Drug Interactions between artemether / lumefantrine and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil
This report displays the potential drug interactions for the following 2 drugs:
- artemether/lumefantrine
- emtricitabine/lopinavir/ritonavir/tenofovir disoproxil
Interactions between your drugs
ritonavir artemether
Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and artemether / lumefantrine
MONITOR CLOSELY: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of artemether and lumefantrine, both of which are primarily metabolized by the isoenzyme. In 13 healthy subjects, concurrent oral administration of the potent inhibitor ketoconazole (400 mg on day 1, followed by 200 mg for 4 days) and a single dose of artemether-lumefantrine (80 mg-480 mg) with food resulted in modest increases in systemic exposure (AUC) to artemether (2.3-fold), its active metabolite dihydroartemisinin (1.5-fold), and lumefantrine (1.6-fold). High plasma levels of artemether and lumefantrine may theoretically increase the risk of QT interval prolongation and ventricular arrhythmias including torsade de pointes. In clinical trials, asymptomatic prolongation of the Fridericia-corrected QT interval (QTcF) by more than 30 msec from baseline was reported in approximately one-third of patients treated with artemether-lumefantrine, and prolongation by more than 60 msec was reported in more than 5% of patients. A few patients (0.4%) in the adult/adolescent population and no patient in the infant/children population experienced a QTcF greater than 500 msec. However, the possibility that these increases were disease-related cannot be ruled out. In a study of healthy adult volunteers, administration of the six-dose regimen of artemether-lumefantrine was associated with mean changes in QTcF from baseline of 7.45, 7.29, 6.12 and 6.84 msec at 68, 72, 96, and 108 hours after the first dose, respectively. There was a concentration-dependent increase in QTcF for lumefantrine. No subject had a greater than 30 msec increase from baseline nor an absolute increase to more than 500 msec.
MONITOR CLOSELY: Coadministration with artemether may decrease the plasma concentrations of CYP450 3A4 substrates such as protease inhibitors, macrolide antibiotics, and azole antifungal agents. In vitro and human studies have demonstrated that artemisinins including artemether have some capacity to induce CYP450 3A4. The clinical significance is unknown.
MANAGEMENT: No dose adjustment of artemether-lumefantrine is necessary when administered in combination with potent CYP450 3A4 inhibitors such as azole antifungal agents, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. However, caution is advised due to increased risk of QT interval prolongation. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. Patients should also be monitored for reduced effects or potential loss of efficacy of the concomitant drug(s), especially antiretroviral agents.
References (3)
- Cerner Multum, Inc. "UK Summary of Product Characteristics."
- Cerner Multum, Inc. "Australian Product Information."
- (2009) "Product Information. Coartem (artemether-lumefantrine)." Novartis Pharmaceuticals
ritonavir lumefantrine
Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and artemether / lumefantrine
MONITOR CLOSELY: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of artemether and lumefantrine, both of which are primarily metabolized by the isoenzyme. In 13 healthy subjects, concurrent oral administration of the potent inhibitor ketoconazole (400 mg on day 1, followed by 200 mg for 4 days) and a single dose of artemether-lumefantrine (80 mg-480 mg) with food resulted in modest increases in systemic exposure (AUC) to artemether (2.3-fold), its active metabolite dihydroartemisinin (1.5-fold), and lumefantrine (1.6-fold). High plasma levels of artemether and lumefantrine may theoretically increase the risk of QT interval prolongation and ventricular arrhythmias including torsade de pointes. In clinical trials, asymptomatic prolongation of the Fridericia-corrected QT interval (QTcF) by more than 30 msec from baseline was reported in approximately one-third of patients treated with artemether-lumefantrine, and prolongation by more than 60 msec was reported in more than 5% of patients. A few patients (0.4%) in the adult/adolescent population and no patient in the infant/children population experienced a QTcF greater than 500 msec. However, the possibility that these increases were disease-related cannot be ruled out. In a study of healthy adult volunteers, administration of the six-dose regimen of artemether-lumefantrine was associated with mean changes in QTcF from baseline of 7.45, 7.29, 6.12 and 6.84 msec at 68, 72, 96, and 108 hours after the first dose, respectively. There was a concentration-dependent increase in QTcF for lumefantrine. No subject had a greater than 30 msec increase from baseline nor an absolute increase to more than 500 msec.
MONITOR CLOSELY: Coadministration with artemether may decrease the plasma concentrations of CYP450 3A4 substrates such as protease inhibitors, macrolide antibiotics, and azole antifungal agents. In vitro and human studies have demonstrated that artemisinins including artemether have some capacity to induce CYP450 3A4. The clinical significance is unknown.
MANAGEMENT: No dose adjustment of artemether-lumefantrine is necessary when administered in combination with potent CYP450 3A4 inhibitors such as azole antifungal agents, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. However, caution is advised due to increased risk of QT interval prolongation. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. Patients should also be monitored for reduced effects or potential loss of efficacy of the concomitant drug(s), especially antiretroviral agents.
References (3)
- Cerner Multum, Inc. "UK Summary of Product Characteristics."
- Cerner Multum, Inc. "Australian Product Information."
- (2009) "Product Information. Coartem (artemether-lumefantrine)." Novartis Pharmaceuticals
lopinavir artemether
Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and artemether / lumefantrine
GENERALLY AVOID: Artemether-lumefantrine may cause prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In clinical trials, asymptomatic prolongation of the Fridericia-corrected QT interval (QTcF) by more than 30 msec from baseline was reported in approximately one-third of patients treated with artemether-lumefantrine, and prolongation by more than 60 msec was reported in more than 5% of patients. A few patients (0.4%) in the adult/adolescent population and no patient in the infant/children population experienced a QTcF greater than 500 msec. However, the possibility that these increases were disease-related cannot be ruled out. In a study of healthy adult volunteers, administration of the six-dose regimen of artemether-lumefantrine was associated with mean changes in QTcF from baseline of 7.45, 7.29, 6.12 and 6.84 msec at 68, 72, 96, and 108 hours after the first dose, respectively. There was a concentration-dependent increase in QTcF for lumefantrine. No subject had a greater than 30 msec increase from baseline nor an absolute increase to more than 500 msec. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).
MANAGEMENT: Coadministration of artemether-lumefantrine with other drugs that can prolong the QT interval should generally be avoided. Caution is recommended when these drugs are used following treatment with artemether-lumefantrine due to the long elimination half-life of lumefantrine (3 to 6 days). Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.
References (4)
- Cerner Multum, Inc. "UK Summary of Product Characteristics."
- EMEA. European Medicines Agency (2007) EPARs. European Union Public Assessment Reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landingpage.jsp&mid
- Cerner Multum, Inc. "Australian Product Information."
- (2009) "Product Information. Coartem (artemether-lumefantrine)." Novartis Pharmaceuticals
lopinavir lumefantrine
Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and artemether / lumefantrine
GENERALLY AVOID: Artemether-lumefantrine may cause prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In clinical trials, asymptomatic prolongation of the Fridericia-corrected QT interval (QTcF) by more than 30 msec from baseline was reported in approximately one-third of patients treated with artemether-lumefantrine, and prolongation by more than 60 msec was reported in more than 5% of patients. A few patients (0.4%) in the adult/adolescent population and no patient in the infant/children population experienced a QTcF greater than 500 msec. However, the possibility that these increases were disease-related cannot be ruled out. In a study of healthy adult volunteers, administration of the six-dose regimen of artemether-lumefantrine was associated with mean changes in QTcF from baseline of 7.45, 7.29, 6.12 and 6.84 msec at 68, 72, 96, and 108 hours after the first dose, respectively. There was a concentration-dependent increase in QTcF for lumefantrine. No subject had a greater than 30 msec increase from baseline nor an absolute increase to more than 500 msec. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).
MANAGEMENT: Coadministration of artemether-lumefantrine with other drugs that can prolong the QT interval should generally be avoided. Caution is recommended when these drugs are used following treatment with artemether-lumefantrine due to the long elimination half-life of lumefantrine (3 to 6 days). Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.
References (4)
- Cerner Multum, Inc. "UK Summary of Product Characteristics."
- EMEA. European Medicines Agency (2007) EPARs. European Union Public Assessment Reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landingpage.jsp&mid
- Cerner Multum, Inc. "Australian Product Information."
- (2009) "Product Information. Coartem (artemether-lumefantrine)." Novartis Pharmaceuticals
ritonavir tenofovir
Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil
MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.
MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.
References (8)
- (2001) "Product Information. Viread (tenofovir)." Gilead Sciences
- Verhelst D, Monge M, Meynard JL, et al. (2002) "Fanconi syndrome and renal failure induced by tenofovir: A first case report." Am J Kidney Dis, 40, p. 1331-3
- Creput C, Gonzalez-Canali G, Hill G, Piketty C, Kazatchkine M, Nochy D (2003) "Renal lesions in HIV-1-positive patient treated with tenofovir." AIDS, 17, p. 935-7
- Karras A, Lafaurie M, Furco A, et al. (2003) "Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, fanconi syndrome, and nephrogenic diabetes insipidus." Clin Infect Dis, 36, p. 1070-3
- Kearney BP, Mittan A, Sayre J, et al. (2003) Pharmacokinetic drug interaction and long term safety profile of tenofovir DF and lopinavir/ritonavir. http://www.icaac.org/ICAAC.asp
- Rollot F, Nazal EM, Chauvelot-Moachon L, et al. (2003) "Tenofovir-related fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-Didanosine." Clin Infect Dis, 37, E174-6
- Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G (2006) "Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions." Clin Infect Dis, 42, p. 283-90
- Kapadia J, Shah S, Desai C, et al. (2013) "Tenofovir induced Fanconi syndrome: a possible pharmacokinetic interaction." Indian J Pharmacol, 45, p. 191-2
lopinavir tenofovir
Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil
MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.
MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.
References (8)
- (2001) "Product Information. Viread (tenofovir)." Gilead Sciences
- Verhelst D, Monge M, Meynard JL, et al. (2002) "Fanconi syndrome and renal failure induced by tenofovir: A first case report." Am J Kidney Dis, 40, p. 1331-3
- Creput C, Gonzalez-Canali G, Hill G, Piketty C, Kazatchkine M, Nochy D (2003) "Renal lesions in HIV-1-positive patient treated with tenofovir." AIDS, 17, p. 935-7
- Karras A, Lafaurie M, Furco A, et al. (2003) "Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, fanconi syndrome, and nephrogenic diabetes insipidus." Clin Infect Dis, 36, p. 1070-3
- Kearney BP, Mittan A, Sayre J, et al. (2003) Pharmacokinetic drug interaction and long term safety profile of tenofovir DF and lopinavir/ritonavir. http://www.icaac.org/ICAAC.asp
- Rollot F, Nazal EM, Chauvelot-Moachon L, et al. (2003) "Tenofovir-related fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-Didanosine." Clin Infect Dis, 37, E174-6
- Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G (2006) "Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions." Clin Infect Dis, 42, p. 283-90
- Kapadia J, Shah S, Desai C, et al. (2013) "Tenofovir induced Fanconi syndrome: a possible pharmacokinetic interaction." Indian J Pharmacol, 45, p. 191-2
Drug and food interactions
ritonavir food
Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil
ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.
MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.
References (1)
- (2001) "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical
lopinavir food
Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil
ADJUST DOSING INTERVAL: Food significantly increases the bioavailability of lopinavir from the oral solution formulation of lopinavir-ritonavir. Relative to fasting, administration of lopinavir-ritonavir oral solution with a moderate-fat meal (500 to 682 Kcal; 23% to 25% calories from fat) increased lopinavir peak plasma concentration (Cmax) and systemic exposure (AUC) by 54% and 80%, respectively, whereas administration with a high-fat meal (872 Kcal; 56% from fat) increased lopinavir Cmax and AUC by 56% and 130%, respectively. No clinically significant changes in Cmax and AUC were observed following administration of lopinavir-ritonavir tablets under fed conditions versus fasted conditions. Relative to fasting, administration of a single 400 mg-100 mg dose (two 200 mg-50 mg tablets) with a moderate-fat meal (558 Kcal; 24.1% calories from fat) increased lopinavir Cmax and AUC by 17.6% and 26.9%, respectively, while administration with a high-fat meal (998 Kcal; 51.3% from fat) increased lopinavir AUC by 18.9% but not Cmax. Relative to fasting, ritonavir Cmax and AUC also increased by 4.9% and 14.9%, respectively, with the moderate-fat meal and 10.3% and 23.9%, respectively, with the high-fat meal.
MANAGEMENT: Lopinavir-ritonavir oral solution should be taken with meals to enhance bioavailability and minimize pharmacokinetic variability. Lopinavir-ritonavir tablets may be taken without regard to meals.
References (1)
- (2001) "Product Information. Kaletra (lopinavir-ritonavir)." Abbott Pharmaceutical
lumefantrine food
Applies to: artemether / lumefantrine
GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of artemether and lumefantrine. The mechanism is decreased clearance due to inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. High plasma levels of artemether and lumefantrine may increase the risk of QT interval prolongation and ventricular arrhythmias including torsade de pointes. In clinical trials, asymptomatic prolongation of the Fridericia-corrected QT interval (QTcF) by more than 30 msec from baseline was reported in approximately one-third of patients treated with artemether-lumefantrine, and prolongation by more than 60 msec was reported in more than 5% of patients. A few patients (0.4%) in the adult/adolescent population and no patient in the infant/children population experienced a QTcF greater than 500 msec. However, the possibility that these increases were disease-related cannot be ruled out. In a study of healthy adult volunteers, administration of the six-dose regimen of artemether-lumefantrine was associated with mean changes in QTcF from baseline of 7.45, 7.29, 6.12 and 6.84 msec at 68, 72, 96, and 108 hours after the first dose, respectively. There was a concentration-dependent increase in QTcF for lumefantrine. No subject had a greater than 30 msec increase from baseline nor an absolute increase to more than 500 msec.
ADJUST DOSING INTERVAL: Food enhances the oral absorption of artemether and lumefantrine. In healthy volunteers, the relative bioavailability of artemether increased by two- to threefold and that of lumefantrine by sixteenfold when administered after a high-fat meal as opposed to under fasted conditions.
MANAGEMENT: Patients receiving artemether-lumefantrine therapy should avoid the consumption of grapefruits and grapefruit juice. To ensure maximal oral absorption, artemether-lumefantrine should be taken with food. Inadequate food intake can increase the risk for recrudescence of malaria. Patients who are averse to food during treatment should be closely monitored and encouraged to resume normal eating as soon as food can be tolerated.
References (3)
- Cerner Multum, Inc. "UK Summary of Product Characteristics."
- Cerner Multum, Inc. "Australian Product Information."
- (2009) "Product Information. Coartem (artemether-lumefantrine)." Novartis Pharmaceuticals
tenofovir food
Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil
Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.
References (1)
- (2001) "Product Information. Viread (tenofovir)." Gilead Sciences
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
Drug Interaction Classification
| Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit. | |
| Moderately clinically significant. Usually avoid combinations; use it only under special circumstances. | |
| 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. | |
| No interaction information available. |
Further information
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.
Check Interactions
To view an interaction report containing 4 (or more) medications, please sign in or create an account.
Save Interactions List
Sign in to your account to save this drug interaction list.