Diltiazem with Cyclosporine Interaction Details

Brand Names Associated with Diltiazem

Brand Names Associated with Cyclosporine

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

Interaction Effect

An increased risk of cycloSPORINE toxicity (renal dysfunction, cholestasis, paresthesias)

Interaction Summary

Diltiazem, verapamil, and nicardipine have been shown to greatly increase cycloSPORINE blood levels. In contrast, nifedipine, isradipine and nitrendipine have been shown to have no effect on cycloSPORINE concentrations. Microemulsion formulations of cycloSPORINE have also been to interact with diltiazem . CycloSPORINE is metabolized by cytochrome P450 3A4 isoenzymes, and diltiazem is known to inhibit CYP3A4, causing elevated cycloSPORINE concentrations . It has been suggested that this interaction be used deliberately to reduce the overall cost of cycloSPORINE therapy by lowering the cycloSPORINE dose required to achieve therapeutic levels . However, one case report suggests that diltiazem may not increase cycloSPORINE levels in all patients .

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

This drug interaction may be used intentionally to reduce the effective dose of cycloSPORINE as a cost saving measure. If this interaction is not desired, use an alternate calcium channel blocker such as isradipine or nitrendipine, which have minimal impact on cycloSPORINE levels. If cycloSPORINE and diltiazem are given concomitantly, monitor circulating cycloSPORINE levels and adjust cycloSPORINE dosage as necessary. Also monitor patients for increased cycloSPORINE toxicity (renal dysfunction, cholestasis, paresthesias).

Mechanism Of Interaction

Inhibition of cytochrome P450 3A4-mediated cycloSPORINE metabolism by diltiazem

Literature Reports

A) A study involving the coadministration of cycloSPORINE and diltiazem in 14 renal transplant patients found a number of alterations in the pharmacokinetics of cycloSPORINE . Maximum concentrations were raised from a mean of 280 ng/mL to 600 ng/mL and the time to peak was prolonged from three hours to five hours. CycloSPORINE trough blood levels increased as the dose of diltiazem increased. To maintain the desired cycloSPORINE trough level, doses were reduced by an average of 60%. Peak concentrations of cycloSPORINE were not as high when diltiazem was given two hours after cycloSPORINE.

B) In two studies, the administration of diltiazem to renal transplant patients was shown to increase the serum level of cycloSPORINE . Although the precise mechanism of action of the interaction is unclear, diltiazem has been said to increase cycloSPORINE absorption, inhibit metabolism, and decrease the volume of distribution. In one study, diltiazem 60 mg given twice daily inhibited human cytochrome P450 activity. This led to an increase in cycloSPORINE activity and resulted in a reduced incidence of transplant failure or rejection episodes. The addition of diltiazem to cycloSPORINE therapy increases the trough levels of cycloSPORINE by 70% and increases the area under the 12-hour concentration-time curve by 50%. Although the cycloSPORINE-sparing effect may be desirable, it is also associated with a worsening of certain cycloSPORINE side effects .

C) The interaction between diltiazem and cycloSPORINE has great economic implications for patients receiving daily cycloSPORINE therapy. Since diltiazem increases the level of cycloSPORINE, the net effect was a significant reduction in the total dosage and drug cost of cycloSPORINE . In one study, concurrent use of diltiazem resulted in a mean cost savings of 14% over one year; rejection rate, time to rejection onset, and survival rate were not different from patients receiving cycloSPORINE alone . For patients with limited economic resources, a sizable reduction in drug cost might allow such patients to continue treatment.

D) One case report describes a 49-year-old female patient with a single lung transplant who did not experience increased cycloSPORINE levels when on diltiazem therapy. Average trough cycloSPORINE concentrations fell by 33% when diltiazem was given concurrently. When diltiazem is prescribed for its cycloSPORINE-sparing effect, the benefit must be proven and can't be assumed .

E) A pharmacokinetic study was conducted to define the dose-response relationship between cycloSPORINE and diltiazem. Eight kidney transplant recipients stabilized on cycloSPORINE therapy were started on diltiazem 10 mg daily and increased to a maximum dose of 180 mg daily. Results showed that cycloSPORINE area under the concentration-time curve (AUC) increased following diltiazem 10 mg daily, and the rate of increase slowed after the dose of diltiazem reached 60 mg daily. However, the cycloSPORINE AUC did continue to increase up to the maximum dose of diltiazem tested. These results suggest that if diltiazem is being administered for its cycloSPORINE-sparing effect, the dose needed may be less than previous thought. In a patient not on previous diltiazem therapy, the dose should be initiated at 30 mg daily and increased to 60 mg daily and then 60 mg twice daily, depending on the magnitude of response. Diltiazem should be administered concurrently with cycloSPORINE to maximize this interaction. If no benefit from diltiazem 60 mg twice daily is noted, diltiazem therapy should be discontinued, since increasing the dose further will not necessarily cause a cycloSPORINE-sparing effect .

F) Twelve adult renal transplant recipients receiving a microemulsion formulation of cycloSPORINE were assessed to determine the effect of diltiazem coadministration. All patients had a therapeutic concentration of cycloSPORINE when diltiazem 180 mg daily was initiated. The average daily dose of microemulsion cycloSPORINE decreased from 5 mg/kg to 3.9 mg/kg when diltiazem was added. Renal function remained stable during the 12-month follow-up time period .

G) In a retrospective chart review involving 103 patients receiving cycloSPORINE in capsule form, the effect of verapamil and diltiazem on cycloSPORINE levels appeared to be independent of the dosage. All patients were receiving a long-acting form of the calcium channel blocker and had been stabilized on their cycloSPORINE dose for two or more weeks. Doses of diltiazem ranging from 120 mg daily to 480 mg daily did not affect the cycloSPORINE plasma level index. These results suggest that once the dose of cycloSPORINE is adjusted when a patient is started on diltiazem, further dosage adjustments of cycloSPORINE are not necessary as long as the dose of diltiazem is only altered but not discontinued .

H) Neurotoxicity induced by a supratherapeutic blood concentration of cycloSPORINE has been reported in a 76-year-old female patient taking cycloSPORINE 100 mg twice daily for steroid-resistant aplastic anemia and thrombocytopenia. Other medications included diltiazem 180 mg daily, prednisone 10 mg three times daily, and famotidine 20 mg daily. Following 13 days of cycloSPORINE therapy, the patient was admitted to the hospital with somnolence that quickly progressed to total unresponsiveness. Her cycloSPORINE blood concentration was 903 ng/mL (normal 100 ng/mL to 300 ng/mL) on admit. She regained consciousness 36 hours after the discontinuation of cycloSPORINE, and her toxic cycloSPORINE level was attributed to a drug interaction 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.

Cyclosporine Overview

• Cyclosporine and cyclosporine (modified) are used with other medications to prevent transplant rejection (attack of the transplanted organ by the immune system of the person who received the organ) in people who have received kidney, liver, and heart transplants. Cyclosporine (modified) is also used alone or with methotrexate (Rheumatrex) to treat the symptoms of rheumatoid arthritis (arthritis caused by swelling of the lining of the joints) in patients whose symptoms were not relieved by methotrexate alone. Cyclosporine (modified) is also used to treat psoriasis (a skin disease in which red, scaly patches form on some areas of the body) in certain patients who have not been helped by other treatments. Cyclosporine and cyclosporine (modified) are in a class of medications called immunosuppressants. They work by decreasing the activity of the immune system.

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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.