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Drug Interactions between ketoconazole and naloxegol

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

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Interactions between your drugs

Major

ketoconazole naloxegol

Applies to: ketoconazole and naloxegol

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of naloxegol, which is primarily metabolized by the isoenzyme. When a single 25 mg dose of naloxegol was administered during multiple dosing of 400 mg once daily ketoconazole, a potent CYP450 3A4 inhibitor, naloxegol peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 9.6- and 12.9-fold, respectively. Increased exposure to naloxegol may precipitate opioid withdrawal symptoms such as hyperhidrosis, lacrimation, rhinorrhea, chills, diarrhea, abdominal pain, anxiety, insomnia, irritability, restlessness, and yawning.

MANAGEMENT: Concomitant use of naloxegol with potent CYP450 3A4 inhibitors such as clarithromycin, telithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, idelalisib, nefazodone, cobicistat, delavirdine, and protease inhibitors is considered contraindicated. Some authorities consider concomitant administration of naloxegol and itraconazole to be contraindicated during and for 2 weeks after treatment with itraconazole.

References

  1. (2002) "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  3. Cerner Multum, Inc. "Australian Product Information."
  4. (2014) "Product Information. Movantik (naloxegol)." Astra-Zeneca Pharmaceuticals
View all 4 references

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Drug and food interactions

Major

naloxegol food

Applies to: naloxegol

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of naloxegol. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In pharmacokinetic studies, naloxegol systemic exposure (AUC) was increased approximately 3.5-fold by the moderate CYP450 3A4 inhibitor diltiazem and nearly 13-fold by the potent inhibitor ketoconazole. The interaction has not been studied with grapefruit juice. 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. Increased exposure to naloxegol may precipitate opioid withdrawal symptoms such as hyperhidrosis, lacrimation, rhinorrhea, chills, diarrhea, abdominal pain, anxiety, insomnia, irritability, restlessness, and yawning.

ADJUST DOSING INTERVAL: Food may increase the rate and extent of naloxegol absorption. When administered with a high-fat meal, naloxegol peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 30% and 45%, respectively. In clinical trials, naloxegol was given on an empty stomach approximately 1 hour prior to the first meal in the morning.

MANAGEMENT: Patients treated with naloxegol should avoid consumption of grapefruit and grapefruit juice. Naloxegol should be taken on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours after the meal.

References

  1. (2014) "Product Information. Movantik (naloxegol)." Astra-Zeneca Pharmaceuticals

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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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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.


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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

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