Diazepam (diazepam)

Dosage of diazepam must be individualized, and the smallest effective dosage should be used (especially in geriatric or debilitated patients or in those with liver disease or low serum albumin) to avoid oversedation. The doses recommended by the manufacturers for IM and IV administration are identical. When parenteral diazepam is used with an opiate analgesic, the dosage of the opiate should be reduced by at least one-third and administered in small increments. Because of the unpredictable response of children to CNS drugs, diazepam therapy should be initiated with the lowest dosage and increased as required. Since diazepam and its metabolites have long elimination half-lives, time to reach steady-state plasma concentrations should be considered when dosage adjustments are made.

In patients who have received prolonged (e.g., for several months) diazepam therapy, abrupt discontinuance of the drug should be avoided since manifestations of withdrawal can be precipitated; if the drug is to be discontinued in such patients, it is recommended that dosage be gradually tapered. It is particularly important that the drugs not be discontinued abruptly in patients with a history of a seizure disorder since seizures may be precipitated.

Diazepam is administered orally, by IV or IM injection, or rectally.

No dosing information is available for this tab.

No dosing information is available for this tab.

No dosing information is available for this tab.

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.

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)

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

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)

Diazepam/Fluconazole; Voriconazole

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

MECHANISM OF ACTION: Fluconazole and voriconazole may inhibit CYP2C19 and CYP3A4, both major pathways of diazepam metabolism.(1-4)

CLINICAL EFFECTS: The concurrent administration of fluconazole or voriconazole with diazepam may result in elevated levels of and increased clinical effects from diazepam. Toxic effects 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 diazepam effects. The dosage of diazepam may need to be decreased or diazepam 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.(5) 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.(6) A study in 12 subjects showed that the AUC of oral midazolam increased 3.6-fold during fluconazole therapy.(7) One study found that a single, 150 mg dose of fluconazole did not significantly effect midazolam pharmacokinetics.(8) Fluconazole has also been shown to inhibit the metabolism of midazolam in vitro.(9) 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.(10)

Parenteral Benzodiazepines/Intramuscular Olanzapine

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

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of intramuscular olanzapine with a parenteral benzodiazepine may result in excessive sedation, cardiorespiratory depression, and death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian,(1) UK,(2) and US(3) manufacturers of olanzapine state that simultaneous injection of intramuscular olanzapine and parenteral benzodiazepines is not recommended. If parenteral benzodiazepine therapy is required in a patient who has received IM olanzapine, wait 1 hour after the administration of IM olanzapine.(2) IM olanzapine should only be considered in patients who have received parenteral benzodiazepines after careful evaluation and they should be closely monitored for excessive sedation and cardiorespiratory depression.(2)

DISCUSSION: In post-marketing reports, temporal association of IM olanzapine with respiratory depression, hypotension, bradycardia, and death have been rarely reported (<0.01%). Many of the patients also received parenteral benzodiazepines.(2) In an analysis of 160 spontaneous reports of adverse events during a review of the first 21 months of olanzapine usage, benzodiazepines were used concurrently in 27% of non serious reports (21/77), 44% of serious nonfatal reports (24/54), and in 66% (19/29) fatal reports.(4) Concurrent use with diazepam has shown to increase orthostatic hypotension. There was no effect on the pharmacokinetics of diazepam or its active metabolite, N-desmethyldiazepam.(3) Concurrent use with intramuscular lorazepam did not affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. Somnolence was increased.(3)

Selected Benzodiazepines/Fluvoxamine

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

MECHANISM OF ACTION: Fluvoxamine, a strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor, may decrease the metabolism of Phase I hepatically metabolized benzodiazepines.

CLINICAL EFFECTS: Concurrent use of fluvoxamine and selected benzodiazepines may result in increased systemic levels and clinical effects of the benzodiazepine including profound sedation, respiratory depression, coma, and/or death. Benzodiazepines linked to this monograph are chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam and quazepam.

PREDISPOSING FACTORS: The interaction may be more severe in patients receiving another CYP3A4 inhibitor.

PATIENT MANAGEMENT: Benzodiazepines that do not undergo extensive Phase I metabolism (lorazepam, oxazepam) may be an alternative in patients receiving fluvoxamine. The US manufacturer of fluvoxamine recommends that fluvoxamine and diazepam not be concurrently administered. If fluvoxamine is started in a patient already receiving a benzodiazepine, 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, unusual dizziness of lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a study in healthy volunteers, administration of fluvoxamine (150 mg daily) decreased the clearance of a single dose of diazepam (10 mg) by 65%. The clearance of N-desmethyldiazepam was too low to measure. Benzodiazepines such as lorazepam or oxazepam, would not be expected to have a pharmacokinetic interaction with fluvoxamine.

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)

Buspirone; Diazepam/Ribociclib

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

MECHANISM OF ACTION: Ribociclib may inhibit the metabolism of buspirone or diazepam by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of ribociclib may result in increased levels of and effects from buspirone or diazepam. Increased effects from diazepam may include profound sedation, respiratory depression, coma, and/or death. Increased effects from buspirone may include lightheadedness, asthenia, dizziness, and somnolence.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with buspirone or diazepam and ribociclib should be monitored for adverse effects. The dosage of buspirone or diazepam may need to be adjusted.(1,2) The manufacturer of buspirone states that when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended.

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-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.

Diazepam/Cobicistat

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

MECHANISM OF ACTION: Cobicistat may inhibit the metabolism of diazepam by CYP3A4.(1-6)

CLINICAL EFFECTS: Inhibition of diazepam metabolism by CYP3A4 may produce increased levels of, as well as increased clinical effects, of diazepam. Toxic effects of increased diazepam levels include profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide states concurrent administration with diazepam should be done in a setting that ensures close clinical monitoring and appropriate medical management in the case of respiratory depression and/or prolonged sedation.(1) The US manufacturer of darunavir/cobicistat states titration of diazepam is recommended and a lower dose of diazepam should be considered with monitoring for increased and prolonged effects or adverse reactions.(2) The US manufacturers of atazanavir/cobicistat(3), cobicistat(4), and elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate(5) state dose reduction of diazepam may be necessary and clinical monitoring is recommended. Monitor patients receiving concurrent therapy with cobicistat and diazepam carefully for increased effects including unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Cobicistat is a strong CYP3A4 inhibitor.(1-5) Diazepam is a substrate of CYP3A4 and use with inhibitors of this pathway may lead to increased and prolonged sedation.(6)

Select Benzodiazepines; Buspirone/Itraconazole;Ketoconazole

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

MECHANISM OF ACTION: Itraconazole and ketoconazole may inhibit the metabolism of brotizolam, buspirone, diazepam, etizolam, flunitrazepam, and midazolam injection by CYP3A4.(1-23)

CLINICAL EFFECTS: Inhibition of benzodiazepine or buspirone 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. Increased effects from buspirone may include lightheadedness, asthenia, dizziness, and somnolence.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of buspirone recommends a low dose of buspirone (2.5 mg daily) be used in patients receiving potent inhibitors of CYP3A4.(23) Monitor patients receiving concurrent therapy with itraconazole or ketoconazole and hepatically metabolized benzodiazepines carefully for increased effects including unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a randomized, double-blind, cross-over study in 10 healthy males, itraconazole (200 mg daily for 4 days) increased the area-under-cure (AUC) and half-life of a single dose of brotizolam (0.5 mg) by 142% and 410%, respectively. Brotizolam clearance decreased by 76%. Brotizolam effects were increased.(6) Ketoconazole has been shown to inhibit brotizolam metabolism in vitro.(7) In a randomized, double-blind, cross-over study in 10 healthy males, itraconazole (200 mg daily for 4 days) increased the AUC and half-life of a single dose of diazepam (5 mg); however, there were no significant effects on diazepam pharmacodynamics.(8) In a randomized, double-blind, cross-over study in 12 healthy males, itraconazole (200 mg daily for 7 days) increased the AUC and half-life of a single dose of etizolam (1 mg) by 53% and 44%, respectively. There were no significant effects on etizolam pharmacodynamics.(9) Ketoconazole has been shown to inhibit flunitrazepam metabolism in vitro.(10) In a study in 9 healthy subjects, itraconazole increased the AUC of oral midazolam by 8-fold. Increased effects were also noted.(11) 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.(12) 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.(13) In a double-blind, cross-over study, itraconazole increased midazolam AUC by 10-fold. Subjects also experienced significantly increased sedation and amnesiac effects.(14) Itraconazole has also been shown to inhibit midazolam metabolism in vitro.(15,16) In a study in healthy subjects, ketoconazole increased the AUC of oral midazolam by 771.9%.(17) In a double-blind, cross-over study, ketoconazole increased midazolam AUC by 15-fold. Subjects also experienced significantly increased sedation and amnesiac effects.(14) 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.(18) In a study in healthy subjects, ketoconazole (200 mg twice daily) reduced the clearance of midazolam 6-fold.(19) Ketoconazole has also been shown to inhibit the metabolism of midazolam in vitro.(15,16,20-22) In a study in 8 healthy subjects, pretreatment with itraconazole (200 mg daily for 4 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of buspirone by 13-fold and 19-fold, respectively.(1,2) However, only the Critical Flicker Fusion test showed statistically significant differences when compared to the administration of buspirone alone.(2) In a study in 6 subjects, pretreatment with itraconazole (200 mg daily for 4 days) increased the Cmax and AUC of buspirone by 10.5-fold and 14.5-fold, respectively. The Cmax and AUC of the piperazine metabolite of buspirone increased by 57% and 50%, respectively.(3) Ketoconazole has been shown to inhibit the metabolism of buspirone in vitro.(4)

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/Fluoxetine; Nefazodone

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

MECHANISM OF ACTION: Fluoxetine, a strong CYP2C19 inhibitor, and nefazodone, a strong CYP3A4 inhibitor, may decrease the metabolism of Phase I hepatically metabolized benzodiazepines. Benzodiazepines linked to this monograph are metabolized by both CYP2C19 and CYP3A4.

CLINICAL EFFECTS: Concurrent use of fluoxetine or nefazodone and selected benzodiazepines may result in increased systemic levels and clinical effects of the benzodiazepine. Toxic effects of increased benzodiazepine levels include profound sedation, respiratory depression, coma, and/or death. Benzodiazepines linked to this monograph are chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam and quazepam.

PREDISPOSING FACTORS: Patients receiving a medication regimen which includes inhibitors of both major benzodiazepine metabolic pathways (i.e. CYP2C19 and CYP3A4).

PATIENT MANAGEMENT: Benzodiazepines that do not undergo extensive Phase I metabolism (lorazepam, oxazepam) may be an alternative to interacting benzodiazepines in patients receiving fluoxetine or nefazodone. The benzodiazepine dose may need to be decreased during concurrent therapy with fluoxetine or nefazodone. If nefazodone or fluoxetine is started in a patient already receiving a benzodiazepine metabolized by CYP2C19 and CYP3A4, then monitor closely and anticipate the need to reduce the benzodiazepine dose. If on review of medication therapy the patient is found to be taking both a strong CYP2C19 and a strong CYP3A4 inhibitor, it would be prudent to convert patient to an alternative benzodiazepine or to an alternative to the inhibiting agent(s). Counsel patient to report excess drowsiness, confusion, memory problems including sleep-driving behaviors, loss of coordination, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Fluoxetine has been shown to increase the area-under-curve (AUC) and half-life (T1/2) of diazepam and to decrease the plasma clearance and formation of N-desmethyldiazepam. Benzodiazepines such as lorazepam, oxazepam, which do not undergo extensive Phase I hepatic metabolism, would not be expected to interact with fluoxetine or nefazodone. Citalopram has been shown not to have clinically significant effects on triazolam. Sertraline has been shown not to have clinically significant effects on diazepam. A statistically significant interaction has been shown to occur between venlafaxine and diazepam. However, the magnitude of the effects does not appear to be sufficient to be clinically important.

Selected Benzodiazepines/Idelalisib

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

MECHANISM OF ACTION: Idelalisib may inhibit the metabolism of benzodiazepines that are metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Inhibition of benzodiazepine CYP3A4 metabolism by idelalisib may produce increased levels of, as well as increased clinical effects, of benzodiazepines. Toxic effects of increased benzodiazepine levels include profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of idelalisib says to avoid coadministration with sensitive CYP3A substrates.(1) The manufacturers of some benzodiazepines (i.e., clonazepam, diazepam, estazolam, midazolam) advise caution when they are coadministered with inhibitors of CYP3A4 and to consider dose reduction of the benzodiazepine.(2-6) Monitor patients receiving concurrent therapy with idelalisib and benzodiazepines carefully for increased effects including unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a study of 12 healthy subjects, multiple doses of idelalisib (150 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam 5 mg by 437 % and 138 %, respectively.(6) In a case report, a 71-year-old female on diazepam as needed was started on idelalisib 150 mg twice daily. She presented in the emergency room ten days later with altered mental status and respiratory failure, which resolved after discontinuation of idelalisib and diazepam. Other causes of her symptoms were ruled out and although the patient's other medications may have been contributory, idelalisib potentiation of diazepam's effects was thought to be the primary cause.(7) Benzodiazepines linked to this monograph include: brotizolam, chlordiazepoxide, clonazepam, clorazepic acid, diazepam, estazolam, etizolam, flunitrazepam, flurazepam, halazepam, midazolam, prazepam, and quazepam.

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/Protease Inhibitors

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

MECHANISM OF ACTION: Protease inhibitors may inhibit the metabolism of benzodiazepines that are metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Inhibition of benzodiazepine CYP3A4 metabolism by protease inhibitors may produce increased levels of, as well as increased clinical effects, of benzodiazepines. Toxic effects of increased benzodiazepine levels include profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The NIH Guidelines for Use of Antiretroviral Agents advise considering use of alternative benzodiazepines that do not undergo CYP metabolism, like lorazepam, oxazepam, and temazepam.(1) The manufacturers of the protease inhibitors recommend close clinical monitoring for respiratory depression and/or prolonged sedation and consideration of dosage adjustment of the benzodiazepine.(2-5) The manufacturers of some benzodiazepines (i.e., diazepam, estazolam, midazolam) advise caution when they are coadministered with inhibitors of CYP3A4 and to consider dose reduction of the benzodiazepine.(6-8) Monitor patients receiving concurrent therapy with protease inhibitors and benzodiazepines carefully for increased effects including unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: The interaction between most benzodiazepines and protease inhibitors has not been studied. Benzodiazepines are primarily metabolized by CYP3A4 and CYP2C19. Protease inhibitors are moderate to strong inhibitors of CYP3A4, and an elevation in benzodiazepine effects and concentrations with concomitant therapy can be expected. Benzodiazepines linked to this monograph include: brotizolam, chlordiazepoxide, clonazepam, clorazepic acid, diazepam, estazolam, etizolam, flunitrazepam, flurazepam, halazepam, non-oral midazolam, prazepam, and quazepam. Protease inhibitors linked to this monograph include: ensitrelvir, ritonavir-boosted lopinavir, nirmatrelvir, saquinavir, tipranavir; cobicistat- or ritonavir-boosted darunavir; cobicistat-boosted, ritonavir-boosted or unboosted atazanavir; ritonavir-boosted or unboosted amprenavir, fosamprenavir, indinavir; and nelfinavir.

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.

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• Lactation

• Alcohol intoxication
• Angle-closure glaucoma
• Chronic obstructive pulmonary disease
• Depression
• Disease of liver
• Pregnancy
• Respiratory depression
• Sleep apnea

• CYp2c19 poor metabolizer
• Drug abuse
• Hypoalbuminemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Open angle glaucoma
• Pulmonary disease

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More Frequent

• Muscle weakness

Less Frequent

• Acute cognitive impairment
• Behavioral disorders
• CNS depression

Rare or Very Rare

• Abnormal hepatic function tests
• Accidental fall
• Agranulocytosis
• Anaphylaxis
• Anemia
• Angioedema
• Aplastic anemia
• Apnea
• Coma
• Depression
• Drug dependence
• Drug-induced psychosis
• Dyspnea
• Eosinophilia
• Hallucinations
• Hemolytic anemia
• Hostility
• Hypotension
• Jaundice
• Leukocytosis
• Leukopenia
• Manic disorder
• Memory impairment
• Neutropenic disorder
• Respiratory depression
• Seizure disorder
• Skin rash
• Sleep walking disorder
• Suicidal ideation
• Thrombocytopenic disorder
• Urinary retention

More Frequent

• Ataxia
• Dizziness
• Drowsy
• Dyspepsia
• Sedation
• Slurred speech

Less Frequent

• Diarrhea
• Fatigue
• General weakness

Rare or Very Rare

• Aggressive behavior
• Agitation
• Alopecia
• Anorexia
• Anticholinergic toxicity
• Blurred vision
• Complex sleep behavior
• Concentration difficulty
• Conjunctivitis
• Constipation
• Cramps
• Delirium
• Depersonalization
• Diplopia
• Disturbance in thinking
• Dream disorder
• Dysarthria
• Dysuria
• Excitement
• Glossitis
• Headache disorder
• Hiccups
• Irritability
• Libido changes
• Menstrual disorder
• Nausea
• Nervousness
• Nightmares
• Nystagmus
• Paranoid disorder
• Polydipsia
• Pruritus of skin
• Sialorrhea
• Sleep disorder
• Stomatitis
• Syncope
• Tachycardia
• Tremor
• Urinary incontinence
• Vertigo
• Visual changes
• Xerostomia
• Yawning

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