Alprazolam with Clarithromycin Interaction Details

Brand Names Associated with Alprazolam

Brand Names Associated with Clarithromycin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Feb 27, 2024

Interaction Effect

Increased alprazolam exposure

Interaction Summary

Concomitant use of alprazolam (CYP3A4 substrate) with a strong CYP3A4 inhibitor (with the exception of ritonavir) is contraindicated due to a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions. Coadministration of alprazolam separately with strong CYP3A4 inhibitors ketoconazole, itraconazole, and nefazodone increased alprazolam AUC by 3.98-fold, 2.66-fold, and 1.98-fold, respectively[1][2].

Severity

Contraindicated

Onset

Unspecified

Evidence

Established

How To Manage Interaction

Concomitant use of alprazolam (CYP3A4 substrate) with a strong CYP3A4 inhibitor (with the exception of ritonavir) is contraindicated due to a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions[1][2].

Mechanism Of Interaction

Inhibition of CYP3A4-mediated metabolism of alprazolam

Literature Reports

A) In in-vivo drug interactions studies, concomitant use of alprazolam with strong CYP3A4 inhibitors increased alprazolam AUC as follows: ketoconazole by 3.98-fold, itraconazole by 2.66-fold, and nefazodone by 1.98-fold [1][2].

B) In a pharmacokinetic study in healthy subjects or chronic hepatitis C patients (n=17), concomitant administration of a single-dose of alprazolam 0.5 mg and telaprevir 750 mg every 8 hours for 10 days resulted in increased in alprazolam AUC (ratio estimate with telaprevir to without telaprevir), 1.35 (90% confidence interval, 1.23 to 1.49) [3].

C) Healthy male volunteers (n=7) participated in a single-dose, 5-way crossover study to determine the magnitude and clinical consequence of the interaction of ketoconazole with alprazolam. The 5 treatment phases consisted of placebo and alprazolam 1 mg, ketoconazole 200 mg and alprazolam 1 mg, and ketoconazole 200 mg and placebo. The elimination t(1/2) of alprazolam increased from 15.2 hours to 59 hours during ketoconazole coadministration, while the total AUC of alprazolam increased from 237 nanogram/mL x hr to 944 nanogram/mL x hr. The oral clearance of alprazolam decreased from 86 mL/min to 27 mL/min. However, the Cmax was not significantly altered by the presence of ketoconazole. Pharmacodynamically, ketoconazole enhanced the benzodiazepine effects of alprazolam but statistical significance was not always achieved due to the degree of variability and the small sample size [4].

D) Itraconazole significantly increased plasma concentrations of alprazolam via its inhibitory effects on alprazolam metabolism and depressed psychomotor function during a randomized crossover study involving healthy volunteers (N=10). Each study participant received itraconazole 200 mg daily or matching placebo for 6 days while ingesting a single oral dose of alprazolam 0.8 mg on day 4. Itraconazole increased the alprazolam AUC from 252 nanogram/mL x hr to 671 nanogram/mL x hr and decreased the oral clearance from 0.89 mL/min/kg to 0.35 mL/min/kg. Alprazolam t(1/2) was also extended from 15.7 hours to 40.3 hours. No significant differences were noted in the alprazolam Cmax or Tmax when itraconazole was present. Measurements of psychomotor function were evaluated by the digit symbol substitution test (DSST), the visual analog scale (VAS), and the Udvalg for kliniske undersogelser (UKU) scales. Itraconazole decreased the AUC (0 to 48 hours) of the DSST and increased the "spacy" item of the VAS and the "sleepiness" item of the UKU [5].

E) Coadministration of alprazolam with nefazodone (strong CYP3A4 inhibitor) was studied in a randomized pharmacokinetic study (N=48). Subjects received either placebo twice daily, alprazolam 1 mg twice daily, nefazodone 200 mg twice daily, or a combination of alprazolam 1 mg and nefazodone 200 mg twice daily for 7 days. Nefazodone significantly increased alprazolam Cmax approximately 2-fold while the Cmax of the alpha-hydroxy alprazolam metabolite decreased by 40% [6].

F) Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect Cmax of alprazolam. The elimination t(1/2) was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax were reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination t(1/2) of alprazolam was not significantly changed [1][2].

References

1 ) Product Information: XANAX(R) oral tablets, alprazolam oral tablets. Pharmacia & Upjohn Co (per FDA), New York, NY, 2021.

2 ) Product Information: Xanax(R) XR oral extended-release tablets, alprazolam oral extended-release tablets. Pharmacia & Upjohn Co (per FDA), New York, NY, 2021.

3 ) Product Information: INCIVEK(TM) film coated oral tablets, telaprevir film coated oral tablets. Vertex Pharmaceuticals Incorporated, Cambridge, MA, 2011.

4 ) Greenblatt DJ, Wright CE, von Moltke LL, et al: Ketoconazole inhibition of triazolam and alprazolam clearance: differential kinetic and dynamic consequences. Clin Pharmacol Ther 1998; 64:237-247.

5 ) Yasui N, Kondo T, Otani K, et al: Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology 1998; 139:269-273.

6 ) Greene DS, Salazar DE, Dockens RC, et al: Coadministration of nefazodone and benzodiazepines: III. A pharmacokinetic interaction study with alprazolam. J Clin Psychopharmacol 1995; 15:399-408.

Alprazolam Overview

• Alprazolam is used to treat anxiety disorders and panic disorder (sudden, unexpected attacks of extreme fear and worry about these attacks). Alprazolam is in a class of medications called benzodiazepines. It works by decreasing abnormal excitement in the brain.

Clarithromycin Overview

• Clarithromycin is used to treat certain bacterial infections, such as pneumonia (a lung infection), bronchitis (infection of the tubes leading to the lungs), and infections of the ears, sinuses, skin, and throat. It also is used to treat and prevent disseminated Mycobacterium avium complex (MAC) infection [a type of lung infection that often affects people with human immunodeficiency virus (HIV)]. It is used in combination with other medications to eliminate H. pylori, a bacterium that causes ulcers. Clarithromycin is in a class of medications called macrolide antibiotics. It works by stopping the growth of bacteria.

• Antibiotics such as clarithromycin will not work for colds, flu, or other viral infections. Taking antibiotics when they are not needed increases your risk of getting an infection later that resists antibiotic treatment.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.