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Drug Interactions between Daliresp and ketoconazole

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

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Interactions between your drugs

Moderate

ketoconazole roflumilast

Applies to: ketoconazole and Daliresp (roflumilast)

MONITOR: Coadministration with ketoconazole may increase the systemic exposure to roflumilast and its pharmacologically active N-oxide metabolite. The proposed mechanism is ketoconazole inhibition of CYP450 3A4, the isoenzyme that partially metabolizes both roflumilast and the metabolite. In 26 healthy volunteers, administration of roflumilast 500 mcg orally once daily for 11 days in combination with a single 200 mg dose of ketoconazole on day 11 resulted in a 34% increase in roflumilast systemic exposure (AUC) and no change in peak plasma concentration (Cmax) compared to administration of roflumilast alone. Single-dose ketoconazole also reduced the Cmax and AUC of roflumilast N-oxide by 20% and 12%, respectively. When a single 500 mcg oral dose of roflumilast was administered in combination with repeated doses of ketoconazole (200 mg twice daily for 13 days) to 16 healthy volunteers, Cmax and AUC of roflumilast increased by 23% and 99%, respectively, while Cmax of roflumilast N-oxide decreased by 38% and AUC increased by 3% (not significant). Total phosphodiesterase 4 inhibitory activity (i.e., combined effect of both roflumilast and roflumilast N-oxide) increased by 9% in association with these changes. No clinically relevant adverse events were observed during the study.

MANAGEMENT: Caution is advised when roflumilast is used in combination with ketoconazole. Treatment with roflumilast should be re-evaluated if an interaction is suspected and persistent intolerability occurs. Patients should be advised to contact their doctor if they experience increased frequency and/or severity of side effects such as diarrhea, nausea, abdominal pain, weight loss, headache, insomnia, depression, and anxiety.

References

  1. Lahu G, Huennemeyer A, von Richter O, et al. (2008) "Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-Oxide." J Clin Pharmacol, 48, p. 1339-49
  2. (2011) "Product Information. Daxas (roflumilast)." Nycomed Inc
  3. (2011) "Product Information. Daliresp (roflumilast)." Astra-Zeneca Pharmaceuticals

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Drug and food interactions

Moderate

ketoconazole food

Applies to: ketoconazole

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

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Minor

roflumilast food

Applies to: Daliresp (roflumilast)

Food intake does not affect the total exposure to roflumilast and its pharmacologically active N-oxide metabolite, but delays the time to maximum concentration (Tmax) of roflumilast by one hour and reduces its peak plasma concentration (Cmax) by approximately 40%. The Tmax and Cmax of
roflumilast N-oxide are unaffected. Roflumilast may be taken with or without food.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. (2011) "Product Information. Daxas (roflumilast)." Nycomed Inc
  3. (2011) "Product Information. Daliresp (roflumilast)." Astra-Zeneca Pharmaceuticals

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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

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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

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