
  • Infants and young children (7 months to 5 years of age) have received doses up to 1 mg/kg, but this may be linked to a higher  incidence of postoperative agitation.

Midazolam (Dormicum) Dose for Sedation in mechanically ventilated patient:

• Infants, Children, and Adolescents: IV:

  • Loading dose:
    • 0.05 - 0.2 mg/kg given slow IV over 2 - 3 minutes, then followed by
  • Continuous IV infusion:
    • 0.06 - 0.12 mg/kg/hour (1 - 2 mcg/kg/minute);
    • Titrate to the desired effect; range: 0.024 - 0.36 mg/kg/hour (0.4 - 6 mcg/kg/minute).

Midazolam (Dormicum) Dose in the acute treatment of Seizures:

Buccal: Limited data available: Reserve for patients without IV access

• Weight-based dosing:

  • Infants ≥3 months, Children, and Adolescents:
    • 0.2 - 0.5 mg/kg once;
    • The maximum dose: 10 mg/dose.

• Age-based dosing:

  • Infants 6 - 11 months: 5 mg.
  • Children 1 - 4 years: 5 mg.
  • Children 5 - 9 years: 5 mg.
  • Children and Adolescents ≥10 years: 10 mg.

IM: Limited data available:

• Infants, Children, and Adolescents:

  • 2 mg/kg/dose; repeat every 10 - 15 minutes
  • Maximum dose: 6 mg/dose.

Intranasal:

• Children ≥12 years and Adolescents: Nasal spray (Nayzilam):

  • One spray of 5 mg can be administered into one nostril; depending on the response and tolerance, the dose may be repeated in 10 minutes in the other nostril.
  • If the patient has trouble breathing or is sedated excessively, avoid repeating the dose;
  • 10 mg/dose maximum each episode (2 sprays)
  • One episode every three days and a maximum of five episodes per month constitute the maximum treatment frequency.
• Parenteral solution for injection product: Limited data available;
  • Reserve for patients without IV access; divide dose between nares:
  • Infants 1 - 5 months: 2 mg/kg once; maximum dose: 10 mg/dose.
  • Infants and Children ≥6 months: 2 mg/kg; maximum dose: 10 mg/dose; can be repeated once to a total maximum of 0.4 mg/kg.

Midazolam (Dormicum) Dose in the treatment of Status epilepticus:

• Standard treatment:

  • Infants, Children, and Adolescents: Limited data available:

  • IM:
    • Weight-based dosing: 2 mg/kg once; maximum dose: 10 mg/dose
    • Fixed dosing:
    • 13 - 40 kg: 5 mg once.
    • >40 kg: 10 mg once.
  • Intranasal: 0.2 mg/kg once; maximum dose: 10 mg/dose
  • Buccal: 0.5 mg/kg once; maximum dose: 10 mg/dose

• Refractory to standard treatment:

Note: Requires mechanical breathing and cardiac monitoring; dose should be adjusted to stop electrographic seizures or suppress bursts.

• Infants, Children, and Adolescents: Limited data available:

  • Loading dose:
    • IV: 0.2 mg/kg followed by a continuous infusion.
  • Continuous IV infusion: 
    • 0.05 - 2 mg/kg/hour (0.83 to 33.3 mcg/kg/minute) titrated to cessation of electrographic seizures or burst suppression.
    • In case of breakthrough status epilepticus while on the continuous infusion, give a bolus of 0.1 - 0.2 mg/kg and increase infusion rate by 0.05 - 0.1 mg/kg/hour (0.83 - 1.66 mcg/kg/minute) every 3 - 4 hours.

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Midazolam (Dormicum) Pregnancy Risk Category: D

• Midazolam crosses the placental barrier
• Midazolam, a benzodiazepine, has some teratogenic properties. Further studies are needed
• Pregnancy can be a time of low birth weight and premature birth due to benzodiazepine use. 
• Neonatal hypoglycemia can lead to respiratory problems and hypoglycemia. Reports of neonatal withdrawal symptoms, including floppy infant syndrome, have been made
• If the expected duration of surgery will exceed 3 hours, the benefit-versus-risk strategy for midazolam exposure should be used
• Although midazolam has been used in obstetrical anesthesia, the manufacturer doesn't recommend it.
• ACOG guidelines in emergency procedures for pregnant women state that midazolam should be administered after delivery.

Use of midazolam while breastfeeding

• Breast milk contains midazolam.
• Midazolam's relative infant dose (RID), is 0.35%. Breastfeeding is fine if the RID of the medication is less than 10%
• Most reports indicate that midazolam or its metabolites found in breast milk fall below the limit for quantification after one dose.
• One study however shows that CNS depression can occur after breastfeeding benzodiazepines.
• It is recommended that it be used with caution by breastfeeding mothers.
• Guidelines recommend breastfeeding infants after consuming >=4 hours' maternal doses of midazolam.
• This is even if the baby was given pre-procedural sedates
• The Academy of Breast-Feeding Medicine suggests delaying elective surgery until breastfeeding and milk supply are established.
• When possible, it is best to express milk before any surgery.
• Breastfeeding can generally be resumed for healthy, full-term infants, provided the mother is awake and in recovery. 
• Infants at higher risk for hypotension, apnea or hypotonia can save their milk to be used later if they are in better health.
• If the mother is alert and stable, small supplemental doses should not be used to stop breastfeeding.

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Midazolam (Dormicum) Dose in Kidney Disease:

The manufacturer has not provided any dose adjustment in labeling; use cautiously. In renal failure, the drug's half-life is extended. Patients with  renal impairment  may need to wait days to receive a continuous infusion that cannot sufficiently remove the active hydroxylated metabolites.

• Intermittent hemodialysis: Supplemental dose is not necessary.
• Continuous venovenous hemofiltration:
  • Effectively not removed: Unconjugated 1-hydroxymidazolam
  • Effectively removed: 1-hydroxymidazolamglucuronide effectively removed
  • sieving coefficient = 0.45
• Peritoneal dialysis: There is no Significant drug removal based on physiochemical characteristics.
• Intranasal (nasal spray):
  • Mild impairment: No dose adjustment required
  • Moderate impairment: Manufacturer has not provided any dose adjustment in labeling; use cautiously
  • Severe impairment: Manufacturer has not provided any dose adjustment; use cautiously

Midazolam (Dormicum) Dose in Liver disease:

The manufacturer has not provided any dose adjustment in labeling; use cautiously.

• IV:
  • Single-dose (eg, induction): No dosage adjustment required; there may be a longer duration of action.
  • Multiple dosing or continuous infusion: There may be a longer duration of action and accumulation; dose reduction may be required

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Common Side Effects of Midazolam (Dormicum):

• Respiratory:

  • Bradypnea
  • Decreased tidal volume

Less Common Side Effects of Midazolam (Dormicum):

• Cardiovascular:

  • Hypotension

• Central Nervous System:

  • Myoclonus
  • Headache
  • Drug Dependence
  • Severe Sedation
  • Seizure-Like Activity
  • Drowsiness

• Gastrointestinal:

  • Hiccups
  • Nausea
  • Vomiting

• Local:

  • Injection Site Reaction
  • Pain At Injection Site

• Ophthalmic:

  • Nystagmus

• Respiratory:

  • Apnea
  • Cough

• Miscellaneous:

  • Paradoxical Reaction

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Contraindications to Midazolam (Dormicum):

Oral injection:

• Hypersensitivity
• injecting parenteral substances with preservatives intrathecally or epidurally, such as benzyl alcohol.
• Infants born prematurely who can take benzyl alcohol via parenteral routes acute narrow-angle vision due to glaucoma
• Oral midazolam combined with protease inhibitors (nelfinavir, ritonavir, saquinavir, saquinavir, tiranavir, atazanavir, cobicistat, and lopinavir)
• Combined use of oral or injectable midazolam with fosamprenavir

Intranasal

• Hypersensitivity
• Glaucoma with acute narrow-angle vision

Canadian labeling: Additional contraindications not in US labeling

• Hypersensitivity to benzodiazepines
• Acute pulmonary insufficiency
• Severe COPD

Although there is not much evidence to support benzodiazepine-benzodiazepine crossover reaction, it can be inferred from similarities in the mechanisms of action and structures.

Warnings and precautions

• Anterograde amnesia

  • Anterograde amnesia has been linked to benzodiazepines.

• Cardiorespiratory effects [US Boxed Warning]

  • Use of it can cause respiratory depression or arrest, which can lead to airway obstruction, desaturation and hypoxia. 
  • Patients with severe pulmonary disease, abnormal airway anatomy, sepsis or cyanotic congenital hearts disease are at greater risk.
  • It should only be used in areas where monitoring of cardiac and respiratory function is possible (e.g pulse oximetry).
  • Staff should be trained in intubation, bag-mask ventilation, and airway management.
  • Patients at high risk for respiratory depression should be given the first dose intranasal midazolam.

• Depression in the CNS:

  • It can cause CNS depression, and it can impair mental or physical abilities.
  • Patients should be warned about its use. Between the last dose of the medication and the return to normal activities, there should be at most one day.
  • As this effect is dose dependent, it is important to be cautious with dosage and route of administration.

• Hypotension

  • Use of it may cause hypotension in children and hemodynamic instability.

• Paradoxical reactions

  • Paradoxically, aggressive behavior hyperactivity, or aggressive behavior, may be present in adolescent/pediatric or geriatric patients.

• Suicidal thoughts:

  • Intranasal. A pooled analysis comparing antiepileptics with different indications showed an increase in suicidal thoughts/behavior.
  • The incidence rate was 0.43% for patients who were treated versus 0.24% for patients who received placebo.
  • This risk was evident as soon as the trial began and continued throughout the duration of the trials (most trials took less than 24 weeks).
  • Watch out for any changes in behavior or thoughts that could indicate depression or suicidal thoughts. Notify your health care provider immediately if you notice these symptoms.

• Acute illness:

  • Intracavenous midazolam should be used with caution in acute, uncompensated conditions such as severe fluid and electrolyte disturbances.

• Cardiovascular disease

  • In the event of heart failure, be cautious
  • Hemodynamic instability in pediatric patients can result from intravenous drug use. It is best to avoid rapid intravenous administration.

• Glaucoma

  • Glaucoma: Use caution; contraindicated for acute narrow-angle or severe glaucoma. Open-angle glaucoma can be used if appropriate therapy is being administered.

• Renal impairment

  • Avoid renal impairment. Its half-life may be extended

• Respiratory disease

  • Avoid use in the case of respiratory disease, e.g. Chronic obstructive lung disease
  • Midazolam can cause respiratory depression. Patients who are sensitive to this effect may be at risk.

Midazolam: Drug Interaction

Risk Factor C (Monitor therapy)
Alcohol (Ethyl)	Alcohol's CNS depressing effect may be amplified by CNS depressants (Ethyl).
Alizapride	CNS depressants may have an enhanced CNS depressant impact.
Aprepitant	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
AtorvaSTATin	May increase the serum concentration of Midazolam.
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Brexanolone	CNS Depressants may enhance the CNS depressant effect of Brexanolone.
Brimonidine (Topical)	May enhance the CNS depressant effect of CNS Depressants.
Bromopride	May enhance the CNS depressant effect of CNS Depressants.
Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Cannabis	May enhance the CNS depressant effect of CNS Depressants.
Chlorphenesin Carbamate	May enhance the adverse/toxic effect of CNS Depressants.
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CNS Depressants	May enhance the adverse/toxic effect of other CNS Depressants.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Dimethindene (Topical)	CNS depressants may have an enhanced CNS depressant impact.
Doxylamine	CNS depressants may have an enhanced CNS depressant impact. Management:  The  producer of the pregnancy-safe drug Diclegis (doxylamine/pyridoxine)  particularly advises  against combining it with other CNS depressants.
Dronabinol	CNS depressants may have an enhanced CNS depressant impact.
Duvelisib	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Elagolix	Midazolam serum concentration can drop.
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Esketamine	CNS depressants may have an enhanced CNS depressant impact.
Fosaprepitant	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Fosnetupitant	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Ginkgo Biloba	Midazolam serum concentration can drop.
HydrOXYzine	CNS depressants may have an enhanced CNS depressant impact.
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Kava Kava	CNS depressants may have an enhanced CNS depressant impact.
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Lofexidine	May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Magnesium Sulfate	CNS depressants may have an enhanced CNS depressant impact.
Melatonin	May enhance the sedative effect of Benzodiazepines.
MetyroSINE	CNS Depressants may enhance the sedative effect of MetyroSINE.
Minocycline (Systemic)	CNS depressants may have an enhanced CNS depressant impact.
Nabilone	CNS depressants may have an enhanced CNS depressant impact.
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Piribedil	CNS depressants may have an enhanced CNS depressant impact.
Pramipexole	CNS depressants may have an enhanced CNS depressant impact.
Propofol	Propofol's serum levels may rise in the presence of midazolam.  Midazolam's serum levels could rise as a result of propofol.
ROPINIRole	CNS depressants may have an enhanced CNS depressant impact.
Rotigotine	CNS depressants may have an enhanced CNS depressant impact.
Roxithromycin	Midazolam serum levels can rise.
Rufinamide	CNS depressants' harmful or toxic effects could be increased. Particularly,  drowsiness and lightheadedness could be worsened.
Sarilumab	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Selective Serotonin Reuptake Inhibitors	Selective serotonin reuptake inhibitors may have a worsened or more  hazardous effect when taken with CNS depressants. Particularly,  there may be an increased risk of psychomotor impairment.
Siltuximab	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Simeprevir	Midazolam serum levels can rise.
Tecovirimat	Midazolam serum concentration can drop.
Teduglutide	Benzodiazepines' serum concentration may rise.
Tetrahydrocannabinol	CNS depressants may have an enhanced CNS depressant impact.
Tetrahydrocannabinol and Cannabidiol	CNS depressants may have an enhanced CNS depressant impact.
Tocilizumab	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Tofisopam	Midazolam serum concentration can drop.
Trimeprazine	CNS depressants may have an enhanced CNS depressant impact.
Yohimbine	May lessen the therapeutic impact of anxiety medications.
Risk Factor D (Consider therapy modification)
Blonanserin	Blonanserin's CNS depressing effects may be enhanced by other CNS depressants.
Buprenorphine	The CNS depressant effect of buprenorphine may be enhanced by CNS depressants.  Treatment: If a patient has a high risk of abusing or injecting themselves with buprenorphine,  consider reducing the doses of other CNS depressants and avoiding such medications.  Buprenorphine should be started at lower doses in patients who are already taking CNS  depressants.
Chlormethiazole	CNS depressants may have an enhanced CNS depressant impact. Management: Keep a  close eye out for signs of severe CNS depression. If such a combination  is required,  it should be taken at a dose that has been suitably  lowered, according  to the instructions  for chlormethiazole.
CloZAPine	Benzodiazepines may intensify CloZAPine's harmful or toxic effects. Prior to starting  clozapine, consider lowering the dose of benzodiazepines  or even stopping them  altogether.
CYP3A4 Inducers (Strong)	May speed up CYP3A4 substrate metabolism (High risk with Inducers).  Management: Take into account a substitute for one of the interfering medications.  Specific contraindications may apply to some combinations.
CYP3A4 Inhibitors (Strong)	May slow down CYP3A4 substrate metabolism (High risk with Inhibitors).
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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).
Droperidol	CNS depressants may have an enhanced CNS depressant impact. Consider lowering the  dosage of droperidol or other CNS agents (such as opioids or barbiturates) when they are used  concurrently. In separate drug interaction monographs, exceptions to this monograph  are covered in more detail.
Enzalutamide	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Treatment: Enzalutamide should  not be used concurrently with CYP3A4 substrates that have a limited therapeutic index. Enzalutamide use,  like with the use of any other CYP3A4 substrate, should be done cautiously and under close observation.
Flunitrazepam	Flunitrazepam's CNS depressing effects may be enhanced by other CNS depressants.
HYDROcodone	The CNS depressive action of HYDROcodone may be enhanced by CNS depressants. Management:  Whenever  feasible, refrain from using hydrocodone and benzodiazepines or other CNS depressants  concurrently. Only in the event that other treatment choices are insufficient should these medications  be combined. Limit the duration and dosage of each medicine when used together.
Lemborexant	CNS depressants may have an enhanced CNS depressant impact. Management: Due to the  possibility of additive CNS depressant effects when lemborexant  and concurrent CNS depressants  are administered concurrently, dosage modifications may be required. Effects of CNS depressants  must be closely monitored.
Lorlatinib	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: Avoid taking  lorlatinib at the same time as any CYP3A4 substrates for which even a small drop in serum levels of the  substrate could result in therapeutic failure and negative clinical outcomes.
Macrolide Antibiotics	Midazolam serum levels can rise. Management: Take into account a less likely to interact option.  Azithromycin is most likely a lower-risk macrolide, while benzodiazepines (such as lorazepam and  oxazepam) that are less  dependent on CYP3A metabolism are also less likely to interact. Azithromycin  (Systemic), Fidaxomicin, Roxithromycin, and Spiramycin are exceptions.
Methadone	The CNS depressive effect of methadone may be strengthened by benzodiazepines. Management: When  at all  possible, clinicians should refrain from combining the use of benzodiazepines with methadone;  nonetheless, any combination should be used with extreme caution.
Methotrimeprazine	The CNS depressing action of methotrimeprazine may be enhanced by CNS depressants. The CNS  depressant  action of CNS Depressants may be strengthened by methotrimeprazine. Management: Start  concurrent methotrimeprazine therapy while reducing the adult dose of CNS depressants by 50%. Only  once a clinically effective dose of methotrimeprazine has been established should  additional  CNS  depressant dosage modifications be made.
MiFEPRIStone	May speed up CYP3A4 substrate metabolism (High risk with Inducers). Management: Take into account  a substitute for one of the interfering medications. Specific contraindications  may apply to some  combinations.  Fentanyl, pimozide, quinidine, sirolimus, and tacrolimus should  all be avoided.  Cyclosporine should  also be avoided.
Mitotane	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Treatment: When  administered in individuals receiving mitotane, doses of CYP3A4 substrates may need to be  significantly modified.
Opioid Agonists	Opioid agonists' CNS depressing effects may be amplified by CNS depressants. Management: When at   all  possible, refrain from using benzodiazepines or other CNS depressants  concurrently with opioid agonists.  Only in the event that other treatment choices are insufficient should  these medications be combined.  Limit the duration and dosage of each medicine when used together.
OxyCODONE	The CNS depressing effects of OxyCODONE may be enhanced by CNS depressants. Management:  Whenever feasible, refrain from using oxycodone and benzodiazepines  or other CNS depressants  concurrently. Only in the event that other treatment choices are insufficient should these  medications  be combined. Limit the duration and dosage of each medicine when used together.
Perampanel	CNS depressants may have an enhanced CNS depressant impact. Treatment: Until they have  experience using the combination, patients taking perampanel  along with any other medication  that has  CNS depressive effects should avoid complex and high-risk activities, especially those  like driving  that call for awareness and coordination.
Stiripentol	May speed up CYP3A4 substrate metabolism (High risk with Inducers). Management: Take into  account a substitute for one of the interfering medications. Specific contraindications may apply to some combinations.
Tapentadol	CNS depressants may have an enhanced CNS depressant impact. Treatment: When feasible, refrain  from using tapentadol and benzodiazepines or other CNS depressants simultaneously. Only in the  event that other treatment choices are insufficient should these medications be combined. Limit the  duration and dosage of each medicine when used together.
Theophylline Derivatives	May reduce benzodiazepine's therapeutic impact.
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.
Risk Factor X (Avoid combination)
Antihepaciviral Combination Products	Midazolam serum levels can rise. Treatment: The use of oral midazolam in combination  with antihepatitis  medicines is not advised. Monitor for increased midazolam effects (e.g., sedation, respiratory depression)  when  taken with intravenous midazolam and think about using a lower midazolam dose.
Azelastine (Nasal)	Azelastine's CNS depressing impact may be amplified by CNS depressants (Nasal).
Bromperidol	CNS depressants may have an enhanced CNS depressant impact.
Cobicistat	Midazolam serum levels can rise. Treatment: Consuming oral midazolam while using medicines  containing cobicistat is not advised. Use of IV midazolam requires care, close supervision, and  consideration of lower IV midazolam dosages.
Conivaptan	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Itraconazole	Midazolam serum levels can rise. Treatment: Consuming oral midazolam while using medicines  containing cobicistat is not advised. Use of IV midazolam requires care, close supervision, and  consideration of lower IV midazolam dosages.
Ketoconazole (Systemic)	Midazolam serum levels can rise.
OLANZapine	May intensify the harmful or negative effects of benzodiazepines. Due to the possibility  of cumulative  negative side effects, avoid using parenteral benzodiazepines  and intramuscular olanzapine concurrently  (e.g., cardiorespiratory depression). There are no particular instructions for oral administration in the  prescribing information for olanzapine.
Orphenadrine	The CNS depressing action of orphenadrine may be enhanced by CNS depressants.
Oxomemazine	CNS depressants may have an enhanced CNS depressant impact.
Paraldehyde	The CNS depressing action of orphenadrine may be enhanced by CNS depressants.
Protease Inhibitors	Midazolam serum levels can rise. Treatment: Consuming oral midazolam while using medicines  containing cobicistat is not advised. Use of IV midazolam requires care, close supervision, and  consideration of lower IV midazolam dosages.
Sodium Oxybate	The CNS depressive effects of Benzodiazepines and Sodium Oxybate may be enhanced.
Thalidomide	CNS Depressants may enhance the CNS depressant effect of Thalidomide.

 

Monitoring parameters:

• Blood pressure
• Respiratory rate
• Oxygen saturation.
• Heart rate
• Level of sedation

Critically ill patients: Assess and adjust sedation according to the scoring system

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How to administer Midazolam (Dormicum)?

Buccal:

• It is not available in the USA. 
• Use an oral syringe to apply between the gums, cheeks, and cheeks; massage the cheek gently; the dose can be divided to both the sides of the mouth.

Intranasal

• Spray on the Nasal:
  • Do not prime before using
  • Only one dose should be administered at a given time.
  • If you need to administer a second dose, do so at an alternate nostril. 
  • Avoid a second dose if you have trouble breathing or are experiencing excessive sedation.

Solution, injection (off label route):

• Low PH may cause burning sensations in the patient.
• An atomizer attaches to a tuberculin needle and can be used to reduce irritation. 
• To minimize the amount of injections that are administered intramuscularly, it is advisable to use a higher dose injectable solution. 
• A smaller volume will result in less irritation and easier swallowing.
• The 1 mL maximum dosage volume is advised for the 5 mg/mL concentration per nare.

Use the 5 mg/mL injection solutionYou can draw the desired dose using a syringe that does not require a needle. It can also be attached to a nasal mucosal-atomization device. 

After dividing the total doses, equalize dose in each nostril.

• Oral:
  • Mix with no liquids and don't give empty stomach
• Parenteral 
  • Do not inject intraarterially
• IM:
  • Apply deep IM undiluted to a sizable muscle.
• Intravenous

  • For procedural sedation, anxiolysis, and forgetfulness, use a slow IV infusion. Use a concentration of 1 mg/mL or a dilution using a concentration of 1 or 5 mg/mL.

  • The bolus for inducing anaesthesia lasts longer than 5 to 15 seconds.

  • Epilepticus refractory: 2 mg/minute loading dose infusion rate

  • For other clinical scenarios, such as sedation in mechanically ventilated patients, a continuous infusion is an option.

Rectal:

• Apply a solution with a 1 to 5 mg/mL concentration using a rectally inserted catheter or tube. Close your buttocks for around five minutes.

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Mechanism of action of Midazolam (Dormicum):

• Midazolam is able to bind to GABA neurons in the central nervous system. 
• It increases neuronal excitability inhibition by GABA and causes increased membrane permeability to chloride ions. 
• It stabilizes and hyperpolarizes the neuron. It works on GABA A receptors, but has no effect on GABA B receptors

The onset of action:

• IM: Sedation:
  • Children: Within 5 minutes
  • Adults: ~15 minutes
  • IV: 3 - 5 minutes
  • Oral: 10 - 20 minutes
• Intranasal (nasal spray): Within 10 minutes
• Intranasal (solution, injection)
  • Children: 5.55 ± 2.22 minutes
  • Adults: Within 5 minutes

Peak effect:

• IM: Children: 15 - 30 minutes; Adults: 30 - 60 minutes
• IV: 3 - 5 minutes
• Intranasal (nasal spray): 30 minutes
• Intranasal (solution, injection): Children: 10 minutes

Duration:

• IM: Up to 6 hours; Mean: 2 hours; Intranasal (solution, injection): Children: 23.1 minutes
• IV: Single dose: <2 hours (dose-dependent)

Absorption:

• IM: Rapid, complete
• Intranasal (nasal spray): Rapid
• Intranasal (solution, injection): Rapid

Distribution:

• Widely distributed in the body including CSF. Distribution is increased in elderly, females, and obese individuals.

Protein binding:

• ~97%, mainly albumin; It decreases in patients with cirrhosis, protein binding is reduced with a free fraction of ~5%.

Metabolism:

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

Bioavailability:

• Oral: 40% - 50%, ~36% (children)
• IM: >90%
• Intranasal (nasal spray): 44%; Intranasal (solution, injection): Children: ~60%
• Rectal: Children: ~40% - 65% (mean: 52%)

Half-life elimination:

• Reduced active metabolite removal in patients with renal impairment may lead to medication buildup and protracted sedation.
• Patients with cirrhosis, congestive heart failure, obesity, renal failure, and the elderly experience longer half-life elimination.
• Preterm infants: GA: 26 - 34 weeks; PNA: 3 - 11 days): IV: Median: 6.3 hours (range: 2.6 to 17.7 hours)
• Neonates: 4 - 12 hours; seriously ill neonates: 6.5 - 12 hours
• Children: IV: 2.9 - 4.5 hours; Syrup: 2.2 - 6.8 hours
• Adults: 3 hours (range: 1.8 - 6.4 hours); IM: 4.2 ± 1.87 hours; Intranasal (nasal spray): 2.1 - 6.2 hours

Time to peak serum concentration:

• IM: 0.5 - 1 hour
• Intranasal (nasal spray): Median 17.3 minutes (7.8 - 28.2 minutes)
• Oral: 0.17 - 2.65 hours

Excretion: Occurs mainly through urine. 2-10% with feces over 5 days

• Intranasal (nasal spray): Urine (primarily as glucuronide conjugates of the hydroxylated metabolites)
• IV: Urine (primarily as metabolites)
• Oral: Urine (~90% within 24 hours; primarily [60% - 70%] as glucuronide conjugates of the hydroxylated metabolites; <0.03% as unchanged drug)

Clearance:

• Preterm infants: GA: 26 - 34 weeks; PNA: 3 - 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 t- 2 mL/minute/kg
• Infants >3 months of age: 9.1 mL/minute/kg
• Children >1 year of age: 3.2 - 13.3 mL/minute/kg
• Healthy adults: 4.2 - 9 mL/minute/kg
• Adults with acute renal failure: 1.9 mL/minute/kg

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International Brand Names of Midazolam:

• Nayzilam
• Anespar
• Buccolam
• Dalam
• Diormicum
• Domi
• Doricum
• Dorlam
• Dormicum
• Dormicum[inj.]
• Dormid
• Dormilat
• Dormitol
• Dormizol
• Dormonid
• Fulsed
• Hipnoz
• Hypnofast
• Hypnovel
• Hypozam
• Ipnodis Medis
• Ipnovel
• Midacum
• Midadorm
• Midafresa
• Midazo
• Midolam
• Midozor
• Miloz
• Mizolam
• Nok
• Omida
• Relacum
• Sedacum
• Sedoz
• Sopnil
• Uzolam
• Versed

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Midazolam Brand Names in Pakistan:

Midazolam Injection 5 Mg in Pakistan
Dazolam	Medicraft Pharmaceuticals (Pvt) Ltd.
Idazol	Bosch Pharmaceuticals (Pvt) Ltd.

 

Midazolam Injection 1 Mg/Ml in Pakistan
Domi	Glaxosmithkline
Dormicum	Roche Pakistan Ltd.
Hypozam	Brookes Pharmaceutical Laboratories (Pak.) Ltd.
Hypozam	Brookes Pharmaceutical Laboratories (Pak.) Ltd.
Midazom	Akhai Pharmaceuticals.
Milam	Indus Pharma (Pvt) Ltd.
Noctrum	Siza International (Pvt) Ltd.

 

Midazolam Injection 5 Mg/Ml in Pakistan
Domi	Glaxosmithkline

 

Midazolam Injection 15 Mg/3ml in Pakistan
Docum	Fumy Enterprises
Midza	Ameer Pharma

 

Midazolam 7.5 Mg Tablets
Dizilam	Panacea Pharmaceuticals
Dorcom	Saydon Pharmaceutical Industries (Pvt) Ltd.
Dormicum	Roche Pakistan Ltd.
Leadolam	Leads Pharma (Pvt) Ltd
M-Lam	Mediate Pharmaceuticals (Pvt) Ltd
Milam	Indus Pharma (Pvt) Ltd.
Mizam	Global Pharmaceuticals
Slewelmilam	Z-Jans Pharmaceutical (Pvt) Ltd.
Somnium	Gray`S Pharmaceuticals
Surgisafe	Danas Pharmaceuticals (Pvt) Ltd
Xepulse	Xenon Pharmaceuticals (Pvt) Ltd.