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Interactions between Agenerase and Halofantrine

1 drug interaction and 11 additional warnings found for the following 2 drugs:

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Drug interactions

Major drug interactions

Major:

amprenavir halofantrine

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

Food/lifestyle interactions

Major food/lifestyle interactions

Major:

halofantrine Food/Lifestyle

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

Moderate food/lifestyle interactions

Moderate:

amprenavir Food/Lifestyle

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

Disease interactions

9 potential interactions Applies to: 8 conditions, including Nephrolithiasis, Diabetes Mellitus, Liver Disease, Vitamin K Deficiency, and Dehydration.

Abnormal Glucose Tolerance

Moderate:

Agenerase

The amprenavir in Agenerase has a moderate potential interaction with Abnormal Glucose Tolerance.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperglycemia, and some cases of diabetic ketoacidosis have been reported during postmarketing surveillance in HIV-infected patients treated with protease inhibitors. Some patients required either initiation or dosage adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, hyperglycemia persisted despite discontinuation of protease inhibitor therapy. A causal relationship has not been established between protease inhibitor therapy and these events. Monitoring patients for hyperglycemia, new onset diabetes mellitus, or exacerbation of diabetes mellitus should be considered during protease inhibitor therapy.

Dehydration

Moderate:

Agenerase

The amprenavir in Agenerase has a moderate potential interaction with Dehydration.

Cases of nephrolithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving amprenavir or fosamprenavir therapy. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. Therapy with amprenavir or fosamprenavir should be administered cautiously in patients with a current or past history of nephrolithiasis. Adequate hydration is recommended. Those who are dehydrated may be at increased risk and should be encouraged to consume additional amounts of liquid or given intravenous fluids if necessary. Patients should be instructed to seek medical attention if they experience potential signs and symptoms of urolithiasis such as flank pain, hematuria, dysuria, and urinary urgency. Temporary interruption or discontinuation of therapy may be required.

Diabetes Mellitus

Moderate:

Agenerase

The amprenavir in Agenerase has a moderate potential interaction with Diabetes Mellitus.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperglycemia, and some cases of diabetic ketoacidosis have been reported during postmarketing surveillance in HIV-infected patients treated with protease inhibitors. Some patients required either initiation or dosage adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, hyperglycemia persisted despite discontinuation of protease inhibitor therapy. A causal relationship has not been established between protease inhibitor therapy and these events. Monitoring patients for hyperglycemia, new onset diabetes mellitus, or exacerbation of diabetes mellitus should be considered during protease inhibitor therapy.

History, Nephrolithiasis

Moderate:

Agenerase

The amprenavir in Agenerase has a moderate potential interaction with History, Nephrolithiasis.

Cases of nephrolithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving amprenavir or fosamprenavir therapy. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. Therapy with amprenavir or fosamprenavir should be administered cautiously in patients with a current or past history of nephrolithiasis. Adequate hydration is recommended. Those who are dehydrated may be at increased risk and should be encouraged to consume additional amounts of liquid or given intravenous fluids if necessary. Patients should be instructed to seek medical attention if they experience potential signs and symptoms of urolithiasis such as flank pain, hematuria, dysuria, and urinary urgency. Temporary interruption or discontinuation of therapy may be required.

Liver Disease

Major:

Agenerase

The amprenavir in Agenerase has a major potential interaction with Liver Disease.

The use of amprenavir oral solution is contraindicated in patients with renal and/or hepatic failure due to the large amount of excipient propylene glycol in the formulation. In general, use of the solution should be limited to patients in whom the capsule formulation or other protease inhibitors are not feasible options. Caution is advised in patients with renal or hepatic impairment due to increased risk of propylene glycol-associated adverse events. All patients receiving the oral solution should be monitored for signs of propylene glycol toxicity including seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis.

Moderate:

Agenerase

The amprenavir in Agenerase has a moderate potential interaction with Liver Disease.

Amprenavir is primarily metabolized by the liver. Patients with liver disease may be at greater risk for adverse effects from amprenavir due to decreased drug clearance. Therapy with amprenavir should be administered cautiously in patients with moderate or severe hepatic impairment, and the dosage should be reduced as follows: 450 mg (three 150 mg capsules) or 513 mg (34 mL oral solution) orally twice a day for Child-Pugh score 5 to 8; 300 mg (two 150 mg capsules) or 342 mg (23 mL oral solution) orally twice a day for Child-Pugh score 9 to 12.

Nephrolithiasis

Moderate:

Agenerase

The amprenavir in Agenerase has a moderate potential interaction with Nephrolithiasis.

Cases of nephrolithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving amprenavir or fosamprenavir therapy. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. Therapy with amprenavir or fosamprenavir should be administered cautiously in patients with a current or past history of nephrolithiasis. Adequate hydration is recommended. Those who are dehydrated may be at increased risk and should be encouraged to consume additional amounts of liquid or given intravenous fluids if necessary. Patients should be instructed to seek medical attention if they experience potential signs and symptoms of urolithiasis such as flank pain, hematuria, dysuria, and urinary urgency. Temporary interruption or discontinuation of therapy may be required.

Renal Dysfunction

Major:

Agenerase

The amprenavir in Agenerase has a major potential interaction with Renal Dysfunction.

The use of amprenavir oral solution is contraindicated in patients with renal and/or hepatic failure due to the large amount of excipient propylene glycol in the formulation. In general, use of the solution should be limited to patients in whom the capsule formulation or other protease inhibitors are not feasible options. Caution is advised in patients with renal or hepatic impairment due to increased risk of propylene glycol-associated adverse events. All patients receiving the oral solution should be monitored for signs of propylene glycol toxicity including seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis.

Vitamin K Deficiency

Minor:

Agenerase

The amprenavir in Agenerase has a minor potential interaction with Vitamin K Deficiency.

Formulations of Agenerase (brand of amprenavir) provide high daily doses of vitamin E exceeding the Reference Daily Intake (adults 30 Intl units, pediatrics approximately 10 Intl units). The effects of long-term, high-dose vitamin E administration in humans are unclear. High levels of vitamin E may exacerbate the blood coagulation defect of vitamin K deficiency caused by anticoagulant therapy or malabsorption.

More resources

Agenerase

A total of 570 drugs are known to interact with Agenerase.

halofantrine

A total of 361 drugs are known to interact with halofantrine.

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.