CLASSES

Anticonvulsants, Benzodiazepines
Anxiolytics, Benzodiazepines
Benzodiazepine Anesthetics
Benzodiazepine Sedative/Hypnotics

BOXED WARNING

Parenteral and oral administration of midazolam requires an experienced clinician trained in the use of resuscitative equipment and skilled in airway management. Use of these dosage forms also requires a specialized care setting that can provide continuous monitoring of respiratory and cardiac functioning; oral midazolam should not be administered at home or outside the care setting in which procedures will be performed. Midazolam has been associated with respiratory depression and respiratory arrest, especially when given via intravenous administration for procedural sedation. Death or hypoxic encephalopathy has resulted in some instances where these symptoms were not recognized or properly treated. Individualize the midazolam dose based on the patient's age, weight, indication, concomitant medications, and disease history. High risk surgical and debilitated patients, patients undergoing upper airway procedures (i.e., endoscopy), and those with hemodynamic compromise may need lower dosages of midazolam with close monitoring. Many of these patients may be vulnerable to hypoventilation or reduced elimination of midazolam. Prior to administration of oral or parenteral dosage forms, ensure the immediate availability of oxygen, resuscitative drugs, and age- and size-appropriate ventilation and intubation equipment. Monitor patients for early signs of respiratory insufficiency, respiratory depression, hypoventilation, airway obstruction, or apnea (i.e., via pulse oximetry), which may lead to hypoxia and/or cardiac arrest. Have flumazenil available for immediate use. For deeply sedated patients receiving midazolam for procedural sedation, a dedicated individual, other than the person performing the procedure, should monitor the patient. When used for sedation/anxiolysis/amnesia, administer IV midazolam over at least 2 minutes and wait an additional 2 minutes to assess sedation before administering an additional dose. For patients who are prescribed intranasal midazolam for seizure rescue and are at increased risk for respiratory depression, consider administration under medical supervision, in the absence of a seizure episode, prior to treatment. Counsel patients and caregivers on appropriate use at home. Continuous monitoring of respiratory and cardiac function is recommended in patients with status epilepticus after treatment with midazolam until the patient is stabilized.

Patients receiving midazolam should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea, i.e., pulse oximetry. Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.[44859] As with other benzodiazepines, midazolam should be used with extreme caution in patients with severe pulmonary disease or conditions associated with respiratory insufficiency such as sleep apnea, cyanotic congenital heart disease, pulmonary hypertension, pneumonia, status asthmaticus, or severe chronic obstructive pulmonary disease (COPD). Midazolam is commonly administered with other agents used in anesthesia, including opioid agonists. However, avoid coadministration with other CNS depressants, especially opioids, unless no other alternatives are available as coadministration significantly increases the risk for respiratory depression, low blood pressure, and death.[44859] [61143] Hypoventilation, airway obstruction, and apnea are more likely to occur when midazolam is administered to patients with decreased pulmonary reserve, significant CNS depression, or ethanol intoxication. Hypercarbia and hypoxia after premedication with oral midazolam may pose a risk to patients with congenital heart disease and pulmonary hypertension. Cardiorespiratory effects may be more likely in ASA-PS III or IV patients. Carefully monitor respiratory status and oxygen saturation in at risk patients. For patients who are prescribed intranasal midazolam for seizure rescue and are at increased risk for respiratory depression, consider administration under medical supervision, in the absence of a seizure episode, prior to treatment. Counsel patients and caregivers on appropriate use at home.

Do not use intranasal midazolam to treat more than 1 episode of acute repetitive convulsions every 3 days and for no more than 5 episodes per month. Chronic daily use may promote tolerance and increase the frequency and/or severity of tonic-clonic convulsions. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. Patients receiving continuous infusion of midazolam in critical care settings over an extended period of time, may experience symptoms of withdrawal following abrupt discontinuation. The risks of physiological dependence and withdrawal increase with longer treatment duration and higher daily dose. Benzodiazepine dependence can occur after administration of therapeutic doses for as few as 1 to 2 weeks and withdrawal symptoms may be seen after the discontinuation of therapy. To reduce the risk of acute withdrawal reactions, use a gradual taper to reduce the dosage or to discontinue benzodiazepines. No standard benzodiazepine tapering schedule is suitable for all patients; therefore, create a patient-specific plan to gradually reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently, decrease the dosage more slowly. Benzodiazepine withdrawal also can be more intense if the benzodiazepine involved possesses a relatively short duration of action such as midazolam. Patients with a history of a seizure disorder should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating seizures; status epilepticus has also been reported. Clinicians should be aware that the use of flumazenil may increase the risk of seizures, particularly in long-term users of benzodiazepines.

Avoid rapid IV administration of midazolam (less than 2 minutes) in neonates due to the risk of severe hypotension, hypoventilation, and/or seizures, particularly if the neonate has received fentanyl. The same precaution applies to rapid injections of fentanyl while the neonate is receiving midazolam continuous infusions. Premature neonates have significantly slower clearance of midazolam compared to other populations; use extreme caution with dosage titration in this population. Some midazolam injectable products contain benzyl alcohol as a preservative; use preservative free products in neonates whenever possible. Although dose ranges for preterm and term newborns are well below that which would lead to benzyl alcohol toxicity, the clinician should be aware of the toxic potential, especially if other drugs containing benzyl alcohol are administered. Excessive amounts of the preservative benzyl alcohol in newborns have been associated with hypotension, metabolic acidosis, and kernicterus. A "gasping syndrome" characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates. However, the minimum amount of benzyl alcohol at which toxicity may occur is unknown and premature and low-birth-weight neonates may be more likely to develop toxicity. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in neonates, infants, and children younger than 3 years, including in utero exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in young children against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development.

Use midazolam with caution in patients with a history of alcoholism or substance abuse due to the potential for psychological dependence. The use of benzodiazepines exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive benzodiazepines routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate treatment in any patient, but requires more intensive counseling and monitoring. To discourage abuse, the smallest appropriate quantity of the benzodiazepine should be prescribed, and proper disposal instructions for unused drug should be given to patients. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, and death. Advise patients to seek immediate medical attention if they experience symptoms such as trouble breathing. Available data suggest the benzodiazepine dependence potential of midazolam is at least equivalent to that of diazepam. No statistically significant or clinically relevant differences in subjective positive effects (e.g., Drug Liking, Overall Drug Liking, Take Drug Again, and High) were reported in a comparative assessment of intranasal and oral midazolam in adult patients with a history of benzodiazepine recreational use; however, subjective positive effects on all these measures were significantly greater for intranasal midazolam when compared to placebo confirming that intranasal midazolam has abuse potential.

DEA CLASS

Rx, schedule IV

DESCRIPTION

Oral/parenteral/intranasal short-acting benzodiazepine
Used for sedation, anxiolysis, amnesia, and acutely for seizures
Black-box warning describing risk of profound sedation and respiratory depression with concomitant opioid use

COMMON BRAND NAMES

Nayzilam, Versed, Versed Syrup

HOW SUPPLIED

Midazolam Hydrochloride/Versed Intramuscular Inj Sol: 1mg, 1mL, 5mg
Midazolam Hydrochloride/Versed/Versed Syrup Oral Syrup: 1mL, 2mg
Midazolam Intravenous Inj Susp: 1mg, 1mL
Midazolam/Midazolam Hydrochloride/Versed Intravenous Inj Sol: 1mg, 1mL, 5mg
Nayzilam Nasal Spray Met: 1actuation, 5mg

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

1 spray (5 mg)/dose intranasal up to 2 doses/episode for acute repetitive seizures; 10 mg IM for status epilepticus. Specific maximum dosage information for other routes or indications is not available; the dose required is dependent on route of administration, indication for therapy, and clinical response.

1 spray (5 mg)/dose intranasal up to 2 doses/episode for acute repetitive seizures; 10 mg IM for status epilepticus. Specific maximum dosage information for other routes or indications is not available; the dose required is dependent on route of administration, indication for therapy, and clinical response.

1 mg/kg (Max: 20 mg) PO total dose for procedural sedation; a total dose up to 10 mg IV may be necessary for amnesia induction; 1 spray (5 mg)/dose intranasal up to 2 doses/episode for acute repetitive seizures; specific maximum dosage information for other routes or indications is not available; the dose required is dependent on route of administration, indication, and clinical response.

12 years: 1 mg/kg (Max: 20 mg) PO total dose for procedural sedation; a total dose up to 0.6 mg/kg (Max: 6 mg) IV may be necessary for amnesia induction; 1 spray (5 mg)/dose intranasal up to 2 doses/episode for acute repetitive seizures; specific maximum dosage information for other routes or indications is not available; the dose required is dependent on route of administration, indication, and clinical response.
1 to 11 years: 1 mg/kg (Max: 20 mg) PO total dose for procedural sedation; a total dose up to 0.6 mg/kg (Max: 6 mg) IV may be necessary for amnesia induction; specific maximum dosage information for other routes or indications is not available; the dose required is dependent on route of administration, indication, and clinical response.

6 to 11 months: 1 mg/kg PO total dose for procedural sedation; a total dose up to 0.6 mg/kg IV may be necessary for amnesia induction; specific maximum dosage information for other routes or indications is not available; the dose required is dependent on route of administration, indication, and clinical response.
1 to 5 months: Specific maximum dosage information is not available; the dose required is dependent on route of administration, indication, and clinical response.

Specific maximum dosage information is not available; the dose required is dependent on route of administration, indication, and clinical response.

DOSING CONSIDERATIONS

Dosage should be modified depending on clinical response and degree of hepatic impairment, but no quantitative recommendations are available.

Dosage adjustment may be necessary in patients with renal impairment as the half-life of midazolam and its active metabolite are prolonged; specific guidelines for dosage adjustments in adult patients with renal impairment are not available.
 
The following initial dosage adjustments have been recommended for pediatric patients :
GFR 30 mL/minute/1.73 m2 or more: No dosage adjustment necessary.
GFR 10 to 29 mL/minute/1.73 m2: Reduce usual dose by 25%.
GFR less than 10 mL/minute/1.73 m2: Reduce usual dose by 50%.
 
Intermittent Hemodialysis and Peritoneal Dialysis
Specific guidelines for dosage adjustments in adult patients are not available. It has been suggested to reduce the initial dose by 50% then titrate to desired clinical effect.

ADMINISTRATION

Administer undiluted on an empty stomach (presedation fasting). Do not mix with any water or juice prior to administration.
Measure dosage using a calibrated oral syringe.
Midazolam syrup is not intended for chronic administration.
Resuscitative medications and size-appropriate equipment for bag/valve/mask ventilation and intubation must be readily available.

Only practitioners trained in maintaining a patent airway should administer midazolam; have age- and size-appropriate resuscitative drugs and equipment readily available.[44859]
Administer parenteral midazolam to patients receiving extracorporeal membrane oxygenation (ECMO) outside of the circuit if possible; the drug is substantially adsorbed by circuit components.[51916]
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.[44859]

NOTE: Midazolam is not FDA-approved for rectal administration.
Studies have utilized the 5 mg/mL solution for injection, administered at a concentration of 1 to 5 mg/mL via a rectally inserted lubricated catheter or tube.
In one study, the original 5 mg/mL solution was diluted with saline to a concentration of 2 mg/mL unless the volume of the dose exceeded 10 mL, in which case the solution was administered undiluted (5 mg/mL).
Hold the buttock cheeks closed for 5 minutes after administration to avoid loss of the drug.

Intranasal Administration
Nayzilam
For patients at increased risk of respiratory depression, consider administration under healthcare professional supervision prior to treatment; this may be performed in the absence of a seizure episode.
Do not test or prime before use; there is only 1 dose of midazolam in the nasal spray unit. Do not open the blister package until ready to use.
Hold the nasal spray unit with a thumb on the plunger and middle and index fingers on each side of the nozzle.
Place the tip of the nozzle into 1 nostril until fingers on either side of the nozzle touch the bottom of the nose.
Press the plunger firmly to deliver the dose using 1 motion. The patient does not need to breathe deeply.
If a second dose is needed, use a new nasal spray unit in the other nostril.
Storage: Each nasal spray unit is for single use only. Throw away the unit and blister packaging into the trash after use.
 
Solution for injection
NOTE: This dosage form is not approved by the FDA for intranasal administration.
Intranasal midazolam may be administered via drop installation with a needleless syringe or spray with a mucosal atomizer device. Use of the mucosal atomizer device improves absorption.
To reduce nasal burning and bitter taste, premedicate with intranasal lidocaine spray (10 mg per puff in the nares) and give an oral drop of cherry syrup afterward. Nasal burning may last 30 seconds.
Clear the nasal passages prior to administration (e.g., suction or have the patient blow their nose).
Place the patient's head at 45 degrees.
Using the 5 mg/mL solution for injection, administer half of the total dose to each nare. Do not use more than 0.5 to 1 mL of medication per nostril. If a higher dose is required, apply it in 2 separate doses a few minutes apart to allow for adequate absorption of the first dose.
For administration with a mucosal atomizer device, compress the device quickly.
For administration with a needleless syringe, apply the calculated dose to the nares over 15 seconds.
The patient should remain in a semi-reclined position for several minutes after administration.
 
Buccal Administration
NOTE: Midazolam is not FDA-approved for buccal administration.
The intravenous or oral solution may be given buccally.
Apply the calculated dose to the buccal cavity between the gum and the cheek using an oral syringe.
Massage the cheek gently after administration.

STORAGE

Generic:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Discard unused portion 48 hours after initial puncture of container
- Discard unused portion. Do not store for later use.
- Protect from freezing
- Store at controlled room temperature (between 68 and 77 degrees F)
Nayzilam:
- Do not open blister until ready to administer
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Versed:
- Protect from freezing
- Protect from light
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Versed Syrup:
- Store at controlled room temperature (between 68 and 77 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

When used for short-term sedation during endotracheal intubation, midazolam does not protect against the characteristic rise in intracranial pressure, heart rate, and/or blood pressure associated with intubation under light general anesthesia.

Midazolam is contraindicated in any patient with a known or suspected hypersensitivity to midazolam or hypersensitivity to any component of the formulation. For example, some of the oral syrup formulations such as those that contain artificial cherry flavor or cherry-burgundy flavor are contraindicated in patients allergic to cherries. Patients with a benzodiazepine hypersensitivity to other benzodiazepines may experience a cross-sensitivity to midazolam. Some midazolam injectable products contain benzyl alcohol as a preservative; these products are contraindicated for intrathecal administration or epidural administration. Limited reports of seizure activity and local reactions have been associated with intraarterial administration, but a clear causal effect cannot be made. Avoid unintended intraarterial injection and local extravasation.

Use midazolam with caution in patients with a history of autism, bipolar disorder, or psychosis. Paradoxical reactions (e.g., agitation, mania) to benzodiazepines are more common in patients with psychiatric and/or personality disorders, particularly in those with a history of anger and aggression. Paradoxical stimulation and disinhibition are both more common in children compared to adults. Though they must be used with caution in this population, longer-acting benzodiazepines (lorazepam, clonazepam, diazepam) are commonly used in clinical practice for the acute management of psychosis and mania, as well as in the treatment of extrapyramidal symptoms associated with antipsychotics. Preexisting depression may emerge or worsen with the use of benzodiazepines. Although use of midazolam is limited to closely monitored inpatient use or intermittent outpatient seizure rescue, it may be prudent to closely monitor patients with a history of depression or suicidal ideation for worsening symptoms during periods of consciousness due to an increased risk of suicidal ideation and behavior in patients receiving antiepileptic drugs (AEDs). Inform patients, caregivers, and families of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Suicidal ideation or behavior has occurred as early as 1 week after AED initiation and may occur any time during treatment. A pooled analysis of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (at least 5 years of age) was conducted. There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor.

Parenteral and oral administration of midazolam requires an experienced clinician trained in the use of resuscitative equipment and skilled in airway management. Use of these dosage forms also requires a specialized care setting that can provide continuous monitoring of respiratory and cardiac functioning; oral midazolam should not be administered at home or outside the care setting in which procedures will be performed. Midazolam has been associated with respiratory depression and respiratory arrest, especially when given via intravenous administration for procedural sedation. Death or hypoxic encephalopathy has resulted in some instances where these symptoms were not recognized or properly treated. Individualize the midazolam dose based on the patient's age, weight, indication, concomitant medications, and disease history. High risk surgical and debilitated patients, patients undergoing upper airway procedures (i.e., endoscopy), and those with hemodynamic compromise may need lower dosages of midazolam with close monitoring. Many of these patients may be vulnerable to hypoventilation or reduced elimination of midazolam. Prior to administration of oral or parenteral dosage forms, ensure the immediate availability of oxygen, resuscitative drugs, and age- and size-appropriate ventilation and intubation equipment. Monitor patients for early signs of respiratory insufficiency, respiratory depression, hypoventilation, airway obstruction, or apnea (i.e., via pulse oximetry), which may lead to hypoxia and/or cardiac arrest. Have flumazenil available for immediate use. For deeply sedated patients receiving midazolam for procedural sedation, a dedicated individual, other than the person performing the procedure, should monitor the patient. When used for sedation/anxiolysis/amnesia, administer IV midazolam over at least 2 minutes and wait an additional 2 minutes to assess sedation before administering an additional dose. For patients who are prescribed intranasal midazolam for seizure rescue and are at increased risk for respiratory depression, consider administration under medical supervision, in the absence of a seizure episode, prior to treatment. Counsel patients and caregivers on appropriate use at home. Continuous monitoring of respiratory and cardiac function is recommended in patients with status epilepticus after treatment with midazolam until the patient is stabilized.

Patients receiving midazolam should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea, i.e., pulse oximetry. Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.[44859] As with other benzodiazepines, midazolam should be used with extreme caution in patients with severe pulmonary disease or conditions associated with respiratory insufficiency such as sleep apnea, cyanotic congenital heart disease, pulmonary hypertension, pneumonia, status asthmaticus, or severe chronic obstructive pulmonary disease (COPD). Midazolam is commonly administered with other agents used in anesthesia, including opioid agonists. However, avoid coadministration with other CNS depressants, especially opioids, unless no other alternatives are available as coadministration significantly increases the risk for respiratory depression, low blood pressure, and death.[44859] [61143] Hypoventilation, airway obstruction, and apnea are more likely to occur when midazolam is administered to patients with decreased pulmonary reserve, significant CNS depression, or ethanol intoxication. Hypercarbia and hypoxia after premedication with oral midazolam may pose a risk to patients with congenital heart disease and pulmonary hypertension. Cardiorespiratory effects may be more likely in ASA-PS III or IV patients. Carefully monitor respiratory status and oxygen saturation in at risk patients. For patients who are prescribed intranasal midazolam for seizure rescue and are at increased risk for respiratory depression, consider administration under medical supervision, in the absence of a seizure episode, prior to treatment. Counsel patients and caregivers on appropriate use at home.

Particular caution is required in determining the interval needed after outpatient ambulatory procedures or surgery or acute convulsions before it is safe for any patient to participate in ambulation, driving or operating machinery, or perform other tasks that require complete mental alertness. It is recommended that patients avoid operating hazardous machinery or driving a motor vehicle until the central nervous system (CNS) depressant effects have subsided or until 1 full day after surgery, whichever is longer. The effects of midazolam are additive to those of other CNS depressants, including alcohol. Patients should be advised on the avoidance of ethanol ingestion during the peri-operative or peri-procedural time frame, as appropriate to the procedure being performed. Because midazolam can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries.[44717] [44859] Injectable midazolam should not be administered to adult or pediatric patients with acute ethanol intoxication who have depression of vital signs.[44859]

Midazolam is metabolized in the liver; use with caution in patients with hepatic disease or hepatic encephalopathy. Similarly, the half-life and volume of distribution are increased in patients with congestive heart failure or obesity. FDA-approved labeling recommends dosing oral and parenteral midazolam based on ideal body weight in obese patients. Although the half-life is not significantly prolonged in patients with chronic renal failure, the peak concentrations of midazolam can be higher. The half-life of midazolam and its metabolites may be prolonged in patients with acute renal failure or renal impairment, and these patients can experience more rapid induction of and prolonged recovery from anesthesia.

Midazolam is contraindicated in patients with acute closed-angle glaucoma. Benzodiazepines can increase intraocular pressure in patients with glaucoma. Midazolam may be used in patients with open-angle glaucoma who are receiving appropriate treatment; these patients may need to have their ophthalmologic status evaluated after midazolam treatment. Measurements of intraocular pressure in patients without eye disease show a moderate lowering after induction of general anesthesia with midazolam; patients with glaucoma have not been studied.

Do not use intranasal midazolam to treat more than 1 episode of acute repetitive convulsions every 3 days and for no more than 5 episodes per month. Chronic daily use may promote tolerance and increase the frequency and/or severity of tonic-clonic convulsions. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. Patients receiving continuous infusion of midazolam in critical care settings over an extended period of time, may experience symptoms of withdrawal following abrupt discontinuation. The risks of physiological dependence and withdrawal increase with longer treatment duration and higher daily dose. Benzodiazepine dependence can occur after administration of therapeutic doses for as few as 1 to 2 weeks and withdrawal symptoms may be seen after the discontinuation of therapy. To reduce the risk of acute withdrawal reactions, use a gradual taper to reduce the dosage or to discontinue benzodiazepines. No standard benzodiazepine tapering schedule is suitable for all patients; therefore, create a patient-specific plan to gradually reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently, decrease the dosage more slowly. Benzodiazepine withdrawal also can be more intense if the benzodiazepine involved possesses a relatively short duration of action such as midazolam. Patients with a history of a seizure disorder should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating seizures; status epilepticus has also been reported. Clinicians should be aware that the use of flumazenil may increase the risk of seizures, particularly in long-term users of benzodiazepines.

Intravenous doses of midazolam should be decreased for debilitated adults or geriatric patients more than 60 years of age. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Geriatric patients are more sensitive to midazolam effects such as drowsiness, hypoxemia, and depressed ventilation. Because midazolam can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. According to the Beers Criteria, avoidance of benzodiazepines is generally recommended, although some agents, like midazolam, may be appropriate for peri-procedural anesthesia and critical care administration. Older adults have an increased sensitivity to benzodiazepines. Due to its primary use in acute procedural, surgical or critical care settings, midazolam is not specifically listed in the Beers Criteria. Avoid other benzodiazepines in geriatric patients when possible in the following due to the potential for symptom exacerbation or adverse effects in older adults: cognitive impairment, delirium (new-onset or worsening delirium), dementia (adverse CNS effects), and falls/fractures. All benzodiazepines increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults due to ataxia, impaired psychomotor function, and syncope. If a benzodiazepine must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk.

Avoid rapid IV administration of midazolam (less than 2 minutes) in neonates due to the risk of severe hypotension, hypoventilation, and/or seizures, particularly if the neonate has received fentanyl. The same precaution applies to rapid injections of fentanyl while the neonate is receiving midazolam continuous infusions. Premature neonates have significantly slower clearance of midazolam compared to other populations; use extreme caution with dosage titration in this population. Some midazolam injectable products contain benzyl alcohol as a preservative; use preservative free products in neonates whenever possible. Although dose ranges for preterm and term newborns are well below that which would lead to benzyl alcohol toxicity, the clinician should be aware of the toxic potential, especially if other drugs containing benzyl alcohol are administered. Excessive amounts of the preservative benzyl alcohol in newborns have been associated with hypotension, metabolic acidosis, and kernicterus. A "gasping syndrome" characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates. However, the minimum amount of benzyl alcohol at which toxicity may occur is unknown and premature and low-birth-weight neonates may be more likely to develop toxicity. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in neonates, infants, and children younger than 3 years, including in utero exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in young children against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development.

Midazolam can cause significant hypotension and should not be administered to patients in shock or coma that is not medically-induced. Use with caution in all patients with cardiac disease, depressed vital signs, and/or uncompensated acute illnesses, such as severe electrolyte imbalance, hypovolemia, and dehydration. If hypotension develops, countermeasures including intravenous fluid therapy, repositioning, and judicious use of vasopressors may be considered. Hypotension may be more pronounced when midazolam is administered with an opioid; when given together, use smaller initial doses of both the opioid and midazolam and titrate the dosages in small increments. In addition, use midazolam with extreme caution in patients with poor ventricular function and elevated ventricular end-diastolic pressure, as it can compromise cardiac output and coronary perfusion.

There are no adequate data on the effects midazolam use during human pregnancy. Recent case-control and cohort studies of benzodiazepine use during pregnancy have not confirmed increased risks of congenital malformations previously reported with early studies of benzodiazepines, including diazepam and chlordiazepoxide. No adverse effects in offspring were observed when rats and rabbits were given intravenous midazolam during organogenesis, late gestation, and early lactation at exposures up to 1.85 the human induction dose of 0.35 mg/kg based on body surface area comparison. Benzodiazepines are not recommended for use in labor or obstetric delivery, including cesarean section due to risks of residual pharmacological effects in the neonate. Monitor neonates exposed to benzodiazepines during pregnancy, labor, or obstetric delivery for signs of sedation, respiratory depression, or lethargy, and manage accordingly. Use of benzodiazepines late in pregnancy may result in a neonatal abstinence syndrome (NAS) or floppy infant syndrome (FIS). Monitor the neonate for hypotonia and withdrawal symptoms, including hyperreflexia, irritability, restlessness, tremors, inconsolable crying, or feeding difficulties and manage accordingly.  The incidence, time to onset, and duration of NAS or FIS symptoms is multi-factorial (e.g., duration of use, drug lipophilicity, placental disposition, degree of accumulation in neonatal tissues). FIS typically occurs after chronic fetal exposure to long-acting benzodiazepines (e.g., chlordiazepoxide), or when benzodiazepines are administered shortly before delivery, resulting in newborn toxicity of variable severity and duration. FIS primarily occurs within the first few hours after labor and may last for up to 14 days. If a benzodiazepine is required during pregnancy, avoid first trimester administration if possible, consider short-acting agents, limit treatment to the lowest effective dosage and duration, and discontinue the drug well before delivery. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures during the third trimester of pregnancy may have negative effects on fetal brain development. Consider the benefits of appropriate anesthesia in pregnant women against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required prior to delivery. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child and/or mother. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development.[61572] Some guidelines support the use of midazolam for endoscopy or other brief procedures when needed, in a single dose, with a preference to avoid use in the first trimester when possible.[63911] There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to antiepileptic drugs such as midazolam; information about the registry can be obtained at https://www.aedpregnancyregistry.org/ or by calling 1-888-233-2334.

Use caution when midazolam is administered during breast-feeding. Midazolam is present in human milk at low concentrations. The effects of midazolam on milk production are unknown. Consider interrupting breast-feeding and pumping for at least 4 to 8 hours after midazolam administration to minimize infant exposure. Monitor breastfed infants exposed to benzodiazepines through breast milk for sedation, poor feeding, and poor weight gain.[44859] [63911]  Midazolam and the hydroxy-midazolam metabolite are distributed into breast milk in detectable concentrations within a few hours after a single IV dose and within 4 to 6 hours after oral dosing.[46778] The median infant midazolam dose over 24 hours was 0.016 mcg/kg after a 2 mg IV dose before general anesthesia induction in 5 lactating women with average milk production of 324 +/- 159 mL in 24 hours.[62842] Consider the benefits of breast-feeding along with the clinical need for midazolam and any potential adverse effects on the breastfed infant from midazolam or the underlying maternal condition.

Use midazolam with caution in patients with a history of alcoholism or substance abuse due to the potential for psychological dependence. The use of benzodiazepines exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive benzodiazepines routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate treatment in any patient, but requires more intensive counseling and monitoring. To discourage abuse, the smallest appropriate quantity of the benzodiazepine should be prescribed, and proper disposal instructions for unused drug should be given to patients. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, and death. Advise patients to seek immediate medical attention if they experience symptoms such as trouble breathing. Available data suggest the benzodiazepine dependence potential of midazolam is at least equivalent to that of diazepam. No statistically significant or clinically relevant differences in subjective positive effects (e.g., Drug Liking, Overall Drug Liking, Take Drug Again, and High) were reported in a comparative assessment of intranasal and oral midazolam in adult patients with a history of benzodiazepine recreational use; however, subjective positive effects on all these measures were significantly greater for intranasal midazolam when compared to placebo confirming that intranasal midazolam has abuse potential.

ADVERSE REACTIONS

apnea / Delayed / 2.8-15.4
renal failure / Delayed / 2.0-2.0
laryngospasm / Rapid / 0-1.0
bronchospasm / Rapid / 0-1.0
bradycardia / Rapid / 0-1.0
visual impairment / Early / 0-1.0
anaphylactoid reactions / Rapid / 0-1.0
seizures / Delayed / 0-1.0
cardiac arrest / Early / Incidence not known
respiratory arrest / Rapid / Incidence not known
neonatal abstinence syndrome / Early / Incidence not known
neonatal respiratory depression / Rapid / Incidence not known

respiratory depression / Rapid / 8.0-23.3
hypotension / Rapid / 0-2.7
erythema / Early / 0.5-2.6
dysarthria / Delayed / 0-2.0
nystagmus / Delayed / 1.1-1.1
amnesia / Delayed / 0-1.0
tachypnea / Early / 0-1.0
dyspnea / Early / 0-1.0
wheezing / Rapid / 0-1.0
premature ventricular contractions (PVCs) / Early / 0-1.0
sinus tachycardia / Rapid / 0-1.0
excitability / Early / 0-1.0
euphoria / Early / 0-1.0
ataxia / Delayed / 0-1.0
delirium / Early / 0-1.0
confusion / Early / 0-1.0
dysphoria / Early / 0-1.0
hallucinations / Early / 0-1.0
dysphonia / Delayed / 0-1.0
blurred vision / Early / 0-1.0
hematoma / Early / 0-1.0
phlebitis / Rapid / 0.4-0.4
tolerance / Delayed / Incidence not known
withdrawal / Early / Incidence not known
physiological dependence / Delayed / Incidence not known
psychological dependence / Delayed / Incidence not known
memory impairment / Delayed / Incidence not known
hypoxia / Early / Incidence not known
hypoventilation / Rapid / Incidence not known
myoclonia / Delayed / Incidence not known
hyperreflexia / Delayed / Incidence not known
mania / Early / Incidence not known
involuntary movements / Delayed / Incidence not known
hostility / Early / Incidence not known
psychosis / Early / Incidence not known

drowsiness / Early / 1.2-10.0
injection site reaction / Rapid / 0-5.6
agitation / Early / 0-4.0
headache / Early / 1.3-4.0
fever / Early / 4.0-4.0
hiccups / Early / 1.2-3.9
rhinorrhea / Early / 0.7-3.0
throat irritation / Early / 3.0-3.0
nausea / Early / 1.5-2.8
vomiting / Early / 0.7-2.6
dysgeusia / Early / 0-2.0
lacrimation / Early / 2.0-2.0
cough / Delayed / 1.3-1.3
yawning / Early / 0-1.0
hyperventilation / Early / 0-1.0
anxiety / Delayed / 0-1.0
restlessness / Early / 0-1.0
nightmares / Early / 0-1.0
vertigo / Early / 0-1.0
insomnia / Early / 0-1.0
emotional lability / Early / 0-1.0
paresthesias / Delayed / 0-1.0
dizziness / Early / 0-1.0
hypersalivation / Early / 0-1.0
diplopia / Early / 0-1.0
rash / Early / 0-1.0
urticaria / Rapid / 0-1.0
pruritus / Rapid / 0-1.0
weakness / Early / 0-1.0
lethargy / Early / 0-1.0
chills / Rapid / 0-1.0
dental pain / Delayed / 0-1.0
sneezing / Early / 0.7-0.7
irritability / Delayed / Incidence not known
tremor / Early / Incidence not known
nasal irritation / Early / Incidence not known

DRUG INTERACTIONS

Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Acetaminophen; Chlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Diphenhydramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Acetaminophen; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Pentazocine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Acrivastine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Adagrasib: (Major) Avoid coadministration of midazolam with adagrasib. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and adagrasib is a CYP3A inhibitor. Concomitant use of adagrasib 400 mg twice daily has been observed to increase midazolam overall exposure by 21-fold and 600 mg twice daily is predicted to increase midazolam overall exposure by 31-fold.
Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS activity. Use with caution.
Alfentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Alogliptin; Pioglitazone: (Minor) Administration of pioglitazone for 15 days followed by a single dose midazolam syrup, 7.5 mg PO, resulted in a 26% reduction in the midazolam AUC. Higher doses of midazolam may be necessary when coadministered with pioglitazone.
Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
Amiodarone: (Moderate) Coadministration of amiodarone, a CYP3A4 inhibitor, and midazolam, a CYP3A4 substrate, may result in increased serum concentrations of midazolam. The sedative effects of midazolam may be potentiated and prolonged. Monitor patients closely and consider a midazolam dosage reduction in patients receiving concurrent amiodarone therapy.
Amobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Amoxapine: (Moderate) Amoxapine may enhance the response to the effects of benzodiazepines and other CNS depressants. Patients should be warned of the possibility of drowsiness that may impair performance of potentially hazardous tasks such as driving an automobile or operating machinery.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Dose adjustments of oral midazolam may be necessary when coadministered with clarithromycin. Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as clarithromycin, can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent. (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as midazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
Apalutamide: (Major) Monitor for withdrawal symptoms or lack of midazolam efficacy if coadministration with apalutamide is necessary. Midazolam is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with apalutamide decreased single-dose midazolam exposure by 92%.
Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and benzodiazepines could result in additive depressant effects.
Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as the anxiolytics, sedatives, and hypnotics, including barbiturates or benzodiazepines.
Aprepitant, Fosaprepitant: (Moderate) Use caution if midazolam and aprepitant are used concurrently and monitor for an increase in midazolam-related adverse effects for several days after administration of a multi-day aprepitant regimen. If a benzodiazepine is necessary, a dosage adjustment of the multi-day regimen may be necessary depending on the clinical situation (e.g., geriatric patients) and degree of monitoring available; no dosage adjustment is needed for a single 40-mg or 150-mg dose of aprepitant. Consider selection of an agent that is not metabolized via CYP3A4 isoenzymes (e.g., lorazepam, oxazepam, temazepam). Midazolam is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of midazolam. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Moderate) Monitor blood pressure and for unusual drowsiness and sedation during coadministration of aripiprazole and benzodiazepines. Intensity of sedation and orthostatic hypotension were greater with the combination of oral aripiprazole and lorazepam compared to aripiprazole alone.
Armodafinil: (Moderate) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Therefore, armodafinil may induce the metabolism of benzodiazepines which are substrates for CYP3A, including midazolam. Concurrent administration of armodafinil with midazolam resulted in a 32% reduction in systemic exposure of midazolam. Dosage adjustments of midazolam may be required during initiation or discontinuation of armodafinil.
Asciminib: (Moderate) Use caution when midazolam is coadministered with asciminib. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and asciminib is a weak CYP3A inhibitor. Coadministration of midazolam with asciminib 40 mg twice daily, 80 mg once daily, and 200 mg twice daily increased the exposure of midazolam by 28%, 24%, and 88%, respectively.
Asenapine: (Moderate) Drugs that can cause CNS depression, if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when asenapine is given in combination with other centrally-acting medications including anxiolytics, sedatives, and hypnotics (including barbiturates), buprenorphine, buprenorphine; naloxone, butorphanol, dronabinol, THC, nabilone, nalbuphine, opiate agonists, pentazocine, acetaminophen; pentazocine, aspirin, ASA; pentazocine, and pentazocine; naloxone.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Aspirin, ASA; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Aspirin, ASA; Omeprazole: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as midazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Atazanavir; Cobicistat: (Major) Use of orally administered midazolam with cobicistat is contraindicated due to the risk for prolonged/increased sedation and respiratory depression. Midazolam is extensively metabolized by CYP3A4; cobicistat is a strong inhibitor of this enzyme. Concurrent use is expected to produce large increases in the plasma concentrations of midazolam. Elevations in midazolam concentrations may also be observed with the parenteral formulation of midazolam; however, this formulation may be administered with cobicistat if given in as setting with close clinical monitoring and appropriate medical management. Consider reducing the dose of parenteral midazolam.
Atropine; Difenoxin: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent.
Avacopan: (Moderate) Use caution when midazolam is coadministered with avacopan. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Azelastine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of azelastine and benzodiazepines. Concurrent use may result in additive CNS depression.
Azelastine; Fluticasone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of azelastine and benzodiazepines. Concurrent use may result in additive CNS depression.
Barbiturates: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Belladonna; Opium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Belumosudil: (Moderate) Use caution when midazolam is coadministered with belumosudil. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and belumosudil is a weak CYP3A inhibitor. Coadministration of belumosudil is predicted to increase the midazolam AUC value by approximately 1.5-fold.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Benztropine: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
Berotralstat: (Major) Avoid coadministration of midazolam with berotralstat. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and berotralstat is a CYP3A4 inhibitor.
Bicalutamide: (Moderate) Use caution when midazolam is coadministered with bicalutamide. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor. Clinical studies have shown that bicalutamide may increase mean midazolam exposure by 1.5-fold for Cmax and 1.9-fold for AUC.
Brexanolone: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
Brompheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Brompheniramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Brompheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Buprenorphine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Buprenorphine; Naloxone: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Bupropion: (Moderate) Bupropion is contraindicated in patients undergoing abrupt withdrawal of benzodiazepines since the risk of seizures associated with bupropion may be increased. Excessive use of benzodiazepines is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion.
Bupropion; Naltrexone: (Moderate) Bupropion is contraindicated in patients undergoing abrupt withdrawal of benzodiazepines since the risk of seizures associated with bupropion may be increased. Excessive use of benzodiazepines is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion.
Buspirone: (Moderate) It is common for patients to overlap anxiety treatment when switching from benzodiazepines to buspirone. Buspirone has a slow onset of action and the drug will not block the withdrawal syndrome often seen with cessation of benzodiazepine therapy in those with benzodiazepine dependence. Therefore, before starting therapy with buspirone, withdraw patients gradually from the benzodiazepine. Alternatively, conversion to buspirone therapy may require treatment overlap to allow for the downward titration of the benzodiazepine while buspirone takes effect. It should be noted that the combination of buspirone and benzodiazepines can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Butabarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Butalbital; Acetaminophen: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Butalbital; Acetaminophen; Caffeine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Butorphanol: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Caffeine; Sodium Benzoate: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and midazolam. CNS depressants can potentiate the effects of cannabidiol.
Carbamazepine: (Moderate) Carbamazepine is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving carbamazepine may require higher doses of midazolam to achieve the desired clinical effect.
Carbinoxamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Carbinoxamine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Carbinoxamine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.
Celecoxib; Tramadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Ceritinib: (Moderate) Monitor for increased sedation and respiratory depression if coadministration of midazolam with ceritinib is necessary. Midazolam is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Daily administration of ceritinib increased the AUC and Cmax of single-dose midazolam by 5.4-fold and 1.8-fold, respectively.
Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with benzodiazepines should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with benzodiazepines should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Chlophedianol; Dexbrompheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorcyclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Dextromethorphan: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Chlorpheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorthalidone; Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
Cimetidine: (Moderate) Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as cimetidine, can potentiate the clinical effects of midazolam.
Ciprofloxacin: (Moderate) Ciprofloxacin is a CYP3A4 inhibitor and may reduce the metabolism of midazolam and increase the potential for benzodiazepine toxicity. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.
Cisapride: (Moderate) Cisapride may enhance the sedative effects of benzodiazepines. Patients should not drive or operate heavy machinery until they know how the combination affects them. Patient counseling is important, as cisapride alone does not cause drowsiness or affect psychomotor function.
Clarithromycin: (Major) Dose adjustments of oral midazolam may be necessary when coadministered with clarithromycin. Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as clarithromycin, can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.
Clemastine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Clobazam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OCT1, and midazolam, an inhibitor of OCT1, may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OCT1 inhibitors.
Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
Clozapine: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Cobicistat: (Major) Use of orally administered midazolam with cobicistat is contraindicated due to the risk for prolonged/increased sedation and respiratory depression. Midazolam is extensively metabolized by CYP3A4; cobicistat is a strong inhibitor of this enzyme. Concurrent use is expected to produce large increases in the plasma concentrations of midazolam. Elevations in midazolam concentrations may also be observed with the parenteral formulation of midazolam; however, this formulation may be administered with cobicistat if given in as setting with close clinical monitoring and appropriate medical management. Consider reducing the dose of parenteral midazolam.
Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Codeine; Guaifenesin: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Codeine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
COMT inhibitors: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Conivaptan: (Major) Avoid coadministration of midazolam with conivaptan. Concomitant use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and conivaptan is a CYP3A inhibitor. In a drug interaction study, concomitant use increase midazolam overall exposure by 100% to 200%.
Crizotinib: (Moderate) Monitor for an increase in midazolam-related adverse reactions (e.g., sedation, respiratory depression) if coadministration with crizotinib is necessary. Midazolam is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with crizotinib increased midazolam exposure by 3.7-fold.
Cyclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Cyproheptadine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dabrafenib: (Major) The concomitant use of dabrafenib and midazolam led to significantly decreased midazolam concentrations in a drug interaction study. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of midazolam efficacy. Dabrafenib is a moderate CYP3A4 inducer and midazolam is a sensitive CYP3A4 substrate. Administration of dabrafenib 150 mg twice daily for 15 days with a single 3 mg dose of midazolam decreased the AUC of midazolam by 65% in a drug interaction study.
Danazol: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs that are CYP3A4 substrates including midazolam.
Daridorexant: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with benzodiazepines. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Darifenacin: (Moderate) Darifenacin 30 mg daily coadministered with a single, oral dose of midazolam 7.5 mg resulted in a 17 percent increase is midazolam exposure.
Darunavir; Cobicistat: (Major) Use of orally administered midazolam with cobicistat is contraindicated due to the risk for prolonged/increased sedation and respiratory depression. Midazolam is extensively metabolized by CYP3A4; cobicistat is a strong inhibitor of this enzyme. Concurrent use is expected to produce large increases in the plasma concentrations of midazolam. Elevations in midazolam concentrations may also be observed with the parenteral formulation of midazolam; however, this formulation may be administered with cobicistat if given in as setting with close clinical monitoring and appropriate medical management. Consider reducing the dose of parenteral midazolam.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Use of orally administered midazolam with cobicistat is contraindicated due to the risk for prolonged/increased sedation and respiratory depression. Midazolam is extensively metabolized by CYP3A4; cobicistat is a strong inhibitor of this enzyme. Concurrent use is expected to produce large increases in the plasma concentrations of midazolam. Elevations in midazolam concentrations may also be observed with the parenteral formulation of midazolam; however, this formulation may be administered with cobicistat if given in as setting with close clinical monitoring and appropriate medical management. Consider reducing the dose of parenteral midazolam.
Deferasirox: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. If these drugs are used together, monitor patients for a decrease in the effects of midazolam.
Delavirdine: (Contraindicated) Concurrent use of delavirdine and midazolam is contraindicated. Delavirdine is a potent inhibitor of the CYP3A4; midazolam is a CYP3A4 substrate. Coadministration may potentiate the clinical effects of midazolam.
Desflurane: (Moderate) Concurrent use with benzodiazepines can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
Desogestrel; Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as midazolam, may have additive effects and worsen drowsiness or sedation.
Dexbrompheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dexchlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dexmedetomidine: (Moderate) Concurrent use of dexmedetomidine and benzodiazepines may result in additive CNS depression. A reduction in dosage of dexmedetomidine or the benzodiazepine may be required.
Dextromethorphan; Bupropion: (Moderate) Bupropion is contraindicated in patients undergoing abrupt withdrawal of benzodiazepines since the risk of seizures associated with bupropion may be increased. Excessive use of benzodiazepines is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Dicyclomine: (Moderate) Dicyclomine can cause drowsiness, so it should be used cautiously in patients receiving CNS depressants like benzodiazepines.
Dienogest; Estradiol valerate: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Diltiazem: (Moderate) Diltiazem may enhance and prolong the sedative effects of midazolam, and dosage reduction of midazolam and close monitoring is recommended during concurrent administration.
Dimenhydrinate: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Diphenhydramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Diphenhydramine; Ibuprofen: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Diphenhydramine; Naproxen: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Diphenhydramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Diphenoxylate; Atropine: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent.
Disulfiram: (Moderate) Disulfiram may decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving midazolam should be monitored for signs of altered benzodiazepine response when midazolam is coadministered.
Doxylamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Doxylamine; Pyridoxine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dronabinol: (Moderate) Use caution if the use of benzodiazepines are necessary with dronabinol, and monitor for additive dizziness, confusion, somnolence, and other CNS effects.
Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Midazolam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
Droperidol: (Major) Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes. In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. Risk factors for the development of prolonged QT syndrome may include the use of benzodiazepines. Also, droperidol and benzodiazepines can both cause CNS depression. If used with a benzodiazepine, droperidol should be initiated at a low dose and adjusted upward, with caution, as needed to achieve the desired effect.
Drospirenone; Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Drospirenone; Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Duvelisib: (Moderate) Consider reducing the dose of midazolam and monitor for signs of toxicity during coadministration with duvelisib. Coadministration may increase the exposure of midazolam. Duvelisib is a moderate CYP3A inhibitor and midazolam is a sensitive CYP3A substrate. In drug interaction studies, coadministration of duvelisib and midazolam increased the AUC of oral midazolam by approximately 4-fold.
Echinacea: (Moderate) Echinacea may inhibit intestinal CYP3A4, but induce hepatic CYP3A4. In a small study, echinacea induced the CYP3A4 metabolism of parenteral midazolam. The effect of echinacea on orally administered midazolam is unknown. Monitor for changes in efficacy or toxicity, until more data are available.
Elagolix: (Moderate) Monitor for altered response to midazolam therapy. Consider increasing the dose of midazolam and individualize therapy based on the patients response. Elagolix is a weak to moderate CYP3A4 inducer and has been shown to decrease the mean peak concentration (Cmax) and exposure (AUC) of midazolam in drug interaction studies.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor for altered response to midazolam therapy. Consider increasing the dose of midazolam and individualize therapy based on the patients response. Elagolix is a weak to moderate CYP3A4 inducer and has been shown to decrease the mean peak concentration (Cmax) and exposure (AUC) of midazolam in drug interaction studies. (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Elbasvir; Grazoprevir: (Moderate) Administering midazolam with elbasvir; grazoprevir may result in elevated midazolam plasma concentrations. Midazolam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Use caution when administering ivacaftor and midazolam concurrently because patients are at increased risk for adverse effects from midazolam. Ivacaftor is a CYP3A inhibitor, and midazolam is a CYP3A substrate. When administered with ivacaftor, midazolam exposure was increased by 1.5-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Use of orally administered midazolam with cobicistat is contraindicated due to the risk for prolonged/increased sedation and respiratory depression. Midazolam is extensively metabolized by CYP3A4; cobicistat is a strong inhibitor of this enzyme. Concurrent use is expected to produce large increases in the plasma concentrations of midazolam. Elevations in midazolam concentrations may also be observed with the parenteral formulation of midazolam; however, this formulation may be administered with cobicistat if given in as setting with close clinical monitoring and appropriate medical management. Consider reducing the dose of parenteral midazolam.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Use of orally administered midazolam with cobicistat is contraindicated due to the risk for prolonged/increased sedation and respiratory depression. Midazolam is extensively metabolized by CYP3A4; cobicistat is a strong inhibitor of this enzyme. Concurrent use is expected to produce large increases in the plasma concentrations of midazolam. Elevations in midazolam concentrations may also be observed with the parenteral formulation of midazolam; however, this formulation may be administered with cobicistat if given in as setting with close clinical monitoring and appropriate medical management. Consider reducing the dose of parenteral midazolam.
Encorafenib: (Moderate) Coadministration of encorafenib with midazolam may result in increased toxicity or decreased efficacy of midazolam. Midazolam is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Enzalutamide: (Major) Avoid the concomitant use of enzalutamide, a strong CYP3A4 inducer, and midazolam, a CYP3A4 substrate, as midazolam plasma exposure may be reduced. Coadministration with enzalutamide decreased midazolam exposure by 86%.
Ergotamine; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Erythromycin: (Major) Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as erythromycin, can potentiate the clinical effects of midazolam. Use this combination with caution.
Esketamine: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Estradiol Cypionate; Medroxyprogesterone: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Estradiol; Levonorgestrel: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Estradiol; Norethindrone: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Estradiol; Norgestimate: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Estradiol; Progesterone: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Eszopiclone: (Moderate) Concomitant administration of benzodiazepines with eszopiclone can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. The concurrent use of eszopiclone with other anxiolytics, sedatives, and hypnotics at bedtime or in the middle of the night is not recommended. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. If used together, a reduction in the dose of one or both drugs may be needed.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Ethinyl Estradiol; Norelgestromin: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Ethinyl Estradiol; Norgestrel: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Ethotoin: (Moderate) Hydantoins are potent inducers of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving these drugs may require higher doses of midazolam to achieve the desired clinical effect.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Etomidate: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Etonogestrel; Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Everolimus: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary. Midazolam is a sensitive CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor. Coadministration with everolimus increased midazolam exposure by 30%.
Fedratinib: (Moderate) Consider reducing the dose of midazolam and monitor for signs of toxicity during coadministration with fedratinib. Coadministration may increase the exposure of midazolam. Fedratinib is a moderate CYP3A inhibitor and midazolam is a sensitive CYP3A substrate. In drug interaction studies, coadministration of fedratinib and midazolam increased the AUC of midazolam by 4-fold.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and benzodiazepines. Concurrent use may result in additive CNS depression.
Fentanyl: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Fluconazole: (Moderate) Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.
Flumazenil: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor is competitive and flumazenil has a much shorter duration of action than do most benzodiazepines, it is possible for the effects of flumazenil to dissipate sooner than the effects of the benzodiazepine. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause dysphoria, agitation, and possibly increased adverse effects. If administered to patients who have received a benzodiazepine chronically, abrupt interruption of benzodiazepine agonism by flumazenil can induce benzodiazepine withdrawal including seizures. Flumazenil has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Fluoxetine: (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including midazolam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Fluvoxamine: (Moderate) Fluvoxamine may inhibit the metabolism of benzodiazepines that undergo hepatic oxidation like midazolam.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Fosphenytoin: (Moderate) Hydantoins are potent inducers of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving these drugs may require higher doses of midazolam to achieve the desired clinical effect.
Gabapentin: (Major) Concomitant use of benzodiazepines with gabapentin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
General anesthetics: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Glycerol Phenylbutyrate: (Moderate) Concomitant use of glycerol phenylbutyrate and midazolam may result in decreased exposure of midazolam. Monitor for decreased efficacy of midazolam during coadministration. Midazolam is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. In a drug interaction study in healthy subjects, coadministration with glycerol phenylbutyrate reduced the mean Cmax and AUC of midazolam by 25% and 32%, respectively, compared to administration of midazolam alone. Additionally, the mean Cmax and AUC for 1-hydroxy midazolam were 28% and 52% higher, respectively, compared to administration of midazolam alone.
Grapefruit juice: (Contraindicated) Clinicians should be aware that grapefruit juice (food) interactions with midazolam are possible. Grapefruit juice inhibits the cytochrome P-450 3A4 isozyme in the gut wall. Grapefruit juice contains furanocoumarins that are metabolized by CYP3A4 to reactive intermediates. These intermediates form a covalent bond to the active site of the CYP3A4 enzyme, causing irreversible inactivation (mechanism-based inhibition). Consequently, CYP3A4 activity in the gut wall is inhibited until de novo synthesis returns the enzyme to its previous level. Grapefruit juice has been shown to increase midazolam peak serum concentrations and AUC by up to 50% when midazolam was administered orally. Increased sedation may be possible. It is recommended that oral midazolam not be taken in conjunction with grapefruit juice. Clinicians should be aware of the possibility of other food interactions (e.g., grapefruit) with orally-administered midazolam.
Green Tea: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products, such as green tea, prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Guaifenesin; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Guanabenz: (Moderate) Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as benzodiazepines, when administered concomitantly.
Guanfacine: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants, such as benzodiazepines, Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Homatropine; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Hydantoins: (Moderate) Hydantoins are potent inducers of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving these drugs may require higher doses of midazolam to achieve the desired clinical effect.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants such as barbiturates, benzodiazepines, opiate agonists, or phenothiazines when administered concomitantly.
Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Hydrocodone; Ibuprofen: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Hydromorphone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydromorphone is initiated in a patient taking a benzodiazepine, reduce the initial dosage of hydromorphone and titrate to clinical response; for hydromorphone extended-release tablets, use 1/3 to 1/2 of the estimated hydromorphone starting dose. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Hydroxyzine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Ibuprofen; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Idelalisib: (Contraindicated) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with midazolam, a CYP3A substrate, as midazolam toxicities may be significantly increased. In healthy subjects, a single oral dose of midazolam 5 mg administered after idelalisib 150 mg by mouth for 15 doses increased the geometric mean Cmax of midazolam by 2.4-fold and the geometric mean AUC of midazolam by 5.4-fold.
Iloperidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with iloperidone, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when iloperidone is given in combination with other centrally-acting medications including anxiolytics, sedatives, and hypnotics.
Imatinib: (Major) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may inhibit midazolam metabolism leading to increased levels and potential toxicity. Monitor patients closely who receive concurrent therapy.
Isavuconazonium: (Moderate) Concurrent administration of isavuconazonium and midazolam resulted in increased midazolam exposure. If these drugs are to be coadministered, use caution and consider reducing the midazolam dose in order to avoid the risk for serious adverse reactions such as excess sedation and/or cardiorespiratory depression. Isavuconazole, the active moiety of isavuconazonium, is an inhibitor of hepatic isoenzyme CYP3A4; midazolam is metabolized by this enzyme.
Isoflurane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Isoniazid, INH: (Moderate) Isoniazid, INH may decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving midazolam should be monitored for signs of altered benzodiazepine response when isoniazid is initiated or discontinued.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of midazolam. Patients receiving rifampin may require higher doses of midazolam to achieve the desired clinical effect. (Moderate) Isoniazid, INH may decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving midazolam should be monitored for signs of altered benzodiazepine response when isoniazid is initiated or discontinued.
Isoniazid, INH; Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of midazolam. Patients receiving rifampin may require higher doses of midazolam to achieve the desired clinical effect. (Moderate) Isoniazid, INH may decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving midazolam should be monitored for signs of altered benzodiazepine response when isoniazid is initiated or discontinued.
Istradefylline: (Moderate) Monitor for midazolam-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Midazolam is a sensitive CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on midazolam exposure when administered with istradefylline 20 mg daily.
Itraconazole: (Contraindicated) Oral midazolam is contraindicated for use during and for 2 weeks after itraconazole therapy due to significantly increased exposure to midazolam. The significance of an interaction between itraconazole and IV midazolam is uncertain, but may be less significant due to absence of an effect on pre-systemic midazolam clearance. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with itraconazole, as these benzodiazepines are not oxidatively metabolized. A study using single oral doses of estazolam showed that itraconazole had no effect on the pharmacokinetics or pharmacodynamics of estazolam. Itraconazole is a strong CYP3A4 inhibitor; midazolam is a sensitive CYP3A4 substrate.
Ivacaftor: (Moderate) Use caution when administering ivacaftor and midazolam concurrently because patients are at increased risk for adverse effects from midazolam. Ivacaftor is a CYP3A inhibitor, and midazolam is a CYP3A substrate. When administered with ivacaftor, midazolam exposure was increased by 1.5-fold.
Ivosidenib: (Moderate) Monitor for loss of efficacy of midazolam during coadministration of ivosidenib; a midazolam dose adjustment may be necessary. Midazolam is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased midazolam concentrations.
Ketamine: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Ketoconazole: (Major) Avoid coadministration of midazolam with ketoconazole. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Dose adjustments of oral midazolam may be necessary when coadministered with clarithromycin. Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as clarithromycin, can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.
Lapatinib: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with lapatinib is necessary. Midazolam is a sensitive CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor. Following coadministration of lapatinib and midazolam, the 24-hour systemic exposure (AUC) of orally administered midazolam increased by 45%, while the 24-hour AUC of IV midazolam increased by 22%.
Larotrectinib: (Moderate) Monitor for more intense and prolonged sedation due to increased midazolam exposure if coadministration with larotrectinib is necessary. Midazolam is a CYP3A4 substrate; larotrectinib is a weak CYP3A4 inhibitor. In a drug interaction study, coadministration with larotrectinib increased the both the midazolam AUC and Cmax by 1.7-fold. The AUC and Cmax of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased 1.4-fold.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and benzodiazepines. Concurrent use may result in additive CNS depression.
Lefamulin: (Moderate) Monitor for signs of midazolam toxicity during coadministration with oral lefamulin. In drug interaction studies, coadministration of oral lefamulin and midazolam increased the AUC of midazolam by 200%. No clinically significant differences in midazolam pharmacokinetics were observed when midazolam was administered with lefamulin injection. Oral lefamulin is a moderate CYP3A inhibitor and midazolam is a sensitive CYP3A substrate.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during use of lemborexant with benzodiazepines. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with lemborexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
Lenacapavir: (Major) Avoid coadministration of midazolam with lenacapavir. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and lenacapavir is a CYP3A inhibitor. Concomitant use was observed to increase midazolam overall exposure by 3.59- to 4.08-fold.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of midazolam; monitor for potential reduction in efficacy. Midazolam is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of midazolam; monitor for potential reduction in efficacy. Midazolam is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Moderate) Closely monitor for midazolam-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Midazolam is a sensitive CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor. Concurrent use of letermovir increased the midazolam AUC and Cmax by 1.47-fold and 1.05-fold, respectively. The combined effect of letermovir and cyclosporine on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with benzodiazepines should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Levoketoconazole: (Major) Avoid coadministration of midazolam with ketoconazole. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Levomilnacipran: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
Levonorgestrel; Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Levorphanol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If levorphanol is initiated in a patient taking a benzodiazepine, reduce the initial dose of levorphanol by approximately 50% or more. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Lonafarnib: (Contraindicated) Coadministration of midazolam and lonafarnib is contraindicated; concurrent use may significantly increase the exposure of midazolam and the risk of adverse effects. Discontinue lonafarnib for 10 to 14 days before and 2 days after administration of midazolam. Midazolam is a sensitive CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with lonafarnib increased the exposure of midazolam by 639%.
Lumacaftor; Ivacaftor: (Major) Concomitant use of midazolam and lumacaftor; ivacaftor is not recommended; if sedation or anxiolysis is needed, consider alternative therapy. Lumacaftor; ivacaftor may decrease the therapeutic effect of midazolam by decreasing systemic exposure. Lumacaftor; ivacaftor is a strong inducer of CYP3A, and midazolam is a CYP3A substrate.
Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and midazolam concurrently because patients are at increased risk for adverse effects from midazolam. Ivacaftor is a CYP3A inhibitor, and midazolam is a CYP3A substrate. When administered with ivacaftor, midazolam exposure was increased by 1.5-fold.
Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and benzodiazepines. Concurrent use may result in additive CNS depression.
Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as anxiolytics, sedatives, and hypnotics, including benzodiazepines. In one study, co-administration of lurasidone and midazolam increased the Cmax and AUC of midazolam by about 21% and 44%, respectively, compared to midazolam alone; however, dosage adjustment of midazolam based upon pharmacokinetic parameters is not required during concurrent use of lurasidone.
Maprotiline: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
Maribavir: (Moderate) Use caution when midazolam is coadministered with maribavir. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and maribavir is a weak CYP3A inhibitor.
Meclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Melatonin: (Major) Use caution when combining melatonin with the benzodiazepines; when the benzodiazepine is used for sleep, co-use of melatonin should be avoided. Use of more than 1 agent for hypnotic purposes may increase the risk for over-sedation, CNS effects, or sleep-related behaviors. Be alert for unusual changes in moods or behaviors. Use caution when combining melatonin with benzodiazepines for other uses. Patients reporting unusual sleep-related behaviors should likely discontinue melatonin use. In animal studies, melatonin has been shown to increase benzodiazepine binding to receptor sites. In one case report, a benzodiazepine-dependent woman with an 11 year history of insomnia weaned and discontinued her benzodiazepine prescription within a few days without rebound insomnia or apparent benzodiazepine withdrawal when melatonin was given. In another case report, the ingestion of excessive melatonin along with normal doses of chlordiazepoxide and an antidepressant resulted in lethargy and short-term amnestic responses. Both cases suggest additive pharmacodynamic effects. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between melatonin and another hypnotic agent one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and coordination compared to the hypnotic agent alone.
Meperidine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Meperidine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Meprobamate: (Moderate) Concomitant administration of benzodiazepines with meprobamate can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed.
Methadone: (Major) Concurrent use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If methadone is initiated for pain in an opioid-naive patient taking a benzodiazepine, use an initial methadone dose of 2.5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial benzodiazepine dose and titrate to response. In patients treated with methadone for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia during methadone maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Methocarbamol: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including skeletal muscle relaxants, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
Methohexital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Methscopolamine: (Moderate) CNS depression can be increased when methscopolamine is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants such as barbiturates, benzodiazepines, opiate agonists, or phenothiazines when administered concomitantly.
Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as benzodiazepines, should be used with caution. Additive drowsiness and/or dizziness is possible.
Metyrosine: (Moderate) The concomitant administration of metyrosine with benzodiazepines can result in additive sedative effects.
Mifepristone: (Major) Midazolam should be used with mifepristone only with caution, close monitoring, and consideration of appropriate midazolam dosage reduction. CNS depression, impaired motor and/or cognitive performance may occur due to increased midazolam exposure. Mifepristone inhibits CYP3A4 when it is used chronically in the treatment of hormonal conditions, such as Cushing's disease. Coadministration of mifepristone may lead to a significant increase in serum concentrations of drugs that are CYP3A4 substrates like midazolam. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
Milnacipran: (Moderate) Concurrent use of many CNS-active drugs with milnacipran or levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with these medications.
Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as benzodiazepines. Caution should be exercised when using these agents concurrently.
Mirtazapine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Mitotane: (Moderate) Use caution if mitotane and midazolam are used concomitantly, and monitor for decreased efficacy of midazolam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and midazolam is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of midazolam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with midazolam.
Monoamine oxidase inhibitors: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and monoamine oxidase inhibitors (MAOIs) due to the risk for additive CNS depression.
Morphine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Morphine; Naltrexone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Nabilone: (Major) Nabilone should not be taken with benzodiazepines or other sedative/hypnotic agents because these substances can potentiate the central nervous system effects of nabilone. Additive drowsiness and CNS depression can occur.
Nalbuphine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Nefazodone: (Major) Nefazodone inhibits the hepatic CYP3A4 isoenzyme and substantially increases the plasma concentrations of some benzodiazepines. Although not studied, a similar interaction may occur with oral midazolam. If possible, this drug combination is best avoided due to the narrow therapeutic index for midazolam. If concurrent use of these drugs is necessary, it would be prudent to reduce the midazolam dosage and monitor the clinical response more closely.
Netupitant, Fosnetupitant; Palonosetron: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as midazolam. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. When administered with netupitant, the systemic exposure to midazolam was significantly increased. Increased midazolam exposure may lead to increased sedation or respiratory depression. Monitor patients closely who receive concurrent therapy.
Nevirapine: (Minor) Monitor for reduced efficacy of midazolam if coadministration with nevirapine is necessary. Concomitant use may decrease midazolam exposure. Midazolam is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Nicardipine: (Moderate) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including midazolam.
Nilotinib: (Major) The concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and midazolam, a CYP3A4 substrate, resulted in a 2.6-fold increase in the systemic midazolam exposure in patients with chronic myelogenous leukemia. Consider a midazolam dose reduction if these drugs are used together.
Nirmatrelvir; Ritonavir: (Major) Concomitant use of ritonavir-boosted nirmatrelvir and oral midazolam is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase midazolam exposure resulting in increased toxicity. The significance of an interaction with IV midazolam is uncertain, but may be less significant due to absence of an effect on pre-systemic midazolam clearance. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ritonavir-boosted nirmatrelvir, as these benzodiazepines are not oxidatively metabolized. Midazolam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as benzodiazepines. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with benzodiazepines.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Norethindrone; Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Norgestimate; Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Olanzapine: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Olanzapine; Fluoxetine: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including midazolam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Olanzapine; Samidorphan: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Oliceridine: (Major) Concomitant use of oliceridine with midazolam may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with midazolam to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Omeprazole: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as midazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as midazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Rifabutin is an inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving rifabutin may require higher doses of midazolam to achieve the desired clinical effect.
Omeprazole; Sodium Bicarbonate: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as midazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
Oritavancin: (Moderate) Administration of oritavancin, a weak inducer of CYP3A4, with midazolam resulted in an 18% reduction in the midazolam mean AUC. Higher doses of midazolam may be necessary when these drugs are administered concurrently.
Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Oxymorphone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxymorphone is initiated in a patient taking a benzodiazepine, use an initial dose of oxymorphone at 1/3 to 1/2 the usual dosage and titrate to clinical response. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, use an initial dosage of 5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Pacritinib: (Moderate) Use caution when midazolam is coadministered with pacritinib. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and pacritinib is a weak CYP3A inhibitor.
Palbociclib: (Moderate) Monitor for an increase in midazolam-related adverse reactions (e.g., sedation, respiratory depression) if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and midazolam is a sensitive CYP3A4 substrate. In a drug interaction trial in healthy subjects (n = 26), coadministration with palbociclib increased the AUC and Cmax of midazolam by 61% and 37%, respectively.
Paliperidone: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Papaverine: (Moderate) Concurrent use of papaverine with potent CNS depressants such as benzodiazepines could lead to enhanced sedation.
Pazopanib: (Moderate) Pazopanib resulted in an approximately 30% increase in mean AUC and Cmax of midazolam, a CYP3A4 substrate, when given concomitantly.
Pentazocine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Pentazocine; Naloxone: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Pentobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Perampanel: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
Phenobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers. (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
Phenothiazines: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Phentermine; Topiramate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Phenytoin: (Moderate) Hydantoins are potent inducers of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving these drugs may require higher doses of midazolam to achieve the desired clinical effect.
Pimozide: (Moderate) Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including benzodiazepines.
Pioglitazone: (Minor) Administration of pioglitazone for 15 days followed by a single dose midazolam syrup, 7.5 mg PO, resulted in a 26% reduction in the midazolam AUC. Higher doses of midazolam may be necessary when coadministered with pioglitazone.
Pioglitazone; Glimepiride: (Minor) Administration of pioglitazone for 15 days followed by a single dose midazolam syrup, 7.5 mg PO, resulted in a 26% reduction in the midazolam AUC. Higher doses of midazolam may be necessary when coadministered with pioglitazone.
Pioglitazone; Metformin: (Minor) Administration of pioglitazone for 15 days followed by a single dose midazolam syrup, 7.5 mg PO, resulted in a 26% reduction in the midazolam AUC. Higher doses of midazolam may be necessary when coadministered with pioglitazone.
Pirtobrutinib: (Moderate) Use caution when midazolam is coadministered with pirtobrutinib. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor. Concomitant use was observed to increase midazolam overall exposure by 70%.
Posaconazole: (Moderate) Posaconazole inhibits CYP3A4 and may increase serum concentrations of benzodiazepines metabolized by this enzyme, including midazolam.
Pramipexole: (Major) Concomitant administration of benzodiazepines with CNS-depressant drugs, including pramipexole, can potentiate the CNS effects.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone, dehydroepiandrosterone, DHEA may inhibit the metabolism of benzodiazepines (e.g., alprazolam, estazolam, midazolam) which undergo CYP3A4-mediated metabolism. In one study of elderly volunteers, half of the patients received DHEA 200 mg/day PO for 2 weeks, followed by a single dose of triazolam 0.25 mg. Triazolam clearance was reduced by close to 30% in the DHEA-pretreated patients vs. the control group; however, the effect of DHEA on CYP3A4 metabolism appeared to vary widely among subjects. While more study is needed, benzodiazepine-induced CNS sedation and other adverse effects might be increased in some individuals if DHEA is co-administered.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone, dehydroepiandrosterone, DHEA may inhibit the metabolism of benzodiazepines (e.g., alprazolam, estazolam, midazolam) which undergo CYP3A4-mediated metabolism. In one study of elderly volunteers, half of the patients received DHEA 200 mg/day PO for 2 weeks, followed by a single dose of triazolam 0.25 mg. Triazolam clearance was reduced by close to 30% in the DHEA-pretreated patients vs. the control group; however, the effect of DHEA on CYP3A4 metabolism appeared to vary widely among subjects. While more study is needed, benzodiazepine-induced CNS sedation and other adverse effects might be increased in some individuals if DHEA is co-administered.
Pregabalin: (Major) Concomitant use of benzodiazepines with pregabalin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
Primidone: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Procarbazine: (Minor) CNS depressants benzodiazepines can potentiate the CNS depression caused by procarbazine therapy, so these drugs should be used together cautiously.
Promethazine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Propofol: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Protease inhibitors: (Major) The use of oral midazolam and anti-retroviral protease inhibitors is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Parenteral midazolam can be used with protease inhibitors in a setting that allows for close clinical monitoring with the ability to manage respiratory depression or sedation should they occur; a reduction in the dose of parenteral midazolam may be warranted. Lorazepam, oxazepam, or temazepam may be safer alternatives, as these benzodiazepines are not oxidatively metabolized. Midazolam is metabolized by hepatic isozyme CYP3A4. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation.
Pseudoephedrine; Triprolidine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Quetiapine: (Moderate) Somnolence is a commonly reported adverse effect of quetiapine; coadministration of quetiapine with anxiolytics, sedatives, and hypnotics, or other CNS depressants may result in additive sedative effects.
Quinine: (Minor) Quinine does not induce the metabolism of midazolam. In a study of 23 subjects receiving multiple doses of quinine for 7 days and a single dose of midazolam, the mean AUC and Cmax of midazolam and 1-hydroxymidazolam were not significantly affected.
Ramelteon: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
Ranitidine: (Moderate) Although conflicting data exist regarding an interaction between ranitidine and midazolam, it may be prudent to monitor patients taking both ranitidine and midazolam for increased sedation. The manufacturer of ranitidine warns that the absorption of midazolam may be increased in patients taking ranitidine due to alterations in pH.
Ranolazine: (Moderate) In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates with a narrow therapeutic index, such as midazolam, potentially leading to adverse reactions. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.
Rasagiline: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including buprenorphine, butorphanol, dronabinol, THC, nabilone, nalbuphine, and anxiolytics, sedatives, and hypnotics. Use these drugs cautiously with MAOIs; warn patients to not drive or perform other hazardous activities until they know how a particular drug combination affects them. In some cases, the dosages of the CNS depressants may need to be reduced.
Relugolix; Estradiol; Norethindrone acetate: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Remifentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
Remimazolam: (Major) The sedative effect of remimazolam can be accentuated by midazolam. Titrate the dose of remimazolam to the desired clinical response and continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation.
Ribociclib: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with ribociclib is necessary. Midazolam is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with ribociclib at a reduced dose of 400 mg once daily increased the midazolam AUC by 3.8-fold; coadministration with the recommended dose of ribociclib is predicted to increase midazolam exposure by 5.2-fold.
Ribociclib; Letrozole: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with ribociclib is necessary. Midazolam is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with ribociclib at a reduced dose of 400 mg once daily increased the midazolam AUC by 3.8-fold; coadministration with the recommended dose of ribociclib is predicted to increase midazolam exposure by 5.2-fold.
Rifabutin: (Moderate) Rifabutin is an inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving rifabutin may require higher doses of midazolam to achieve the desired clinical effect.
Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of midazolam. Patients receiving rifampin may require higher doses of midazolam to achieve the desired clinical effect.
Rifapentine: (Moderate) Rifapentine induces hepatic isoenzymes CYP3A4 and CYP2C8, and 9. Midazolam is metabolized by CYP3A4 and CYP2C8, and 9 and may require dosage adjustments when administered concurrently with rifapentine.
Risperidone: (Moderate) Due to the primary CNS effects of risperidone, caution should be used when risperidone is given in combination with other centrally acting medications including anxiolytics, sedatives, and hypnotics.
Rotigotine: (Major) Concomitant use of rotigotine with other CNS depressants, such as benzodiazepines, can potentiate the sedative effects of rotigotine.
Rucaparib: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary. Midazolam is a sensitive CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Concomitant use increased the AUC of midazolam by 1.4-fold.
Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as midazolam, may occur during concurrent use with rufinamide.
Safinamide: (Moderate) Dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Because of possible additive effects, advise patients about the potential for increased somnolence during concurrent use of safinamide with other sedating medications, such as benzodiazepines.
Scopolamine: (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
Secobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Sedating H1-blockers: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
Selegiline: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and selegiline due to the risk for additive CNS depression.
Sevoflurane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Simeprevir: (Moderate) Coadministration of orally administered midazolam with simeprevir, an intestinal CYP3A4 inhibitor, results in increased midazolam plasma concentrations. Caution is advised if these drugs are administered concurrently.
Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by benzodiazepines. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of procedure results.
Skeletal Muscle Relaxants: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Sodium Oxybate: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
Spironolactone: (Moderate) Use caution when midazolam is coadministered with spironolactone. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Use caution when midazolam is coadministered with spironolactone. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
St. John's Wort, Hypericum perforatum: (Major) St. John's Wort induces the hepatic CYP3A4 metabolism of midazolam which is metabolized by oxidation. St. John's Wort, in doses of 900 mg/day, reduces the AUC of oral midazolam by about 50%. It would be prudent to avoid co-administration of St. John's Wort with midazolam. Benzodiazepines that are not metabolized by CYP3A4 such as oxazepam or lorazepam may be alternatives if a benzodiazepine is required in combination with St. John's Wort.
Stiripentol: (Moderate) Consider a dose adjustment of midazolam when coadministered with stiripentol. Coadministration may alter plasma concentrations of midazolam resulting in an increased risk of adverse reactions and/or decreased efficacy. Additive somnolence and sedation may occur. Midazolam is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Streptogramins: (Moderate) Monitor for increased midazolam adverse effects if coadministered with dalfopristin; quinupristin. Concomitant administration of dalfopristin; quinupristin and midazolam (intravenous bolus dose) in healthy volunteers increased the midazolam AUC by 33%.
Sufentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
Tapentadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If tapentadol is initiated in a patient taking a benzodiazepine, a reduced initial dosage of tapentadol is recommended. If the extended-release tapentadol tablets are used concurrently with a benzodiazepine, use an initial tapentadol dose of 50 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Tazemetostat: (Moderate) Monitor for reduced efficacy of midazolam if coadministration with tazemetostat is necessary as concurrent use may decrease midazolam exposure. Midazolam is a sensitive CYP3A4 substrate; tazemetostat is a weak CYP3A4 inducer. Coadministration of tazemetostat with oral midazolam decreased midazolam exposure by 40%.
Tecovirimat: (Moderate) Monitor for reduced midazolam efficacy during concurrent use of tecovirimat. In a drug interaction study, the maximum plasma concentration (Cmax) and exposure (AUC) of midazolam were reduced in patients receiving concurrent tecovirimat therapy. Midazolam is a sensitive CYP3A4 substrate; tecovirimat is a weak inducer of this enzyme.
Teduglutide: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and midazolam concurrently because patients are at increased risk for adverse effects from midazolam. Ivacaftor is a CYP3A inhibitor, and midazolam is a CYP3A substrate. When administered with ivacaftor, midazolam exposure was increased by 1.5-fold.
Thalidomide: (Major) The use of benzodiazepine anxiolytics, sedatives, or hypnotics with thalidomide may cause an additive sedative effect and should be avoided. Thalidomide frequently causes drowsiness and somnolence. Dose reductions may be required. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Advise patients as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery.
Theophylline, Aminophylline: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
Thiothixene: (Moderate) Thiothixene can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
Tiagabine: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
Topiramate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
Tramadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Tramadol; Acetaminophen: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Trandolapril; Verapamil: (Major) A clinically significant interaction has occurred with verapamil, a CYP3A4 inhibitor and oral midazolam, a CYP3A4 substrate. When verapamil and midazolam are coadministered, the AUC and half-life of midazolam are increased and the associated sedation is more pronounced. The significance of an interaction between verapamil and IV midazolam is uncertain, however, but may be less significant due to absence of an effect by verapamil on presystemic midazolam clearance.
Trazodone: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
Tricyclic antidepressants: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Trihexyphenidyl: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of trihexyphenidyl.
Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like the benzodiazepines, may potentiate the effects of either trimethobenzamide or the benzodiazepine.
Triprolidine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Tucatinib: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with tucatinib is necessary; a dose adjustment of midazolam may be necessary. Concurrent use may increase midazolam exposure. Midazolam is a sensitive CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor.
Valerian, Valeriana officinalis: (Major) Any substances that act on the CNS, including psychoactive drugs and drugs used as anesthetic adjuvants (e.g., barbiturates, benzodiazepines), may theoretically interact with valerian, Valeriana officinalis. The valerian derivative, dihydrovaltrate, binds at barbiturate binding sites; valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain; the non-volatile monoterpenes (valepotriates) have sedative activity. These interactions are probably pharmacodynamic in nature. There is a possibility of interaction with valerian at normal prescription dosages of anxiolytics, sedatives, and hypnotics (including barbiturates and benzodiazepines). Patients who are taking barbiturates or other sedative/hypnotic drugs should avoid concomitant administration of valerian. Patients taking medications such as tricyclic antidepressants, lithium, MAOIs, skeletal muscle relaxants, SSRIs and serotonin norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine) should discuss the use of herbal supplements with their health care professional prior to consuming valerian; combinations should be approached with caution in the absence of clinical data. Patients should not abruptly stop taking their prescribed psychoactive medications.
Vemurafenib: (Moderate) The concomitant use of vemurafenib, a CYP3A4 substrate and inducer, and oral midazolam, a CYP3A4 substrate, resulted in decreased concentrations of midazolam in a drug interaction study performed in cancer patients. In this study, the mean midazolam AUC value was decreased by 39% when a single dose of midazolam was administered after 15 days of vemurafenib 960 mg PO twice daily.
Verapamil: (Major) A clinically significant interaction has occurred with verapamil, a CYP3A4 inhibitor and oral midazolam, a CYP3A4 substrate. When verapamil and midazolam are coadministered, the AUC and half-life of midazolam are increased and the associated sedation is more pronounced. The significance of an interaction between verapamil and IV midazolam is uncertain, however, but may be less significant due to absence of an effect by verapamil on presystemic midazolam clearance.
Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given in combination with benzodiazepines.
Vilazodone: (Moderate) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as the benzodiazepines.
Viloxazine: (Moderate) Use caution when midazolam is coadministered with viloxazine. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor.
Vonoprazan; Amoxicillin: (Moderate) Use caution when midazolam is coadministered with vonoprazan. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Dose adjustments of oral midazolam may be necessary when coadministered with clarithromycin. Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as clarithromycin, can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent. (Moderate) Use caution when midazolam is coadministered with vonoprazan. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Voriconazole: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with voriconazole is necessary. Midazolam is a sensitive CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the midazolam AUC by 3.8-fold.
Voxelotor: (Major) Avoid coadministration of midazolam with voxelotor. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and voxelotor is a CYP3A inhibitor.
Zafirlukast: (Moderate) Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as zafirlukast, can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam.
Zaleplon: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
Zileuton: (Moderate) Zileuton may inhibit CYP3A4 and may potentially reduce the metabolism of midazolam. When midazolam is co-administered with zileuton, monitor for an increase in CNS or respiratory depression. Consider midazolam dose reduction if clinically warranted.
Ziprasidone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
Zolpidem: (Major) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.

PREGNANCY AND LACTATION

Use caution when midazolam is administered during breast-feeding. Midazolam is present in human milk at low concentrations. The effects of midazolam on milk production are unknown. Consider interrupting breast-feeding and pumping for at least 4 to 8 hours after midazolam administration to minimize infant exposure. Monitor breastfed infants exposed to benzodiazepines through breast milk for sedation, poor feeding, and poor weight gain.[44859] [63911]  Midazolam and the hydroxy-midazolam metabolite are distributed into breast milk in detectable concentrations within a few hours after a single IV dose and within 4 to 6 hours after oral dosing.[46778] The median infant midazolam dose over 24 hours was 0.016 mcg/kg after a 2 mg IV dose before general anesthesia induction in 5 lactating women with average milk production of 324 +/- 159 mL in 24 hours.[62842] Consider the benefits of breast-feeding along with the clinical need for midazolam and any potential adverse effects on the breastfed infant from midazolam or the underlying maternal condition.

MECHANISM OF ACTION

Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. Recent evidence indicates that benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives.
 
Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ1 receptors are located in the cerebellum and cerebral cortex, the BNZ2 receptors in the cerebral cortex and spinal cord, and the BNZ3 receptors in peripheral tissues. Activation of the BNZ1 receptor is thought to mediate sleep while the BNZ2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ1 and BNZ2 which ultimately enhances the effects of GABA. Midazolam has twice the affinity for benzodiazepine receptors than does diazepam. Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
 
The antianxiety action of benzodiazepines may be a result of their ability to block cortical and limbic arousal following stimulation of the reticular pathways while muscle relaxation properties are mediated by inhibiting both mono- and polysynaptic pathways. Benzodiazepine can also depress muscle and motor nerve function directly. Animal studies of the anticonvulsant actions suggest that benzodiazepines augment presynaptic inhibition of neurons, thereby limiting the spread of electrical activity, although they do not actually inhibit the abnormally discharging focus. Benzodiazepines alleviate insomnia by decreasing the latency to sleep and increasing sleep continuity and total sleep time through their effects on GABA.

PHARMACOKINETICS

Midazolam is approved for oral, parenteral, and intranasal administration, although it has also been administered via buccal and rectal routes off-label. Midazolam is widely distributed, crossing both the blood-brain and placental barriers; it has been detected in human milk and CSF. Midazolam is approximately 97% protein-bound, primarily to albumin. Extensive hydroxylation occurs in the liver. The primary metabolite is alpha-hydroxymidazolam (also termed 1-hydroxymidazolam), which is equipotent to midazolam. Up to 80% of midazolam is recovered in the urine as alpha-hydroxymidazolam glucuronide. Roughly 4% of the dose is metabolized to 4-hydroxymidazolam and 1,4-dihydroxylmidazolam; these minor metabolites have less pharmacologic activity than midazolam and are conjugated by the liver with subsequent renal excretion. Less than 0.03% of a dose is excreted unchanged in the urine. In healthy adults, the mean Vd is 1 to 3.1 L/kg and the half-life is approximately 2 to 6 hours (mean: approximately 3 hours). The Vd in non-neonatal pediatric patients is similar to or slightly larger than that of adults, and the half-life is similar to or shorter than that of adults. Clearance is reduced in patients with significant liver disease and conditions that reduce cardiac output and hepatic blood flow.[44717] [44859] [64166]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
Midazolam is metabolized by the hepatic isozyme CYP3A4.[28001] Inhibitors of this pathway can potentiate the clinical effects of midazolam.[28556] Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.