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  • CLASSES

    Anxiolytics, Benzodiazepines
    Benzodiazepine Sedative/Hypnotics
    Other General Anesthetics

    BOXED WARNING

    Intravenous administration, requires a specialized care setting, respiratory depression, respiratory insufficiency

    Midazolam has been associated with respiratory depression and respiratory arrest, especially when used intravenously for conscious sedation. Death or hypoxic encephalopathy has resulted in some instances where these symptoms were not recognized or properly treated. Administration of midazolam requires a specialized care setting which can provide continuous monitoring of respiratory and cardiac functioning. The dose of midazolam should always be individualized based on a patient's age, weight, indication, concomitant medications and disease history. Specific dosing recommendations apply to adults and pediatrics. Prior to intravenous administration, the immediate availability of oxygen, resuscitative drugs, age and size appropriate ventilation and intubation equipment, and skilled personnel to maintain a patent airway should be ensured. Patients should be monitored 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. Flumazenil should be available for immediate use. When used for sedation/anxiolysis/amnesia, IV midazolam should be titrated over at least 2 minutes with an additional 2 minutes for assessment of sedation. Dilution of the dose may be required to facilitate slow IV injection. Rapid IV administration of midazolam (less than 2 minutes) should be avoided in adults and newborns due to the risk of severe hypotensive reactions, hypoventilation and/or seizure disorder, particularly if the newborn has received fentanyl. The same precaution applies to rapid injections of fentanyl while the neonate is receiving continuous midazolam infusions. Adverse respiratory events have also occurred with oral midazolam, especially when used in combination with other CNS depressant medications; oral midazolam should NOT be administered at home or outside of the care setting in which procedures will be performed. Oral midazolam syrup should not be used with itraconazole, a CYP3A4 inhibitor, and caution should be exercised when midazolam syrup is used with other 3A4 inhibitors due to an increased risk of adverse reactions secondary to elevated serum concentrations of midazolam.

    Children, infants, neonates, premature neonates

    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. 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.

    Apnea, chronic obstructive pulmonary disease (COPD), CNS depression, coadministration with other CNS depressants, congenital heart disease, dental work, pulmonary disease, sleep apnea, status asthmaticus

    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. 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, 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. Midazolam is more likely to cause respiratory depression when administered to patients with significant CNS depression, use of alcohol, barbiturates or opiate agonists, head trauma, or other illness. Midazolam does not protect against increases in intracranial pressure, heart rate, and/or blood pressure readings when used for short-term sedation during endotracheal intubation. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental work and care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Oral and parenteral very short-acting benzodiazepine; primarily used for sedation, anxiolysis, and amnesia preprocedure or as an adjunct to regional anesthesia; also used for conscious sedation.

    COMMON BRAND NAMES

    Versed

    HOW SUPPLIED

    Midazolam Hydrochloride/Versed Intramuscular Inj Sol: 1mL, 1mg, 5mg
    Midazolam Hydrochloride/Versed Intravenous Inj Sol: 1mg, 1mL, 5mg
    Midazolam Hydrochloride/Versed Oral Syrup: 1mL, 2mg

    DOSAGE & INDICATIONS

    For procedural sedation and amnesia induction.
    For sedation and amnesia induction before short diagnostic procedures or endoscopy.
    Oral dosage
    Infants >= 6 months and Children up to 16 years

    0.25—0.5 mg/kg PO (maximum 20 mg) as a single dose 30—45 minutes before procedure. In clinical trials, the most common reported effective dose was 0.5 mg/kg PO. The degree of sedation achieved is dependent on dose administered. Anxiolysis does not appear to be dose-dependent. Some children may require up to 1 mg/kg PO (maximum 20 mg) for desired clinical response.

    Intravenous dosage
    Adults

    Titrate slowly to achieve the desired effect. The usual dosage range is between 1—5 mg IV given over a 2-minute period, immediately before the procedure. Initially, do not exceed 2.5 mg (or 1.5 mg for elderly, debilitated, or those receiving other CNS depressants). If an adequate response is not achieved after 2-minutes, titrate upward in small increments. A total dose of 5 mg is generally sufficient for normal healthy adults and 3.5 mg for geriatric or debilitated patients. Premedication with an opiate agonist may potentiate the response to midazolam, reduce the midazolam dose by 30—50%.

    Children

    0.05—0.1 mg/kg IV given 3 minutes before procedure.

    For preoperative sedation induction, amnesia induction, and to control preoperative anxiety.
    Oral dosage
    Infants >= 6 months and Children up to 16 years

    0.25—0.5 mg/kg PO (maximum 20 mg) as a single dose before surgery. In clinical trials, the most common reported effective dose was 0.5 mg/kg PO. The degree of sedation achieved is dependent on dose administered. Anxiolysis does not appear to be dose-dependent. Some children may require up to 1 mg/kg PO (maximum 20 mg) for desired clinical response.

    Intramuscular dosage
    Adults

    0.07—0.08 mg/kg IM (about 5 mg for an average healthy adult) administered 30—60 minutes before surgery. Reduced doses recommended for debilitated or geriatric patients.

    Children

    Doses of 0.1—0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Usual Max 10 mg. If given with an opiate agonist, the initial dose of both drugs must be reduced.

    Intravenous dosage
    Children 6—12 years

    The initial dose is 0.025—0.05 mg/kg IV; a total dose up to 0.4 mg/kg IV may be necessary. Usual Max 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

    Infants >= 6 months and Children up to 5 years

    The initial dose is 0.05—0.1 mg/kg IV; a total dose up to 0.6 mg/kg IV may be necessary. Usual Max 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

    Infants < 6 months

    Limited information is available; dosing recommendations are unclear vs. older infants. Infants < 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.

    Intranasal dosage†
    Children

    0.2 mg/kg as a single dose intranasally; repeated in 5—15 minutes if needed. Doses range from 0.2—0.3 mg/kg.

    For general anesthesia induction and general anesthesia maintenance.
    NOTE: Midazolam should be administered as an inducing agent only by those trained in anesthesia.
    Intravenous dosage
    Adults < 55 years

    Initially, 200—350 mcg/kg, administered IV over 20—30 seconds. Anesthesia should be induced in 2 minutes. If necessary, additional doses of 20% of the original dose may be administered to complete induction or to maintain anesthesia. For premedicated patients, reduce the initial dose by 50 mcg/kg.

    Adults > 55 years, including the Geriatric: ASA I or II

    Initially 150—300 mcg/kg, administered IV over 30 seconds. For ASA III or IV patients limit initial dose to 250 mcg/kg for nonpremedicated patients and 150 mcg/kg for premedicated patients.

    Children†

    The manufacturer states that a safe and effective dosage has not been established. However, doses in the range 50—200 mcg/kg IV have been suggested.

    For sedation maintenance in mechanically-ventilated patients†, to alleviate agitation† and/or anxiety.
    Intravenous dosage
    Adults

    For mechanically-ventilated patients only. A loading dose of 0.01—0.05 mg/kg (usually 0.5—4 mg) IV given slowly or infused over several minutes. Repeat loading dose at 10—15 minute intervals until adequate sedation is achieved. For maintenance sedation, the usual initial infusion rate is 1—7 mg/hr (0.02—0.1 mg/kg/hr) IV. Higher doses or infusion rates may be required in some patients. Use the lowest recommended doses in patients with residual effects from anesthetic drugs, or who are concurrently receiving other sedatives or opioids. The infusion rate should be titrated to the desired level of sedation using 25—50% adjustments in dosage. After the desired level of sedation has been achieved, the infusion rate should be decreased by 10—25% every few hours to find the minimum effective infusion rate.

    Children

    For mechanically-ventilated patients only. 0.05—0.2 mg/kg IV initially over at least 2—3 minutes; followed by infusion at a rate of 1—2 mcg/kg/min IV. Rates may be titrated to a range of 0.4—6 mcg/kg/min.

    Neonates > 32 weeks

    For mechanically-ventilated patients only. Initiate infusion at a rate of 1 mcg/kg/min IV. Intravenous loading doses should not be used; infusions may be run more rapidly for the the first several hours to obtain therapeutic response.

    Neonates < 32 weeks

    For mechanically-ventilated patients only. Initiate infusion at a rate of 0.5 mcg/kg/min IV. Intravenous loading doses should not be used; infusions may be run more rapidly for the the first several hours to obtain therapeutic response.

    For the treatment of status epilepticus† refractory to standard therapy.
    Intravenous dosage
    Infants > 2 months and Children

    For mechanically-ventilated patients only. 0.15 mg/kg IV followed by a continuous infusion of 1 mcg/kg/min IV. Dose should be titrated upward every 5 minutes until seizures are controlled. In one study, the mean infusion rate was 2.3 mcg/kg/min IV with a range of 1—18 mcg/kg/min IV.

    For the treatment of alcohol withdrawal†, including symptomatic treatment of delirium tremens†.
    Intravenous dosage
    Adults

    Midazolam may considered as an alternative to commonly used benzodiazepines (e.g., lorazepam) for the treatment of alcohol withdrawal syndrome (AWS). Doses of 1—5 mg IV every 1—2 hours for mild to moderate alcohol withdrawal symptoms and 1—20 mg every 1—2 hours by continuous IV infusion for delirium tremens have been suggested following a retrospective analysis of 102 patients with an ICD-9 diagnosis of alcohol withdrawal who received various drug treatments during 112 hospitalizations. The pharmacokinetic characteristics of midazolam (e.g., short half-life, rapid onset, short duration of effect, water solubility) were considered advantageous for administration by continuous IV infusion for delirium tremens. Unlike the other benzodiazepines evaluated, midazolam was not recommended for alcohol withdrawal prophylaxis. Patients were considered for inclusion in the review if they had an active history of alcohol abuse equivalent to at least a half pint of whiskey per day. Respiratory depression occurred in some cases, necessitating a midazolam taper prior to extubation in two patients. Due to the high protein binding capacity of midazolam, the authors noted that it is possible to produce a higher potency per unit dose in nutritionally depleted patients, such as those with a serum albumin less than 3 g/dL. In one case report, delirium tremens was successfully treated with a total of 2,850 mg of midazolam administered over a 5-day period, with a rate of infusion ranging from 20—55 mg/hour. Respiratory depression was not observed. In a separate case, a continuous infusion initiated at 50 mg/hour with subsequent titration to a maximum rate of 520 mg/hour was discontinued following the development of metabolic acidosis and acute renal failure. These complications resolved following cessation of the infusion and initiation of IV diazepam therapy. Until more data become available, the lowest effective dose should be used in conjunction with close monitoring for potential adverse effects on respiratory and cardiovascular function. It is advisable to periodically assess the patient for signs of fluid overload.

    †Indicates off-label use

    MAXIMUM DOSAGE

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

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

    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

    Oral Administration

    NOTE: Oral administration of midazolam should only be performed by those trained in maintaining a patent airway. Age and size appropriate resuscitative drugs and equipment should be readily available. Midazolam syrup is not intended for chronic administration.
    Administer undiluted on an empty stomach (presedation fasting). Do not mix with any water or juice prior to administration.
    Dosage should be measured using a calibrated oral syringe.
    An oral solution can be extemporaneously compounded† using midazolam injection.

    Extemporaneous Compounding-Oral

    The oral solution is made by combining the 5 mg/ml injection with a flavored, dye-free syrup (Syrpalata) in a 1:1 ratio. The resulting solution (2.5 mg/ml of midazolam) is stable for 56 days at 7, 20, or 40 degrees C.

    Injectable Administration

    Midazolam is administered intramuscularly or intravenously. Midazolam is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Injection:
    NOTE: Intravenous administration of midazolam should only be performed by those trained in maintaining a patent airway. Resuscitative drugs and equipment should be readily available.
    For induction of anesthesia: Inject IV over 20—30 seconds.
    For conscious sedation: Inject IV over 2 or more minutes at intervals of at least 2 minutes. Midazolam should not be administered by rapid or single bolus intravenous administration; the 1 mg/ml formulation is recommended to facilitate slower injection.
     
    Infusion:
    NOTE: Intravenous administration of midazolam should only be performed by those trained in maintaining a patent airway. Resuscitative drugs and equipment should be readily available.
    Midazolam may be diluted in D5W, NS, or lactated Ringer's solution. At a concentration of 0.5 mg/ml, midazolam is compatible with D5W and NS for up to 24 hours and for up to 4 hours with lactated Ringer's. Both the 1 mg/ml and 5 mg/ml formulations may be diluted with D5W or NS.

    Intramuscular Administration

    Inject deeply into a large muscle mass. Aspirate prior to injection to avoid injection into a blood vessel.

    Other Administration Route(s)

    Intranasal Administration†
    Administer using a 1 ml needleless syringe.
    Using the 5 mg/ml solution, apply the calculated dose to the nares over 15 seconds.
    Use 1/2 of the dose on each nare.

    STORAGE

    Versed:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Benzodiazepine hypersensitivity, benzyl alcohol hypersensitivity, epidural administration, extravasation, intraarterial administration, intrathecal administration

    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. Additionally, midazolam injection should be avoided in patients with a benzyl alcohol hypersensitivity. Midazolam injection is contraindicated for intrathecal administration or epidural administration due to the presence of the preservative benzyl alcohol in the injectable dosage form. Limited reports of seizure activity and local reactions have been associated with intraarterial administration, but a clear causal effect cannot be made. Unintended intraarterial injection and local extravasation should be avoided. 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 low blood pressure, metabolic acidosis, and kernicterus. Patients with a benzodiazepine hypersensitivity to other benzodiazepines may experience a cross-sensitivity to midazolam.

    Intravenous administration, requires a specialized care setting, respiratory depression, respiratory insufficiency

    Midazolam has been associated with respiratory depression and respiratory arrest, especially when used intravenously for conscious sedation. Death or hypoxic encephalopathy has resulted in some instances where these symptoms were not recognized or properly treated. Administration of midazolam requires a specialized care setting which can provide continuous monitoring of respiratory and cardiac functioning. The dose of midazolam should always be individualized based on a patient's age, weight, indication, concomitant medications and disease history. Specific dosing recommendations apply to adults and pediatrics. Prior to intravenous administration, the immediate availability of oxygen, resuscitative drugs, age and size appropriate ventilation and intubation equipment, and skilled personnel to maintain a patent airway should be ensured. Patients should be monitored 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. Flumazenil should be available for immediate use. When used for sedation/anxiolysis/amnesia, IV midazolam should be titrated over at least 2 minutes with an additional 2 minutes for assessment of sedation. Dilution of the dose may be required to facilitate slow IV injection. Rapid IV administration of midazolam (less than 2 minutes) should be avoided in adults and newborns due to the risk of severe hypotensive reactions, hypoventilation and/or seizure disorder, particularly if the newborn has received fentanyl. The same precaution applies to rapid injections of fentanyl while the neonate is receiving continuous midazolam infusions. Adverse respiratory events have also occurred with oral midazolam, especially when used in combination with other CNS depressant medications; oral midazolam should NOT be administered at home or outside of the care setting in which procedures will be performed. Oral midazolam syrup should not be used with itraconazole, a CYP3A4 inhibitor, and caution should be exercised when midazolam syrup is used with other 3A4 inhibitors due to an increased risk of adverse reactions secondary to elevated serum concentrations of midazolam.

    Children, infants, neonates, premature neonates

    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. 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.

    Abrupt discontinuation

    Abrupt discontinuation of midazolam after prolonged use can cause seizures in susceptible patients. Abrupt discontinuation of benzodiazepine therapy has been reported to cause withdrawal symptoms including irritability, nervousness, and insomnia. Benzodiazepine withdrawal is more likely to occur following abrupt cessation after excessive or prolonged doses, but it can occur following the discontinuance of therapeutic doses administered for as few as 1 to 2 weeks. Benzodiazepine withdrawal also can be more intense if the benzodiazepine involved possesses a relatively short duration of action such as midazolam. Benzodiazepines should be withdrawn cautiously and slowly, using a very gradual dosage-tapering schedule.

    Dementia, geriatric

    Intravenous doses of midazolam should be decreased for geriatric patients over 60 years of age and for debilitated adult patients. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Geriatric adult patients are more sensitive to midazolam effects such as drowsiness, hypoxemia, and depressed ventilation. According to the Beers Criteria, avoidance of benzodiazepines is generally recommended, although some agents from this class, 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. In general, the Beers expert panel recommends avoiding other benzodiazepines in geriatric patients when possible due to the potential for exacerbation of the condition or increased risk of adverse effects in older adults: cognitive impairment, delirium (possible new-onset or worsening delirium), dementia (adverse CNS effects), falls/fractures and/or motor vehicle accidents (due to ataxia, impaired psychomotor function, 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.

    Driving or operating machinery, ethanol ingestion, ethanol intoxication

    Particular caution is required in determining the interval needed after outpatient ambulatory procedures or surgery before it is safe for any patient to participate safely in ambulation, driving or operating machinery, or perform other tasks that require complete mental alertness. The manufacturer of midazolam recommends that no patient operates hazardous machinery or drives 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. Injectable midazolam should not be administered to adult or pediatric patients with acute ethanol intoxication who have depression of vital signs.

    Apnea, chronic obstructive pulmonary disease (COPD), CNS depression, coadministration with other CNS depressants, congenital heart disease, dental work, pulmonary disease, sleep apnea, status asthmaticus

    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. 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, 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. Midazolam is more likely to cause respiratory depression when administered to patients with significant CNS depression, use of alcohol, barbiturates or opiate agonists, head trauma, or other illness. Midazolam does not protect against increases in intracranial pressure, heart rate, and/or blood pressure readings when used for short-term sedation during endotracheal intubation. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental work and care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.

    Neuromuscular disease, Parkinson's disease, psychosis

    Midazolam should be used with caution in patients with a neuromuscular disease, such as muscular dystrophy, myotonia, or myasthenia gravis, because these conditions can be exacerbated. Patients with late stage Parkinson's disease may experience worsening of their psychosis or impaired cognition with administration of benzodiazepines. Benzodiazepines may also cause incoordination or paradoxical reactions that may worsen symptoms of Parkinson's disease.

    Bipolar disorder, mania

    Midazolam should be used cautiously in patients with bipolar disorder because mania and hypomania have been reported in conjunction with the use of benzodiazepines in depressive disorders.

    Cardiac disease, dehydration, electrolyte imbalance, heart failure, hypotension, hypovolemia, shock

    Midazolam has caused hypotension and cardiac arrest; therefore, patients with cardiac disease or hypovolemia should be monitored closely during treatment with midazolam, particularly with parenteral use. Injectable midazolam should not be administered to adult or pediatric patients in shock or coma. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as dehydration or other severe fluid or electrolyte imbalance. Patients with congestive heart failure eliminate midazolam more slowly and these patients can experience prolonged recovery from anesthesia. Rapid IV administration of midazolam (less than 2 minutes) should be avoided in neonates due to the risk of severe hypotension, hypoventilation and/or seizure disorder, particularly if the neonate has received fentanyl. The same precaution applies to rapid injections of fentanyl while the neonate is receiving continuous midazolam infusions.

    Hepatic disease, hepatic encephalopathy, obesity, renal failure, renal impairment

    Midazolam is metabolized in the liver and should be used with caution in patients with hepatic disease or hepatic encephalopathy. Similarly, the mean half-life is increased, primarily due to a volume of distribution increase, in patients with obesity; clearance is not substantially affected. Adult and pediatric patients with renal impairment, especially chronic renal failure, eliminate midazolam more slowly. Patients with renal impairment may have longer elimination half-lives for midazolam and its metabolites which may result in slower recovery from sedation when the drug is discontinued.

    Closed-angle glaucoma

    Midazolam is contraindicated in patients with acute closed-angle glaucoma. Midazolam may be used in patients with open-angle glaucoma who are receiving appropriate treatment. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied. The mechanistic rational for this contraindication has been questioned, as benzodiazepines do not have antimuscarinic activity and do not raise intraocular pressure.

    Labor, obstetric delivery, pregnancy

    Midazolam is classified as FDA pregnancy category D. Although animal studies have not indicated teratogenic effects, other benzodiazepines have been associated with congenital abnormalities when used during pregnancy. Such effects have not been reported with midazolam, but no adequate human data are available. If this drug is to be used during pregnancy, the patient should be apprised of the potential hazard to the fetus. 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. 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. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal central nervous system depression, midazolam is not recommended for obstetrical use during labor or obstetric delivery.

    Breast-feeding

    According to the manufacturer, midazolam is excreted in human milk and the drug should be used cautiously during breast-feeding. Midazolam and the hydroxy-midazolam metabolite are distributed into breast milk in detectable concentrations within a few hours after a single intravenous dose and within 4 to 6 hours following oral dosing. With sufficient time passed after a single dose orally or intravenously for brief procedures, such as endoscopy, a female may be able to resume breast-feeding schedules, with observation for somnolence or other effects in the nursing infant. It is less clear what effect repeat doses would have on a nursing infant, although some data suggest repeat dosing or continuous infusions may cause concern. The American Academy of Pediatrics (AAP) classifies midazolam as a drug for which the potential effects on a nursing infant are unknown but may be of concern. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    apnea / Delayed / 2.8-15.4
    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
    respiratory arrest / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known
    neonatal respiratory depression / Rapid / Incidence not known
    teratogenesis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known

    Moderate

    respiratory depression / Rapid / 8.0-23.3
    hypotension / Rapid / 0-2.7
    erythema / Early / 0.5-2.6
    nystagmus / Delayed / 1.1-1.1
    amnesia / Delayed / 0-1.0
    tachypnea / Early / 0-1.0
    wheezing / Rapid / 0-1.0
    dyspnea / Early / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    premature ventricular contractions (PVCs) / Early / 0-1.0
    excitability / Early / 0-1.0
    delirium / Early / 0-1.0
    confusion / Early / 0-1.0
    dysarthria / Delayed / 0-1.0
    hallucinations / Early / 0-1.0
    ataxia / Delayed / 0-1.0
    dysphonia / Delayed / 0-1.0
    euphoria / Early / 0-1.0
    dysphoria / Early / 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
    psychological dependence / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    involuntary movements / Delayed / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    injection site reaction / Rapid / 0-5.6
    hiccups / Early / 1.2-3.9
    nausea / Early / 1.5-2.8
    vomiting / Early / 0.7-2.6
    drowsiness / Early / 1.2-1.6
    headache / Early / 1.3-1.5
    cough / Delayed / 1.3-1.3
    hyperventilation / Early / 0-1.0
    yawning / Early / 0-1.0
    anxiety / Delayed / 0-1.0
    restlessness / Early / 0-1.0
    agitation / Early / 0-1.0
    insomnia / Early / 0-1.0
    emotional lability / Early / 0-1.0
    vertigo / Early / 0-1.0
    nightmares / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    dizziness / Early / 0-1.0
    hypersalivation / Early / 0-1.0
    dysgeusia / Early / 0-1.0
    diplopia / Early / 0-1.0
    pruritus / Rapid / 0-1.0
    urticaria / Rapid / 0-1.0
    rash (unspecified) / Early / 0-1.0
    chills / Rapid / 0-1.0
    dental pain / Delayed / 0-1.0
    lethargy / Early / 0-1.0
    weakness / Early / 0-1.0
    sneezing / Early / 0.7-0.7
    rhinorrhea / Early / 0.7-0.7
    tremor / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: 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; Butalbital: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Acetaminophen; Butalbital; Caffeine: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. 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; Butalbital; Caffeine; Codeine: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. 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. 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: 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. 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; Magnesium Salicylate; Phenyltoloxamine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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; Phenyltoloxamine; Salicylamide: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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; Dextromethorphan; Phenylephrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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: 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: 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: 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: 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; Dichloralphenazone; Isometheptene: The CNS depressant effects of dichloralphenazone can be potentiated by benzodiazepines.
    Acetaminophen; Diphenhydramine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Guaifenesin; Phenylephrine: 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: 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: 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; Pentazocine: 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.
    Acetaminophen; Propoxyphene: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. The dose of any opiate agonist administered with parenteral diazepam should be reduced by at least one-third.
    Acetaminophen; Tramadol: 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.
    Acrivastine; Pseudoephedrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Aldesleukin, IL-2: 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: 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: 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: Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Amiodarone: 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: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Amoxapine: CNS depressants should be combined cautiously with amoxapine because they could cause additive depressant effects and possible respiratory depression or hypotension. This combination is considered to be safe as long as patients are monitored for excessive adverse effects from either agent.
    Amoxicillin; Clarithromycin; Lansoprazole: 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.
    Amoxicillin; Clarithromycin; Omeprazole: 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. 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.
    Amyl Nitrite: Administration of nitrates such as amyl nitrite to patients receiving other hypotension-producing agents, such as benzodiazepines, can cause additive hypotensive or orthostatic effects.
    Apomorphine: Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
    Apraclonidine: 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: 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: Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.
    Armodafinil: 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.
    Asenapine: 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: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. 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: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. 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. 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; Dihydrocodeine: 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. 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: 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: 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: 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: 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 inhibits 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.
    Atracurium: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Atropine; Difenoxin: Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent.
    Atropine; Diphenoxylate: Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    Azelastine: An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including benzodiazepines.
    Azelastine; Fluticasone: An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including benzodiazepines.
    Barbiturates: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Belladonna; Opium: 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.
    Benztropine: CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
    Boceprevir: Concurrent use of oral midazolam and boceprevir is contraindicated due to the risk of life threatening reactions, such as prolonged or increased sedation or respiratory depression. Boceprevir is a potent inhibitor of CYP3A4, which is responsible for the metabolism orally administered midazolam. Coadministration may result in large increases in midazolam serum concentrations, which could cause fatal toxicities. Increased midazolam serum concentrations resulting from boceprevir CYP3A4 inhibition are higher for oral midazolam than for the intravenous formulation; use of intravenous midazolam is not contraindicated with boceprevir, although dosage adjustments and close monitoring for respiratory depression and/or prolonged sedation is recommended. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with boceprevir, as they are not oxidatively metabolized.
    Bosentan: Bosentan may theoretically increase the clearance of midazolam by inducing CYP3A4. However, this interaction has not been studied.
    Brigatinib: Monitor for decreased efficacy of midazolam if coadministration with brigatinib is necessary. Midazolam is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of midazolam may decrease.
    Brimonidine: 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: 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: 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: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Carbetapentane; Phenylephrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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. 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: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Guaifenesin; Hydrocodone: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Hydrocodone; Pseudoephedrine: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Pseudoephedrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Buprenorphine: 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. 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. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buprenorphine; Naloxone: 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. 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. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupropion: 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: 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: 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: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Butorphanol: 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: 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; Ergotamine: 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.
    Carbamazepine: 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.
    Carbetapentane; Chlorpheniramine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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.
    Carbetapentane; Chlorpheniramine; Phenylephrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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. The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Diphenhydramine; Phenylephrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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. The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Guaifenesin: 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.
    Carbetapentane; Guaifenesin; Phenylephrine: 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. The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine: 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. The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine; Pyrilamine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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. The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Pseudoephedrine: 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.
    Carbetapentane; Pyrilamine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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.
    Carbinoxamine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Carbinoxamine; Hydrocodone; Phenylephrine: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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; Hydrocodone; Pseudoephedrine: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Carbinoxamine; Phenylephrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Cariprazine: 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.
    Ceritinib: Avoid the use of ceritinib, a time-dependent inhibitor of CYP3A4, with substrates that are primarily metabolized by CYP3A4, such as midazolam, as midazolam exposure may be increased. If co-administration is unavoidable, consider a midazolam dose reduction and monitor for midazolam toxicity.
    Cetirizine: Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, including benzodiazepines.
    Cetirizine; Pseudoephedrine: Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, including benzodiazepines.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlophedianol; Guaifenesin; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorcyclizine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Codeine: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Dextromethorphan: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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; Dihydrocodeine; Phenylephrine: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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; Dihydrocodeine; Pseudoephedrine: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Hydrocodone: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Hydrocodone; Phenylephrine: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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; Pseudoephedrine: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Phenylephrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorthalidone; Clonidine: Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Cimetidine: Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as cimetidine, can potentiate the clinical effects of midazolam.
    Ciprofloxacin: 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: 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.
    Cisatracurium: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Clarithromycin: 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: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Clobazam: Concomitant administration of clobazam with other CNS depressant drugs including anxiolytics, sedatives, and hypnotics, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. In addition, concurrent use of clobazam and other benzodiazepines should generally be avoided since this may represent duplicative therapy, and centrally-mediated adverse effects may be potentiated. Results of one pharmacokinetic study indicated that clobazam decreased the AUC and Cmax of midazolam by 27% and 24%, respectively, and increased the AUC and Cmax of the active metabolite of midazolam by 4-fold and 2-fold, respectively. Midazolam is a substrate of CYP3A4 and clobazam is a mild inducer of this isoenzyme. According to the manufacturer, dosage adjustments of CYP3A4 substrates are not considered necessary.
    Clofarabine: 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: Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Clozapine: 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: 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 inhibits 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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: 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 inhibits 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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: 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 inhibits 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: 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: 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: 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. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines. 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: 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. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines.
    COMT inhibitors: Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Conivaptan: Concomitant use of conivaptan and midazolam, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean AUC values of midazolam by approximately 2-fold and 3-fold when coadministered with midazolam 1 mg IV or 2 mg PO, respectively. Subsequent treatment with CYP3A substrates, such as midazolam, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: Concomitant use of of crizotinib (250 mg PO bid for 28 days) and midazolam increased the midazolam AUC by 3.7-fold as compared to midazolam alone. Midazolam is a CYP3A4 substrate and crizotinib is a CYP3A4 substrate/inhibitor.
    Cyclizine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Cyproheptadine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dabrafenib: The concomitant use of dabrafenib, a CYP3A4 substrate and a moderate CYP3A4 inducer, and midazolam, a CYP3A4 substrate, may decrease plasma concentrations of midazolam. Concurrent use of dabrafenib 150 mg twice daily for 15 days and a single 3 mg dose of midazolam decreased the AUC of midazolam by 74%. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for reduced efficacy of midazolam.
    Danazol: Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs that are CYP3A4 substrates including midazolam.
    Darifenacin: 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: 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 inhibits 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.
    Dasatinib: Dasatinib is a time-dependent, weak inhibitor of CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme like midazolam are administered concurrently with dasatinib as increased adverse reactions may occur.
    Deferasirox: 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: 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: Concurrent use with benzodiazepines can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
    Desloratadine: Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness when used concurrently with other CNS depressants such as benzodiazepines.
    Desloratadine; Pseudoephedrine: Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness when used concurrently with other CNS depressants such as benzodiazepines.
    Deutetrabenazine: 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.
    Dexchlorpheniramine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dexmedetomidine: Co-administration of dexmedetomidine with benzodiazepines is likely to lead to an enhancement of CNS depression.
    Dextromethorphan; Diphenhydramine; Phenylephrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. 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: 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; Promethazine: Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines.
    Dicyclomine: Dicyclomine can cause drowsiness, so it should be used cautiously in patients receiving CNS depressants like benzodiazepines.
    Dienogest; Estradiol valerate: 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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: 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.
    Diltiazem: Diltiazem may enhance and prolong the sedative effects of midazolam, and dosage reduction of midazolam and close monitoring is recommended during concurrent administration.
    Dimenhydrinate: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine; Hydrocodone; Phenylephrine: 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. Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Diphenhydramine; Ibuprofen: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine; Phenylephrine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Disulfiram: 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.
    Doxacurium: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Doxylamine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Doxylamine; Pyridoxine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dronabinol, THC: Use caution if the use of benzodiazepines are necessary with dronabinol, and monitor for additive dizziness, confusion, somnolence, and other CNS effects.
    Dronedarone: 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: 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: 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: 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: 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.
    Echinacea: 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.
    Elbasvir; Grazoprevir: 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.
    Enflurane: Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Enzalutamide: Avoid the concomitant use of enzalutamide, a strong CYP3A4 inducer, and midazolam, a CYP3A4 substrate, as midazolam plasma exposure may be reduced. In a drug interaction trial in patients with castration-resistant prostate cancer, the AUC and Cmax of midazolam was decreased following a single oral dose of midazolam 2 mg administered after at least 55 days of oral enzalutamide 160 mg/day.
    Erythromycin: 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.
    Erythromycin; Sulfisoxazole: 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.
    Estradiol Cypionate; Medroxyprogesterone: 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: 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: 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: 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: 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: 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: Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Ethinyl Estradiol: 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; Desogestrel: 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; Ethynodiol Diacetate: 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; Etonogestrel: 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: 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: 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: 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: 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; Ferrous fumarate: 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: 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; Ferrous fumarate: 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; Norgestimate: 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: 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: 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.
    Etomidate: Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Everolimus: Everolimus is a substrate and inhibitor of CYP3A4 and midazolam is a substrate of CYP3A4. In a study in healthy subjects, concomitant use of oral midazolam with everolimus resulted in increased exposure of midazolam (Cmax increased by 25% and AUC increased by 30%). The clinical significance of this interaction is unknown.
    Fentanyl: 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: 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: 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: Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including midazolam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
    Fluoxetine; Olanzapine: 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. 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: Fluvoxamine may inhibit the metabolism of benzodiazepines that undergo hepatic oxidation like midazolam.
    Food: Coadministration of marijuana with benzodiazepines may result in an exaggerated sedative effect. Instruct patients receiving these medications concurrently not to drive or operate machinery.
    Fosphenytoin: 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.
    Fospropofol: Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    General anesthetics: Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Glimepiride; Pioglitazone: 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.
    Glycerol Phenylbutyrate: 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: 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: 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: 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: 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: 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: Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as benzodiazepines, when administered concomitantly.
    Guanfacine: Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Guarana: Caffeine, an active constituent of guarana, is a CNS stimulant associated with heightened attentiveness and insomnia, and is used to treat or prevent drowsiness or fatigue; patients taking benzodiazepines for insomnia should not use guarana-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine or zolpidem.
    Haloperidol: 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.
    Halothane: Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Homatropine; Hydrocodone: 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: 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: 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: 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: 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; Phenylephrine: 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. The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Hydrocodone; Potassium Guaiacolsulfonate: 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; Potassium Guaiacolsulfonate; Pseudoephedrine: 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: 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: 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: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Ibuprofen; Oxycodone: 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: 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: 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, STI-571: 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.
    Iohexol: A higher incidence of adverse reactions has been reported with contrast media in anesthetized patients. This may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia.
    Iopamidol: A higher incidence of adverse reactions has been reported with contrast media in anesthetized patients. This may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia.
    Iopromide: A higher incidence of adverse reactions has been reported with contrast media in anesthetized patients. This may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia.
    Ioversol: A higher incidence of adverse reactions has been reported with contrast media in anesthetized patients. This may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia.
    Isavuconazonium: 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: Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Isoniazid, INH: 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: 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. 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: 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. 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.
    Isosulfan Blue: A higher incidence of adverse reactions has been reported with contrast media in anesthetized patients. This may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia.
    Itraconazole: Coadministration of itraconazole with certain benzodiazepines (e.g., alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam, or triazolam) may result in prolonged sedation and respiratory depression due to inhibition of hepatic oxidative metabolism of the benzodiazepine by itraconazole. Concurrent use of itraconazole with oral midazolam, alprazolam, or triazolam is contraindicated. Additionally, use of oral midazolam and triazolam for up to 2 weeks after discontinuation of itraconazole treatment is contraindicated. 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.
    Ivacaftor: 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.
    Kava Kava, Piper methysticum: The German Commission E warns that any substances that act on the CNS, including psychotropic agents, may interact with kava kava. While the interactions can be pharmacodynamic in nature, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with agents that undergo oxidative metabolism (e.g., selected benzodiazepines) are also possible. Patients on benzodiazepine therapy should avoid concomitant administration of kava kava. Patients should discuss the use of herbal supplements with their health care professional prior to consuming kava kava and should not abruptly stop taking their prescribed medications.
    Ketamine: Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Ketoconazole: Concomitant use of ketoconazole with oral midazolam and triazolam is contraindicated due to the risk of serious adverse events, such as prolonged hypnotic and/or sedative effects. Ketoconazole has been shown to dramatically inhibit the hepatic metabolism of midazolam and triazolam in healthy volunteers. Because the interaction with midazolam occurred with oral midazolam, the significance of an interaction between ketoconazole 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 ketoconazole, as these benzodiazepines are not oxidatively metabolized.
    Lapatinib: After the coadministration of lapatinib and midazolam, the 24-hour systemic exposure (AUC) of orally administered midazolam increased by 45% and 24-hour AUC of intravenously administered midazolam increased by 22%. Lapatinib is a CYP3A4 enzyme inhibitor and midazolam is a CYP3A4 substrate.
    Lesinurad: 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.
    Levocetirizine: Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, including benzodiazepines.
    Levomethadyl: Concomitant administration of benzodiazepines with CNS-depressant drugs, including opiate agonists, can potentiate the CNS effects of either agent.
    Levomilnacipran: 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.
    Levorphanol: 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.
    Lithium: Because lithium has the potential to impair cognitive and motor skills, caution is advisable during concurrent use of other medications with centrally-acting effects including anxiolytics, sedatives, and hypnotics.
    Loratadine: Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness when used concurrently with other CNS depressants like benzodiazepines.
    Loratadine; Pseudoephedrine: Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness when used concurrently with other CNS depressants like benzodiazepines.
    Lumacaftor; Ivacaftor: 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: 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.
    Lurasidone: 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.
    Magnesium Salts: 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.
    Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: 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.
    Maprotiline: 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.
    Meclizine: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Melatonin: Use caution when combining melatonin with the benzodiazepines; when the benzodiazepine is used for sleep, co-use of melatonin should be avoided. 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. Use of more than one 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.Patients reporting unusual sleep-related behaviors likely should discontinue melatonin use.
    Meperidine: 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: 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. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines.
    Mephobarbital: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Meprobamate: 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.
    Metformin; Pioglitazone: 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.
    Methadone: 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 methadone is initiated in a patient taking a benzodiazepine, reduced dosages are recommended; in opioid-naive adults, use an initial dose of methadone 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 dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methocarbamol: 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: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Methscopolamine: CNS depression can be increased when methscopolamine is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
    Methyldopa: 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: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Metyrapone: 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: The concomitant administration of metyrosine with benzodiazepines can result in additive sedative effects.
    Mifepristone, RU-486: Mifepristone, RU-486 inhibits CYP3A4 in vitro. Coadministration of mifepristone may lead to an increase in serum levels drugs metabolized via CYP3A4, such as midazolam. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    Milnacipran: 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: 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: Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Mitotane: 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.
    Mivacurium: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Monoamine oxidase inhibitors: The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines.
    Morphine: 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: 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: Concomitant use of nabilone with other CNS depressants can potentiate the effects of nabilone on respiratory depression.
    Nalbuphine: 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: 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; Palonosetron: 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.
    Neuromuscular blockers: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Nevirapine: Nevirapine may induce the metabolism of certain benzodiazepines that are metabolized through the cytochrome P450 system including midazolam. Patients should be monitored closely for loss of clinical effects.
    Nicardipine: 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: 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.
    Nitroglycerin: 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.
    Non-Ionic Contrast Media: A higher incidence of adverse reactions has been reported with contrast media in anesthetized patients. This may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia.
    Olanzapine: 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.
    Omeprazole: 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; Sodium Bicarbonate: 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: 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.
    Oxybutynin: Additive CNS depression may occur when oxybutynin is used concomitantly with other CNS-depressant drugs, including anxiolytics, sedatives, and hypnotics.
    Oxycodone: 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: 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.
    Palbociclib: 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: Drugs that can cause CNS depression, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when paliperidone is given in combination with other centrally-acting medications including anxiolytics, sedatives, and hypnotics, buprenorphine, butorphanol, dronabinol, THC, ethanol, nabilone, nalbuphine, opiate agonists, and pentazocine.
    Pancuronium: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Papaverine: Concurrent use of papaverine with potent CNS depressants such as benzodiazepines could lead to enhanced sedation.
    Pazopanib: Pazopanib resulted in an approximately 30% increase in mean AUC and Cmax of midazolam, a CYP3A4 substrate, when given concomitantly.
    Pentazocine: 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: 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: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Perampanel: 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: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Phenothiazines: Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Phentermine; Topiramate: 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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Phenylephrine; Promethazine: Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines. 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: 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: Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including benzodiazepines.
    Pioglitazone: 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.
    Posaconazole: Posaconazole inhibits CYP3A4 and may increase serum concentrations of benzodiazepines metabolized by this enzyme, including midazolam.
    Pramipexole: Concomitant administration of benzodiazepines with CNS-depressant drugs, including pramipexole, can potentiate the CNS effects.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): 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): 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: Pregabalin 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.
    Primidone: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Probenecid: Probenecid may inhibit the metabolism of the benzodiazepines, including those which are metabolized by conjugation (e.g., lorazepam) or oxidation (e.g., midazolam). Probenecid has been shown to decrease lorazepam clearance by about 50% and increase its elimination half-life. In addition, pretreatment with probenecid shortened the induction time (85 vs. 109 seconds) of midazolam in presurgical patients. Patients receiving alprazolam therapy should be monitored for signs of altered benzodiazepine response when probenecid is initiated or discontinued.
    Procarbazine: CNS depressants benzodiazepines can potentiate the CNS depression caused by procarbazine therapy, so these drugs should be used together cautiously.
    Promethazine: Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines.
    Propofol: Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Propoxyphene: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. The dose of any opiate agonist administered with parenteral diazepam should be reduced by at least one-third.
    Protease inhibitors: The use of oral midazolam and anti-retroviral protease inhibitors is contraindicated. Midazolam is metabolized by hepatic isozyme CYP3A4; inhibitors of this pathway can potentiate the clinical effects of midazolam. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation. Lorazepam, oxazepam, or temazepam may be safer alternatives, as these benzodiazepines are not oxidatively metabolized. 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.
    Quetiapine: 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: 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: 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: 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: 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.
    Rapacuronium: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Rasagiline: 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.
    Remifentanil: 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.
    Ribociclib: Use caution if coadministration of ribociclib with midazolam is necessary, as the systemic exposure of midazolam was significantly increased in a drug interaction study. Adjust the dose of midazolam if necessary. Ribociclib is a moderate CYP3A4 inhibitor and midazolam is a CYP3A4 substrate. In a drug interaction study in healthy volunteers, the midazolam AUC (0-inf) and Cmax values were increased 3.8-fold and 2.1-fold, respectively, when midazolam was administered following 8 days of ribociclib 400 mg daily compared with midazolam administered alone.
    Ribociclib; Letrozole: Use caution if coadministration of ribociclib with midazolam is necessary, as the systemic exposure of midazolam was significantly increased in a drug interaction study. Adjust the dose of midazolam if necessary. Ribociclib is a moderate CYP3A4 inhibitor and midazolam is a CYP3A4 substrate. In a drug interaction study in healthy volunteers, the midazolam AUC (0-inf) and Cmax values were increased 3.8-fold and 2.1-fold, respectively, when midazolam was administered following 8 days of ribociclib 400 mg daily compared with midazolam administered alone.
    Rifabutin: 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: 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: 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.
    Rifaximin: Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A clinical drug-drug interaction study showed that rifaximin administered as 200 mg PO tid for 3 or 7 days did not alter the pharmacokinetics of IV or PO midazolam presystemically or systemically, demonstrating a lack of induction of intestinal or hepatic CYP 3A4 isoenzyme. Rifaximin was also administered as 550 mg PO bid for 7 or 14 days with oral midazolam in healthy subjects. The mean AUC of a single 2 mg oral dose of midazolam was 3.8 to 8.8% lower than when midazolam was administered alone. The mean Cmax of midazolam was decreased by 4 to 5% when administered for 7 to 14 days prior to midazolam administration. However, this degree of interaction was not considered clinically significant.
    Risperidone: 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.
    Rocuronium: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Rotigotine: Concomitant use of rotigotine with other CNS depressants, such as benzodiazepines, can potentiate the sedative effects of rotigotine.
    Rufinamide: 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: 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: Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    Secobarbital: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Sedating H1-blockers: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Sevoflurane: Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Simeprevir: 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: 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: 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.
    Sodium Oxybate: 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.
    St. John's Wort, Hypericum perforatum: 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.
    Streptogramins: Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme including midazolam.
    Succinylcholine: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Sufentanil: 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: 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: 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.
    Teduglutide: Teduglutide may increase absorption of benzodiazepines or other psychotropic agents because of it's pharmacodynamic effect of improving intestinal absorption. In studies with teduglutide, one of the subjects was receiving concomitant treatment with prazepam and experienced dramatic deterioration in mental status progressing to coma during her first week of teduglutide therapy. Upon admission to the ICU, her benzodiazepine level was reported as >300 mcg/L. Both drugs were discontinued, and the coma resolved 5 days later. Careful monitoring and possible dose adjustment of the psychotropic agent is recommended.
    Telaprevir: Concurrent use of oral midazolam and telaprevir is contraindicated due to the risk of life threatening reactions, such as prolonged or increased sedation or respiratory depression. Telaprevir is an inhibitor of CYP3A4, which is responsible for the metabolism of orally administered midazolam. Coadministration may result in large increases in midazolam serum concentrations, which could cause fatal toxicities. Increased midazolam serum concentrations resulting from telaprevir CYP3A4 inhibition are higher for oral midazolam than for the intravenous formulation; use of intravenous midazolam is not contraindicated with telaprevir, although dosage adjustments and close monitoring for respiratory depression and/or prolonged sedation is recommended. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with telaprevir, as they are not oxidatively metabolized.
    Telithromycin: Concomitant administration of telithromycin with midazolam results in increases in the AUC of midazolam. This interaction is due to decreased midazolam metabolism through telithromycin-induced CYP3A4-inhibition. Patients should be monitored and dosage adjustment of midazolam should be considered if necessary.
    Telotristat Ethyl: Use telotristat ethyl and midazolam together with caution; the systemic exposures of midazolam and its active metabolite were significantly decreased in a pharmacokinetic study. If these drugs are used together, monitor patients for suboptimal efficacy of midazolam; consider increasing the dose of midazolam if necessary. When a single midazolam 3-mg PO dose was administered after treatment with telotristat ethyl 500 mg PO 3 times daily (twice the recommended dosage) for 5 days, the mean midazolam Cmax decreased by 25% and the mean midazolam AUC(0-inf) decreased by 48% compared with Cmax and AUC values when midazolam was administered alone. Additionally, the mean Cmax and AUC(0-inf) values for the active metabolite, 1-hydroxymidazolam, were decreased by 34%, and 48%, respectively. The mechanism of this drug interaction appears to be that telotristat ethyl increases glucuronidation resulting in decreased systemic exposure of midazolam and its active metabolite.
    Tetrabenazine: 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.
    Thalidomide: Thalidomide frequently causes drowsiness and somnolence and may enhance the sedative activity of benzodiazepines.
    Theophylline, Aminophylline: Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines. Theophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of theophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If theophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Thiopental: Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Thiothixene: 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: 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: 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: 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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Tramadol: 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: 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: CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Tricyclic antidepressants: Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Trihexyphenidyl: CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of trihexyphenidyl.
    Trimethobenzamide: 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: Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Tubocurarine: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Valerian, Valeriana officinalis: 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.
    Vecuronium: Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, 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.
    Vemurafenib: 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: 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: 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: Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as anxiolytics, sedatives, and hypnotics.
    Voriconazole: Voriconazole may increase midazolam serum concentrations due to CYP3A4 inhibition. Clinicians should be alert to the possibility of an exaggerated or a prolonged response to some benzodiazepines when given with voriconazole.
    Zafirlukast: 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: In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Zileuton: 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: 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: 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

    Pregnancy

    Midazolam is classified as FDA pregnancy category D. Although animal studies have not indicated teratogenic effects, other benzodiazepines have been associated with congenital abnormalities when used during pregnancy. Such effects have not been reported with midazolam, but no adequate human data are available. If this drug is to be used during pregnancy, the patient should be apprised of the potential hazard to the fetus. 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. 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. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal central nervous system depression, midazolam is not recommended for obstetrical use during labor or obstetric delivery.

    MECHANISM OF ACTION

    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 only for oral or parenteral administration in the US, although it has also been administered via buccal, intranasal, and rectal routes off-label. Midazolam is widely distributed, crossing both the blood-brain and placental barriers. It is unknown if distribution into breast milk occurs. Midazolam is 94% to 97% protein-bound and has a half-life of 1 to 5 hours. Extensive hydroxylation occurs in the liver. The primary metabolite is alpha-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 1-hydroxymidazolam and 1,4-hydroxylmidazolam; 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.

    Oral Route

    After oral administration, midazolam undergoes extensive first pass metabolism. Oral midazolam bioavailability is roughly 36%, and is independent of age or weight. Onset of anxiolytic and sedative effects usually occur within 10 to 30 minutes of oral administration, with the degree of sedation dependent on the dose administered and the presence or absence of other medications. Food does not appear to affect the extent of absorption, but the indications for oral midazolam often preclude feeding. Recovery times are similar to intravenous administration of a single dose.

    Intravenous Route

    The onset of action following IV administration of midazolam occurs in 1.5 to 5 minutes. Maximum effects are seen in 20 to 60 minutes, with a recovery time of 2 to 6 hours.

    Intramuscular Route

    Following intramuscular administration, the absorption of midazolam is rapid, with a mean bioavailability greater than 90%. Onset of action following IM in 5 to 15 minutes. Maximum effects are seen in 20 to 60 minutes, with a recovery time of 2 to 6 hours.