Skip to main content

Drug Interactions between levoketoconazole and rifabutin

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

Edit list (add/remove drugs)

Interactions between your drugs

Major

rifabutin levoketoconazole

Applies to: rifabutin and levoketoconazole

GENERALLY AVOID: Coadministration with rifamycins may significantly decrease the plasma concentrations of itraconazole, levoketoconazole and ketoconazole. The proposed mechanism is accelerated clearance of the azoles due to induction of CYP450 3A4-mediated metabolism by rifamycins. Pharmacokinetic studies and case reports have demonstrated that rifampin can reduce itraconazole and ketoconazole systemic exposure by at least 80% and sometimes even to undetectable levels. Treatment failure has been reported. Rifabutin, a less potent CYP450 3A4 inducer, has been found in one study to decrease itraconazole systemic exposure by 74%. Conversely, itraconazole, levoketoconazole and ketoconazole are potent inhibitors of CYP450 3A4 and may substantially increase the plasma levels of rifabutin and its pharmacologically active metabolite, 25-O-desacetylrifabutin. This may increase the risk of adverse effects such as leukopenia, uveitis, arthralgia, joint disorder, and skin discoloration. By contrast, itraconazole reportedly has no effect on rifampin pharmacokinetics. Ketoconazole has been found in some studies to decrease rifampin plasma levels, but interaction is apparently minimized when they are given 12 hours apart.

MANAGEMENT: The manufacturers recommend that itraconazole and ketoconazole not be used concomitantly or within 2 weeks of treatment with rifamycins, unless the benefits outweigh the risk of potentially reduced antifungal efficacy. If coadministration is required, the antifungal activity should be monitored and the azole dosage increased as necessary. With rifabutin, however, consideration should also be given to the potential for increased risk of rifabutin toxicity, particularly when the azole dosage is increased. Therapeutic drug monitoring for rifabutin is therefore advisable, and the dosage adjusted if needed. In addition, a complete blood count should be performed at least weekly and as clinically indicated to monitor for development of neutropenia. Levoketoconazole manufacturer recommends avoiding its concomitant use or within 2 weeks of treatment with rifamycins.

References (19)
  1. Venkatesan K (1992) "Pharmacokinetic drug interactions with rifampicin." Clin Pharmacokinet, 22, p. 47-65
  2. Borcherding SM, Baciewicz AM, Self TH (1992) "Update on rifampin drug interactions." Arch Intern Med, 152, p. 711-6
  3. Abadie-Kemmerly S, Pankey GA, Dalvisio JR (1988) "Failure of ketoconazole treatment of blastomyces dermatidis due to interaction of isoniazid and rifampin." Ann Intern Med, 109, p. 844-5
  4. Blomley M, Teare E, De Belder A, et al. (1990) "Itraconazole and anti-tuberculosis drugs." Lancet, 336, p. 1255
  5. Brass C, Galgiani JN, Blaschke TF, et al. (1982) "Disposition of ketoconazole, an oral antifungal, in humans." Antimicrob Agents Chemother, 21, p. 151-8
  6. Engelhard D, Stutman HR, Marks MI (1984) "Interaction of ketoconazole with rifampin and isoniazid." N Engl J Med, 311, p. 1681-3
  7. Tucker RM, Denning DW, Hanson LH, et al. (1992) "Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations." Clin Infect Dis, 14, p. 165-74
  8. Doble N, Shaw R, Rowland-Hill C, et al. (1988) "Pharmacokinetic study of the interaction between rifampicin and ketoconazole." J Antimicrob Chemother, 21, p. 633-5
  9. (2001) "Product Information. Nizoral (ketoconazole)." Janssen Pharmaceuticals, 1992
  10. Meunier F (1986) "Serum fungistatic and fungicidal activity in volunteers receiving antifungal agents." Eur J Clin Microbiol, 5, p. 103-9
  11. (2002) "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals
  12. Schaferkorting M (1993) "Pharmacokinetic optimisation of oral antifungal therapy." Clin Pharmacokinet, 25, p. 329-41
  13. Drayton J, Dickinson G, Rinaldi MG (1994) "Coadministration of rifampin and itraconazole leads to undetectable levels of serum itraconazole." Clin Infect Dis, 18, p. 266
  14. Lefort A, Launay O, Carbon C (1996) "Uveitis associated with rifabutin prophylaxis and itraconazole therapy." Ann Intern Med, 125, p. 939-40
  15. Strayhorn VA, Baciewicz AM, Self TH (1997) "Update on rifampin drug interactions, III." Arch Intern Med, 157, p. 2453-8
  16. Jaruratanasirikul S, Sriwiriyajan S (1998) "Effect of rifampicin on the pharmacokinetics of itraconazole in normal volunteers and AIDS patients." Eur J Clin Pharmacol, 54, p. 155-8
  17. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  18. Pharmaceutical Society of Australia (2006) APPGuide online. Australian prescription products guide online. http://www.appco.com.au/appguide/default.asp
  19. Cerner Multum, Inc. "Australian Product Information."

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 (4)
  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

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