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: This medicine is recommended to start and continue general anesthesia as part of a balanced approach.

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

  • Intramuscular (IM): It's given to make you calm before surgery, to reduce anxiety, and to cause forgetfulness.

    Intravenous (IV): Used to calm nerves, reduce anxiety, and induce forgetfulness before or during endoscopic procedures or surgery.

    Oral: Given before endoscopic procedures or before anesthesia in children to make them calm, reduce anxiety, and induce forgetfulness.

• Sedation for mechanically-ventilated patients:

  • Intravenous (IV): It is used as part of anesthesia in patients who are breathing through a tube, or it can be given continuously in critical care situations.

• Acute intermittent treatment of seizures:

  • Nasal Spray: Doctors recommend it for children under 12 with epilepsy who are having repeated seizures in clusters, which are different from their usual seizure patterns.

• Off Label Use of Midazolam in Adults:

  • Status Epilepticus:

    • This refers to a prolonged and continuous seizure or a series of seizures without recovery in between.
    • It's a medical emergency that requires immediate attention to prevent serious complications.

  • Refractory Status Epilepticus:

    • This term is used when seizures in status epilepticus do not respond to initial treatments.
    • It indicates a more challenging and severe form of the condition that may require specialized interventions or medications.

  • Palliative Sedation:

    • This involves the administration of sedative medications to manage symptoms such as pain, anxiety, or distress in patients with serious illnesses, especially when curative treatments are no longer effective or appropriate.
    • It aims to provide comfort and improve the quality of life in the final stages of an illness.

---

Midazolam Dose in Adults:

Important Note: The dosage should be tailored to the individual based on factors such as age, underlying health conditions, and other medications being taken concurrently.

For elderly individuals, those with chronic illnesses, or debilitated patients, as well as those using opioids or other central nervous system depressants, consider reducing the dose by 20% to 50%.

This adjustment helps ensure the safety and appropriateness of the medication for each person's unique circumstances.

Midazolam (Dormicum) Dose as an anesthetic: IV:

• Induction for Adults Under 55 Years:

• Unpremeditated patients: Initially, administer 0.3 - 0.35 mg/kg over 20 - 30 seconds.

• In resistant cases, repeat the dose after 2 minutes and 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, a safe anesthesia can be achieved within 30 seconds with 0.2 mg/kg delivered over 5 to 10 seconds.

• When combined with other anesthetic medications (coinduction), the dosage is 0.1 mg/kg.

• For patients with ASA physical status >P3 or debilitation, reduce the dose by at least 20%.

• Maintenance:Use 0.05 mg/kg as needed or administer through continuous infusion at a rate of 0.015 to 0.06 mg/kg/hour (equivalent to 0.25 - 1 mcg/kg/minute).

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

Important Note: Consult closely with a skilled palliative care professional before using midazolam for this purpose. Ensure accessibility to flumazenil in case of accidental overdose.

Subcutaneous (SubQ) Perpetual Infusion:

• Initial: Start at 0.5 to 1 mg/hour and adjust based on the patient's needs.
• Usual dosing range: 1 to 20 mg/hour; additional intermittent doses of 1 to 5 mg may be given as needed.
• Some experts suggest initiating with a bolus dose of 5 to 10 milligrams, with the dose size depending on patient weight, age, and the degree of debility.

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

• For healthy adults under 60 years of age:

• Intranasal (Solution, Injection):

  • 15 minutes before surgery or a procedure, give 0.1 mg/kg using an injectable solution containing 5 mg/mL.

• Intramuscular (IM):

  • Administer 0.07 - 0.08 mg/kg 30 - 60 minutes before surgery/procedure, with the usual dose being 5 mg.

• Intravenous (IV):

  • Initial dose is 0.5 - 2 mg over at least 2 minutes; titrate and repeat every 2 - 3 minutes if needed, with a usual total dose of 2.5 - 5 mg.
  • Note: Some patients may respond to doses as low as 1 mg, and a total dose greater than 5 mg is generally not needed.
  • Premedicated patients: Reduce the initial dose by 30%.
  • Maintenance: Use 25% of the dose that was needed to achieve the sedative effect.

• Adults ≥60 years of age, debilitated, or chronically ill:

  • Refer to geriatric dosing.
  • Note: The dosing in the prescribed information may not necessarily reflect current clinical practice.

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

Important Note: Nonbenzodiazepine sedation may be preferred.

Intravenous (IV):

• Initial: Administer 0.01 - 0.05 mg/kg (~0.5 - 4 mg); may repeat at 10 - 15 minute intervals until adequate sedation is achieved.
• Maintenance infusion: Use 0.02 - 0.1 mg/kg/hour (equivalent to 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 agitation occurs after stopping the drip, restart it at 50% of the previous dose.

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

• Intranasal (Nasal Spray):

• Depending on the reaction and tolerance, a repeat dose of 5 mg (one spray) in a different nostril may be given after 10 minutes (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):

• Intramuscular (IM):

• Administer 10 mg once or 0.2 mg/kg once (maximum dose: 10 mg). IM is preferred if there is no IV access.

• Prehospital Status Epilepticus:

• IM: Paramedics use 10 mg once if intermittent convulsions persist for more than five minutes or if the patient is not regaining consciousness.

• Intranasal (Solution, Injection):

• Administer 0.2 mg/kg. Use a 5 mg/mL injectable concentrated solution to deliver the dose.

• Buccal:

• Administer 0.5 mg/kg.

• Note: While buccal and intranasal routes have been used, they are considered off-label and have less research supporting their use.

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

Important Note: Mechanical breathing and cardiovascular monitoring are necessary; 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 (equivalent to 0.83 - 33.2 mcg/kg/minute)
• If refractory status epilepticus emerges during the continuous infusion:
  • Administer a bolus of 0.1 - 0.2 mg/kg
  • Increase the 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 have been studied
• Note: To avoid a repeat, gradually remove the continuous infusion while continuing electrographic control for at least 24 to 48 hours.

---

Midazolam (Dormicum) Dose in Children:

• Dosage should be individualized, considering the patient's age, underlying conditions, current medications, and the desired effect.

  If opioids or other CNS depressants are also administered, reduce the dose by 30%. Allow 3 to 5 minutes between doses to minimize the risk of oversedation.

• Administer multiple small doses and titrate to achieve the desired sedative effect.

  For lesser intranasal dosages, the parenteral solution for injection can be used.

• However, note that the nasal spray formulation provides a fixed dose of 5 mg and should not be universally used for all pediatric patients.

  Ensure the correct product selection and administration method are used.

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

Intramuscular (IM) for Infants, Children, and Adolescents:

• Usual Dose: 0.1 - 0.15 mg/kg given 30 - 60 minutes before surgery or procedure (range: 0.05 - 0.15 mg/kg).
• Higher doses up to 0.5 mg/kg have been used in more anxious patients.
• Maximum Total Dose: 10 mg.

Intravenous (IV) for different age groups:

1. 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.

2. 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.

3. 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.

4. 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 reduce discomfort and subsequent agitation, some researchers recommend premedication with intranasal lidocaine.

1. Infants 1 to 5 months:

   • 2 mg/kg (single dose).

2. Infants ≥6 months, Children, and Adolescents:

   • Initial dose: 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).

3. Oral for Infants >6 months, Children, and Adolescents <16 years:

   • Single dose: 0.25 - 0.5 mg/kg once, based on patient condition and desired effect.
   • Usual dose: 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:

• For Infants >6 months and Children:

  • Usual Dose: 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:

• For Infants, Children, and Adolescents:

  Intravenous (IV):

  • • Loading Dose: 0.05 - 0.2 mg/kg given slowly over 2 - 3 minutes.
    • Continuous IV Infusion: 0.06 - 0.12 mg/kg/hour (1 - 2 mcg/kg/minute).
    • Titrate to the desired effect; the range is 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; reserved for patients without IV access.

  Weight-based dosing:

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

Intramuscular (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):

• Administer one spray of 5 mg into one nostril.
• Depending on the response and tolerance, the dose may be repeated in the other nostril after 10 minutes.
• Avoid repeating the dose if the patient has trouble breathing or is excessively sedated.
• Maximum dose: 10 mg/dose each episode (2 sprays).
• Maximum treatment frequency: One episode every three days, with a maximum of five episodes per month.

Parenteral Solution for Injection Product:

• Limited data available; reserved for patients without IV access.

• Divide the 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:

  Intramuscular (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.

• • Buccal:

  • 0.5 mg/kg once; maximum dose: 10 mg/dose.

  • Intranasal:

  • 0.2 mg/kg once; maximum dose: 10 mg/dose.

• Refractory to standard treatment:

Note: Requires mechanical breathing and cardiac monitoring; the 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 (equivalent to 0.83 to 33.3 mcg/kg/minute) titrated to the 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 the infusion rate by 0.05 - 0.1 mg/kg/hour (0.83 - 1.66 mcg/kg/minute) every 3 - 4 hours.

---

Midazolam (Dormicum) Pregnancy Risk Category: D

• Midazolam crosses the placental barrier, and as a benzodiazepine, it shows some potential teratogenic properties. Further studies are needed to fully understand its effects during pregnancy.

• The use of benzodiazepines, including midazolam, during pregnancy has been associated with a risk of low birth weight and premature birth.

• Neonatal hypoglycemia, which can lead to respiratory problems, has also been reported.

• There have been cases of neonatal withdrawal symptoms, such as floppy infant syndrome.

• If the expected duration of surgery is anticipated to exceed 3 hours, a careful consideration of the benefit-versus-risk strategy for midazolam exposure should be employed.

• While midazolam has been used in obstetrical anesthesia, it's important to note that the manufacturer does not specifically recommend its use in pregnancy.

• According to guidelines from the American College of Obstetricians and Gynecologists (ACOG) for emergency procedures involving pregnant women, midazolam should be administered after delivery.

Use of midazolam while breastfeeding

• Midazolam is present in breast milk, and its relative infant dose (RID) is 0.35%.

• Breastfeeding is generally considered acceptable when the RID is below 10%.

• Most reports suggest that midazolam or its metabolites in breast milk typically fall below quantifiable levels after a single dose.

• However, caution is advised as some studies indicate that central nervous system (CNS) depression can occur in infants after breastfeeding mothers have taken benzodiazepines.

• Guidelines recommend that breastfeeding should be done cautiously after the mother has consumed midazolam, particularly after doses given within the preceding 4 hours.

• This caution applies even if the baby has received pre-procedural sedatives.

• The Academy of Breastfeeding Medicine suggests delaying elective surgery until breastfeeding is well-established and the milk supply is stable.

• Whenever possible, expressing milk before surgery is recommended.

• Breastfeeding can generally be resumed for healthy, full-term infants once the mother is awake and in recovery.

• However, for infants at higher risk for hypotension, apnea, or hypotonia, it may be advisable to save expressed milk for later use when the baby is in better health.

• Additionally, if the mother is alert and stable, the use of small supplemental doses of midazolam should not be a reason to stop breastfeeding.

---

Midazolam (Dormicum) Dose in Kidney Disease:

The medicine's label doesn't say how much to use if someone has kidney problems, so be careful.

If the kidneys aren't working well, the medicine stays in the body for a longer time.

People with kidney problems might have to wait several days to get a constant drip of the medicine that can effectively get rid of its active forms.

For intermittent hemodialysis, you don't need an extra dose. For continuous venovenous hemofiltration:

• Not effectively removed: Unconjugated 1-hydroxymidazolam
• Effectively removed: 1-hydroxymidazolamglucuronide (removed well)
• Sieving coefficient is 0.45 (shows how well it's removed)

For peritoneal dialysis, the medicine isn't significantly removed based on its characteristics.

If you're using the medicine as a nasal spray:

• For mild impairment, you don't need to change the dose.
• For moderate impairment, the label doesn't say how much to use, so be careful.
• For severe impairment, the label also doesn't say how much to use; be cautious.

Midazolam (Dormicum) Dose in Liver disease:

The instructions from the maker don't tell you how much medicine to use, so be careful.

For intravenous (IV) use:

• For a single dose, like when starting treatment, you don't need to change the amount used.
• However, the effects might last longer.
• If you're taking the medicine multiple times or continuously, the effects might last longer and build up in your system. You might need to use a smaller amount to avoid this.

---

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

---

Contraindications to Midazolam (Dormicum):

Don't use this medication orally if:

• You're allergic to it.
• You're injecting substances with preservatives directly into the spinal cord or the space around it, like benzyl alcohol.
• Premature infants who can receive benzyl alcohol through injections.
• You have acute narrow-angle vision caused by glaucoma.

Also, be cautious if you're using oral midazolam with certain protease inhibitors (nelfinavir, ritonavir, saquinavir, tipranavir, atazanavir, cobicistat, and lopinavir), or if you're combining 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

  • Benzodiazepines have been associated with a type of memory loss called anterograde amnesia.

  • This means that people may have difficulty forming new memories while under the influence of these medications.

• Cardiorespiratory effects [US Boxed Warning]

  • Using benzodiazepines can result in respiratory depression or even complete stoppage of breathing, leading to issues like blocked airways, decreased oxygen levels, and a condition called hypoxia.

  • This risk is higher for patients with severe lung disease, unusual airway structures, sepsis, or congenital heart disease causing bluish skin.

    To use this medication safely:

  • It should only be administered in places where continuous monitoring of the heart and breathing is feasible, for example, using pulse oximetry.
  • The medical staff should be trained in critical procedures like intubation, bag-mask ventilation, and overall airway management.

  • For patients with a high risk of breathing problems, the initial dose should be given using intranasal midazolam, a method that delivers the medication through the nose.

  • This helps manage potential respiratory issues more effectively.

• Depression in the CNS:

  • This medication can lead to central nervous system (CNS) depression, affecting mental and physical abilities.

  • Patients need to be informed about its potential effects.

  • There should be a maximum of one day between taking the last dose and resuming normal activities.

    Since the impact is influenced by the dosage and how the medication is given, it's crucial to be careful about both the amount taken and the method of administration.

• Hypotension

  • The use of this medication in children may result in low blood pressure (hypotension) and instability in the cardiovascular system (hemodynamic instability).

• Paradoxical reactions

  • Interestingly, in adolescent/pediatric or geriatric patients, there might be a paradoxical occurrence of aggressive behavior or hyperactivity instead of the expected calming effect.

• Suicidal thoughts:

  • When comparing different antiepileptic medications used through intranasal administration, a combined analysis revealed a higher occurrence of suicidal thoughts or behaviors.

  • The incidence rate was 0.43% for treated patients compared to 0.24% for those who received a placebo.

  • This risk was noticeable from the beginning of the trials and persisted throughout, with most trials lasting less than 24 weeks.

  • It's crucial to be vigilant for any alterations in behavior or thoughts that may signal depression or suicidal tendencies. If you observe these symptoms, promptly inform your healthcare provider.

• Acute illness:

  • The use of intravenous midazolam should be approached carefully in situations of acute, uncompensated conditions, such as severe imbalances in fluids and electrolytes.

• Cardiovascular disease

  • Exercise caution in cases of heart failure.

  • In pediatric patients, intravenous drug administration can lead to hemodynamic instability, so it's advisable to avoid rapid infusion.

• Glaucoma

  • In cases of glaucoma, use this medication cautiously, and avoid it if the glaucoma is acute and narrow-angle or severe.
  • However, if appropriate treatment for open-angle glaucoma is already in progress, it can be considered.

• Renal impairment

  • Steer clear of using this medication in individuals with renal impairment, as it may result in a prolonged half-life of the drug.

• Respiratory disease

  • Do not use midazolam in individuals with respiratory diseases, such as chronic obstructive lung disease.

  • Midazolam has the potential to cause respiratory depression, and patients who are particularly 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

---

How to administer Midazolam (Dormicum)?

Buccal administration of this medication is not accessible in the USA.

To use it, employ an oral syringe to apply the dose between the gums and cheeks.

Gently massage the cheek, and the dose can be split between both 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):

• A low pH of the medication may cause a burning sensation in the patient. To reduce irritation, an atomizer attached to a tuberculin needle can be used.

  To minimize intramuscular injections, consider using a higher-dose injectable solution. A smaller volume results in less irritation and easier swallowing. For the 5 mg/mL concentration, a maximum dosage volume of 1 mL per nostril is recommended.

  Use the 5 mg/mL injection solution and draw the desired dose with a needle-free syringe or attach it to a nasal mucosal atomization device for administration.

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

• For oral administration:

• Mix the medication without any liquids.
• Avoid giving it on an empty stomach.

• For parenteral administration:

• Do not inject intraarterially (into an artery).

• For intramuscular (IM) injection:

• Administer the undiluted solution deep into a sizable muscle.

• Intravenous administration:

• For procedural sedation, anxiety relief, and inducing forgetfulness, use a slow IV infusion.

• Opt for a concentration of 1 mg/mL or dilute it using a concentration of 1 or 5 mg/mL.

• The bolus for inducing anesthesia should last longer than 5 to 15 seconds.

• In cases of refractory epilepticus:

• Use a loading dose infusion rate of 2 mg per minute.

• For various clinical scenarios, such as sedation in mechanically ventilated patients:

• A continuous infusion is a suitable option.

Rectal administration:

• Apply a solution with a concentration of 1 to 5 mg/mL using a rectally inserted catheter or tube.
• Keep your buttocks closed for approximately five minutes after administration.

---

Mechanism of action of Midazolam (Dormicum):

• Midazolam acts by binding to GABA (gamma-aminobutyric acid) neurons in the central nervous system.
• It enhances the inhibitory effects of GABA, leading to increased neuronal excitability inhibition.
• This occurs through heightened membrane permeability to chloride ions, which, in turn, stabilizes and hyperpolarizes the neuron.
• Specifically, midazolam affects GABA A receptors, but it does not have any impact on GABA B receptors.

The onset of action:

• The onset times for sedation with midazolam vary depending on the method of administration:

• Intramuscular (IM) for Sedation:

  • Children: Within 5 minutes
  • Adults: Approximately 15 minutes

• Intravenous (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:

• The onset times for midazolam administration are as follows:

• Intramuscular (IM):

  • Children: 15 - 30 minutes
  • Adults: 30 - 60 minutes

• Intravenous (IV):

  • 3 - 5 minutes

• Intranasal (Nasal Spray):

  • 30 minutes

• Intranasal (Solution, Injection):

  • Children: 10 minutes

Duration:

• The duration of action for midazolam is as follows:

• Intramuscular (IM):

  • Up to 6 hours (variable)
  • Mean: 2 hours

• Intranasal (Solution, Injection):

  • Children: 23.1 minutes

• Intravenous (IV):

  • Single dose: Less than 2 hours (duration may be dose-dependent)

Absorption:

• The absorption characteristics of midazolam for different administration routes are described as follows:

• Intramuscular (IM):

  • Rapid and complete absorption.

• Intranasal (Nasal Spray):

  • Rapid absorption.

• Intranasal (Solution, Injection):

  • Rapid absorption.

Distribution:

• Midazolam is extensively distributed throughout the body, including the cerebrospinal fluid (CSF).

• The distribution of midazolam is heightened in certain populations, such as the elderly, females, and obese individuals.

Protein binding:

• Approximately 97% of midazolam in the bloodstream is bound to proteins, primarily to albumin.

• However, in patients with cirrhosis (a liver condition), the protein binding of midazolam decreases, resulting in a reduced level of binding with a free fraction of around 5%.

Metabolism:

• The main enzyme responsible for the metabolism of midazolam is hepatic CYP3A4.
• Approximately 60% to 70% of the biotransformed midazolam is converted into the active metabolite known as 1-hydroxy-midazolam, or alpha-hydroxymidazolam.

Bioavailability:

• The bioavailability of midazolam, or the proportion of the administered dose that reaches the systemic circulation, varies based on the route of administration:

• Oral:

  • Generally, 40% to 50%.
  • In children, approximately 36%.

• Intramuscular (IM):

  • Greater than 90%.

• Intranasal (Nasal Spray):

  • Approximately 44%.

• Intranasal (Solution, Injection):

  • In children, approximately 60%.

• Rectal:

  • In children, approximately 40% to 65%, with a mean of 52%.

Half-life elimination:

• The elimination of the active metabolite is reduced in patients with renal impairment, potentially leading to an accumulation of the medication and prolonged sedation.

• Longer half-life elimination is observed in patients with cirrhosis, congestive heart failure, obesity, renal failure, and the elderly.

  For different age groups:

• Preterm infants (GA: 26 - 34 weeks; PNA: 3 - 11 days):

  • IV: Median half-life is 6.3 hours (range: 2.6 to 17.7 hours).

• Neonates:

  • Generally, 4 - 12 hours.
  • Seriously ill neonates: 6.5 - 12 hours.

• Children:

  • IV: 2.9 - 4.5 hours.
  • Syrup: 2.2 - 6.8 hours.

• Adults:

  • Generally, 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:

• The onset times for midazolam are as follows:

• Intramuscular (IM):

  • Typically within 0.5 - 1 hour.

• Intranasal (Nasal Spray):

  • Median onset time is 17.3 minutes (range: 7.8 - 28.2 minutes).

• Oral:

  • Onset time ranges from 0.17 to 2.65 hours.

The excretion of midazolam primarily occurs through urine, with a small percentage eliminated via feces over a 5-day period (approximately 2-10%).

For specific routes of administration:

• Intranasal (Nasal Spray):

  • Excretion is through urine, primarily as glucuronide conjugates of the hydroxylated metabolites.

• Intravenous (IV):

  • Excretion occurs through urine, primarily as metabolites.

• Oral:

  • Approximately 90% of the drug is excreted in urine within 24 hours.
  • The primary form is as glucuronide conjugates of the hydroxylated metabolites (60% - 70%).
  • Less than 0.03% is excreted as unchanged drug. 

Clearance:

• The clearance rates of midazolam (volume of blood from which the drug is completely removed per unit time) vary across different age groups and health conditions:

• 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.
  • 39 weeks GA: 1.84 mL/minute/kg.
  • Seriously ill neonates: 1.2 to 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.

---

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 

---

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.