Midazolam Hcl (midazolam HCl)

Midazolam is commercially available as midazolam or the hydrochloride salt; dosage is expressed in terms of midazolam. Midazolam is a potent sedative that requires individualized dosing.

When midazolam is used for sedation or anesthesia, dosage must be carefully adjusted according to individual requirements and response, age, body weight, physical and clinical status, underlying pathologic condition(s), type and amount of premedication or concomitant medication, and the nature and duration of the surgical or other procedure; however, individual response to the drug also may vary independent of these factors. Titration should be more gradual in patients 60 years of age and older for procedural sedation, in those 55 years of age and older for induction of anesthesia, and in patients with chronic debilitating diseases. Excessive doses or rapid or single large IV injections may result in respiratory depression and/or arrest, particularly in geriatric or debilitated patients and in patients receiving other cardiorespiratory depressants concomitantly. The smallest effective dose should be used, especially in geriatric and/or debilitated patients.

It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure performed. For example, simple light sedation in the preoperative period is different from the deeper sedation required for a therapeutic or diagnostic procedure (e.g., endoscopy); therefore, there is a broad dosage range. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate the midazolam dose and the dose of other concomitant drugs slowly for the desired clinical effect. Unlike adults, pediatric patients generally receive increments of midazolam on a mg/kg basis; drug dose in obese pediatric patients should be calculated on the basis of ideal body weight. Pediatric patients generally require higher dosages of midazolam on a mg/kg basis than adults, and pediatric patients younger than 6 years of age generally require higher dosages on a mg/kg basis than older pediatric patients and may require closer monitoring.

When midazolam is used for sedation in geriatric patients, the initial dose should be reduced, since some degree of organ impairment frequently is present. Dosage requirements in this age group generally appear to decrease with increasing age, and the possibility of profound and/or prolonged effects should be considered in older and/or debilitated patients. Low doses of midazolam usually are required in high-risk surgical patients, debilitated patients, and geriatric patients when the drug is administered with or without premedication.

Midazolam hydrochloride is administered orally, by IM or slow IV injection, or by IV infusion. Midazolam also has been used in IV patient-controlled analgesia (PCA). Midazolam is administered intranasally. Midazolam also has been orally administered as the maleate salt+; however, midazolam maleate currently is not commercially available in the US.

Because serious and life-threatening adverse cardiorespiratory effects can occur during therapy with midazolam, provision should be made for monitoring, detecting, and correcting such effects in every patient in whom the drug is administered, regardless of age or health status.

When IV or oral midazolam is used for sedation or anesthesia, the drug should be administered in a hospital or ambulatory care setting equipped to provide continuous monitoring of cardiorespiratory function. Resuscitative equipment, drugs, and personnel for airway and ventilation management should be immediately available. For deeply sedated pediatric patients, a dedicated individual other than the clinician performing the procedure should monitor the patient throughout the procedure.

When IM midazolam is used for status epilepticus, the drug should be administered in a monitored setting that allows for immediate access to resuscitative drugs, and the patient's cardiorespiratory function should be continuously monitored until stabilized.

When midazolam nasal spray is used, consideration should be given to administering the drug under the supervision of a healthcare professional.

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There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Alprazolam; Midazolam; Triazolam/Delavirdine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Delavirdine may inhibit the metabolism of alprazolam, midazolam, and triazolam by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of delavirdine with alprazolam, midazolam, or triazolam may result in elevated levels of alprazolam, midazolam, or triazolam and toxicity, including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of delavirdine states that concurrent use of delavirdine with alprazolam, midazolam, or triazolam is contraindicated.(1) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Because delavirdine inhibits CYP3A4, the concurrent use of agents that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentration are associated with serious and/or life-threatening events, such as alprazolam, midazolam, or triazolam, is contraindicated by the manufacturer of delavirdine.(1)

Midazolam/Conivaptan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Conivaptan may inhibit the metabolism of midazolam via CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of midazolam and conivaptan may result in increased levels of midazolam, which may lead to increased clinical effects and toxicity, including respiratory depression.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of conivaptan states the concurrent use of agents primarily metabolized by CYP3A4, such as midazolam, should be avoided. Treatment with midazolam may be initiated no sooner than 1 week after the infusion of conivaptan is completed.(1)

DISCUSSION: Conivaptan is a potent inhibitor of CYP3A4. In an evaluation of the combination of intravenous conivaptan (40 mg) with either an intravenous dose of midazolam (1 mg) or an oral dose of midazolam (2 mg), mean area under the curve (AUC) values of midazolam were increased 2- and 3-fold, respectively.(1)

Midazolam/Lonafarnib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The metabolism of midazolam by CYP3A4 may be inhibited by lonafarnib.(1)

CLINICAL EFFECTS: The concurrent administration of lonafarnib may result in elevated levels of midazolam, which may result in increased adverse effects including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of lonafarnib states that concurrent use of midazolam is contraindicated. Temporarily discontinue lonafarnib 10-14 days before and 2 days after administration of midazolam.(1) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a study in healthy subjects, concomitant administration of midazolam (3 mg single dose) with lonafarnib (100 mg twice daily for 5 days) increased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam by 180% and 639%, respectively.(1)

Oral Midazolam/Selected Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The metabolism of midazolam by CYP3A4 may be inhibited by strong CYP3A4 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of strong CYP3A4 inhibitors may result in elevated levels of midazolam, which may result in increased adverse effects including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of boceprevir,(1) cobicistat,(2) and telaprevir(3) state that concurrent use of oral midazolam is contraindicated. The US manufacturers of adagrasib,(4) idelalisib,(5) and relacorilant(6) state that concurrent use of oral midazolam should be avoided. Patients receiving intravenous midazolam should be closely monitored. Consideration should be given to lowering the dose of intravenous midazolam in patients maintained on strong CYP3A4 inhibitors. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Boceprevir (800 mg 3 times daily for 6 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single oral dose of midazolam (4mg) by 2.77-fold and 5.30-fold, respectively.(1) In a study in 21 subjects, telaprevir (750mg every 8 hours for 11 days) increased the Cmax and AUC of a single oral dose of midazolam (2 mg) by 2.86-fold and 8.96-fold, respectively.(3) In a study in 22 subjects, telaprevir (750mg every 8 hours for 9 days) increased the Cmax and AUC of a single intravenous dose of midazolam (0.5 mg) by 2% and 3.40-fold, respectively.(3,7) Coadministration of adagrasib 400 mg twice daily and 600 mg twice daily with midazolam increased the Cmax of midazolam by 4.8-fold and 3.1-fold, respectively, and increased the AUC of midazolam by 21-fold and 31-fold, respectively.(4) Coadministration of idelalisib with midazolam increased the Cmax and AUC of midazolam by 2.4-fold and 5.4-fold, respectively.(5) Coadministration of relacorilant with midazolam increased the Cmax and AUC of midazolam by 3.1-fold and 8.9-fold, respectively.(6) Selected CYP3A4 inhibitors linked include: adagrasib, boceprevir, cobicistat, idelalisib, relacorilant, and telaprevir.

Oral Midazolam; Triazolam/Protease Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The protease inhibitors may inhibit the metabolism of the benzodiazepines midazolam and triazolam at CYP3A4.(1-30)

CLINICAL EFFECTS: Concurrent administration may result in increased levels and clinical effects of the benzodiazepines, which may result in profound sedation, respiratory depression, coma, and/or death.(1-30) Higher triazolam levels may increase risk for anterograde amnesia, "sleep driving" and other complex behavior disorders.(30)

PREDISPOSING FACTORS: The elderly are particularly sensitive to increased plasma concentrations of triazolam.(30)

PATIENT MANAGEMENT: The manufacturers of the protease inhibitors and US guidelines on use of antiretroviral agents (31) state that concurrent administration of triazolam or oral midazolam with ritonavir-boosted(1-3) darunavir,(4-6) lopinavir,(7-9) nirmatrelvir,(10) paritaprevir,(11) saquinavir,(12-14) or tipranavir (15-17); ritonavir-boosted or unboosted amprenavir,(18-19) atazanavir,(20-21) fosamprenavir,(22-23) indinavir,(24-26); or nelfinavir,(27-29) is contraindicated. Midazolam may be administered by the intravenous route in patients with close clinical monitoring for respiratory depression and/or prolonged sedation. Caution should be exercised and dosage adjustments should be considered if these effects occur.

DISCUSSION: In an open-label, randomized study in 14 subjects, lopinavir/ ritonavir (400/100 mg twice daily) decreased the metabolism of single doses of oral and intravenous midazolam (0.025 mg/kg and 5 mg, respectively) by 77% and 92%, respectively.(32) In a double-blind, randomized, cross-over study in 12 subjects, concurrent administration of saquinavir base with oral midazolam increased the bioavailability of oral midazolam from 41% to 90%. The midazolam maximum concentration (Cmax) and area-under-curve (AUC) increased two-fold and five-fold, respectively. The concurrent administration of saquinavir base with intravenous midazolam resulted in a decrease in midazolam clearance by 56% and increased the midazolam half-life from 4.1 hours to 9.5 hours.(33) In a study in 6 healthy subjects, saquinavir base (1200 mg twice daily) increased the AUC and Cmax of a single dose of midazolam (7.5 mg) by 514% and 235%, respectively.(12) In a study in 16 healthy subjects, saquinavir/ritonavir (1000/100 mg twice daily) increased the AUC and Cmax of a single dose of midazolam (7.5 mg) by 1144% and 327%, respectively.(14) In a double-blind study, ritonavir (four doses of 200 mg) decreased the clearance of a single dose of triazolam (0.125 mg) by 96%.(34) Amprenavir,(35), lopinavir,(36) and ritonavir(33,34) have been shown to inhibit triazolam metabolism in vitro in human liver microsomes. In a clinical trial of 13 healthy patients patients receiving concurrent midazolam (3mg) and ritonavir (100 mg three times daily), midazolam AUC increased by a factor of 28.4 +/- 4.2 and oral clearance was reduced to 4.2% of normal.(37) Protease inhibitors linked to this monograph include: amprenavir, atazanavir, fosamprenavir, darunavir, ensitrelvir, indinavir, lopinavir, nelfinavir, nirmatrelvir, paritaprevir, saquinavir, and tipranavir. Ritonavir, as a pharmacokinetic booster, will alert through the primary protease inhibitor.

Sedative Hypnotics; Alcohol/Sodium Oxybate

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Oxybate may be associated with respiratory depression. As oxybate is taken at bedtime, concurrent use with alcohol or hypnotics may increase the risk for respiratory depression or loss of consciousness.(1-3) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for respiratory depression and profound sedation or coma.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)

PATIENT MANAGEMENT: The FDA states that sodium oxybate is contraindicated in patients also taking hypnotics or alcohol.(1,2) Significant quantities of alcohol may be present in medicinal products. Alcohol is is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (4): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended upward dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

Selected Cyp3a4 Substrates/Mifepristone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme.(1)

CLINICAL EFFECTS: Lovastatin, simvastatin and CYP3A4 substrates with a narrow therapeutic window such as alprazolam, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and tacrolimus or CYP3A4 substrates with a high first pass effect such as oral midazolam, sildenafil, and triazolam are particularly susceptible to significant toxicity.(1,2)

PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with lovastatin, simvastatin, CYP3A4 substrates with a narrow therapeutic range, or CYP3A4 substrates with a high first pass effect is contraindicated.(1)

DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.

Slt Benzodiazepines/Itraconazol;Ketoconazol;Levoketoconaz

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Itraconazole, ketoconazole, and levoketoconazole may inhibit the metabolism of alprazolam, estazolam, midazolam, and triazolam by CYP3A.(1-29)

CLINICAL EFFECTS: Inhibition of benzodiazepine metabolism may produce increased levels of these agents, as well as increased clinical effects. Toxic effects of increased benzodiazepine levels include profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of alprazolam,(1) estazolam,(2) or triazolam(3-5) with itraconazole or ketoconazole or levoketoconazole is contraindicated. The concurrent use of oral midazolam with itraconazole(3) or ketoconazole(4) is contraindicated by the manufacturer of the azole antifungals. The manufacturer of oral midazolam states that the agents should only be used concurrently if absolutely necessary and if appropriate equipment and personnel are available to respond to respiratory insufficiency.(6) The concurrent use of injectable midazolam and itraconazole(3,7) or ketoconazole(4,7) should be approached with special precaution and patient monitoring. The US manufacturer of itraconazole states that concomitant administration with triazolam or oral midazolam is contraindicated during and two weeks after itraconazole treatment.(3) The US manufacturer of levoketoconazole states concurrent use with sensitive CYP3A4 substrates is contraindicated.(29) The Australian manufacturer of alprazolam states coadministration with ketoconazole, itraconazole or other azole antifungals is not recommended.(30,31)

DISCUSSION: In a double-blind cross-over study in 10 healthy subjects, itraconazole increased alprazolam area-under-curve (AUC) and half-life by 1.67-fold and by 1.56-fold, respectively. Alprazolam clearance was decreased by 60%.(8) In a double-blind cross-over study, concurrent ketoconazole decreased alprazolam clearance by 68.6% and increased alprazolam half-life by 2.9-fold.(9) Ketoconazole has also been shown to inhibit alprazolam metabolism in vitro.(10,11) In a double-blind, randomized cross-over study, itraconazole had no effects on the pharmacokinetics of a single dose of estazolam.(12) However, itraconazole was shown to inhibit the metabolism of estazolam in vitro(13) and the manufacturer of estazolam states that concurrent use with either itraconazole or ketoconazole is expected to increase estazolam levels and thus concurrent use is contraindicated.(2) In a study in 9 healthy subjects, itraconazole increased the AUC of oral midazolam by 8-fold. Increased effects were also noted.(14) In a double-blind cross-over study in 12 subjects, itraconazole increased the AUC, maximum concentration (Cmax) and half-life of oral midazolam by 6-fold, 2.5-fold, and 2-fold, respectively. Increased effects were also noted.(15) In a cross-over study in 12 subjects, one dose of itraconazole increased the AUC and Cmax of oral midazolam by 3.5-fold and by 2-fold, respectively. Six doses of itraconazole increased the AUC of oral midazolam by almost 7-fold. Increased midazolam effects were seen.(16) In a double-blind, cross-over study, itraconazole increased midazolam AUC by 10-fold. Subjects also experienced significantly increased sedation and amnesiac effects.(17) Itraconazole has also been shown to inhibit midazolam metabolism in vitro.(18,19) In a study in healthy subjects, ketoconazole increased the AUC of oral midazolam by 771.9%.(20) In a double-blind, cross-over study, ketoconazole increased midazolam AUC by 15-fold. Subjects also experienced significantly increased sedation and amnesiac effects.(17) In a study in 11 healthy subjects, administration of ketoconazole (400 mg daily) for 1 day, 2 days, and 5 days increased the AUC of a single dose of oral midazolam (2 mg) by 10.28-fold, 13.14-fold, and 13.96-fold, respectively, and the Cmax by 5.01-fold, 5.29-fold, and 5.42-fold, respectively.(21) In a study in healthy subjects, ketoconazole (200 mg twice daily) reduced the clearance of midazolam 6-fold.(22) Ketoconazole has also been shown to inhibit the metabolism of midazolam in vitro.(18,19,23-25) In a randomized, cross-over study in 10 healthy subjects, itraconazole ingested simultaneously, or 3, 12, or 24 hours before triazolam increased triazolam AUC by 3.1-fold, 4.8-fold, 4.6-fold, and 3.8-fold, respectively. The increased in triazolam Cmax ranged from 1.4-fold to 1.8-fold. Subjects noted increased triazolam effects.(23) In a double-blind cross-over study in 9 subjects, itraconazole increased triazolam AUC by 27-fold.(24) In a double-blind cross-over study in 9 subjects, ketoconazole increased triazolam AUC by 22-fold.(24) In a double-blind cross-over study, concurrent ketoconazole decreased triazolam clearance by 91%. Triazolam half-life and Cmax increased 5.1-fold and 1.1-fold, respectively.(9) Ketoconazole has also been shown to inhibit triazolam metabolism in vitro.(23,25)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Alprazolam; Estazolam; Midazolam; Triazolam/Nefazodone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Nefazodone is a strong inhibitor of CYP3A4 and may decrease metabolism of benzodiazepines cleared by this pathway.

CLINICAL EFFECTS: Concurrent administration of nefazodone and benzodiazepines metabolized by CYP3A4 may result in increased clinical effects of benzodiazepines, including toxic effects profound sedation, respiratory depression, coma, and/or death. CYP3A4 is the major or only hepatic metabolism pathway for the phase I elimination of alprazolam, estazolam, midazolam, and triazolam.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Benzodiazepines that do not undergo extensive CYP hepatic metabolism (e.g. lorazepam, oxazepam) may be an alternative in nefazodone patients. If nefazodone is administered in combination with triazolam, the manufacturer of nefazodone recommends that the initial dose triazolam be reduced by 75%. In interaction studies nefazodone 200 mg twice daily increased triazolam exposure (area-under-curve, AUC) 4-fold. However, because not all commercially available triazolam dosage forms permit a sufficient dosage adjustment, the manufacturer of nefazodone recommends that the combination of nefazodone and triazolam be avoided in most patients, especially the elderly. When nefazodone is coadministered with alprazolam, AUC and half-life increased approximately 2-fold. The US manufacturers of nefazodone recommend a 50% reduction in the initial dose of alprazolam. The US manufacturer of estazolam recommends caution and consideration of an appropriate dose reduction when concomitant therapy is considered. Two other strong CYP3A4 inhibitors, itraconazole and oral ketoconazole, are contraindicated with estazolam use. It would be prudent to avoid the combination of nefazodone and estazolam. If nefazodone is started in a patient already receiving a benzodiazepine primarily metabolized by CYP3A4, then monitor closely and anticipate the need to reduce the benzodiazepine dose. Counsel patient to report excess drowsiness, confusion, memory problems including sleep-driving behaviors, loss of coordination, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In an interaction study, nefazodone 200 mg twice daily increased triazolam exposure (area-under-curve, AUC) 4-fold. When nefazodone is coadministered with alprazolam, AUC and half-life increased approximately 2-fold.

Benzodiazepines/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Some benzodiazepines may increase clozapine levels.(1)

CLINICAL EFFECTS: Concurrent administration of clozapine with a benzodiazepine may result in orthostatic hypotension, delirium, collapse, profound sedation, respiratory arrest, and/or cardiac arrest.(2-3)

PREDISPOSING FACTORS: Patients with preexisting cardiovascular, liver, organic brain disease(1) or sleep apnea may be predisposed to the interaction. The interaction may be more likely when initiating clozapine therapy, when restarting clozapine after a brief clozapine-free interval, or when adding clozapine to benzodiazepine therapy.(1,2)

PATIENT MANAGEMENT: The concurrent use of clozapine with benzodiazepines should be approached with caution, especially in patients who have recently started or restarted clozapine therapy. Monitor patients for excessive sedation, decreased respiratory rate, and ataxia.(3)

DISCUSSION: Collapse has been reported in a patients in whom clozapine and clonazepam were initiated simultaneously.(4) Somnolence, confusion, ataxia, and disorientation were reported in a patient following the addition of clozapine to clonazepam therapy.(5) Collapse has been reported in three patients maintained on diazepam in whom clozapine was initiated.(6,7) Cardiac arrest and death during sleep were reported in a patient in whom clozapine and oxazepam were initiated simultaneously.(4) Delirium has been reported in four clozapine-treated patients in whom lorazepam was initiated.(5,8) Respiratory arrest and death were reported in one patient in whom clozapine was initiated who had been maintained on oral lorazepam. The patient received three supplemental doses of intravenous lorazepam for increased psychosis and was found dead 12 hours later.(9)

Benzodiazepines/Ethyl Alcohol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use may result in additive central nervous system depressant effects. Concurrent use may also result in altered absorption, altered distribution, or decreased elimination leading to higher concentrations of the benzodiazepine in the brain.(1-4)

CLINICAL EFFECTS: Concurrent use of benzodiazepines and alcohol-containing products may result in enhanced disruption of psychomotor performance and increased central nervous system depression. Increased CNS depression may result in profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should be informed that alcohol consumption may result in significant decreased psychomotor performance and its associated risks. Use of a short acting benzodiazepine may minimize the potential for extreme effects. If suicide or drug abuse is a concern, benzodiazepine use may be ill advised, since alcohol tends to greatly increase benzodiazepine-induced CNS depression in acute overdosage. Patients should be informed about unsuspected sources of alcohol such as medications. Alcohol is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (18): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation

DISCUSSION: Several articles have detailed enhanced disruption of psychomotor performance and increased CNS depression with concurrent use of diazepam and alcohol.(1-6) Evidence shows that temazepam and the other short-acting or intermediate-acting benzodiazepines (e.g., alprazolam, halazepam, triazolam) tend to result in less profound alcohol interactions.(7) Although one study showed no effect on triazolam pharmacokinetics, a clinically significant pharmacodynamic interaction cannot be ruled out.(8) Other reports have shown clinically significant effects from concurrent triazolam and alcohol use.(9,10) In 8 healthy subjects, concurrent midazolam and alcohol resulted in impairment of immediate recall.(11) In a similar study, the hypnotic effect of midazolam was augmented by alcohol.(12) In a study involving 9 subjects, measurements of total reaction time were longer after concurrent alcohol and lorazepam as compared to the use of either agent alone.(13) Reports have been conflicting regarding the actions of chlordiazepoxide when combined with alcohol. Differences in time of exposure, dosage, and response parameters have been used to explain the inconsistent findings with chlordiazepoxide.(14)

Benzodiazepines/Opioids (Cough And Cold)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of opioids and benzodiazepines may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as benzodiazepines, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Avoid prescribing opioid-including cough medications for patients taking CNS depressants such as benzodiazepines.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) A study of 315,428 privately insured patients who filled at least one prescription for an opioid from 2001 to 2013 were enrolled in a retrospective study. Concurrent use of a benzodiazepine was recorded as having at least one day of overlap in a given calendar year. Baseline characteristics among opioid users with concurrent use of a benzodiazepine were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%, p<0.001), and had a higher prevalence rate of every comorbidity examined (p<0.001). The proportion of opioid users with concurrent benzodiazepine use nearly doubled from 9% in 2001 to 17% in 2013. The primary outcome was an emergency room visit or inpatient admission for opioid overdose within a calendar year. Among all opioid users, the annual adjusted incidence for the primary outcome was 1.16% without concurrent benzodiazepine use compared to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24; p<0.001). Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI 1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95% CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the primary outcome with concurrent benzodiazepine use compared to without concurrent benzodiazepine use, respectively.(10) In a nested case-control study of adults with a new opioid dispensing between 2010-2018, patients with concurrent use of an opioid with a benzodiazepine were significantly more likely to have opioid-related overdose compared to patients receiving opioids, benzodiazepines, or neither (OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90 days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of opioid-related overdose (p<0.01). Patients with overlapping prescriptions during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times more likely to experience an overdose (p<0.01).(11)

Midazolam/Ribociclib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ribociclib is a strong inhibitor of CYP3A4 and may decrease metabolism of midazolam.

CLINICAL EFFECTS: Concurrent administration of ribociclib and midazolam, metabolized by CYP3A4, may result in increased clinical effects (e.g. profound sedation, respiratory depression, coma, and/or death) of midazolam. CYP3A4 is the major or only hepatic metabolism pathway for the phase I elimination of midazolam.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Benzodiazepines that do not undergo extensive CYP hepatic metabolism (e.g. lorazepam, oxazepam) may be an alternative in ribociclib patients. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a study in healthy subjects, concomitant administration of ribociclib (400 mg once daily for 8 days) with midazolam increased the midazolam maximum concentration (Cmax) and area under the curve (AUC) by 2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

Midazolam; Triazolam/Diltiazem; Verapamil

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Diltiazem and verapamil may inhibit the metabolism of midazolam and triazolam by CYP3A4.(1-7)

CLINICAL EFFECTS: Concurrent use of diltiazem or verapamil may result in elevated levels of and clinical effects, including profound sedation, respiratory depression, coma, and/or death, from midazolam and triazolam.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the use of alternative agents to midazolam and triazolam in patients maintained on diltiazem or verapamil. The concurrent use of midazolam or triazolam with diltiazem or verapamil should be approached with caution. The dose of midazolam or triazolam should be reduced and patients should be observed for increased benzodiazepine effects such as prolonged sedation.(1-4) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a double-blind, randomized, cross-over study in 9 healthy subjects, pretreatment with diltiazem (60 mg 3 times daily for 2 days) increased the area-under-curve (AUC) of a single oral dose of midazolam (15 mg) by 2.75-fold. Midazolam maximum concentration (Cmax) doubled and half-life (T1/2) was prolonged. These changes were associated with profound and prolonged sedative effects.(1) In a double-blind, randomized, cross-over study in 9 healthy subjects, pretreatment with verapamil (80 mg 3 times daily for 2 days) increased the AUC of a single oral dose of midazolam (15 mg) by 1.9-fold. Midazolam Cmax doubled and T1/2 was prolonged. These changes were associated with profound and prolonged sedative effects.(1) In a randomized, cross-over study in 7 healthy males, pretreatment with diltiazem (180 mg daily for 3 days) increased the AUC, Cmax, and T1/s of a single oral dose of triazolam (0.25 mg) by 1.275-fold, 71%, and 85%, respectively. Pharmacodynamic effects of triazolam were significantly increased as measured by peak saccadic velocity of eye movements (PSV), electroencephalogram (EEG), and visual analogue scale (VAS).(2) In a randomized, double-blind, cross-over study in 10 healthy subjects, pretreatment with diltiazem (60 mg 3 times daily for 2 days) increased the AUC, Cmax, and T1/2 of a single oral dose of triazolam (0.25 mg) by 3-fold, 2-fold, and 2-fold, respectively. These changes were associated with increased and prolonged pharmacodynamic effects.(3) Studies have shown that diltiazem increases midazolam and triazolam AUC by 3-fold to 4-fold, Cmax by 2-fold, and T1/2 by 1.5-fold to 2.5-fold.(4)

Oral Midazolam/Macrolide Antibiotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Macrolides may inhibit the metabolism and first-pass clearance of oral midazolam through inhibition of CYP3A4.(1)

CLINICAL EFFECTS: Serum concentrations of midazolam may be increased, enhancing its pharmacological effects. Toxic effects of increased midazolam levels include profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of oral midazolam with macrolide antibiotics vary between products and between regions. The Australian, Canadian, and UK manufacturers of clarithromycin state that concurrent use of oral midazolam is contraindicated.(2-4) The US manufacturers of clarithromycin, midazolam, and telithromycin advise caution when using oral midazolam with CYP3A4 inhibitors. Patients should be counseled about possible increased sedation and observed for this side effect. Decreasing the dose of midazolam may be necessary.(1,5,6) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a study of 12 healthy volunteers, clarithromycin (250 mg twice daily for 5 days) increased the area-under-curve (AUC) of oral midazolam (15 mg) by 3.57-fold.(7) Sixteen elderly volunteers who received clarithromycin pre-treatment (500 mg twice daily for 7 days) had increases in the AUC of oral midazolam of 8-fold and of IV midazolam of 3.2-fold.(8) In a study involving 12 healthy volunteers, oral erythromycin (500 mg three times daily for 7 days) was followed by a single oral 15 mg midazolam dose. Concomitant administration of erythromycin and oral midazolam produced a decrease in midazolam clearance and an increase in the half-life and serum concentration of midazolam, with an AUC increase of 4.4-fold. Sedation produced by midazolam was pronounced and long-lasting. When midazolam was given IV, first-pass metabolism was avoided and the effects of the interaction were less profound. A single IV dose of 0.15 mg/kg midazolam given after 1 week of erythromycin 500 mg three times daily resulted in a 54% decrease in midazolam clearance.(9) Oral use of midazolam and IV erythromycin has been associated with unconsciousness in an 8-year-old boy.(10,11) In a study of 10 healthy volunteers, roxithromycin (300 mg daily for 6 days) increased the AUC of oral midazolam (15 mg) by 1.5-fold.(12) Concurrent administration of telithromycin increased the AUC of IV and oral midazolam by 2-fold and 6-fold, respectively.(6)

Selected Cyp3a4 Substrates/Ceritinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ceritinib inhibits CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of ceritinib with drugs primarily metabolized by CYP3A4 may lead to elevated drug levels and increased side effects of these agents. Drugs with a narrow therapeutic window that are metabolized by this isoenzyme include: cyclosporine, felodipine, hydroquinidine, midazolam, nisoldipine, quinidine, and sirolimus.(1,2)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP3A4 inhibition. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, dosage adjustment of the CYP3A4 substrate should be considered when initiating or discontinuing ceritinib.(1) Patients maintained on ceritinib may need lower initial doses of the CYP3A4 substrate. Monitor patients receiving concurrent therapy for adverse effects.

DISCUSSION: In a study, ceritinib (750 mg daily for 3 weeks) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a CYP3A4 substrate) by 5.4-fold and 1.8-fold, respectively, compared to midazolam alone.(1) Thus, ceritinib is expected to increase levels of cyclosporine, felodipine, hydroquinidine, midazolam, nisoldipine, quinidine, and sirolimus.

Selected Cyp3a4 Substrates/Crizotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Crizotinib inhibits CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of crizotinib with drugs primarily metabolized by CYP3A4 may lead to elevated drug levels and increased side effects of these agents.(1) Drugs with a narrow therapeutic window that are metabolized by this isoenzyme include: abemaciclib, cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam, nisoldipine, quinidine, simvastatin, and sirolimus.(1-2)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP3A4 inhibition.

PATIENT MANAGEMENT: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, dosage adjustment of the CYP3A4 substrate should be considered when initiating or discontinuing crizotinib.(1) Patients maintained on crizotinib may need lower initial doses of the CYP3A4 substrate. Monitor patients receiving concurrent therapy for adverse effects. Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(3)

DISCUSSION: Crizotinib (250 mg twice daily for 28 days) increased the area-under-curve (AUC) of oral midazolam by 3.7-fold.(1) Thus, crizotinib is expected to increase levels of abemaciclib, cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam, nisoldipine, quinidine, and simvastatin.

Selected Cyp3a4 Substrates/Pexidartinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Pexidartinib is a moderate inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of pexidartinib may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pexidartinib states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be avoided. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1)

DISCUSSION: Coadministration of pexidartinib 400 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: everolimus, felodipine, fentanyl, hydroquinidine, midazolam, nisoldipine, quinidine, sirolimus, tacrolimus, ticagrelor, and triazolam.(1-3)

Selected Cyp3a4 Substrates/Sotorasib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sotorasib is a moderate inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of sotorasib may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of sotorasib states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be avoided. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1)

DISCUSSION: Coadministration of sotorasib with midazolam, a sensitive CYP3A4 substrate, decreased midazolam area-under-curve (AUC) by 53% and maximum concentration (Cmax) by 48%.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: felodipine, fentanyl, hydroquinidine, parenteral lefamulin, midazolam, nisoldipine, quinidine, tacrolimus, ticagrelor, and triazolam.(2,3)

Selected Sensitive Cyp3a4 Substrates/Oral Lefamulin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,3)

CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2)

DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, ticagrelor, triazolam, and ulipristal.(1,3,5)

Selected Sensitive Cyp3a4 Substrates/Tucatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tucatinib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Tucatinib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus.

CLINICAL EFFECTS: Concurrent use of tucatinib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tucatinib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, consider dose reduction of the CYP3A4 substrate.(1) The manufacturer of tucatinib states that the dose of P-gp substrates may need to be reduced with coadministration with tucatinib.(1)

DISCUSSION: In a study, tucatinib increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (2 mg) by 5.7-fold and 3-fold, respectively.(1) In a study, tucatinib increased the AUC and Cmax of digoxin (0.5 mg single dose) by 1.5-fold and 2.4-fold, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: cyclosporine, midazolam, nisoldipine, and sirolimus.(1-3)

Selected Sensitive Cyp3a4 Substrates/Voxelotor

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Voxelotor is an inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of voxelotor may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: A greater risk for serious adverse events would be expected from drugs having a narrow therapeutic window.

PATIENT MANAGEMENT: The manufacturer of voxelotor states that co-administration of sensitive CYP3A4 substrates with a narrow therapeutic index should be avoided. If concomitant use is unavoidable, consider dose reduction of the sensitive substrate.(1)

DISCUSSION: In a study, voxelotor increased the AUC of a single dose of midazolam by 1.6-fold. After multiple doses of midazolam, a 2.5-fold increase in AUC is predicted.(1) Sensitive CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: avanafil, conivaptan, cyclosporine, dihydroergotamine, eplerenone, ergotamine, everolimus, felodipine, fentanyl, lomitapide, lovastatin, methylergonovine, midazolam, nisoldipine, sildenafil, simvastatin, ticagrelor, tolvaptan, triazolam, and vardenafil.(2,3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Benzodiazepines/Buprenorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Buprenorphine is a partial agonist at mu-opioid receptors leading to ceiling effects which limit agonist activity, including respiratory depression, at high doses. However, concomitant benzodiazepine use (e.g. taken shortly after buprenorphine dose) or high doses of benzodiazepines may lead to potentiation of respiratory depression, counteracting the ceiling effect.(1,2) Concurrent use of buprenorphine and benzodiazepines may result in additive CNS depression.(3)

CLINICAL EFFECTS: Concurrent use may result in profound sedation, respiratory depression, coma, and/or death. Fatal respiratory depression has occurred with the combination of buprenorphine and a benzodiazepine.(1-2,4-7) High benzodiazepine levels have been identified in 80% or more of buprenorphine fatalities.(6)

PREDISPOSING FACTORS: Patients with a history of alcohol or benzodiazepine abuse may be at risk for relapse and overuse or abuse of prescribed benzodiazepines.(1,2,4,6) Individuals with significant obstructive pulmonary disease (COPD), sleep apnea, the elderly, and debilitated patients are at greater risk for respiratory depression from either agent.(1,2,8)

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as benzodiazepines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management.(3) Medication assisted therapy (MAT) with buprenorphine is not contraindicated in patients taking CNS depressants; however discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering may be appropriate. In others gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. For buprenorphine patients newly starting a benzodiazepine, consider beginning the benzodiazepine at a lower than usual dose, especially if predisposing factors (e.g. COPD, sleep apnea, debilitation, elderly) are present. High doses of benzodiazepines are associated with a greater risk for respiratory depression. Use the lowest effective dose and monitor for excessive sedation or respiratory depression, particularly in patients with predisposing risk factors for respiratory compromise.(1,2) Buprenorphine-naloxone combination products are used for maintenance treatment of opioid dependence. Patients with comorbid benzodiazepine dependence, on high doses of benzodiazepines, or a history of benzodiazepine abuse may require benzodiazepine detoxification prior to initiation of office-based buprenorphine treatment.(3) For patients receiving opioid maintenance treatment, it would be prudent to assure all controlled substance prescriptions are approved or written by the buprenorphine-naloxone provider.(5) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(9) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(3) Discuss opioid reversal agents (e.g., naloxone or nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing opioid reversal agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(10)

DISCUSSION: Buprenorphine is a partial agonist at mu-opioid receptors leading to ceiling effects which limits agonist activity, including respiratory depression, at high doses. However, concomitant benzodiazepine use (e.g. taking shortly after buprenorphine dose) or high doses of benzodiazepines may counteract the ceiling effect leading to potentiation of respiratory depression or sedative effects. High benzodiazepine levels have identified in 80% or more of buprenorphine fatalities.(6) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(11) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(12) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(13) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(14) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(15) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(16) A study of 315,428 privately insured patients who filled at least one prescription for an opioid from 2001 to 2013 were enrolled in a retrospective study. Concurrent use of a benzodiazepine was recorded as having at least one day of overlap in a given calendar year. Baseline characteristics among opioid users with concurrent use of a benzodiazepine were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%, p<0.001), and had a higher prevalence rate of every comorbidity examined (p<0.001). The proportion of opioid users with concurrent benzodiazepine use nearly doubled from 9% in 2001 to 17% in 2013. The primary outcome was an emergency room visit or inpatient admission for opioid overdose within a calendar year. Among all opioid users, the annual adjusted incidence for the primary outcome was 1.16% without concurrent benzodiazepine use compared to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24; p<0.001). Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI 1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95% CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the primary outcome with concurrent benzodiazepine use compared to without concurrent benzodiazepine use, respectively.(17)

Benzodiazepines/Cimetidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cimetidine may decrease the metabolism of Phase I hepatically metabolized benzodiazepines. At doses of 800-2400 mg daily, cimetidine is a weak inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4.

CLINICAL EFFECTS: Concurrent use may result in increased pharmacologic or toxic effects of certain benzodiazepines. Toxic effects include profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Benzodiazepines that do not undergo extensive Phase I metabolism (lorazepam, oxazepam) may be an alternative to interacting benzodiazepines in patients receiving cimetidine or by administering another H-2 antagonist (e.g., ranitidine, famotidine, nizatidine). Cimetidine use at higher doses of 200-400 mg four times daily would have an increased risk of inhibiting the metabolism of benzodiazepines. Lower doses and over-the-counter doses of cimetidine would be expected to have a diminished effect. Consider using alternative H2 antagonists when long-term concurrent therapy with benzodiazepines is indicated. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Cimetidine increases the half-life and serum concentration and decreases the clearance of benzodiazepines that undergo oxidative metabolism (e.g., alprazolam, bromazepam, diazepam, flurazepam, midazolam, triazolam). In a clinical study, cimetidine 1,200 mg daily decreased the clearance of bromazepam by 50% and increased its half-life from 23 hours to 29 hours.(22) The sedative effects of benzodiazepines have been reported to be increased during concurrent administration of cimetidine. This interaction does not appear to occur with benzodiazepines that undergo glucuronide conjugation.

Benzodiazepines/Gabapentinoids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use may result in profound sedation, respiratory depression, coma, and/or death.(1-3)

CLINICAL EFFECTS: Concurrent use of benzodiazepines may result in elevated levels of and toxicity from gabapentin and pregabalin, including profound sedation, respiratory depression, coma, and/or death.(1-3)

PREDISPOSING FACTORS: Patients who are elderly, are taking other CNS depressants, have decreased renal function, and/or have conditions that reduce lung function (e.g. Chronic Obstructive Pulmonary Disease [COPD]) may be at a higher risk of this interaction.

PATIENT MANAGEMENT: Limit prescribing benzodiazepines and gabapentinoids to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a gabapentinoid with an benzodiazepine, prescribe a lower initial dose of the gabapentinoid than indicated in the absence of an opioid and titrate based upon clinical response. If a benzodiazepine is indicated (other than an indication of epilepsy) in a patient already taking a gabapentinoid, prescribe a lower dose of the benzodiazepine and titrate based upon clinical response.(1) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1)

DISCUSSION: Clinical trials have shown no pharmacokinetic interaction between pregabalin (300 mg BID) and lorazepam (1 mg single dose).(2) Among 49 case reports submitted to FDA over a 5 year period (2012-2017), 12 people died from respiratory depression with gabapentinoids. Two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals were reviewed. A trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. Three observational studies showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after surgery. Several animal studies also showed that pregabalin plus opioids can depress respiratory function. Benzodiazepines are expected to have a similar effect when used with gabapentinoids.(1)

Benzodiazepines/Opioids (Extended Release)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and benzodiazepines may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as benzodiazepines, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as benzodiazepines to patients for whom alternatives are ineffective, not tolerated, or otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) A study of 315,428 privately insured patients who filled at least one prescription for an opioid from 2001 to 2013 were enrolled in a retrospective study. Concurrent use of a benzodiazepine was recorded as having at least one day of overlap in a given calendar year. Baseline characteristics among opioid users with concurrent use of a benzodiazepine were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%, p<0.001), and had a higher prevalence rate of every comorbidity examined (p<0.001). The proportion of opioid users with concurrent benzodiazepine use nearly doubled from 9% in 2001 to 17% in 2013. The primary outcome was an emergency room visit or inpatient admission for opioid overdose within a calendar year. Among all opioid users, the annual adjusted incidence for the primary outcome was 1.16% without concurrent benzodiazepine use compared to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24; p<0.001). Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI 1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95% CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the primary outcome with concurrent benzodiazepine use compared to without concurrent benzodiazepine use, respectively.(10) In a nested case-control study of adults with a new opioid dispensing between 2010-2018, patients with concurrent use of an opioid with a benzodiazepine were significantly more likely to have opioid-related overdose compared to patients receiving opioids, benzodiazepines, or neither (OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90 days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of opioid-related overdose (p<0.01). Patients with overlapping prescriptions during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times more likely to experience an overdose (p<0.01).(11)

Benzodiazepines/Opioids (Immediate Release)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and benzodiazepines may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as benzodiazepines, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as benzodiazepines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) A study of 315,428 privately insured patients who filled at least one prescription for an opioid from 2001 to 2013 were enrolled in a retrospective study. Concurrent use of a benzodiazepine was recorded as having at least one day of overlap in a given calendar year. Baseline characteristics among opioid users with concurrent use of a benzodiazepine were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%, p<0.001), and had a higher prevalence rate of every comorbidity examined (p<0.001). The proportion of opioid users with concurrent benzodiazepine use nearly doubled from 9% in 2001 to 17% in 2013. The primary outcome was an emergency room visit or inpatient admission for opioid overdose within a calendar year. Among all opioid users, the annual adjusted incidence for the primary outcome was 1.16% without concurrent benzodiazepine use compared to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24; p<0.001). Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI 1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95% CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the primary outcome with concurrent benzodiazepine use compared to without concurrent benzodiazepine use, respectively.(10) In a nested case-control study of adults with a new opioid dispensing between 2010-2018, patients with concurrent use of an opioid with a benzodiazepine were significantly more likely to have opioid-related overdose compared to patients receiving opioids, benzodiazepines, or neither (OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90 days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of opioid-related overdose (p<0.01). Patients with overlapping prescriptions during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times more likely to experience an overdose (p<0.01).(11)

Benzodiazepines/Selected Opioids For Mat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of diacetylmorphine or methadone and benzodiazepines may result in additive CNS depression.(1,2) Levomethadone is an enantiomer of methadone.(3)

CLINICAL EFFECTS: Concurrent use of diacetylmorphine or methadone and other CNS depressants, such as benzodiazepines, may result in profound sedation, respiratory depression, coma, and/or death.(1,2)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Medication assisted treatment (MAT) with diacetylmorphine or methadone is not contraindicated in patients taking benzodiazepines or other CNS depressants; however, discontinuation of benzodiazepines and other CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the benzodiazapine or CNS depressant is appropriate. Consider other medications and nonpharmacologic treatments to address anxiety or insomnia. Ensure that other health care providers prescribing benzodiazepines or other CNS depressants are aware of the patient's methadone treatment.(4) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Educate patients about the risks of concurrent use and monitor for use of prescribed and illicit benzodiazepines or other CNS depressants.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(6)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(7) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(8) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(9) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(10) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(11) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(12) A study of 315,428 privately insured patients who filled at least one prescription for an opioid from 2001 to 2013 were enrolled in a retrospective study. Concurrent use of a benzodiazepine was recorded as having at least one day of overlap in a given calendar year. Baseline characteristics among opioid users with concurrent use of a benzodiazepine were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%, p<0.001), and had a higher prevalence rate of every comorbidity examined (p<0.001). The proportion of opioid users with concurrent benzodiazepine use nearly doubled from 9% in 2001 to 17% in 2013. The primary outcome was an emergency room visit or inpatient admission for opioid overdose within a calendar year. Among all opioid users, the annual adjusted incidence for the primary outcome was 1.16% without concurrent benzodiazepine use compared to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24; p<0.001). Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI 1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95% CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the primary outcome with concurrent benzodiazepine use compared to without concurrent benzodiazepine use, respectively.(13) In a nested case-control study of adults with a new opioid dispensing between 2010-2018, patients with concurrent use of an opioid with a benzodiazepine were significantly more likely to have opioid-related overdose compared to patients receiving opioids, benzodiazepines, or neither (OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90 days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of opioid-related overdose (p<0.01). Patients with overlapping prescriptions during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times more likely to experience an overdose (p<0.01).(14) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(4)

Benzodiazepines/Selected Stimulants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Benzodiazepines and stimulants exhibit opposing effects on the CNS.

CLINICAL EFFECTS: Concurrent use of benzodiazepines and stimulants may reduce the clinical effectiveness of both the benzodiazepine and the stimulant. In addition, concurrent use may mask overdose symptoms of the benzodiazepine, such as drowsiness and inability to focus.

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing benzodiazepines with CNS stimulants such as amphetamines to patients for whom alternatives are inadequate. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Monitor patients receiving concurrent therapy for signs of substance abuse.

DISCUSSION: Analysis of the 2015 and 2016 National Survey on Drug Use and Health found that misuse of benzodiazepines was strongly associated with misuse of or dependences on stimulants.(1) Benzodiazepines are used to reduce the adverse effects of stimulant use, such as insomnia.(2) Patients abusing benzodiazepines in combination with other drugs tend to consume higher dosages of benzodiazepines than patients abusing only benzodiazepines.(3)

Midazolam/Ginkgo Biloba

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ginkgo biloba may inhibit the metabolism of midazolam by CYP3A4.

CLINICAL EFFECTS: The concurrent use of midazolam and ginkgo biloba may result in an increase in the midazolam area-under curve (AUC) and clinical effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of midazolam and ginkgo biloba should be approached with caution. The patient should be monitored for a possible change in midazolam clinical effect if ginkgo biloba is added to or removed from concurrent therapy.

DISCUSSION: A study involving ten healthy nonsmoking volunteers found that concurrent use of ginkgo biloba and midazolam showed an increase in the midazolam AUC of 25%.(1)

Midazolam/Letermovir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Letermovir is a moderate inhibitor of CYP3A4 and may decrease metabolism of midazolam.(1)

CLINICAL EFFECTS: Concurrent administration of letermovir and midazolam, metabolized by CYP3A4, may result in increased clinical effects (e.g. profound sedation, respiratory depression, coma, and/or death) of midazolam. CYP3A4 is the major or only hepatic metabolism pathway for the phase I elimination of midazolam.

PREDISPOSING FACTORS: Concurrent use with cyclosporine.

PATIENT MANAGEMENT: Caution is advised when midazolam is administered with drugs known to inhibit CYP3A4, such as letermovir.(1) Benzodiazepines that do not undergo extensive CYP hepatic metabolism (e.g. lorazepam, oxazepam) may be an alternative in letermovir patients. When letermovir is coadministered with cyclosporine, the combined effect on midazolam may be similar to a strong CYP3A4 inhibitor. Monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a study, concomitant administration of letermovir (480 mg once daily) with midazolam (1 mg single dose intravenous) increased the midazolam area under the curve (AUC) and C24hr by 1.47-fold and 2.74-fold, respectively. Concomitant administration of letermovir (480 mg once daily) with midazolam (2 mg single dose oral) increased the midazolam AUC and maximum concentration (Cmax) by 2.25-fold and 1.72-fold.(1)

Midazolam; Triazolam/Lenacapavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lenacapavir is a moderate inhibitor of CYP3A4 and may decrease metabolism of midazolam and triazolam.(1-3)

CLINICAL EFFECTS: Concurrent administration of lenacapavir and midazolam or triazolam may result in increased clinical effects (e.g. profound sedation, respiratory depression, coma, and/or death) of midazolam or triazolam.(1-3) CYP3A4 is the major or only hepatic metabolism pathway for the phase I elimination of midazolam.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lenacapavir states concurrent use with midazolam or triazolam should be approached with caution.(1-3) Monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Concurrent administration of lenacapavir 600 mg with a single 2.5 mg dose of midazolam increased midazolam maximum concentration (Cmax) and area-under-curve (AUC) by 1.94-fold and 3.59-fold, respectively.(1-3)

Selected Benzodiazepines/Barbiturates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Barbiturates and phenobarbital, CYP3A4 inducers, may induce the metabolism of some benzodiazepines. In addition, barbiturates, phenobarbital and benzodiazepines are CNS depressants. Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent or recent use of barbiturates or phenobarbital may result in decreased levels and loss of effectiveness of some benzodiazepines. Concurrent use of barbiturates and benzodiazepines may result in additive CNS depression (e.g. respiratory depression, increased somnolence).

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Monitor patients receiving phenobarbital or who have received doses in the previous 2 weeks for decreased benzodiazepine effectiveness. The dose of the benzodiazepine may need to be adjusted or an alternative agent used. Patients on chronic benzodiazepine therapy who are started on phenobarbital should be initially monitored for additive CNS sedation or respiratory depression, particularly when predisposing factors (e.g. COPD, sleep apnea, debilitation, elderly) are present. Continued use of phenobarbital leads to induction of benzodiazepine metabolism. The onset is gradual and may not peak for several weeks. If phenobarbital is discontinued, benzodiazepine levels will gradually rise as induction effects diminish. Monitor for increased benzodiazepine effects and adjust the dose accordingly.

DISCUSSION: In a study in 95 healthy subjects, rifampin, a CYP3A4 inducer (450 mg daily for 5 days), decreased the plasma concentrations of a single oral dose of alprazolam (1 mg) by 79%.(1) In another study in 4 healthy subjects, rifampin (given for 4 days) decreased the area-under-curve (AUC) of a single oral dose of alprazolam (1 mg) by 88%.(2) In a double-blind, randomized, cross-over trial in 13 healthy subjects, rifampin (450 mg daily for 7 days) decreased the maximum concentration (Cmax), area-under-curve (AUC), and half-life of a single oral dose of brotizolam (0.5 mg) by 69%, 90%, and 69%, respectively. Concurrent rifampin increased scores on the Digit Symbol Substitution Test (DSST) and decreased scores on the Stanford Sleepiness Scale.(3) In a study in 21 healthy subjects, rifampin (600 mg or 1200 mg daily for 7 days) increased total body clearance of diazepam by 300%.(4) An in vitro study in human hepatocytes found that rifampin increased the biotransformation of diazepam and midazolam by 1.9-fold.(5) In a study in 24 healthy subjects, rifampin (600 mg daily for 10 days) increased the clearance of a single intravenous dose of lorazepam by 140%.(6) In an open-label cross-over study in 19 healthy subjects, rifampin (600 mg daily for 9 days) increased the clearance of a single oral dose of midazolam (0.075 mg/kg) by 7-fold.(7) In a study in 57 healthy subjects, rifampin increased the systemic and oral clearance of midazolam by 2-fold and 16-fold, respectively.(8) In a study in 8 healthy subjects, rifampin (given for 6 days) significantly increased the clearance of midazolam.(9) In a study in 9 healthy subjects, received a single oral dose of midazolam (15 mg) before, one day after the administration of rifampin (600 mg daily for 5 days), and 4 days after the last dose of rifampin. One day after rifampin, the AUC of midazolam was decreased by 97.7% when compared to the administration of midazolam prior to rifampin. Four days after the completion of rifampin, the AUC of midazolam was decreased by 87% when compared to the administration of midazolam prior to rifampin.(10) In a double-blind, randomized, cross-over study in 10 healthy subjects, rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of a single oral dose of midazolam (15 mg) by 94%, 96%, and 58%, respectively. The pharmacodynamic effects of midazolam were also significantly decreased during rifampin therapy.(11) In a study in 16 healthy subjects, rifampin (600 mg daily for 7 days) increased the clearance of nitrazepam by 83%. There were no significant effects on the pharmacokinetics of temazepam.(12) In a randomized, double-blind, cross-over study in 10 healthy subjects, rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of a single dose of triazolam (0.5 mg) by 87.6%, 94.9%, and 54%, respectively. The pharmacodynamic effects of triazolam were also significantly decreased during rifampin therapy.(13) In an open-label, randomized, cross-over study in 27 healthy subjects, rifaximin (200 mg three times daily for 7 days) had no effect on the pharmacokinetics of single doses of oral or intravenous midazolam.(14) In a study in 98 patients with schizophrenia or bipolar disorder, the expression of CYP3A4 was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and bodyweight (1263 +/- 482.9 and 558.5 +/- 202.4 ng/mL per mg/kg bodyweight in low and normal expressers, respectively, p<0.0001).(18)

Selected Benzodiazepines/Fluconazole; Voriconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fluconazole and voriconazole may inhibit the metabolism of benzodiazepines by CYP3A4.

CLINICAL EFFECTS: The concurrent administration of fluconazole or voriconazole with benzodiazepines metabolized by CYP3A4 may result in elevated levels of and increased clinical effects from the benzodiazepines. Toxic effects of increased levels of benzodiazepines include profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with fluconazole or voriconazole should be monitored for increased benzodiazepine effects. The dosage of the benzodiazepine may need to be decreased or the benzodiazepine may need to be discontinued. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a study in 12 healthy subjects, pretreatment with fluconazole (400 mg twice daily Day 1, 200 mg twice daily Day 2) increased the area-under-curve (AUC) and half-life of a single dose of diazepam (5 mg) by 2.5-fold and 1.4-fold, respectively. Pharmacodynamic effects were increased slightly.(1) In a study in 12 healthy subjects, pretreatment with voriconazole (400 mg twice daily Day 1, 200 mg twice daily Day 2) increased the AUC and half-life of a single dose of diazepam (5 mg) by 2.2-fold and 100%, respectively. Pharmacodynamic effects were increased slightly.(1) A study in 10 patients showed that fluconazole (400 mg initially, then 200 mg intravenously) increased intravenous midazolam concentrations by 0-4-fold.(2) A study in nine subjects showed that fluconazole (400 mg) increased the midazolam AUC, maximum concentration (Cmax), and half-life by 2-3 fold, 2-2.5-fold, and 2.5-fold, respectively. The pharmacokinetic changes were larger when fluconazole was given orally when compared to intravenous fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects.(3) A study in 12 subjects showed that the AUC of oral midazolam increased 3.6-fold during fluconazole therapy.(4) One study found that a single, 150 mg dose of fluconazole did not significantly effect midazolam pharmacokinetics.(5) Fluconazole has also been shown to inhibit the metabolism of midazolam in vitro.(6) In a randomized, cross-over study in 10 healthy male volunteers, voriconazole (400 mg twice daily on the first day and 200 mg twice daily on the second day) reduced the clearance on intravenous midazolam (0.05 mg/kg) by 72% and increased its elimination half-life by 3-fold. Voriconazole increased the mean Cmax and the AUC of oral midazolam (7.5 mg) by 3.8 and 10.3-fold, respectively. Voriconazole also prolonged the half-life of oral midazolam by 3.5-fold, and increased the oral bioavailability of midazolam by 2.7-fold. Voriconazole profoundly increased the psychomotor effects of oral midazolam but only weakly increased the effects of intravenous midazolam.(7) In a study in 12 healthy subjects, fluconazole had no significant effects on the pharmacokinetics or pharmacodynamics of oral or rectal bromazepam.(8)

Selected Benzodiazepines/Posaconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Posaconazole may inhibit the metabolism of benzodiazepines by CYP3A4.(1,2)

CLINICAL EFFECTS: The concurrent administration of posaconazole with benzodiazepines metabolized by CYP3A4 may result in elevated levels of and increased clinical effects from the benzodiazepines.(1,2) Toxic effects of increased levels of benzodiazepines include profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with posaconazole should be monitored for increased benzodiazepine effects. The dosage of the benzodiazepine may need to be decreased or the benzodiazepine may need to be discontinued. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Posaconazole (200 mg daily for 10 days) increased the AUC of a single dose of intravenous midazolam (30 minute infusion of 0.05 mg/kg) by 83%.(1) Posaconazole (200 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of intravenous midazolam (0.4 mg) by 30% and 362%, respectively. Posaconazole (200 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of oral midazolam (2 mg) by 169% and 470%, respectively. Posaconazole (400 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of intravenous midazolam (0.4 mg) by 62% and 524%, respectively. Posaconazole (400 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of oral midazolam (2 mg) by 138% and 397%, respectively.(2) In a study of 12 healthy volunteers (11 male and 1 female), posaconazole (200mg twice daily for 7 days and 400mg twice daily for 7 days) increased midazolam Cmax up to 1.3 and 2.4 fold, respectively, and midazolam AUC 4.6 and 6.2 fold, respectively. Midazolam half-life was also increased.(3)

Selected Benzodiazepines/Selected Cyp3a4 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of some benzodiazepines.

CLINICAL EFFECTS: Concurrent or recent use of CYP3A4 inducers may result in decreased levels and loss of effectiveness of some benzodiazepines.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Monitor patients receiving CYP3A4 inducers or who have received these agents in the previous 2 weeks for decreased benzodiazepine effectiveness. The dose of the benzodiazepine may need to be adjusted or an alternative agent used. If the CYP3A4 inducer is discontinued, benzodiazepine levels will gradually rise as induction effects diminish. Monitor for increased benzodiazepine effects and adjust the dose accordingly.

DISCUSSION: In a study in 95 healthy subjects, rifampin (450 mg daily for 5 days) decreased the plasma concentrations of a single oral dose of alprazolam (1 mg) by 79%.(1) In another study in 4 healthy subjects, rifampin (given for 4 days) decreased the area-under-curve (AUC) of a single oral dose of alprazolam (1 mg) by 88%.(2) In a double-blind, randomized, cross-over trial in 13 healthy subjects, rifampin (450 mg daily for 7 days) decreased the maximum concentration (Cmax), AUC, and half-life of a single oral dose of brotizolam (0.5 mg) by 69%, 90%, and 69%, respectively. Concurrent rifampin increased scores on the Digit Symbol Substitution Test (DSST) and decreased scores on the Stanford Sleepiness Scale.(3) In a study in 21 healthy subjects, rifampin (600 mg or 1200 mg daily for 7 days) increased total body clearance of diazepam by 300%.(4) An in vitro study in human hepatocytes found that rifampin increased the biotransformation of diazepam and midazolam by 1.9-fold.(5) In a study in 24 healthy subjects, rifampin (600 mg daily for 10 days) increased the clearance of a single intravenous dose of lorazepam by 140%.(6) In an open-label cross-over study in 19 healthy subjects, rifampin (600 mg daily for 9 days) increased the clearance of a single oral dose of midazolam (0.075 mg/kg) by 7-fold.(7) In a study in 57 healthy subjects, rifampin increased the systemic and oral clearance of midazolam by 2-fold and 16-fold, respectively.(8) In a study in 8 healthy subjects, rifampin (given for 6 days) significantly increased the clearance of midazolam.(9) In a study in 9 healthy subjects, received a single oral dose of midazolam (15 mg) before, one day after the administration of rifampin (600 mg daily for 5 days), and 4 days after the last dose of rifampin. One day after rifampin, the AUC of midazolam was decreased by 97.7% when compared to the administration of midazolam prior to rifampin. Four days after the completion of rifampin, the AUC of midazolam was decreased by 87% when compared to the administration of midazolam prior to rifampin.(10) In a double-blind, randomized, cross-over study in 10 healthy subjects, rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of a single oral dose of midazolam (15 mg) by 94%, 96%, and 58%, respectively. The pharmacodynamic effects of midazolam were also significantly decreased during rifampin therapy.(11) In a study in 16 healthy subjects, rifampin (600 mg daily for 7 days) increased the clearance of nitrazepam by 83%. There were no significant effects on the pharmacokinetics of temazepam.(12) In a randomized, double-blind, cross-over study in 10 healthy subjects, rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of a single dose of triazolam (0.5 mg) by 87.6%, 94.9%, and 54%, respectively. The pharmacodynamic effects of triazolam were also significantly decreased during rifampin therapy.(13) In an open-label, randomized, cross-over study in 27 healthy subjects, rifaximin (200 mg three times daily for 7 days) had no effect on the pharmacokinetics of single doses of oral or intravenous midazolam.(14) In a study in 98 patients with schizophrenia or bipolar disorder, the expression of CYP3A4 was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and bodyweight (1263 +/- 482.9 and 558.5 +/- 202.4 ng/mL per mg/kg bodyweight in low and normal expressers, respectively, p<0.0001).(18) Selected CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort.

Selected Sensitive Cyp3a4 Substrates/Schisandra

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)

CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(8)

DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)

Slt Po Benzodiazepines/Aprepitant (<= 40 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aprepitant doses greater than 40 mg per day are classified as moderate inhibitors of CYP3A4 and may inhibit the CYP3A4 mediated absorption and metabolism of alprazolam, midazolam or triazolam. Aprepitant doses < or = to 40 mg per day would be expected to inhibit CYP3A4 to a lesser extent.(1-3)

CLINICAL EFFECTS: Concurrent administration of aprepitant may result in increased levels of and effects from the benzodiazepines.(1-4) Toxic effects of increased levels of benzodiazepines include profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Depending on patient tolerance, the benzodiazepine dosage may need to be reduced or an alternative agent not metabolized by CYP3A4 (e.g. lorazepam, temazepam) may be used. Patients receiving concurrent therapy with aprepitant and alprazolam, midazolam, or triazolam should be closely monitored and counseled regarding possible adverse effects due to increased benzodiazepine exposure. Due to its long half-life, the effects of a single dose of netupitant persist for 4 or more days.

DISCUSSION: In an open-label, randomized single-period study in 16 healthy subjects, administration of aprepitant (125 mg on Day 1, 80 mg on Days 2-5) increased the area-under-curve (AUC) of a single oral dose of midazolam (2 mg on Day 1 and Day 5) by 2.3-fold on Day 1 and by 3.3-fold on Day 5 when compared to midazolam alone. Midazolam maximum concentration (Cmax) increased by 1.5-fold on Day 1 and by 1.9-fold on Day 5.(1,4) Midazolam half-life increased from 1.7 hours for midazolam alone to 3.3 hours on Day 1 and Day 5. In the second group, administration of aprepitant (40 mg on Day 1, 25 mg on Days 2-5) with midazolam had no significant effects on midazolam AUC, Cmax, or half-life.(5) In a study, administration of a single dose of aprepitant (40 mg) increased the AUC of a single dose of oral midazolam (2 mg) by 1.2-fold. This was not considered clinically significant.(1) In a study in 12 healthy subjects, administration of aprepitant (125 mg on Day 1, 80 mg on Days 2-3) increased the AUC of a single dose of intravenous midazolam (2 mg on Days 4, 8, and 15) by 25% on Day 4. The AUC of midazolam was decreased by 19% on Day 8. These effects were not considered clinically significant.(1,4) In a study, administration of a single dose of intravenous midazolam (2 mg) 1 hour after a single dose of aprepitant (125 mg) increased midazolam AUC by 1.5-fold.(1)

Slt Po Benzodiazepines/Aprepitant (>40 Mg);Netupitant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Netupitant and aprepitant doses greater than 40 mg per day are classified as moderate inhibitors of CYP3A4 and may inhibit the CYP3A4 mediated absorption and metabolism of midazolam or triazolam.(1-4)

CLINICAL EFFECTS: Concurrent administration of aprepitant or netupitant may result in increased levels of and effects from the benzodiazepines.(1-4) Toxic effects of increased levels of benzodiazepines include profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Depending on patient tolerance, the benzodiazepine dosage may need to be reduced or an alternative agent not metabolized by CYP3A4 (e.g. lorazepam, temazepam) may be used. Patients receiving concurrent therapy with aprepitant or netupitant and midazolam or triazolam should be closely monitored and counseled regarding possible adverse effects due to increased benzodiazepine exposure. Due to its long half-life, the effects of a single dose of netupitant persist for 4 or more days.

DISCUSSION: In an open-label, randomized single-period study in 16 healthy subjects, administration of aprepitant (125 mg on Day 1, 80 mg on Days 2-5) increased the area-under-curve (AUC) of a single oral dose of midazolam (2 mg on Day 1 and Day 5) by 2.3-fold on Day 1 and by 3.3-fold on Day 5 when compared to midazolam alone. Midazolam maximum concentration (Cmax) increased by 1.5-fold on Day 1 and by 1.9-fold on Day 5.(1,5) Midazolam half-life increased from 1.7 hours for midazolam alone to 3.3 hours on Day 1 and Day 5. In the second group, administration of aprepitant (40 mg on Day 1, 25 mg on Days 2-5) with midazolam had no significant effects on midazolam AUC, Cmax, or half-life.(6) In a study, administration of a single dose of aprepitant (40 mg) increased the AUC of a single dose of oral midazolam (2 mg) by 1.2-fold. This was not considered clinically significant.(1) In a study in 12 healthy subjects, administration of aprepitant (125 mg on Day 1, 80 mg on Days 2-3) increased the AUC of a single dose of intravenous midazolam (2 mg on Days 4, 8, and 15) by 25% on Day 4. The AUC of midazolam was decreased by 19% on Day 8. These effects were not considered clinically significant.(1,5) In a study, administration of a single dose of intravenous midazolam (2 mg) 1 hour after a single dose of aprepitant (125 mg) increased midazolam AUC by 1.5-fold.(1) In a study, co-administration of a single dose of netupitant 300 mg and oral midazolam 7.5 mg led to an increase in the Cmax and AUC of midazolam by 36% and 126% respectively.(4)

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• Angle-closure glaucoma

• Acute renal failure
• Chronic obstructive pulmonary disease
• Coma
• Drug abuse
• Hemodynamic instability
• Pregnancy
• Respiratory depression
• Shock

• Chronic heart failure
• Hepatic cirrhosis
• Peripheral vasoconstriction

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More Frequent

• Respiratory depression

Less Frequent

• Bradycardia
• Hypoxia

Rare or Very Rare

• Allergic dermatitis
• Apnea
• Cardiac arrhythmia
• Delirium
• Dyspnea
• Excitement
• Hypercapnia
• Hypotension
• Hypoventilation
• Irritability
• Laryngismus
• Nervousness
• Pruritus of skin
• Tachycardia
• Tremor
• Urticaria
• Wheezing

More Frequent

• Sedation

Less Frequent

• Agitation
• Hiccups
• Nausea
• Vomiting

Rare or Very Rare

• Accidental fall
• Aggressive behavior
• Anticholinergic toxicity
• Ataxia
• Blurred vision
• Cough
• Dizziness
• Drowsy
• Dysarthria
• Dysphoric mood
• Hallucinations
• Headache disorder
• Mood changes
• Rhinorrhea
• Sialorrhea
• Skin rash
• Sneezing
• Stridor
• Syncope
• Vertigo
• Visual changes

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An increased risk of congenital malformations associated with the use of benzodiazepines (e.g., chlordiazepoxide, diazepam) during pregnancy has been suggested by several retrospective studies in humans. Midazolam has been shown to cross the placenta in humans. Reproduction studies in rabbits and rats using IV midazolam in doses up to 1.85 times the human induction dose have not revealed evidence of fetal malformation. If the drug is administered during pregnancy, the patient should be informed of the potential hazard to the fetus. Use of midazolam injection for obstetric procedures or during labor and delivery is not recommended, since such use has not been evaluated and use of other benzodiazepines during the last weeks of pregnancy has caused CNS depression in the neonate.

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including midazolam, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus. The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs.

Midazolam is distributed into milk in humans, and caution should be exercised when midazolam is administered to nursing women.

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