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Product Name
:
DORMITA (tab)
Chemical Name
:
Midazolam
Therapeutic Category
:
Central nervous system drugs
Pharmacologic Category
:
Benzodiazepine
Pharmaceutical Form
:
Tablets
Composition
:
Midazolam 7.5mg / 15mg
Monitoring Parameters
Dosing
 
Dosing: Adult
The dose of midazolam needs to be individualized based on the patient's age, underlying diseases, and concurrent medications. Consider reducing dose by 30% to 50% in elderly or debilitated patients and those receiving opioids or other CNS depressants.

Preoperative sedation:

I.M.: 0.07-0.08 mg/kg 30-60 minutes prior to surgery/procedure; usual dose: 5 mg
I.V.: 0.02-0.04 mg/kg; repeat every 5 minutes as needed to desired effect or up to 0.1-0.2 mg/kg
Intranasal (unlabeled route): 0.1 mg/kg; administer 10-20 minutes prior to surgery/procedure (Uygur-Bayramiçli, 2002). Note: Use 5 mg/mL injectable solution to deliver dose. Due to the low pH of the solution, burning upon administration is likely to occur.

Conscious sedation:
I.V.: Initial: 0.5-2 mg slow I.V. over at least 2 minutes; slowly titrate to effect by repeating doses every 2-3 minutes if needed; usual total dose: 2.5-5 mg
Healthy adults <60 years:
Initial: Some patients respond to doses as low as 1 mg; no more than 2.5 mg should be administered over a period of 2 minutes. Additional doses of midazolam may be administered after a 2-minute waiting period and evaluation of sedation after each dose increment. A total dose >5 mg is generally not needed.
Maintenance: 25% of dose used to reach sedative effect
Adults ≥60 years, debilitated, or chronically ill: Refer to geriatric dosing.

Anesthesia:
I.V.:
Induction:
Unpremedicated patients: 0.3-0.35 mg/kg (up to 0.6 mg/kg in resistant cases)
Premedicated patients: 0.15-0.35 mg/kg
Maintenance: 0.05-0.3 mg/kg as needed, or continuous infusion 0.25-1.5 mcg/kg/minute

Sedation in mechanically ventilated patients:
Per the manufacturer: I.V.: Initial dose: 0.01-0.05 mg/kg (~0.5-4 mg); may repeat at 5- to 15-minute intervals until adequate sedation achieved; maintenance infusion: 0.02-0.1 mg/kg/hour. Titrate to reach desired level of sedation.
or
I.V.: Initial dose: 0.02-0.08 mg/kg (~1-5 mg in 70 kg adult); may repeat at 5- to 15-minute intervals until adequate sedation achieved; maintenance infusion: 0.04-0.2 mg/kg/hour. Titrate to reach desired level of sedation (Jacobi, 2002).

Refractory status epilepticus (unlabeled use): Note:
Intubation required; adjust dose based on hemodynamics, seizure activity, and EEG. I.V.: 0.15-0.3 mg/kg (usual dose: 5-15 mg); may repeat every 10-15 minutes as needed or 0.2 mg/kg bolus followed by a continuous infusion of 0.05-0.6 mg/kg/hour (Lowenstein, 2005; Meierkord, 2010)

Dosing: Pediatric

The dose of midazolam needs to be individualized based on the patient's age, underlying diseases, and concurrent medications. Decrease dose (by ~30%) if opioids or other CNS depressants are administered concomitantly. Children <6 years may require higher doses and closer monitoring than older children; calculate dose based on ideal body weight.

Conscious sedation for procedures or preoperative sedation:

Oral, rectal: 0.5-0.75 mg/kg as a single dose preprocedure (maximum: 20 mg); administer 20-30 minutes prior to procedure. Children <6 years or less cooperative patients may require as much as 1 mg/kg as a single dose; 0.25 mg/kg may suffice for children 6-16 years of age (Bozkurt, 2007).
I.M.: 0.1-0.15 mg/kg 30-60 minutes before surgery or procedure; range: 0.05-0.15 mg/kg; maximum total dose: 10 mg
I.V.:
Infants <6 months: Limited information is available in nonintubated infants; dosing recommendations not clear; infants <6 months are at higher risk for airway obstruction and hypoventilation; titrate dose in small increments to desired effect
Infants 6 months to Children 5 years: Initial: 0.05-0.1 mg/kg; total dose of 0.6 mg/kg may be required; maximum total dose: 6 mg
Children 6-12 years: Initial: 0.025-0.05 mg/kg; total doses of 0.4 mg/kg may be required; maximum total dose: 10 mg
Children 12-16 years: Dose as adults; maximum total dose: 10 mg

Conscious sedation during mechanical ventilation:
I.V.: Children: Loading dose: 0.05-0.2 mg/kg, followed by initial continuous infusion: 0.06-0.12 mg/kg/hour (1-2 mcg/kg/minute); usual range: 0.4-6 mcg/kg/minute

Status epilepticus refractory to standard therapy (unlabeled use): Note:
Intubation required; adjust dose based on hemodynamics, seizure activity, and EEG. I.V.: Infants >2 months and Children: Loading dose: 0.15 mg/kg followed by a continuous infusion of 0.06 mg/kg/hour (1 mcg/kg/minute); titrate dose upward every 5 minutes until clinical seizure activity is controlled; mean infusion rate required in 24 children was 0.14 mg/kg/hour (2.3 mcg/kg/minute) with a range of 0.06-1.1 mg/kg/hour (1-18.3 mcg/kg/minute) (Rivera, 1993).
A more aggressive approach has been demonstrated to provide control of status epilepticus within 30 minutes of initiation: Loading dose: 0.5 mg/kg followed by 0.12 mg/kg/hour (2 mcg/kg/minute). If seizures persist or recur, administer 0.5 mg/kg bolus with an increase in the infusion rate to 0.24 mg/kg/hour (4 mcg/kg/minute); if seizures continue to persist/recur, administer 0.1 mg/kg bolus and increase infusion to 0.48 mg/kg/hour (8 mcg/kg/minute); continue to repeat this last incremental increase until seizure control or a maximum dose of 1.44 mg/kg/hour (24 mcg/kg/minute) is reached; do not allow >5 minutes to elapse between each dose increment while seizures persist (dose range within clinical trial: 0.12-1.92 mg/kg/hour or 2-32 mcg/kg/minute) (Morrison, 2006).

Dosing: Geriatric

The dose of midazolam needs to be individualized based on the patient's age, underlying diseases, and concurrent medications. Consider reducing dose by 30% to 50% in elderly or debilitated patients and those receiving opioids or other CNS depressants.
I.V.: Conscious sedation: Initial: 0.5 mg slow I.V.; give no more than 1.5 mg in a 2-minute period. If additional titration is needed, give no more than 1 mg over 2 minutes, waiting another 2 or more minutes to evaluate sedative effect. A total dose >3.5 mg is rarely necessary.

Dosing: Renal Impairment
There are no dosage adjustments provided in manufacturer's labeling; use with caution.
Hemodialysis: Supplemental dose is not necessary.
Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics.

Dosing: Hepatic Impairment

Severe hepatic impairment: Reduce dose by 50%.
Use
 
Preoperative sedation; moderate sedation prior to diagnostic or radiographic procedures; ICU sedation (continuous infusion); induction and maintenance of general anesthesia
Use - Unlabeled/Investigational
Anxiety, status epilepticus
Adverse Reactions
 
As reported in adults unless otherwise noted:
>10%: Respiratory: Decreased tidal volume and/or respiratory rate decrease, apnea (3% children)
1% to 10%:
Cardiovascular: Hypotension (3% children)
Central nervous system: Drowsiness (1%), oversedation, headache (1%), seizure-like activity (1% children)
Gastrointestinal: Nausea (3%), vomiting (3%)
Local: Pain and local reactions at injection site (4% I.M., 5% I.V.; severity less than diazepam)
Ocular: Nystagmus (1% children)
Respiratory: Cough (1%)
Miscellaneous: Physical and psychological dependence with prolonged use, hiccups (4%, 1% children), paradoxical reaction (2% children)
<1% (Limited to important or life-threatening): Agitation, amnesia, bigeminy, bronchospasm, emergence delirium, euphoria, hallucinations, laryngospasm, rash
Contraindications
 
Hypersensitivity to midazolam or any component of the formulation; intrathecal or epidural injection of parenteral forms containing preservatives (ie, benzyl alcohol); acute narrow-angle glaucoma; concurrent use of potent inhibitors of CYP3A4 (amprenavir, atazanavir, or ritonavir)
Warnings / Precautions Drug
 
Boxed warnings:
• Debilitated patients: See “Special populations” below.
• Elderly: See “Special populations” below.
• Neonates: See “Special populations” below.
• Respiratory depression: See “Concerns related to adverse effects” below.

Concerns related to adverse effects:

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). A minimum of 1 day should elapse after midazolam administration before attempting these tasks.
• Hypotension: May cause hypotension; hemodynamic events are more common in pediatric patients or patients with hemodynamic instability. Hypotension may occur more frequently in patients who have received opioid analgesics.
• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients.
• Respiratory depression: [U.S. Boxed Warning]: May cause severe respiratory depression, respiratory arrest, or apnea. Use with extreme caution, particularly in noncritical care settings. Appropriate resuscitative equipment and qualified personnel must be available for administration and monitoring. Initial dosing must be cautiously titrated and individualized, particularly in elderly or debilitated patients, patients with hepatic impairment (including alcoholics), or in renal impairment, particularly if other CNS depressants (including opiates) are used concurrently.

Disease-related concerns:

• Heart failure (HF): Use with caution in patients with HF.
• Impaired gag reflex: Use with caution in patients with an impaired gag reflex.
• Renal impairment: Use with caution in patients with renal impairment; half-life of midazolam and metabolites may be prolonged.
• Respiratory disease: Use with caution in patients with respiratory disease.

Concurrent drug therapy issues:

• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated.

Special populations:

• Debilitated patients: [U.S. Boxed Warning]: Initial doses in debilitated patients should be conservative; start at the lower end of dosing range.
• Elderly: [U.S. Boxed Warning]: Initial doses in elderly should be conservative; start at the lower end of dosing range.
• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.
• Obese patients: Use with caution in obese patients; may have prolonged action when discontinued.
• Neonates: [U.S. Boxed Warning]: Do not administer by rapid I.V. injection in neonates; severe hypotension and seizures have been reported; risk may be increased with concomitant fentanyl use.

Dosage form specific issues:

• Benzyl alcohol: Some parenteral dosage forms may contain benzyl alcohol which has been associated with “gasping syndrome” in neonates.

Other warnings/precautions:

• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Does not protect against increases in heart rate or blood pressure during intubation. Should not be used in shock, coma, or acute alcohol intoxication. Avoid intra-arterial administration or extravasation of parenteral formulation. Use during upper airway procedures may increase risk of hypoventilation. Prolonged responses have been noted following extended administration by continuous infusion (possibly due to metabolite accumulation) or in the presence of drugs which inhibit midazolam metabolism.
• Cherry flavoring: Some formulations may contain cherry flavoring.
• Withdrawal: Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
Controlled Substance
C-IV
Metabolism/Transport Effects
Substrate of CYP2B6 (minor), 3A4 (major); Inhibits CYP2C8 (weak), 2C9 (weak), 3A4 (weak)
Interactions
 
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Management: The following combinations are specifically contraindicated: itraconazole with alprazolam, estazolam, oral midazolam, or triazolam; ketoconazole with alprazolam, estazolam, or triazolam. Consider initial dose reductions of other benzodiazepines. Risk D: Consider therapy modification
Aprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Atorvastatin: May increase the serum concentration of Midazolam. Risk C: Monitor therapy
Boceprevir: May increase the serum concentration of Midazolam. Risk X: Avoid combination
Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Bepridil [Off Market]. Risk D: Consider therapy modification
CarBAMazepine: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Cimetidine: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
Contraceptives (Estrogens): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Contraceptives (Progestins): May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Efavirenz: May increase the serum concentration of Midazolam. Risk X: Avoid combination
Fluconazole: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
Fosaprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Specifically, the active metabolite aprepitant is likely responsible for this effect. Risk C: Monitor therapy
Fosphenytoin: Benzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Risk C: Monitor therapy
Ginkgo Biloba: May decrease the serum concentration of Midazolam. Risk C: Monitor therapy
Grapefruit Juice: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Isoniazid: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Macrolide Antibiotics: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin (Systemic); Spiramycin. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Nefazodone: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Risk X: Avoid combination
Phenytoin: Benzodiazepines may increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Risk C: Monitor therapy
Propofol: May increase the serum concentration of Midazolam. Midazolam may increase the serum concentration of Propofol. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with all protease inhibitors. IV midazolam contraindicated with fosamprenavir and nelfinavir; other protease inhibitors recommend caution, close monitoring, and consideration of lower IV midazolam doses with concurrent use. Risk X: Avoid combination
Proton Pump Inhibitors: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Exceptions: Lansoprazole; Pantoprazole; RABEprazole. Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Citalopram; Escitalopram; PARoxetine; Sertraline. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
St Johns Wort: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Telaprevir: May increase the serum concentration of Midazolam. Management: Use of oral midazolam with telaprevir is contraindicated. IV midazolam use may pose a lower risk, but dose reductions should be considered and patients should be monitored closely for signs/symptoms of toxicity. Risk X: Avoid combination
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy
Pregnancy
 
D
Pregnancy Implications
Adverse events were not observed in animal teratology studies. Midazolam has been found to cross the human placenta and can be detected in the serum of the umbilical vein and artery, as well as the amniotic fluid. Teratogenic effects have been observed with some benzodiazepines; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) have been reported with some benzodiazepines.
Lactation
 
Enters breast milk/use caution (AAP rates “of concern”; AAP 2001 update pending)
Breast-Feeding Considerations
Midazolam and hydroxymidazolam can be detected in breast milk. Based on information from two women, 2-3 months postpartum, the half-life of midazolam in breast milk is ~1 hour. Milk concentrations were below the limit of detection (<5 nmol/L) 4 hours after a single maternal dose of midazolam 15 mg. Drowsiness, lethargy, or weight loss in nursing infants have been observed in case reports following maternal use of some benzodiazepines.
Mechanism of Action
 
Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization.
Pharmacodynamics / Kinetics
 
Onset of action: I.M.: Sedation: ~15 minutes; I.V.: 3-5 minutes; Oral: 10-20 minutes
Peak effect: I.M.: 0.5-1 hour
Duration: I.M.: Up to 6 hours; Mean: 2 hours
Absorption: Oral: Rapid
Distribution: Vd: 1-3.1 L/kg; increased in females, elderly, and obesity
Protein binding: ~97%
Metabolism: Extensively hepatic via CYP3A4
Bioavailability: 36% (oral, children); >90% (I.M.)
Half-life elimination: 2-6 hours; prolonged in cirrhosis, congestive heart failure, obesity, and elderly
Excretion: Urine (as glucuronide conjugated metabolites); feces (~2% to 10%)
 
   
 
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