Skip to main content

Drug Interactions between levoketoconazole and Tikosyn

This report displays the potential drug interactions for the following 2 drugs:

Edit list (add/remove drugs)

Interactions between your drugs

Major

dofetilide levoketoconazole

Applies to: Tikosyn (dofetilide) and levoketoconazole

CONTRAINDICATED: Coadministration with inhibitors of organic cation transporter 2 (OCT-2) may increase the plasma concentrations of dofetilide, which is primarily eliminated by glomerular filtration and active tubular secretion via OCT-2, with minor contribution from CYP450 3A4-mediated metabolism. In 20 healthy male subjects given a 500 mcg oral dose of dofetilide on day 2 of treatment with cimetidine (an OCT-2 and weak CYP450 3A4 inhibitor) 100 mg or 400 mg twice daily for 4 days, dofetilide peak plasma concentration (Cmax) increased by 11% and 29%, respectively, while systemic exposure (AUC) increased by 11% and 48%, respectively, compared to dofetilide plus placebo. Renal clearance of dofetilide decreased by 13% and 33%, respectively, and nonrenal clearance decreased by 5% and 21%, respectively. In addition, the mean maximum change in QTc interval from baseline increased by 22% and 33%, respectively. In another study with 24 healthy volunteers, coadministration of dofetilide 500 mcg twice daily with cimetidine 400 mg twice daily for 7 days increased Cmax and AUC of dofetilide by 50% and 58%, respectively. However, QTc interval was not significantly altered compared to dofetilide alone. In a similar study with 12 healthy male volunteers, dofetilide 500 mcg twice daily given with verapamil (an OCT-2 and moderate CYP450 3A4 inhibitor) 80 mg three times daily for 3 days resulted in a 43% increase in Cmax and 26% increase in AUC (0 to 4 hours) of dofetilide, which corresponded to a 6 msec increase in mean maximum change in QTc from baseline relative to dofetilide alone. In an analysis of patient data from the dofetilide clinical development program, concomitant administration with verapamil was also found to be associated with a higher occurrence of torsade de pointes according to the manufacturer. Dofetilide 500 mcg twice daily given with ketoconazole (an OCT-2 and potent CYP450 3A4 inhibitor) 400 mg daily for 7 days increased dofetilide Cmax and AUC by 53% and 41% respectively, in males, and 97% and 69%, respectively, in females. The same dosage of dofetilide coadministered with trimethoprim (an OCT-2 inhibitor) 160 mg and sulfamethoxazole 800 mg twice daily for 4 days increased dofetilide Cmax by 93% and AUC by 103%.

MANAGEMENT: Given the risk of concentration-dependent QT prolongation, concomitant use of dofetilide with OCT-2 inhibitors is considered contraindicated.

References

  1. (2001) "Product Information. Tikosyn (dofetilide)." Pfizer U.S. Pharmaceuticals
  2. Abel S, Nichols DJ, Brearley CJ, Eve MD (2000) "Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide." Br J Clin Pharmacol, 49, p. 64-71
  3. Johnson BF, Cheng SL, Venitz J (2001) "Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic." J Clin Pharmacol, 41, p. 1248-56

Switch to consumer interaction data

Drug and food interactions

Moderate

levoketoconazole food

Applies to: levoketoconazole

GENERALLY AVOID: Excessive use of alcohol or products containing alcohol together with ketoconazole or levoketoconazole may potentiate the risk of liver injury. Serious hepatotoxicity has been reported with levoketoconazole. Hepatotoxicity requiring liver transplantation has been reported with the use of oral ketoconazole, of which levoketoconazole is an enantiomer. Some patients had no obvious risk factors for liver disease. In addition, use of alcohol or products containing alcohol during ketoconazole or levoketoconazole therapy may result in a disulfiram-like reaction in some patients. Symptoms of disulfiram-like reaction include flushing, rash, peripheral edema, nausea, and headache.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of ketoconazole or levoketoconazole. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Inhibition of hepatic CYP450 3A4 may also contribute. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

When administered to healthy volunteers with a high-fat meal (875 calories; 62% fat), levoketoconazole systemic exposure (AUC) increased by 30% while peak plasma concentration (Cmax) did not change and the time to reach Cmax (Tmax) was delayed from 2 to 4 hours, compared to fasted conditions.

MANAGEMENT: Levoketoconazole may be administered with or without food. Excessive consumption of alcohol should generally be avoided during ketoconazole or levoketoconazole therapy. Patients should preferably avoid or limit consumption of grapefruit, grapefruit juice, or any supplement containing grapefruit extract during ketoconazole or levoketoconazole therapy. Patients receiving ketoconazole or levoketoconazole should be instructed to contact their doctor immediately if they experience swelling, skin rash, itching, loss of appetite, fatigue, nausea, vomiting, abdominal pain, dark colored urine, light colored stools, and/or yellowing of the skin or eyes, as these may be signs and symptoms of liver damage.

References

  1. (2019) "Product Information. Ketoconazole (ketoconazole)." Mylan Pharmaceuticals Inc
  2. (2022) "Product Information. Recorlev (levoketoconazole)." Xeris Pharmaceuticals Inc
  3. Auchus R, Pivonello R, Fleseriu M, et al. (2022) Levoketoconazole: a novel treatment for endogenous Cushing's syndrome. https://www.tandfonline.com/doi/pdf/10.1080/17446651.2021.1945440
  4. (2021) "Product Information. Ketoconazole (ketoconazole)." Burel Pharmaceuticals Inc
View all 4 references

Switch to consumer interaction data

Minor

dofetilide food

Applies to: Tikosyn (dofetilide)

In vitro data suggest that grapefruit juice may inhibit the CYP450 3A4 first-pass metabolism of dofetilide. Decreased first-pass metabolism may increase dofetilide concentrations and increase the risk of QT interval prolongation and arrhythmias. The clinical significance is unknown, since dofetilide has a high oral bioavailability and a low affinity for CYP450 3A4. The manufacturer recommends caution.

References

  1. (2001) "Product Information. Tikosyn (dofetilide)." Pfizer U.S. Pharmaceuticals

Switch to consumer interaction data

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

See also

Report options

Loading...
QR code containing a link to this page

Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer