Clarithromycin with Midazolam Interaction Details

Brand Names Associated with Clarithromycin

Brand Names Associated with Midazolam

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 08, 2023

Interaction Effect

Increased triazolobenzodiazepine exposure resulting in increased and prolonged sedation

Interaction Summary

Coadministration of clarithromycin (strong CYP3A4 inhibitor) and a triazolobenzodiazepine (CYP3A4 substrates: alprazolam, estazolam, midazolam, triazolam) may result in increased triazolobenzodiazepine exposure. In 16 volunteers, clarithromycin produced a 64% decrease in systemic clearance and a 86% decrease in oral clearance of IV and oral midazolam . In another study in 12 healthy volunteers coadministered clarithromycin and triazolam, the Cmax of triazolam increased 2-fold, t(1/2) increased 3- to 4-fold, and AUC increased 4- to 5-fold . Monitor patients for increased and prolonged sedation when used concomitantly.

Severity

Major

Onset

Rapid

Evidence

Established

How To Manage Interaction

Coadministration of clarithromycin (strong CYP3A4 inhibitor) and a triazolobenzodiazepine (CYP3A4 substrates: alprazolam, estazolam, midazolam, and triazolam) may result in increased triazolobenzodiazepine exposure. Monitor patient for increased and prolonged sedation.

Mechanism Of Interaction

Inhibition of CYP3A4-mediated triazolobenzodiazepine metabolism by clarithromycin

Literature Reports

A) A study comparing the pharmacokinetics of triazolam given concurrently with macrolide antibiotics determined that erythromycin and clarithromycin increased triazolam Cmax 2-fold in 12 healthy volunteers. In addition, t(1/2) was increased 3- to 4-fold, and the AUC was increased 4- to 5-fold. Apparent oral clearance was decreased significantly as well. Azithromycin was also included in the study, but demonstrated no significant effects on pharmacokinetics of triazolam .

B) Patients (N=16) received simultaneous doses of IV midazolam 0.05 mg/kg over 30 minutes and oral midazolam 4 mg on day 1 of a fixed order study design. Clarithromycin 500 mg twice daily orally was started on day 2 and continued for seven days. IV and oral doses of midazolam were repeated 2 hours after the final dose of clarithromycin on day 8. The midazolam AUC during the IV dosing increased from a control value of 127 to 349 mcg/L/hr following clarithromycin pretreatment. IV midazolam clearance decreased from 27.8 to 10.1 L/hr while the t(1/2) increased from 3.8 to 10.1 hours. Following oral midazolam dosing, the AUC increased from 48 to 336 mcg/L/hr and the oral clearance decreased from 103 to 15 L/hr in the presence of clarithromycin. In addition, sleep time increased from 45 minutes during control to 97 minutes following clarithromycin therapy .

C) An 8-year-old boy undergoing adenoidectomy was premedicated with oral midazolam 0.5 mg/kg and oral atropine 0.03 mg/kg, followed in 1 hour by erythromycin 400 mg IV. The patient lost consciousness 40 minutes later after 200 mg had been infused; other vital signs remained normal, and he regained consciousness after 45 minutes. At 170 minutes post-medication, his midazolam plasma concentration was 134 nanograms/mL. Other children (n=6) who were similarly premedicated (midazolam 0.5 mg/kg and atropine 0.03 mg/kg) but did not receive erythromycin had a mean midazolam level of 73 nanograms/mL .

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.

Midazolam Overview

• Midazolam is given to children before medical procedures or before anesthesia for surgery to cause drowsiness, relieve anxiety, and prevent any memory of the event. Midazolam is in a class of medications called benzodiazepines. It works by slowing activity in the brain to allow relaxation and sleep.

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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.