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Drug Interactions between amprenavir and halofantrine

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

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Interactions between your drugs

Major

amprenavir halofantrine

Applies to: amprenavir and halofantrine

MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of halofantrine, resulting in an increased risk of QT interval prolongation and ventricular arrhythmias. The mechanism is inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of halofantrine. Halofantrine has been associated with QT interval prolongation, ventricular arrhythmias, and sudden death, even at recommended dosages.

MANAGEMENT: Caution and close monitoring is recommended if halofantrine is prescribed with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, conivaptan, idelalisib, nefazodone, cobicistat, delavirdine, and most protease inhibitors. The manufacturer recommends performing an ECG before initiating halofantrine therapy and cardiac monitoring during and for 8 to 12 hours after completion of therapy.

References

  1. Giao PT, de Vries PJ "Pharmacokinetic interactions of antimalarial agents." Clin Pharmacokinet 40 (2001): 343-73
  2. "Product Information. Halfan (halofantrine)." GlaxoSmithKline (2003):
  3. Charbit B, Becquemont L, Lepere B, Peytavin G, Funck-Bretano C "Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine." Clin Pharmacol Ther 72 (2002): 514-23
  4. Abernethy DR, Wesche DL, Barbey JT, et al. "Stereoselective halofantrine disposition and effect: concentration-related QTc prolongation." Br J Clin Pharmacol 51 (2001): 231-7
  5. Baune B, Flinois JP, Furlan V, et al. "Halofantrine metabolism in microsomes in man: major role of CYP 3A4 and CYP 3A5." J Pharm Pharmacol 51 (1999): 419-26
View all 5 references

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Drug and food interactions

Major

halofantrine food

Applies to: halofantrine

GENERALLY AVOID: Grapefruit juice may increase the plasma concentration of halofantrine. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. After administration of 500 mg with 250 mL regular-strength grapefruit juice daily for 3 days, average halofantrine AUC increased 2.8-fold and peak plasma concentrations increased 3.2-fold, compared to water, in healthy subjects (n=12). QT interval prolongation increased from an average of 17 ms with water to 31 ms with grapefruit juice. Halofantrine, even at recommended doses, can cause dose-related prolongation of the QT interval, resulting in an elevated risk of potentially fatal ventricular arrhythmias including ventricular tachycardia and torsade de pointes.

ADJUST DOSING INTERVAL: The presence of food may increase the absorption and toxicity of halofantrine. Peak plasma concentrations increased seven-fold and AUC increased three-fold in healthy subjects when halofantrine was administered with high-fat food.

MANAGEMENT: The authors of the study recommend that grapefruit juice be avoided during halofantrine therapy. The manufacturer recommends performing an ECG before initiating halofantrine therapy and cardiac monitoring during and for 8 to 12 hours after completion of therapy. Halofantrine should be taken on an empty stomach at least 1 hour before or 2 hours after food.

References

  1. Giao PT, de Vries PJ "Pharmacokinetic interactions of antimalarial agents." Clin Pharmacokinet 40 (2001): 343-73
  2. "Product Information. Halfan (halofantrine)." GlaxoSmithKline (2003):
  3. Charbit B, Becquemont L, Lepere B, Peytavin G, Funck-Bretano C "Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine." Clin Pharmacol Ther 72 (2002): 514-23
  4. Abernethy DR, Wesche DL, Barbey JT, et al. "Stereoselective halofantrine disposition and effect: concentration-related QTc prolongation." Br J Clin Pharmacol 51 (2001): 231-7
View all 4 references

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Moderate

amprenavir food

Applies to: amprenavir

GENERALLY AVOID: Administration with a high-fat meal may decrease the oral bioavailability of amprenavir. The mechanism is unknown. In healthy volunteers, consumption of a standardized high-fat meal decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amprenavir (1200 mg single oral dose) by 36% and 21%, respectively, compared to administration in the fasted state. The time to reach Cmax (Tmax) was increased 44% following a high-fat meal.

Grapefruit juice does not appear to significantly affect the pharmacokinetics of amprenavir. In 12 healthy volunteers, administration with grapefruit juice (200 mL) decreased the mean peak plasma concentration (Cmax) of amprenavir (1200 mg single oral dose) by 22% compared to water. The median time to reach Cmax (Tmax) was prolonged from 0.75 to 1.13 hours. These pharmacokinetic changes are not thought to be clinically significant, since antiretroviral response is more closely associated with systemic exposure (AUC) and trough plasma concentration (Cmin), which were not affected in the study.

MANAGEMENT: Amprenavir may be taken with or without food, but should not be taken with a high-fat meal.

References

  1. "Product Information. Agenerase (amprenavir)." Glaxo Wellcome PROD (2001):
  2. Demarles D, Gillotin C, Bonaventure-Paci S, Vincent I, Fosse S, Taburet AM "Single-dose pharmacokinetics of amprenavir coadministered with grapefruit juice." Antimicrob Agents Chemother 46 (2002): 1589-1590

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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

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