Midazolam

The manifestations of midazolam overdosage reported are similar to those observed with other benzodiazepines, including sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma and untoward effects on vital signs. No evidence of specific organ toxicity from midazolam overdosage has been reported.

Treatment of Overdosage

Treatment of injectable midazolam overdosage is the same as that followed for overdosage with other benzodiazepines. Respiration, pulse rate and blood pressure should be monitored and general supportive measures should be employed. Attention should be given to the maintenance of a patent airway and support of ventilation, including administration of oxygen. An intravenous infusion should be started. Should hypotension develop, treatment may include intravenous fluid therapy, repositioning, judicious use of vasopressors appropriate to the clinical situation, if indicated, and other appropriate countermeasures. There is no information as to whether peritoneal dialysis, forced diuresis or hemodialysis are of any value in the treatment of midazolam overdosage.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. There are anecdotal reports of reversal of adverse hemodynamic responses associated with midazolam following administration of flumazenil to pediatric patients. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, assure adequate ventilation, and establish adequate intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. Flumazenil will only reverse benzodiazepine- induced effects but will not reverse the effects of other concomitant medications. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk patients. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted prior to use.

Injectable:

Midazolam has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. Use only in settings that can provide for continuous monitoring of respiratory and cardiac function. The initial dose and all subsequent doses should always be titrated slowly. Midazolam injection should not be administered by rapid injection in the neonatal population as severe hypotension and seizures have been reported.

Syrup:

Midazolam has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. Use only in settings that can provide for continuous monitoring of respiratory and cardiac function.

In the U.S.

• Versed

Available Dosage Forms:

• Tablet
• Syrup
• Solution

Therapeutic Class: Sedative-Hypnotic

Pharmacologic Class: Benzodiazepine, Short or Intermediate Acting

Midazolam is used to produce sleepiness or drowsiness and to relieve anxiety before surgery or certain procedures. Midazolam is also given to produce amnesia (loss of memory) so that the patient will not remember any discomfort or undesirable effects that may occur after a surgery or procedure.

Midazolam is a benzodiazepine. Benzodiazepines belong to the group of medicines called central nervous system (CNS) depressants, which are medicines that slow down the nervous system.

midazolam is given only by or under the immediate supervision of a doctor trained to use midazolam.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Anxiety
• chest pain or discomfort
• choking
• confusion
• difficult or troubled breathing
• drowsiness
• dry mouth
• fast heartbeat
• hyperventilation
• irregular heartbeats
• irregular, fast or slow, or shallow breathing
• irritability
• lightheadedness, dizziness, or fainting
• nausea
• nervousness
• noisy breathing
• pale or blue lips, fingernails, or skin
• restlessness
• shaking
• shortness of breath
• slow or irregular heartbeat
• tightness in the chest
• trouble sleeping
• unable to speak
• unusual tiredness
• weakness
• wheezing

• Attack, assault, or force
• changes in patterns and rhythms of speech
• feeling of constant movement of self or surroundings
• headache
• lack or loss of self-control
• loss of balance
• mood swings
• noisy breathing
• not breathing
• restlessness
• seeing, hearing, or feeling things that are not there
• sensation of spinning
• shakiness and unsteady walk
• sleepiness
• slow to respond
• slurred speech
• trouble in speaking
• unconsciousness
• unsteadiness, trembling, or other problems with muscle control or coordination

Get emergency help immediately if any of the following symptoms of overdose occur:

• Change in consciousness
• difficulty with coordination
• loss of consciousness
• sleepiness or unusual drowsiness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Vomiting

• Rash

• Blurred vision
• double vision
• gagging
• hiccups
• seeing double
• watering of mouth and drooling

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• Midazolam HCl
• Midazolam Hydrochloride
• Versed

Elimination half-life is prolonged and clearance is reduced.

Seizures (children/adolescents)

Data from a clinical trial comparing the use of intramuscular midazolam and intravenous diazepam in children with motor seizures of at least 10 minutes in duration supports the use of intramuscular midazolam in this setting [Chamberlain 1997]. Additional trials may be necessary to further define the role of midazolam for this condition.

Based on the American Academy of Pediatrics, the use of intramuscular midazolam is an effective and recommended treatment for seizures in children and adolescents [AAP [Hegenbarth 2008]].

Status epilepticus (children/adolescents/adults)

Data from a double-blind, randomized, noninferiority trial comparing the use of intramuscular midazolam to intravenous lorazepam in both children and adults supports the use of intramuscular midazolam for the treatment of status epilepticus [Silbergleit 2012].

Based on the Neurocritical Care Society Guidelines for the Evaluation and Management of Status Epilepticus and the American Epilepsy Society Guidelines for the Treatment of Convulsive Status Epilepticus in Children and Adults, the use of intramuscular midazolam is an effective and recommended treatment and is the drug of choice when intramuscular administration is necessary for emergent control of status epilepticus in children, adolescents, and adults.

Status epilepticus, refractory (adults)

Data from four retrospective studies and one prospective, open-label study suggests that intravenous midazolam may be beneficial for the treatment of patients with refractory status epilepticus [Claassen 2001], [Fernandez 2014], [Kumar 1992], [Prasad 2001], [Ulvi 2002]. Additional trials may be necessary to further define the role of midazolam for this condition.

Based on the Neurocritical Care Society Guidelines for the Evaluation and Management of Status Epilepticus, the use of intravenous midazolam is an effective and recommended treatment for refractory status epilepticus in adults.

Status epilepticus, refractory (children/adolescents)

Data from a number of clinical trials in children and adolescents with refractory status epilepticus supports the use of intravenous midazolam for the treatment of this condition [Iguarta 1999], [Koul 1997], [Koul 2002], [Morrison 2006], [Ozdemir 2005], [Yoshikawa 2000].

Based on the Neurocritical Care Society Guidelines for the Evaluation and Management of Status Epilepticus and the American Academy of Pediatrics, the use of intravenous midazolam is an effective and recommended treatment for refractory status epilepticus in children and adolescents [AAP [Hegenbarth 2008]], [NCS [Brophy 2012]].

Palliative sedation

Data from a prospective trial suggests that a protocol utilizing midazolam as a continuous infusion for palliative sedation in patients with advanced cancer may be beneficial for intolerable suffering refractory to other therapies [Mercadante 2014]. Additional data may be necessary to further define the role of midazolam in this setting. Due to its short half-life, palliative care experts consider the use of midazolam as a subcutaneous or intravenous continuous infusion as first-line therapy for respite sedation (ie, transient use to relieve severe symptoms [eg, pain, agitation] not necessarily refractory) [Protus 2015]. Note: Use of midazolam in this setting should be done in close consult with or by an experienced palliative care provider.

Based on the ESMO clinical practice guidelines for the management of refractory symptoms at the end of life and the use of palliative sedation, the use of midazolam is an effective and recommended sedative agent to relieve severe and refractory symptoms at the end of life [ESMO [Cherney 2014]].

There are no dosage adjustments provided in the manufacturer's labeling; use with caution; half-life of midazolam and metabolites may be prolonged. Patients with renal failure receiving a continuous infusion cannot adequately eliminate the active hydroxylated metabolites (eg, 1-hydroxymidazolam) contributing to prolonged sedation sometimes for days after discontinuation (Spina 2007).

Intermittent hemodialysis: Supplemental dose is not necessary.

Continuous venovenous hemofiltration (CVVH): Unconjugated 1-hydroxymidazolam not effectively removed; 1-hydroxymidazolamglucuronide effectively removed; sieving coefficient = 0.45 (Swart 2005).

Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics.

Avoid grapefruit juice with oral syrup.

Applies to midazolam: oral solution, oral syrup, oral tablet

Other dosage forms:

• injection solution

Along with its needed effects, midazolam may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking midazolam:

• Anxiety
• chest pain or discomfort
• choking
• confusion
• difficult or troubled breathing
• drowsiness
• dry mouth
• fast heartbeat
• hyperventilation
• irregular heartbeats
• irregular, fast or slow, or shallow breathing
• irritability
• lightheadedness, dizziness, or fainting
• nausea
• nervousness
• noisy breathing
• pale or blue lips, fingernails, or skin
• restlessness
• shaking
• shortness of breath
• slow or irregular heartbeat
• tightness in the chest
• trouble sleeping
• unable to speak
• unusual tiredness
• weakness
• wheezing

• Attack, assault, or force
• changes in patterns and rhythms of speech
• feeling of constant movement of self or surroundings
• headache
• lack or loss of self-control
• loss of balance
• mood swings
• noisy breathing
• not breathing
• restlessness
• seeing, hearing, or feeling things that are not there
• sensation of spinning
• shakiness and unsteady walk
• sleepiness
• slow to respond
• slurred speech
• trouble in speaking
• unconsciousness
• unsteadiness, trembling, or other problems with muscle control or coordination

Get emergency help immediately if any of the following symptoms of overdose occur while taking midazolam:

• Change in consciousness
• difficulty with coordination
• loss of consciousness
• sleepiness or unusual drowsiness

Some side effects of midazolam may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Vomiting

• Rash

• Blurred vision
• double vision
• gagging
• hiccups
• seeing double
• watering of mouth and drooling

Parenteral:
CONTINUOUS INFUSION:
Preterm and term neonates:
Less than 32 weeks with tracheal intubation:
-Initial dose: 0.03 mg/kg/hr (0.5 mcg/kg/min) IV

Over 32 weeks with tracheal intubation:
-Initial dose: 0.06 mg/kg/hr (1 mcg/kg/min) IV

Non-neonates and children:
Unpremedicated patients with tracheal intubation:
-Loading dose: 0.05 to 0.2 mg/kg IV once, administered over 2 to 3 minutes
-Initial dose: 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min)

Premedicated patients with tracheal intubation:
-Initial dose: 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min)

Hemodynamically compromised patients:
-Loading dose: The usual loading dosed should be increased in small increments.

Comments:
-To establish therapeutic plasma levels in neonates, the infusion should be run more rapidly for the first several hours.
-Infusion rates should be reassessed to ensure that the lowest effective dose is used, especially after the first 24 hours.
-Extreme caution should be used in current/former preterm patients who do not have tracheal intubation.
-The rate of continuous infusion may be increased or decreased (e.g., usually by 25% of the initial/subsequent rate) as necessary in premedicated non-neonates. Supplemental IV doses may be given to increase/maintain the desired effect.
-Patients should be monitored closely for hemodynamic instability, respiratory rate, and oxygen saturation, especially when this drug is used in those with hemodynamic instability.

Use: Sedation of intubated and mechanically ventilated patients during treatment in a critical care setting

Data not available

This drug is only recommended for use during pregnancy when there are no alternatives and the benefit outweighs the risk. AU TGA pregnancy category: C US FDA pregnancy category: D Comments: -If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. -Neonates exposed to this drug in the last weeks of pregnancy or in high doses during labor and delivery should be monitored for irregularities in fetal heart rate, hypotonia, poor sucking, hypothermia, and moderate respiratory depression. -If used during pregnancy, monitor the newborn for acute withdrawal syndrome symptoms during the postnatal period.

Human studies suggest that benzodiazepine-associated teratogenicity and congenital malformations could occur with use. There are no data on exposed pregnancies during the first 2 trimesters, and use during the third trimester could affect brain development. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Summary of Use during Lactation

The small amounts of midazolam excreted into breastmilk would not be expected to cause adverse effects in most breastfed infants. Two expert panels advocates waiting for at least 4 hours after a single intravenous dose of midazolam (e.g., for endoscopy) before resuming nursing.[1][2] However, no waiting period or discarding of milk might be necessary before resuming breastfeeding after a single dose of midazolam in the mothers of infants over 2 months of age. After general anesthesia, breastfeeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia to nurse.[3][4][5] When a combination of anesthetic agents is used for a procedure, follow the recommendations for the most problematic medication used during the procedure. With prolonged use (days) of intravenous therapy, an active metabolite can accumulate in the mother and might affect the infant, but data in breastfeeding are lacking.

Drug Levels

Midazolam is about 36% bioavailable orally in adults. It is metabolized to 1-hydroxymidazolam (60 to 70%) and 4-hydroxymidazolam (5%) which are about equipotent to midazolam. The half-life of 1-hydroxymidazolam is about 12 hours in adults and can accumulate with prolonged or repeated doses or in renal impairment.

Maternal Levels. Twelve mothers were given a total of 30 doses of oral midazolam 15 mg for sleep in the first 5 days postpartum if they requested it. In 11 of the mothers, midazolam was unmeasurable (<3 mcg/L) in breastmilk 7 hours after the dose. One of the mothers accidentally took a second tablet (30 mg total) on one occasion and had a 7-hour milk level of 9 mcg/L. No accumulation occurred with repeated nightly doses in any of the mothers. Two additional women who were 2 to 3 months postpartum had hourly milk sampling after a single 15 mg dose. Peak milk levels of both the drug and metabolite occurred at 1 and 2 hours after the dose in the 2 patients. Peak milk levels of midazolam plus 1-hydroxymidazolam were about 13 mcg/L and the average milk level over the 7-hour period was 6.7 mcg/L.[6] Using these values, an infant exclusively nursing for 7 hours after a dose would receive about 0.3 mcg of the drug plus metabolite.

A mother undergoing surgery received a single 6 mg dose of midazolam intravenously for anesthesia induction. Breastmilk concentration of midazolam was 25 mcg/L at 30 minutes after the dose, 12 mcg/L at 1 hour after the dose and 7 mcg/L at 2 hours after the dose. From 4 hours onward the drug was unmeasurable (<5 mcg/L). Hydroxymidazolam was not measured.[7]

Five women who were 6 to 15 weeks postpartum were given a single dose of 2 mg of midazolam intravenously before undergoing general anesthesia. Several milk samples were collected between 5 and 24 hours after the injection from each woman. The authors estimated that the infants would receive an average of 0.016 mcg/kg in the 24 hours after a single dose of midazolam. This corresponds to 0.06% of the maternal weight-adjusted dosage. Hydroxymidazolam was not measured. The women's milk output following the surgical procedure was less than half of the normal milk output of nursing mothers. The authors concluded that this amount of midazolam in milk is unlikely to affect a healthy, term infant.[5][8] The infants of mothers not undergoing a surgical procedure might receive a greater dose of midazolam in breastmilk, but it would be unlikely to be a large dose.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

In a telephone follow-up study, 124 mothers who took a benzodiazepine while nursing reported whether their infants had any signs of sedation. Nineteen mothers took midazolam (presumably orally) while breastfeeding and none reported sedation in her infant.[9]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

(Intravenous Sedation) Methohexital, Propofol, (Sleep) Zaleplon, Zolpidem

References

1. Shergill AK, Ben-Menachem T, Chandrasekhara V et al. Guidelines for endoscopy in pregnant and lactating women. Gastrointest Endosc. 2012;76:18-24. PMID: 22579258

2. Vargo JJ, Delegge MH, Feld AD et al. Multisociety sedation curriculum for gastrointestinal endoscopy. Gastroenterology. 2012;143:e18-41. PMID: 22624720

3. Lee JJ, Rubin AP. Breast feeding and anaesthesia. Anaesthesia. 1993;48:616-25. PMID: 8346780

4. Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand. 1994;38:94-103. PMID: 8171959

5. Nitsun M, Szokol JW, Saleh HJ et al. Pharmacokinetics of midazolam, propofol, and fentanyl transfer to human breast milk. Clin Pharmacol Ther. 2006;79:549-57. PMID: 16765143

6. Matheson I, Lunde PKM, Bredesen JE. Midazolam and nitrazepam in the maternity ward: milk concentrations and clinical effects. Br J Clin Pharmacol. 1990;30:787-93. PMID: 2288825

7. Koitabashi T, Satoh N, Takino Y. Intravenous midazolam passage into breast milk. J Anesth. 1997;11:242-3.

8. Avram MJ, Nitsun M et al. Midazolam elimination in human breast milk. Clin Pharmacol Ther. 2006;79 (Suppl S) :P7. Abstract OII-C DOI: doi:10.1016/j.clpt.2005.12.021

9. Kelly LE, Poon S, Madadi P, Koren G. Neonatal benzodiazepines exposure during breastfeeding. J Pediatr. 2012;161:448-51. PMID: 22504099

LactMed Record Number

369

Last Revision Date

20140708

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.