Alprazolam (Xanax) Interactions
- Amiodarone
Anti-retroviral protease inhibitors
Anticonvulsants
Antipsychotics
Anxiolytics, Sedatives, and Hypnotics
- Aprepitant
Barbiturates
- Bosentan
- Buprenorphine
- Butorphanol
- Carbamazepine
- Cimetidine
- Clarithromycin
- Clozapine
- Conivaptan
- Cyclosporine
- Dalfopristin; Quinupristin
- Delavirdine
- Desipramine
- Digoxin
- Diltiazem
- Disulfiram
- Dronabinol, THC
- Echinacea
- Efavirenz
- Entacapone
- Ergotamine
- Erythromycin
- Ethanol
- Ethotoin
- Fluconazole
- Flumazenil
- Fluoxetine
- Fluvoxamine
- food
- Fosphenytoin
General Anesthetics
- grapefruit juice
- Imatinib, STI-571
- Imipramine
- Indinavir
- Isoniazid, INH
- Itraconazole
- Kava Kava, Piper methysticum
- Ketoconazole
- Melatonin
- Mibefradil
- Miconazole
- Mifepristone, RU-486
- Nabilone
- Nalbuphine
- Nefazodone
- Nevirapine
- Nicardipine
- Nifedipine
Opiate agonists
Oral contraceptives
- Oxcarbazepine
- Paroxetine
- Pentazocine
- Phenytoin
- Pramipexole
- Prasterone, Dehydroepiandrosterone, DHEA
- Pregabalin
- Probenecid
Radiopaque Contrast Agents
- Ranolazine
- Rifabutin
- Rifampin
- Rifapentine
- Ropinirole
Sedating H1-blockers
- Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous
- St. John’s Wort, Hypericum perforatum
- Telithromycin
- Theophylline, Aminophylline
- Tolcapone
- Tramadol
Tricyclic antidepressants
- Troglitazone
- Troleandomycin
- Valerian, Valeriana officinalis
- Verapamil
- Voriconazole
- Zafirlukast
- Zileuton
Alprazolam Interactions
Alprazolam is metabolized in the liver and is a known substrate for cytochrome P450 (CYP) isoenzyme 3A4. Drugs that inhibit the CYP3A4 isoenzyme may have a profound effect on the clearance of alprazolam.
Clinicians should be aware that a selected food interaction may occur between alprazolam and grapefruit. Alprazolam is metabolized via the cytochrome CYP3A4 isozyme. Grapefruit juice has been shown to significantly increase peak serum concentrations and AUC of triazolam and oral midazolam. According to the manufacturer, a similar interaction may theoretically occur with alprazolam ; however, one in-vivo pharmacokinetic study demonstrated that the bioavailability of alprazolam is unlikely to be effected by coadministration with grapefruit juice. Patients should still be informed of the remote possibility for enhanced CNS effects if they combine grapefruit juice with alprazolam; however, if their consumption of grapefruit juice remains constant the potential for an interaction appears unlikely.
In general, nefazodone is not recommended for use with alprazolam in most patients. The initial dose of alprazolam should be reduced by 50% when concurrent use cannot be avoided. Nefazodone inhibits the hepatic CYP3A4 isoenzyme and substantially increases the plasma concentrations of alprazolam; nefazodone elevated plasma concentrations of alprazolam by 34% in one study. Alprazolam AUC and half-life are increased 2-fold by the addition of nefazodone. Benzodiazepines are metabolized via oxidation and should be used cautiously in those patients receiving nefazodone. Nefazodone does not appear to interact with benzodiazepines that are eliminated through conjugation, such as lorazepam, oxazepam or temazepam.
Coadministration of indinavir with alprazolam contraindicated. Indinavir is expected to significantly inhibit the CYP3A4 metabolism of alprazolam, producing large increases in the plasma concentrations which may lead to excessive sedation and potentially respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with indinavir, as these benzodiazepines are not oxidatively metabolized.
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes. According to the manufacturer of alprazolam, the coadministration of ketoconazole or itraconazole is considered contraindicated with alprazolam, as these medications significantly impair alprazolam metabolism by the CYP3A4 isoenzyme. When a single dose of alprazolam was administered to healthy patients receiving itraconazole, the mean AUC was increased 2.7 fold and the half-life increased 2.7 fold. Another pharmacokinetic study has noted that the clinical impact of this interaction with ketoconazole is less for alprazolam than for triazolam. Fluconazole or voriconazole may also impair alprazolam clearance in this manner; dosage adjustment of alprazolam may be needed. The potency of fluconazole as a CYP3A4 inhibitor is much lower than ketoconazole or itraconazole. Clinical interactions of CYP3A substrates with fluconazole are of lesser magnitude, and are generally observed only with fluconazole dosages of > or =200 mg/day. Due to potent inhibition of alprazolam metabolism, it is recommended that alprazolam be avoided or reduced doses given when coadministered with anti-retroviral protease inhibitors , delavirdine, or efavirenz (CYP3A4 inducer or inhibitor). Coadministration of alprazolam should be avoided with other potent CYP3A4 inhibitors such as cimetidine , fluoxetine , fluvoxamine , mibefradil , and nefazodone. In patients taking drugs that inhibit CYP3A isoenzymes to a significant but lesser degree, use alprazolam with caution and consider alprazolam dose reduction (up to 50% dosage reduction). Other drugs that may theoretically inhibit CYP3A4 metabolism of alprazolam include amiodarone, clarithromycin , cyclosporine , diltiazem , dalfopristin; quinupristin , ergotamine , erythromycin , imatinib, STI-571 , IV miconazole , mifepristone, RU-486 , nicardipine , nifedipine , ranolazine , troleandomycin , verapamil, zileuton , and zafirlukast. This list is not inclusive of all agents that may inhibit CYP3A4. Telithromycin, a ketolide antibiotic, can compete with alprazolam for metabolism by CYP3A4.
Oral contraceptives can increase the effects of alprazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to alprazolam. Alprazolam clearance has been reduced by 22% and half-life increased by 29% when coadministered with oral contraceptives. Low-dose estrogen-containing oral contraceptives have not been shown to significantly influence the metabolic clearance of alprazolam in a pharmacokinetic study.
The concomitant administration of alprazolam with CNS-depressant drugs, including tricyclic antidepressants, can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
Disulfiram , isoniazid, INH, and probenecid can decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving alprazolam therapy should be monitored for signs of altered benzodiazepine response when any of these concurrent medications are initiated or discontinued.
Several hepatic enzyme inducers can theoretically increase the clearance of alprazolam, leading to lower alprazolam serum concentrations. These may include barbiturates, bosentan , carbamazepine , ethotoin , nevirapine, phenytoin or fosphenytoin , rifamycins (e.g., rifampin , rifabutin , and rifapentine ), St. John’s Wort , and troglitazone. Additive sedation may occur initially when barbiturates are given concurrently with alprazolam. It may take several days for the enzyme induction effects to become apparent.
Oxcarbazepine and its active metabolite, MHD, are dose-dependent inducers of the hepatic CYP3A4/5 isoenzymes thereby having the potential to lower the plasma levels of medications metabolized through these pathways. The effectiveness of medications such as alprazolam could theoretically be decreased.
Benzodiazepines should be combined cautiously with clozapine because they could cause additive CNS depressant effects. Severe confusion, hypotension and respiratory depression have occurred rarely in those patients receiving clozapine concurrently or following benzodiazepine therapy. In patients receiving concomitant clozapine, the starting doses of the benzodiazepine should be approximately one-half of the usual dose until experience with the patient has been gained.
Concomitant administration of alprazolam with CNS-depressant drugs , including anticonvulsants, antipsychotics, buprenorphine, butorphanol, dronabinol, THC, ethanol, entacapone, general anesthetics, nabilone , nalbuphine, opiate agonists, pentazocine, pramipexole, pregabalin, ropinirole, sedating H1-blockers, tolcapone, tramadol, or other anxiolytics, sedatives, and hypnotics, can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. According to the manufacturer, the coadministration of propoxyphene decreased alprazolam clearance by 38% and increased the half-life by 29%.
An interaction between digoxin with alprazolam has been reported. Digoxin toxicity has occurred in a patient receiving alprazolam and digoxin. This interaction may be the result of increased plasma protein binding of digoxin and/or an effect of the benzodiazepine at the renal tubules that results in decreased digoxin elimination. A subsequent interaction study of intravenous digoxin with alprazolam revealed no significant effect of alprazolam on the pharmacokinetics of digoxin. Pending further clarification of this interaction, patients receiving alprazolam and digoxin concurrently should be monitored for increased serum digoxin levels. This interaction may be more prevalent in the elderly > 65 years.
Flumazenil and benzodiazepines are pharmacological opposites. Flumazenil is specifically used to reverse the actions of benzodiazepines. Clinicians should note that the duration of action for some benzodiazepines may be much longer than that of flumazenil and repeat doses of flumazenil may be necessary.
It appears prudent to recommend caution when alprazolam is prescribed in conjunction with melatonin. In animal studies, melatonin has been shown to increase benzodiazepine binding to receptor sites, and this may result in clinically significant drug interactions. Case reports exist of concomitant benzodiazepine and melatonin use in humans; the cases resulted in lethargy, short-term amnestic responses, or prolonged benzodiazepine activity. These apparent interactions could have been the result of a pharmacokinetic or pharmacodynamic enhancement of benzodiazepine activity by melatonin.
The German Commission E warns that any substances that act on the CNS, including psychotropic agents, may interact with kava kava. While the interactions can be pharmacodynamic in nature leading to additive sedation, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with agents that undergo oxidative metabolism (e.g., selected benzodiazepines) are also possible. A single case report of an interaction of kava kava, Piper methysticum with benzodiazepines has been reported in the medical literature. Patients on benzodiazepine therapy should avoid concomitant administration of kava kava. Patients should discuss the use of herbal supplements with their health care professional prior to consuming kava kava and should not abruptly stop taking their prescribed medications.
Any substances that act on the CNS, including benzodiazepines, may interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature. Patients who are on alprazolam should avoid concomitant administration of valerian.
Prasterone, dehydroepiandrosterone, DHEA may inhibit the metabolism of triazolam, and other benzodiazepines (e.g., alprazolam, midazolam) which undergo CYP3A4-mediated metabolism. In one study of elderly volunteers, half of the patients received DHEA 200 mg/day PO for 2 weeks, followed by a single dose of triazolam 0.25 mg. Triazolam clearance was reduced by close to 30% in the DHEA-pretreated patients vs. the control group; however, the effect of DHEA on CYP3A4 metabolism appeared to vary widely among subjects. While more study is needed, benzodiazepine-induced CNS sedation and other adverse effects might be increased in some individuals if DHEA is coadministered.
Theophylline has been reported to counteract the pharmacodynamic effects (e.g., sedative and anxiolytic effects) of diazepam. A proposed mechanism is competitive binding of theophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If theophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
Consider the potential for increased CNS side effects when aprepitant (a moderate CYP3A4 inhibitor) is administered with benzodiazepines that are CYP3A4 substrates (e.g., alprazolam, diazepam, midazolam, triazolam); reduced benzodiazepine dosages may be needed. If a benzodiazepine must be used with aprepitant, it would be prudent to select an agent that is not metabolized via CYP3A4 isoenzymes (e.g., lorazepam, oxazepam, temazepam).
The manufacturer of alprazolam states that in vitro studies suggest paroxetine may inhibit the metabolism of alprazolam via inhibition of cytochrome P450 isoenzyme (CYP) 3A4. In general, paroxetine is typically considered a major inhibitor of the CYP2D6 isoenzyme, for which alprazolam is not a substrate. Nonetheless, if these 2 agents are coadministered, it may be prudent to monitor the patient for excess CNS adverse effects due to alprazolam.
The use of intrathecal radiopaque contrast agents is associated with a risk of seizures. Patients should be instructed to continue using benzodiazepines during procedures or exams that require the use of intrathecal radiopaque contrast agents as abrupt discontinuation of benzodiazepines may also increase seizure risk.
Conivaptan should be used with caution with CYP3A4 substrates. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean AUC values by approximately 2-fold and 3-fold when coadministered with midazolam 1 mg IV or 2 mg PO, respectively. Use conivaptan with caution with midazolam or other oxidized benzodiazepines such as alprazolam , chlordiazepoxide , clonazepam, clorazepate , diazepam , estazolam , flurazepam , midazolam , prazepam, quazepam , and triazolam. The concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4 should be closely monitored, or the combination should be avoided. If a clinical decision is made to discontinue concomitant drugs at recommended doses, allow an appropriate time interval following the conivaptan administration before resuming these drugs.
Alprazolam is metabolized by CYP3A4. The effects of echinacea on CYP3A4 are complex. In vitro data suggest that echinacea can inhibit the CYP3A4 isoenzyme; however, the clinical significance of these data are not yet known, as some authors have reported the in vivo activity in humans to be minor. Other limited in vivo data indicate that echinacea inhibits intestinal CYP3A4, but induces hepatic CYP3A4. In 6 subjects administered echinacea plus intravenous midazolam a probe for CYP3A4), the systemic clearance of midazolam increased by 34% and the AUC decreased to 75% (90% CI 63 - 88%). However, when oral midazolam was administered, the oral availability increased leading to no change in the overall clearance of oral midazolam. The overall effects on orally administered drugs metabolized by CYP3A4 are unknown and may be negligible. However, because the effects are unknown, it may be prudent to closely monitor for changes in efficacy or toxicity when echinacea is coadministered with drugs that are metabolized by CYP3A4, including alprazolam, until more data are available.
Sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous should be used with caution in patients at a higher risk of seizures. The abrupt withdrawal of benzodiazepines may increase the risk of seizures. There have been reports of tonic-clonic seizures and/or loss of consciousness in patients who are undergoing withdrawal from benzodiazepines.
[ Last revised: 5/23/2007 10:51:00 AM ]
References
649. Fleishaker JC et al. A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 1994;46:35.
1800. US Department of Health and Human Services (DHHS) and National Institutes of Health (NIH). The Living Document: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Retrieved May 11, 2007. Available on the World Wide Web at http://www.aidsinfo.nih.gov.
1839. Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med 1996;125:940 - 41.
2974. Frye RF, Kroboth PD, Folan MM, et al. Effect of DHEA on CYP3A4-mediated metabolism of triazolam (Abstract PI-82). Clin Pharmacol Ther 2000;67:109.
3935. Dundee JW, Halliday NJ, McMurray TJ. Aspirin and probenecid pretreatment influences the potency of thiopentone and the onset of action of midazolam. Eur J Anaesthesiol 1986;3:247 - 51.
4718. Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein, with Footnotes. In: The Top 100 Drug Interactions - A guide to Patient Management. 2007 Edition. Freeland, WA: H&H Publications; 2007:159 - 175.
4760. Xanax® (alprazolam) package insert. Kalamazoo, MI: Pharmacia & Upjohn Company; 2003 Jan.
4761. Guven H, Tuncok Y, Guneri S, et al. Age-related digoxin-alprazolam interaction. Clin Pharmacol Ther. 1993;54:42 - 4.
4762. Raghavendra V, Naidu PS, Kulkarni SK. Reversal of reserpine-induced vacuous chewing movements in rats by melatonin: involvement of peripheral benzodiazepine receptors. Brain Res. 2001;904:149 - 52.
4763. McIntyre IM, Norman TR, Burrows GD, et al. Alterations to plasma melatonin and cortisol after evening alprazolam administration in humans. Chronobiol Int. 1993;10:205 - 13.
4764. Mattila MJ, Nuotto E. Caffeine and theophylline counteract diazepam effects in man. Med Biol. 1983;61:337 - 43.
4781. Wellbutrin XL® (bupropion) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2006 June.
4880. Ketek™ (telithromycin) package insert. Kansas City, MO: Aventis Pharmaceuticals; 2005 Feb.
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