Diltiazem with Midazolam Interaction Details

Brand Names Associated with Diltiazem

Brand Names Associated with Midazolam

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 13, 2023

Interaction Effect

Increased/prolonged sedation

Interaction Summary

A randomized, double-blind, placebo-controlled study demonstrated that both diltiazem and verapamil significantly increased the AUC, peak plasma concentration, and elimination half-life of midazolam compared to placebo. Sedation was also more profound and prolonged with concurrent use of the calcium antagonist compared to placebo. Another study also indicated that diltiazem prolongs midazolam half-life and increases the AUC . Diltiazem is known to inhibit the cytochrome P450 3A4 enzyme system, and midazolam metabolism is mediated through CYP450 3A4. When given concurrently, prolonged and intensified sedation may occur due to a reduction in the plasma clearance of midazolam .

Severity

Moderate

Onset

Rapid

Evidence

Probable

How To Manage Interaction

Midazolam dose adjustments may be necessary in patients receiving concomitant diltiazem and midazolam. Monitor for signs of midazolam toxicity (eg, sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma).

Mechanism Of Interaction

Inhibition by diltiazem of cytochrome P450 3A-mediated metabolism of midazolam

Literature Reports

A) When diltiazem (60 mg three times daily) and midazolam were coadministered to nine subjects in a three-way crossover study, the half-life of midazolam increased from 5 to 7 hours .

B) A double-blind, randomized, placebo-controlled study of 30 patients undergoing coronary artery bypass surgery was conducted to determine the effects of diltiazem on midazolam and alfentanil pharmacokinetics. Two hours prior to surgery, fifteen patients received diltiazem 60 mg orally while fifteen patients received placebo. Diltiazem (0.1 mg/kg/hr) or placebo (saline) infusions were initiated prior to anesthesia and continued until the next morning. Anesthesia was induced with midazolam 0.1 mg/kg, alfentanil 50 mcg/kg, and propofol. Continuous infusions of midazolam 1 mcg/kg/min and alfentanil 1 mcg/kg/min were started at the beginning of induction and were maintained until skin closure. From the induction time to 23 hours post-operatively, diltiazem increased the area under the concentration-time curve (AUC) of midazolam by 15% and alfentanil by 24%. When evaluating the data from the end of surgery to 23 hours post-op, the AUC of midazolam and alfentanil was increased by 24% and 40%, respectively. The mean half-life of midazolam and alfentanil was increased by 43% and 50%, respectively, when compared to the placebo group. In patients receiving diltiazem, extubation was 2.5 hours later on average than the placebo controls. These results indicate that diltiazem inhibits the cytochrome P450 3A enzymes which are responsible for midazolam and alfentanil metabolism .

C) Increased clinical effects, such as prolonged sedation, can occur with coadministration of midazolam and diltiazem. Concomitant administration of midazolam and diltiazem may result in an increase in area under the curve (AUC) of midazolam by 3-4 fold and maximum plasma concentration by 2-fold, when compared to placebo. An increase in elimination half-life of midazolam by 1.5-2.5 fold has also been shown to occur during coadministration with diltiazem .

Diltiazem Overview

• Diltiazem is used to treat high blood pressure and to control angina (chest pain). Diltiazem is in a class of medications called calcium-channel blockers. It works by relaxing the blood vessels so the heart does not have to pump as hard. It also increases the supply of blood and oxygen to the heart.

• High blood pressure is a common condition, and when not treated it can cause damage to the brain, heart, blood vessels, kidneys, and other parts of the body. Damage to these organs may cause heart disease, a heart attack, heart failure, stroke, kidney failure, loss of vision, and other problems. In addition to taking medication, making lifestyle changes will also help to control your blood pressure. These changes include eating a diet that is low in fat and salt, maintaining a healthy weight, exercising at least 30 minutes most days, not smoking, and using alcohol in moderation.

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.