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Drug overview for XANAX (alprazolam):
Generic name: ALPRAZOLAM (al-PRA-zoe-lam)
Drug class: Benzodiazepines
Therapeutic class: Central Nervous System Agents
Alprazolam is a benzodiazepine.
No enhanced Uses information available for this drug.
Generic name: ALPRAZOLAM (al-PRA-zoe-lam)
Drug class: Benzodiazepines
Therapeutic class: Central Nervous System Agents
Alprazolam is a benzodiazepine.
No enhanced Uses information available for this drug.
DRUG IMAGES
XANAX 0.25 MG TABLET
XANAX 0.5 MG TABLET
XANAX 1 MG TABLET
XANAX 2 MG TABLET
The following indications for XANAX (alprazolam) have been approved by the FDA:
Indications:
Anxiety with depression
Anxiety
Generalized anxiety disorder
Panic disorder
Professional Synonyms:
Anxiety associated with depression
Mixed anxiety and depressive disorder
Panic reaction
Panic-like sensation
Indications:
Anxiety with depression
Anxiety
Generalized anxiety disorder
Panic disorder
Professional Synonyms:
Anxiety associated with depression
Mixed anxiety and depressive disorder
Panic reaction
Panic-like sensation
The following dosing information is available for XANAX (alprazolam):
Dosage of alprazolam must be individualized, and the smallest effective dosage should be used (especially in geriatric or debilitated patients and in those with liver disease, low serum albumin, or obesity) to avoid oversedation. If early morning anxiety occurs or emergence of symptoms occurs between doses of an immediate-release preparation in patients previously stabilized, the need for dosage adjustment or maintenance of the same daily dosage but divided and administered at more frequent intervals should be considered.
The following recommendations for maintenance dosage in adults with panic disorder apply to both immediate- and extended-release alprazolam preparations on a daily basis. However, the dosage should be divided as evenly as possible during waking hours on a 3- or 4-times daily schedule for immediate-release preparations whereas the dosage is given once daily, preferably in the morning, for extended-release tablets.
Patients being switched from immediate-release alprazolam therapy to the extended-release tablets can receive the same total daily dosage administered once daily rather than in divided doses. If the therapeutic response is not adequate after switching to the same dosage administered once daily, the dosage may be increased in the usual fashion.
Effective treatment of panic disorder with alprazolam often has required dosages exceeding 4 mg daily in adults. Dosage (as immediate-release preparations) generally has averaged 5-6 mg daily, but has ranged from 1-10 mg daily; about 20% of patients required maximum alprazolam dosages exceeding 7 mg daily, with about one-third of these requiring maximum dosages exceeding 9 mg daily. An alprazolam dosage of 3-6 mg daily as extended-release tablets generally has been effective, but dosage has ranged from 1-10 mg daily.
Occasionally, a dosage of 10 mg daily has been required for adequate response.
For patients receiving dosages exceeding 4 mg daily, periodic reassessment and consideration of dosage reduction is recommended. In a controlled postmarketing dose-response study, patients receiving alprazolam at dosages exceeding 4 mg daily for 3 months were able to taper their daily maintenance dosage by 50% without apparent loss of clinical benefit.
Reduction of alprazolam dosage must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of dosage tapering be attempted. Although not systematically evaluated, a reduction by 0.5
mg daily at 3-day intervals has been suggested, although more gradual reductions may be necessary in some patients. When this suggested tapering schedule was compared with a slower dosage taper, there was no difference in the proportion of patients able to completely discontinue alprazolam, but the slower tapering schedule was associated with fewer withdrawal symptoms. Some patients may prove resistant to all discontinuance regimens.
The following recommendations for maintenance dosage in adults with panic disorder apply to both immediate- and extended-release alprazolam preparations on a daily basis. However, the dosage should be divided as evenly as possible during waking hours on a 3- or 4-times daily schedule for immediate-release preparations whereas the dosage is given once daily, preferably in the morning, for extended-release tablets.
Patients being switched from immediate-release alprazolam therapy to the extended-release tablets can receive the same total daily dosage administered once daily rather than in divided doses. If the therapeutic response is not adequate after switching to the same dosage administered once daily, the dosage may be increased in the usual fashion.
Effective treatment of panic disorder with alprazolam often has required dosages exceeding 4 mg daily in adults. Dosage (as immediate-release preparations) generally has averaged 5-6 mg daily, but has ranged from 1-10 mg daily; about 20% of patients required maximum alprazolam dosages exceeding 7 mg daily, with about one-third of these requiring maximum dosages exceeding 9 mg daily. An alprazolam dosage of 3-6 mg daily as extended-release tablets generally has been effective, but dosage has ranged from 1-10 mg daily.
Occasionally, a dosage of 10 mg daily has been required for adequate response.
For patients receiving dosages exceeding 4 mg daily, periodic reassessment and consideration of dosage reduction is recommended. In a controlled postmarketing dose-response study, patients receiving alprazolam at dosages exceeding 4 mg daily for 3 months were able to taper their daily maintenance dosage by 50% without apparent loss of clinical benefit.
Reduction of alprazolam dosage must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of dosage tapering be attempted. Although not systematically evaluated, a reduction by 0.5
mg daily at 3-day intervals has been suggested, although more gradual reductions may be necessary in some patients. When this suggested tapering schedule was compared with a slower dosage taper, there was no difference in the proportion of patients able to completely discontinue alprazolam, but the slower tapering schedule was associated with fewer withdrawal symptoms. Some patients may prove resistant to all discontinuance regimens.
Immediate-release preparations of alprazolam (i.e., conventional and orally disintegrating tablets, oral solution concentrate) are administered orally in divided doses. Because concomitant oral administration of grapefruit juice with other similarly metabolized benzodiazepines has been reported to increase the bioavailability of these drugs, caution is advised if grapefruit juice is ingested concomitantly with alprazolam. (See Drug Interactions: Grapefruit Juice under Drug Interactions in the Benzodiazepines General Statement 28:24.08.) When alprazolam oral concentrate is used, the dose should be added to 30 mL or more of diluent (e.g., water, juices, carbonated or soda-like beverages) or to semi-solid foods (e.g., applesauce, pudding) just before administration.
The orally disintegrating tablets should be administered immediately after the tablet is removed from the container by the patient; if only half a tablet is administered, the unused portion should be discarded immediately since it may not remain stable. The orally disintegrating tablet should be removed with a dry hand and placed on the tongue, where it disintegrates rapidly in saliva, and then subsequently can be swallowed with or without water. Any cotton that is present in the container when initially opened should be discarded, and the container should be resealed tightly to prevent the introduction of moisture, which might cause tablet disintegration.
Although peak plasma concentrations are achieved 15 minutes sooner when the orally disintegrating tablets are administered with water, the peak concentration and oral bioavailability are not affected by administration with water. Administration of the orally disintegrating tablets with a high-fat meal does not affect the extent of absorption but may delay and reduce peak plasma concentrations of the drug by about 2 hours and 25%, respectively. If the orally disintegrating tablets are used in the presence of conditions or in conjunction with drugs that increase gastric pH or cause dry mouth, disintegration or dissolution of the tablets might be slower, potentially resulting in reduced or slower absorption of alprazolam.
Alprazolam extended-release tablets are administered once daily, preferably in the morning. When the extended-release tablets are administered at night rather than in the morning, peak plasma concentrations are about 30% higher and occur about 1 hour sooner. The extended-release tablets should be swallowed whole and should not be chewed, crushed, or broken.
The relative oral bioavailability of alprazolam when administered as extended-release tablets is 100% that of conventional (immediate-release) tablets; however, the rate of GI absorption is slower. The slower absorption rate results in a relatively constant plasma concentration of the drug that is maintained between 5-11 hours after dosing. Multiple-dose studies indicate that the metabolism and elimination of the drug are similar with the immediate- and extended-release tablets.
Food affects the rate but not the extent of absorption of alprazolam extended-release tablets. Peak plasma concentrations are increased by 25% when alprazolam extended-release tablets are administered within 2 hours after a high-fat meal; time to peak plasma concentrations may be reduced by about one-third if the dose is administered immediately after a meal but may be increased by about one-third if administered 1 hour or more before a meal.
The orally disintegrating tablets should be administered immediately after the tablet is removed from the container by the patient; if only half a tablet is administered, the unused portion should be discarded immediately since it may not remain stable. The orally disintegrating tablet should be removed with a dry hand and placed on the tongue, where it disintegrates rapidly in saliva, and then subsequently can be swallowed with or without water. Any cotton that is present in the container when initially opened should be discarded, and the container should be resealed tightly to prevent the introduction of moisture, which might cause tablet disintegration.
Although peak plasma concentrations are achieved 15 minutes sooner when the orally disintegrating tablets are administered with water, the peak concentration and oral bioavailability are not affected by administration with water. Administration of the orally disintegrating tablets with a high-fat meal does not affect the extent of absorption but may delay and reduce peak plasma concentrations of the drug by about 2 hours and 25%, respectively. If the orally disintegrating tablets are used in the presence of conditions or in conjunction with drugs that increase gastric pH or cause dry mouth, disintegration or dissolution of the tablets might be slower, potentially resulting in reduced or slower absorption of alprazolam.
Alprazolam extended-release tablets are administered once daily, preferably in the morning. When the extended-release tablets are administered at night rather than in the morning, peak plasma concentrations are about 30% higher and occur about 1 hour sooner. The extended-release tablets should be swallowed whole and should not be chewed, crushed, or broken.
The relative oral bioavailability of alprazolam when administered as extended-release tablets is 100% that of conventional (immediate-release) tablets; however, the rate of GI absorption is slower. The slower absorption rate results in a relatively constant plasma concentration of the drug that is maintained between 5-11 hours after dosing. Multiple-dose studies indicate that the metabolism and elimination of the drug are similar with the immediate- and extended-release tablets.
Food affects the rate but not the extent of absorption of alprazolam extended-release tablets. Peak plasma concentrations are increased by 25% when alprazolam extended-release tablets are administered within 2 hours after a high-fat meal; time to peak plasma concentrations may be reduced by about one-third if the dose is administered immediately after a meal but may be increased by about one-third if administered 1 hour or more before a meal.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| XANAX 0.25 MG TABLET | Maintenance | Adults take 1 tablet (0.25 mg) by oral route 3 times per day |
| XANAX 0.5 MG TABLET | Maintenance | Adults take 1 tablet (0.5 mg) by oral route 3 times per day |
| XANAX 1 MG TABLET | Maintenance | Adults take 1 tablet (1 mg) by oral route 3 times per day |
| XANAX 2 MG TABLET | Maintenance | Adults take 1 tablet (2 mg) by oral route 3 times per day |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| ALPRAZOLAM 0.25 MG TABLET | Maintenance | Adults take 1 tablet (0.25 mg) by oral route 3 times per day |
| ALPRAZOLAM 0.5 MG TABLET | Maintenance | Adults take 1 tablet (0.5 mg) by oral route 3 times per day |
| ALPRAZOLAM 1 MG TABLET | Maintenance | Adults take 1 tablet (1 mg) by oral route 3 times per day |
| ALPRAZOLAM 2 MG TABLET | Maintenance | Adults take 1 tablet (2 mg) by oral route 3 times per day |
The following drug interaction information is available for XANAX (alprazolam):
There are 7 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Itraconazole; Ketoconazole; Levoketoconazole/Selected Benzodiazepines 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) 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) |
ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, RECORLEV, SPORANOX, TOLSURA |
| Sodium Oxybate/Sedative Hypnotics; Alcohol 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) |
LUMRYZ, LUMRYZ STARTER PACK, SODIUM OXYBATE, XYREM, XYWAV |
| 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. |
KORLYM, MIFEPREX, MIFEPRISTONE |
| Alprazolam; Estazolam; Triazolam/Ribociclib 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: Ribociclib may inhibit the metabolism of alprazolam, estazolam, and triazolam by CYP3A4.(1-4) CLINICAL EFFECTS: Inhibition of benzodiazepine metabolism may produce increased levels of these agents, as well as increased clinical effects, including 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) with strong CYP3A4 inhibitors is contraindicated. 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.(4) |
KISQALI |
| Alprazolam; Triazolam/Selected Strong 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: Strong CYP3A4 inhibitors may inhibit the metabolism of alprazolam and triazolam.(1,2) CLINICAL EFFECTS: The concurrent administration of alprazolam or triazolam with strong CYP3A4 inhibitors may result in elevated levels of alprazolam or triazolam, 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 alprazolam and triazolam state that concurrent use with strong CYP3A4 inhibitors is contraindicated.(1,2) DISCUSSION: Many of the strong CYP3A4 inhibitors linked to this monograph have not been studied in combination with alprazolam or triazolam. However, other strong CYP3A4 have been well studied and are expected to cause a similar effect. In a study coadministration with ketoconazole increased alprazolam area-under-curve (AUC) by 3.98-fold.(1) In a study of 12 healthy volunteers, clarithromycin (500 mg twice daily for 2 days) increased the AUC of triazolam by 5-fold.(3) 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 increase in triazolam Cmax ranged from 1.4-fold to 1.8-fold. Subjects noted increased triazolam effects.(4) In a double-blind cross-over study in 9 subjects, itraconazole increased triazolam AUC by 27-fold.(5) In a double-blind cross-over study in 9 subjects, ketoconazole increased triazolam AUC by 22-fold.(4) 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.(6) Serum concentrations and the half-life of triazolam were increased by troleandomycin by as much as 258%.(7) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib, josamycin, lonafarnib, mibefradil, posaconazole, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(8) |
CLARITHROMYCIN, CLARITHROMYCIN ER, GENVOYA, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, NOXAFIL, OMECLAMOX-PAK, POSACONAZOLE, PREZCOBIX, STRIBILD, SYMTUZA, TUKYSA, VFEND, VFEND IV, VOQUEZNA TRIPLE PAK, VORICONAZOLE, VORICONAZOLE (HPBCD), ZOKINVY, ZYDELIG, ZYKADIA |
| Lemborexant (Greater Than 5 mg)/Weak 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: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, anamorelin, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, vonoprazan, and ziftomenib.(1,2) |
DAYVIGO |
| Ubrogepant (Greater Than 50 mg)/Weak 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: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1) CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, anamorelin, asciminib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, vonoprazan, and ziftomenib.(2,3) |
UBRELVY |
There are 9 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Selected Protease Inhibitors/Alprazolam SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Protease inhibitors, including amprenavir, atazanavir, darunavir, fosamprenavir, lopinavir, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, saquinavir, and tipranavir, may inhibit the metabolism of alprazolam by CYP3A4.(1-3) CLINICAL EFFECTS: The concurrent administration of amprenavir, atazanavir, darunavir, fosamprenavir, lopinavir, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, saquinavir, and tipranavir may result in increased levels and clinical effects of alprazolam, which may result in extreme sedation and respiratory depression.(1-3) PREDISPOSING FACTORS: Inhibition of alprazolam may be greater in patients who have recently started therapy with a protease inhibitor.(1) PATIENT MANAGEMENT: Consider alternative benzodiazepines such as lorazepam, temazepam, or oxazepam. If concurrent use is necessary, patients receiving amprenavir, atazanavir, darunavir, fosamprenavir, lopinavir, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, saquinavir, or tipranavir should be observed for increased alprazolam effects. The dosage of alprazolam may need to adjusted, or alprazolam may need to be discontinued.(1-3) DISCUSSION: In a study in healthy subjects, the administration of a single dose of alprazolam (1.0 mg) following 12 days of ritonavir therapy (titrated up to 500 mg daily) resulted in a decrease in the alprazolam area-under-curve (AUC) by 12%.(1,3) The maximum concentration (Cmax) of alprazolam decreased by 16%.(1) In contrast to this, in a double-blind study in 10 healthy subjects, the administration of a single dose of alprazolam (1.0 mg) following four doses of ritonavir (200 mg) resulted in a decrease in alprazolam clearance by 59%. Ritonavir has been shown to inhibit and induce CYP3A4.(3) In a study in 17 subjects, telaprevir (750 mg every 8 hours for 10 days) increased the AUC of a single dose of alprazolam (0.5 mg) by 35%.(4) |
APTIVUS, ATAZANAVIR SULFATE, DARUNAVIR, EVOTAZ, FOSAMPRENAVIR CALCIUM, KALETRA, LOPINAVIR-RITONAVIR, PAXLOVID, PREZCOBIX, PREZISTA, REYATAZ, SYMTUZA, VIRACEPT |
| Clozapine/Benzodiazepines 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) |
CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ |
| Ethyl Alcohol/Benzodiazepines 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) |
ALCOHOL,DEHYDRATED |
| 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. |
NEFAZODONE HCL |
| Lomitapide/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve). CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1) PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1) PATIENT MANAGEMENT: When initiating lomitapide in patients taking a stable dose of a weak CYP3A4 inhibitor, follow the recommended dose and titration schedule per labeling. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide, decrease the dose of lomitapide by 50%. The maximum recommended lomitapide dose with concurrent weak CYP3A4 inhibitors should be: -Adults (age 18 years and older): 30 mg daily, -Age group 11 to 17 years: 20 mg daily, -Age group 2 to 10 years: 10 mg daily. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction.(1) DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1) Weak CYP3A4 inhibitors linked to this interaction include alprazolam, amiodarone, amlodipine, anamorelin, asciminib, atorvastatin, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, vonoprazan, ziftomenib, and zileuton.(1-3) |
JUXTAPID |
| Opioids (Cough and Cold)/Benzodiazepines 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) |
HYCODAN, HYDROCODONE-CHLORPHENIRAMNE ER, HYDROCODONE-HOMATROPINE MBR, HYDROMET, PROMETHAZINE-CODEINE, TUXARIN ER |
| Eliglustat/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP2D6, eliglustat metabolism can be further inhibited.(1) CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP3A4 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1) PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP2D6, is a poor metabolizer of CYP2D6, and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The concurrent use of eliglustat with weak inhibitors of CYP3A4 in poor metabolizers of CYP2D6 should be avoided.(1) The dosage of eliglustat with weak inhibitors of CYP3A4 in extensive metabolizers of CYP2D6 with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 4-fold and 4.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and 5.4-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) Weak inhibitors of CYP3A4 include: alprazolam, amlodipine, anamorelin, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, vonoprazan, and ziftomenib.(3,4) |
CERDELGA |
| 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.(1,4) 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.(5) 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) 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.(3) 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, alfentanil, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, sirolimus, ticagrelor, triazolam, and ulipristal.(1,4,6) |
XENLETA |
| Alprazolam/Selected Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of alprazolam.(1) CLINICAL EFFECTS: Concurrent use may result in increased pharmacologic or toxic effects of alprazolam. Toxic effects include profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concomitant use with moderate CYP3A4 inhibitors. Consider reducing the dose of alprazolam when coadministered with a moderate CYP3A4 inhibitor. If fluvoxamine is concurrently administered with alprazolam, the manufacturer of fluvoxamine recommends that the initial dose of alprazolam be reduced by 50%, followed by titration to the lowest effective dose.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. DISCUSSION: Coadministration of cimetidine, a moderate CYP3A4 inhibitor, increased the maximum concentration (Cmax) of alprazolam by 82%.(1) Coadministration with erythromycin, a moderate CYP3A4 inhibitor, increased the area-under-curve (AUC) of alprazolam by 1.61-fold.(1) Coadministration of fluvoxamine 100 mg daily and alprazolam 1 mg given 4 times per day resulted in a 2-fold increase of AUC, Cmax, and half-life of alprazolam.(2) Selected moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3,4) |
AKYNZEO, APREPITANT, CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, CINVANTI, CLOFAZIMINE, CONIVAPTAN-D5W, COPIKTRA, CRESEMBA, DANZITEN, DIACOMIT, DIFLUCAN, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, E.E.S. 200, E.E.S. 400, EMEND, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, FLUCONAZOLE, FLUCONAZOLE-NACL, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, GLEEVEC, GRAFAPEX, IMATINIB MESYLATE, IMKELDI, INREBIC, MATZIM LA, MULTAQ, NILOTINIB D-TARTRATE, NILOTINIB HCL, ORLADEYO, PREVYMIS, SUNLENCA, TASIGNA, TAVNEOS, TIADYLT ER, TIAZAC, TRANDOLAPRIL-VERAPAMIL ER, VAPRISOL-5% DEXTROSE, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR, WAYRILZ, XALKORI, YEZTUGO |
There are 15 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| 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. |
BRAFTOVI, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, EQUETRO, ERLEADA, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, ORKAMBI, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, RIFABUTIN, RIFADIN, RIFAMPIN, TALICIA, TEGRETOL, TEGRETOL XR, TIBSOVO, XTANDI |
| Buprenorphine/Benzodiazepines 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) |
BELBUCA, BRIXADI, BUPRENORPHINE, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, BUTRANS, SUBLOCADE, SUBOXONE, ZUBSOLV |
| Alprazolam/Fluoxetine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Alprazolam is primarily metabolized by CYP3A4.(1) Fluoxetine and its long-acting active metabolite norfluoxetine are both weak inhibitors and inducers of CYP3A4.(2) While the onset of enzyme inhibition is an early effect, the onset of induction may take weeks for maximal effect. CLINICAL EFFECTS: Addition of fluoxetine to existing alprazolam therapy may be associated with increased alprazolam concentrations and clinical effects, including profound sedation, respiratory depression, coma, and/or death. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If fluoxetine is started in a patient already receiving alprazolam, the alprazolam dose may need to be decreased. With continued (i.e. chronic) fluoxetine therapy the interaction may wane due to the counteracting effect of weak CYP3A4 induction by fluoxetine. Monitor and adjust the alprazolam dose as needed. If clinically appropriate, a benzodiazepine which does not undergo extensive Phase I metabolism (lorazepam, oxazepam), or clonazepam(3) may be an alternative to alprazolam in patients receiving fluoxetine. Counsel patient to report excess drowsiness, confusion, memory problems including sleep-driving behaviors, loss of coordination, slowed or difficult breathing, or unresponsiveness. DISCUSSION: Manufacturer prescribing information describes an interaction study where fluoxetine increased the maximum concentration (Cmax) of alprazolam by 46%, decreased clearance by 21% and increased half-life by 17% leading to decreased measured psychomotor performance.(1) Details regarding the patient population, drug dosage, and duration of therapy were not provided. The effect of fluoxetine on the pharmacokinetics of a single dose of alprazolam was studied in 11 male volunteers. Subjects received fluoxetine 20 mg every 12 hours for 9 days followed by a single dose of alprazolam 1 mg. The mean elimination half-life of alprazolam increased from 17.4 to 20.3 hours, area-under-curve (AUC) increased 26%. Clinical effects, e.g. impairment of memory or psychomotor performance were not measured.(3) A study was performed to better understand the interactions of chronic fluoxetine therapy on the activity of CYP2D6, CYP2C19 and CYP3A4 enzymes. In this study chronic fluoxetine therapy did significantly affect the AUC, clearance or half-life of the following CYP3A4 substrates: midazolam, lovastatin, cortisone or 6-beta-hydroxycortisol. Evaluation of this outcome revealed that fluoxetine (and its active metabolite) both inhibit and induce CYP3A4 to a similar degree. During chronic fluoxetine therapy, these two opposing activities were balanced, resulting in no clinical effect. |
FLUOXETINE DR, FLUOXETINE HCL, OLANZAPINE-FLUOXETINE HCL, PROZAC |
| Opioids (Extended Release)/Benzodiazepines 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) |
CONZIP, FENTANYL, HYDROCODONE BITARTRATE ER, HYDROMORPHONE ER, HYSINGLA ER, MORPHINE SULFATE ER, MS CONTIN, NUCYNTA ER, OXYCODONE HCL ER, OXYCONTIN, OXYMORPHONE HCL ER, TAPENTADOL ER, TRAMADOL HCL ER, XTAMPZA ER |
| Opioids (Immediate Release)/Benzodiazepines 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) |
ACETAMIN-CAFF-DIHYDROCODEINE, ACETAMINOPHEN-CODEINE, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BELLADONNA-OPIUM, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTORPHANOL TARTRATE, CARISOPRODOL-ASPIRIN-CODEINE, CODEINE PHOSPHATE, CODEINE SULFATE, DEMEROL, DIHYDROCODEINE BITARTRATE, DILAUDID, DSUVIA, DURAMORPH, ENDOCET, FENTANYL CITRATE, FENTANYL CITRATE-0.9% NACL, FENTANYL CITRATE-D5W, FENTANYL CITRATE-STERILE WATER, FENTANYL CITRATE-WATER, FENTANYL-BUPIVACAINE-0.9% NACL, FENTANYL-BUPIVACAINE-NACL, FENTANYL-ROPIVACAINE-0.9% NACL, FENTANYL-ROPIVACAINE-NACL, HYDROCODONE BITARTRATE, HYDROCODONE-ACETAMINOPHEN, HYDROCODONE-IBUPROFEN, HYDROMORPHONE HCL, HYDROMORPHONE HCL-0.9% NACL, HYDROMORPHONE HCL-D5W, HYDROMORPHONE HCL-NACL, HYDROMORPHONE HCL-WATER, INFUMORPH, LEVORPHANOL TARTRATE, MEPERIDINE HCL, MEPERIDINE HCL-0.9% NACL, METHADONE HCL, METHADONE HCL-0.9% NACL, METHADONE HCL-NACL, MITIGO, MORPHINE SULFATE, MORPHINE SULFATE-0.9% NACL, MORPHINE SULFATE-NACL, NALBUPHINE HCL, NALOCET, NUCYNTA, OPIUM TINCTURE, OXYCODONE HCL, OXYCODONE HYDROCHLORIDE, OXYCODONE-ACETAMINOPHEN, OXYMORPHONE HCL, PENTAZOCINE-NALOXONE HCL, PERCOCET, PRIMLEV, PROLATE, QDOLO, REMIFENTANIL HCL, ROXICODONE, ROXYBOND, SUFENTANIL CITRATE, TAPENTADOL HCL, TRAMADOL HCL, TRAMADOL HCL-ACETAMINOPHEN, TREZIX, ULTIVA, XYVONA |
| 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) |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, DONNATAL, FIORICET, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PRIMIDONE, SEZABY, TENCON |
| Selected Opioids for MAT/Benzodiazepines 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) |
DISKETS, METHADONE HCL, METHADONE INTENSOL, METHADOSE |
| Select Oral Benzodiazepines/Aprepitant (Less Than or Equal To 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) |
APONVIE, APREPITANT |
| 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 benzodiazepine and stimulants may have unpredictable effects and 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) |
ADDERALL, ADDERALL XR, ADZENYS XR-ODT, AMPHETAMINE ER ODT, AMPHETAMINE SULFATE, APTENSIO XR, ARYNTA, AZSTARYS, CONCERTA, COTEMPLA XR-ODT, DAYTRANA, DESOXYN, DEXEDRINE, DEXMETHYLPHENIDATE HCL, DEXMETHYLPHENIDATE HCL ER, DEXTROAMPHETAMINE SULFATE, DEXTROAMPHETAMINE SULFATE ER, DEXTROAMPHETAMINE-AMPHET ER, DEXTROAMPHETAMINE-AMPHETAMINE, DYANAVEL XR, EVEKEO, FOCALIN, FOCALIN XR, JORNAY PM, LISDEXAMFETAMINE DIMESYLATE, METADATE CD, METHAMPHETAMINE HCL, METHYLIN, METHYLPHENIDATE, METHYLPHENIDATE ER, METHYLPHENIDATE ER (LA), METHYLPHENIDATE HCL, METHYLPHENIDATE HCL CD, METHYLPHENIDATE HCL ER (CD), MYDAYIS, PROCENTRA, QUILLICHEW ER, QUILLIVANT XR, RELEXXII, RITALIN, VYVANSE, XELSTRYM, ZENZEDI |
| Tacrolimus/Moderate and Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate and weak inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus.(1) CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The US manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and reducing tacrolimus dose if needed.(1) Consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a study of 26 renal transplant recipients, conjugated estrogens 3.75 mg daily increased the tacrolimus dose-corrected concentration of tacrolimus by 85.6%. Discontinuation of the conjugated estrogens led to a decrease in tacrolimus concentration of 46.6%.(3) A case report describes a 65-year-old kidney transplant recipient who was stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL. Ten days after starting on estradiol gel 0.5 mg per day, her tacrolimus level rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at baseline to 2 mg/dL. Tacrolimus dose was reduced by 60%, and trough levels and Scr normalized after two weeks.(4) A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir 200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%, while the maximum concentration (Cmax) of tacrolimus was decreased by 40%.(5) An analysis of FAERS data from 2004-2017, found a significant association between transplant rejection and concurrent use of tacrolimus and clotrimazole (reporting odds ratio 1.92, 95% CI). A retrospective study of 7 heart transplant patients on concurrent tacrolimus and clotrimazole troche showed a significant correlation between tacrolimus trough concentration and AUC after clotrimazole discontinuation. Tacrolimus clearance and bioavailability after clotrimazole discontinuation was 2.2-fold greater (0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7) A retrospective study of 26 heart transplant patients found that discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5 expresser group had a 3.3-fold increase in apparent oral clearance and AUC of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8) A study of 6 adult kidney transplant recipients found that clotrimazole (5-day course) increased the tacrolimus AUC 250% and the blood trough concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance decreased 60% with coadministration of clotrimazole.(9) A case report describes a 23-year-old kidney transplant recipient who was stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily, prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche 10 mg four times daily. Discontinuation of clotrimazole resulted in a decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting in an increased tacrolimus level of 19.2 ng/ml.(10) A retrospective study in 95 heart transplant recipients on concurrent clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7% was required after clotrimazole discontinuation. Tacrolimus trough concentration was found to have decreased 42.5% after clotrimazole discontinuation.(11) A retrospective study in 65 pancreas transplant patients on concurrent tacrolimus, clotrimazole, cyclosporine, and prednisone found that clotrimazole discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions.(12) A case report describes a 6-year-old kidney transplant recipient who was on a regimen of tacrolimus and mycophenolate mofetil. The patient was started letermovir 240 mg via G-tube 2 months post kidney transplant. One week after starting letermovir, the routine tacrolimus level showed a supratherapeutic concentration of 22.9 ng/L. A 36% dose reduction of tacrolimus was required. Upon discontinuation of letermovir, the tacrolimus level decreased by 42%.(13) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, berotralstat, conivaptan, fluvoxamine, lenacapavir, letermovir, netupitant, nirogacestat, sevabertinib, stiripentol, and tofisopam.(6) Weak CYP3A4 inhibitors linked to this monograph include: alprazolam, avacopan, baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cimetidine, cranberry juice, daclatasvir, daridorexant, delavirdine, diosmin, elinzanetant, estrogens, flibanserin, fosaprepitant, fostamatinib, ginkgo biloba, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, linagliptin, lomitapide, lumateperone, lurasidone, peppermint oil, piperine, propiverine, ranitidine, resveratrol, rimegepant, simeprevir, sitaxsentan, skullcap, suvorexant, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan-amoxicillin.(6) |
ASTAGRAF XL, ENVARSUS XR, PROGRAF, TACROLIMUS, TACROLIMUS XL |
| Lemborexant (Less Than or Equal To 5 mg)/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, anamorelin, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, vonoprazan, and ziftomenib.(1,2) |
DAYVIGO |
| Ubrogepant (Less Than or Equal To 50 mg)/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1) CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, anamorelin, asciminib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, vonoprazan, and ziftomenib.(2,3) |
UBRELVY |
| Gabapentinoids/Benzodiazepines 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) |
GABAPENTIN, GABAPENTIN ER, GABARONE, GRALISE, HORIZANT, LYRICA, LYRICA CR, NEURONTIN, PREGABALIN, PREGABALIN ER, RELGAABI |
| Sirolimus Protein-Bound/Slt Moderate and Weak CYP3A4 Inhibit SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate and weak CYP3A4 inhibitors may inhibit the metabolism of sirolimus by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: 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.(1) DISCUSSION: In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(2) Moderate and weak CYP3A4 inhibitors linked to this monograph include: alprazolam, amlodipine, anamorelin, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, daclatasvir, daridorexant, delavirdine, diosmin, elinzanetant, entrectinib, erythromycin, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, rimegepant, roxithromycin, scutellarin, sevabertinib, simeprevir, sitaxsentan, stiripentol, suvorexant, ticagrelor, tofisopam, tolvaptan, trofinetide, and vonoprazan.(3,4) |
FYARRO |
| Mavacamten/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Weak CYP3A4 inhibitors may decrease the metabolism of mavacamten.(1) CLINICAL EFFECTS: Concurrent use of weak CYP3A4 inhibitors may increase the plasma levels and the incidence and severity of adverse reactions of mavacamten.(1) PREDISPOSING FACTORS: CYP2C19 poor metabolizers may experience an increased incidence or severity of adverse effects.(1) PATIENT MANAGEMENT: The UK manufacturer of mavacamten states no dose adjustment is necessary when starting mavacamten in patients on weak CYP3A4 inhibitors or in intermediate, normal, rapid, or ultra-rapid CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor. In poor CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor, reduce mavacamten 5 mg to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks. If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of 2.5 mg daily.(1) DISCUSSION: In a PBPK model, concomitant use of mavacamten (15 mg daily) with cimetidine 400 mg twice daily, a weak CYP3A4 inhibitor, was predicted to increase mavacamten area-under-curve (AUC) by 6% and maximum concentration (Cmax) by 4% in poor CYP2C19 metabolizers and by 3% and 2%, respectively, in both intermediate and normal CYP2C19 metabolizers.(2) Weak CYP3A4 inhibitors include: alprazolam, amiodarone, amlodipine, anamorelin, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, ciprofloxacin, clotrimazole, cranberry, cyclosporine, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, istradefylline, ivacaftor, lacidipine, lapatinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, pazopanib, peppermint oil, propiverine, propofol, ranitidine, resveratrol, roxithromycin, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, and viloxazine.(4,5) |
CAMZYOS |
The following contraindication information is available for XANAX (alprazolam):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 1 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Lactation |
There are 7 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Alcohol intoxication |
| Depression |
| Drug abuse |
| Pregnancy |
| Respiratory depression |
| Sleep apnea |
| Suicidal ideation |
There are 7 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Asthma |
| Chronic obstructive pulmonary disease |
| Debilitation |
| Disease of liver |
| Kidney disease with reduction in glomerular filtration rate (GFr) |
| Obesity |
| Tobacco smoker |
The following adverse reaction information is available for XANAX (alprazolam):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 12 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Dyskinesia Dyspnea |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Angioedema Drug dependence Drug-induced hepatitis Hepatic failure Hypotension Manic disorder Respiratory depression Seizure disorder Stevens-johnson syndrome |
There are 75 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Depression Drowsy Fatigue Libido changes Sedation |
Abnormal sexual function Acute cognitive impairment Agitation Allergic dermatitis Anorexia Appetite changes Arthralgia Ataxia Constipation Diarrhea Disturbance of attention Dizziness Dream disorder Dysmenorrhea Headache disorder Hypersomnia Hyperventilation Hypoesthesia Insomnia Lethargy Menstrual disorder Myalgia Nausea and vomiting Nervousness Pain in extremities Paresthesia Premenstrual syndrome Sensation of warmth Sialorrhea Skin rash Symptoms of anxiety Weight gain Weight loss |
| Rare/Very Rare |
|---|
|
Accidental fall Acquired dystonia Acute abdominal pain Back pain Behavioral disorders Blurred vision Chest pain Concentration difficulty Cramps Depersonalization Dysarthria Dyspepsia Dysuria Galactorrhea not associated with childbirth General weakness Gynecomastia Hyperhidrosis Hyperprolactinemia Hypomania Increased libido Irritability Malaise Memory impairment Muscle fasciculation Muscle spasm Muscle weakness Nasal congestion Nightmares Palpitations Peripheral edema Pruritus of skin Slurred speech Tremor Urinary retention Vertigo Visual changes Xerostomia |
The following precautions are available for XANAX (alprazolam):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
No enhanced Pregnancy information available for this drug.
No enhanced Lactation information available for this drug.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for XANAX (alprazolam):
WARNING: Alprazolam has a risk for abuse and addiction, which can lead to overdose and death. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems (especially opioid medications such as codeine, hydrocodone) may cause very serious side effects, including death. To lower your risk, your doctor should have you take the smallest dose of alprazolam that works, and take it for the shortest possible time.
Be sure you know how to take alprazolam and what other drugs you should avoid taking with it. See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up.
Suddenly stopping this medication may cause serious (possibly fatal) withdrawal, especially if you have used it for a long time or in high doses. To prevent withdrawal, your doctor may lower your dose slowly. Tell your doctor or pharmacist right away if you have any withdrawal symptoms such as headaches, trouble sleeping, restlessness, hallucinations/confusion, depression, nausea, or seizures. Withdrawal symptoms may sometimes last weeks to months.
WARNING: Alprazolam has a risk for abuse and addiction, which can lead to overdose and death. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems (especially opioid medications such as codeine, hydrocodone) may cause very serious side effects, including death. To lower your risk, your doctor should have you take the smallest dose of alprazolam that works, and take it for the shortest possible time.
Be sure you know how to take alprazolam and what other drugs you should avoid taking with it. See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up.
Suddenly stopping this medication may cause serious (possibly fatal) withdrawal, especially if you have used it for a long time or in high doses. To prevent withdrawal, your doctor may lower your dose slowly. Tell your doctor or pharmacist right away if you have any withdrawal symptoms such as headaches, trouble sleeping, restlessness, hallucinations/confusion, depression, nausea, or seizures. Withdrawal symptoms may sometimes last weeks to months.
The following icd codes are available for XANAX (alprazolam)'s list of indications:
| Anxiety | |
| F06.4 | Anxiety disorder due to known physiological condition |
| F10.180 | Alcohol abuse with alcohol-induced anxiety disorder |
| F10.280 | Alcohol dependence with alcohol-induced anxiety disorder |
| F10.980 | Alcohol use, unspecified with alcohol-induced anxiety disorder |
| F12.180 | Cannabis abuse with cannabis-induced anxiety disorder |
| F12.280 | Cannabis dependence with cannabis-induced anxiety disorder |
| F12.980 | Cannabis use, unspecified with anxiety disorder |
| F14.180 | Cocaine abuse with cocaine-induced anxiety disorder |
| F14.280 | Cocaine dependence with cocaine-induced anxiety disorder |
| F14.980 | Cocaine use, unspecified with cocaine-induced anxiety disorder |
| F15.180 | Other stimulant abuse with stimulant-induced anxiety disorder |
| F15.280 | Other stimulant dependence with stimulant-induced anxiety disorder |
| F15.980 | Other stimulant use, unspecified with stimulant-induced anxiety disorder |
| F16.180 | Hallucinogen abuse with hallucinogen-induced anxiety disorder |
| F16.280 | Hallucinogen dependence with hallucinogen-induced anxiety disorder |
| F16.980 | Hallucinogen use, unspecified with hallucinogen-induced anxiety disorder |
| F18.180 | Inhalant abuse with inhalant-induced anxiety disorder |
| F18.280 | Inhalant dependence with inhalant-induced anxiety disorder |
| F18.980 | Inhalant use, unspecified with inhalant-induced anxiety disorder |
| F19.180 | Other psychoactive substance abuse with psychoactive substance-induced anxiety disorder |
| F19.280 | Other psychoactive substance dependence with psychoactive substance-induced anxiety disorder |
| F19.980 | Other psychoactive substance use, unspecified with psychoactive substance-induced anxiety disorder |
| F40 | Phobic anxiety disorders |
| F40.0 | Agoraphobia |
| F40.00 | Agoraphobia, unspecified |
| F40.01 | Agoraphobia with panic disorder |
| F40.02 | Agoraphobia without panic disorder |
| F40.1 | Social phobias |
| F40.10 | Social phobia, unspecified |
| F40.11 | Social phobia, generalized |
| F40.8 | Other phobic anxiety disorders |
| F40.9 | Phobic anxiety disorder, unspecified |
| F41 | Other anxiety disorders |
| F41.0 | Panic disorder [episodic paroxysmal anxiety] |
| F41.1 | Generalized anxiety disorder |
| F41.3 | Other mixed anxiety disorders |
| F41.8 | Other specified anxiety disorders |
| F41.9 | Anxiety disorder, unspecified |
| F93.0 | Separation anxiety disorder of childhood |
| Anxiety with depression | |
| F41.8 | Other specified anxiety disorders |
| Generalized anxiety disorder | |
| F41.1 | Generalized anxiety disorder |
| F41.9 | Anxiety disorder, unspecified |
| Panic disorder | |
| F40.01 | Agoraphobia with panic disorder |
| F41.0 | Panic disorder [episodic paroxysmal anxiety] |
Formulary Reference Tool