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Drug Interactions between elbasvir / grazoprevir and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

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

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Interactions between your drugs

Major

ritonavir grazoprevir

Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and elbasvir / grazoprevir

CONTRAINDICATED: Coadministration with inhibitors of organic anion transporting polypeptides (OATP) 1B1 and/or 1B3 may significantly increase the plasma concentrations of grazoprevir, which is a substrate of the hepatic uptake transporters. In 12 study subjects, administration of a single 200 mg dose of grazoprevir with a single 600 mg intravenous dose of rifampin, a potent OATP1B1 inhibitor, resulted in greater than 10-fold increases in grazoprevir peak plasma concentration (Cmax) and systemic exposure (AUC) compared to administration of grazoprevir alone. A single 600 mg oral dose of rifampin administered during multiple-dosing of grazoprevir 200 mg once daily increased the Cmax and AUC of grazoprevir by 6.5- and 8.4-fold, respectively. Pharmacokinetic studies with other OATP1B1 inhibitors have reported similar results. In one study, administration of grazoprevir 200 mg once daily with atazanavir/ritonavir 300 mg/100 mg once daily increased grazoprevir Cmax, AUC and Cmin by 6.2-, 10.6- and 11.6-fold, respectively (n=12). Likewise, administration with darunavir/ritonavir 600 mg/100 mg twice daily increased grazoprevir Cmax, AUC and Cmin by 5.3-, 7.5- and 8.1-fold, respectively (n=13), while administration with lopinavir/ritonavir 400 mg/100 mg twice daily increased grazoprevir Cmax, AUC and Cmin by 7.3-, 12.9- and 21.7-fold, respectively (n=13). A single 400 mg dose of cyclosporine increased grazoprevir Cmax, AUC and Cmin by 17.0-, 15.2- and 3.4-fold, respectively (n=14). High plasma levels of grazoprevir may increase the risk of adverse effects such as alanine aminotransferase (ALT) elevations.

MANAGEMENT: Concomitant use of elbasvir-grazoprevir with OATP 1B1 or 1B3 inhibitors is considered contraindicated.

References (5)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2016) "Product Information. Zepatier (elbasvir-grazoprevir)." Merck & Co., Inc
  4. (2020) "Product Information. Nexlizet (bempedoic acid-ezetimibe)." Esperion Therapeutics
  5. (2020) "Product Information. Nexletol (bempedoic acid)." Esperion Therapeutics

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Major

lopinavir grazoprevir

Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and elbasvir / grazoprevir

CONTRAINDICATED: Coadministration with inhibitors of organic anion transporting polypeptides (OATP) 1B1 and/or 1B3 may significantly increase the plasma concentrations of grazoprevir, which is a substrate of the hepatic uptake transporters. In 12 study subjects, administration of a single 200 mg dose of grazoprevir with a single 600 mg intravenous dose of rifampin, a potent OATP1B1 inhibitor, resulted in greater than 10-fold increases in grazoprevir peak plasma concentration (Cmax) and systemic exposure (AUC) compared to administration of grazoprevir alone. A single 600 mg oral dose of rifampin administered during multiple-dosing of grazoprevir 200 mg once daily increased the Cmax and AUC of grazoprevir by 6.5- and 8.4-fold, respectively. Pharmacokinetic studies with other OATP1B1 inhibitors have reported similar results. In one study, administration of grazoprevir 200 mg once daily with atazanavir/ritonavir 300 mg/100 mg once daily increased grazoprevir Cmax, AUC and Cmin by 6.2-, 10.6- and 11.6-fold, respectively (n=12). Likewise, administration with darunavir/ritonavir 600 mg/100 mg twice daily increased grazoprevir Cmax, AUC and Cmin by 5.3-, 7.5- and 8.1-fold, respectively (n=13), while administration with lopinavir/ritonavir 400 mg/100 mg twice daily increased grazoprevir Cmax, AUC and Cmin by 7.3-, 12.9- and 21.7-fold, respectively (n=13). A single 400 mg dose of cyclosporine increased grazoprevir Cmax, AUC and Cmin by 17.0-, 15.2- and 3.4-fold, respectively (n=14). High plasma levels of grazoprevir may increase the risk of adverse effects such as alanine aminotransferase (ALT) elevations.

MANAGEMENT: Concomitant use of elbasvir-grazoprevir with OATP 1B1 or 1B3 inhibitors is considered contraindicated.

References (5)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2016) "Product Information. Zepatier (elbasvir-grazoprevir)." Merck & Co., Inc
  4. (2020) "Product Information. Nexlizet (bempedoic acid-ezetimibe)." Esperion Therapeutics
  5. (2020) "Product Information. Nexletol (bempedoic acid)." Esperion Therapeutics

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Moderate

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)
  1. (2001) "Product Information. Viread (tenofovir)." Gilead Sciences
  2. 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
  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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Kapadia J, Shah S, Desai C, et al. (2013) "Tenofovir induced Fanconi syndrome: a possible pharmacokinetic interaction." Indian J Pharmacol, 45, p. 191-2

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Moderate

ritonavir elbasvir

Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and elbasvir / grazoprevir

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of elbasvir, which is a substrate of the isoenzyme. In 10 study subjects, administration of elbasvir (50 mg once daily) with the potent CYP450 3A4 inhibitors atazanavir/ritonavir (300 mg/100 mg once daily) increased elbasvir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 4.15-fold, 4.76-fold and 6.45-fold, respectively, compared to elbasvir alone. Likewise, administration with lopinavir/ritonavir 400 mg/100 mg twice daily increased elbasvir Cmax, AUC, and Cmin by 2.87-, 3.71-, and 4.58-fold, respectively (n=10), while administration with darunavir/ritonavir 600 mg/100 mg twice daily increased elbasvir Cmax, AUC, and Cmin by 1.67-, 1.66-, and 1.82-fold, respectively (n=10). Another potent CYP450 3A4 inhibitor, ketoconazole (400 mg once daily), increased the Cmax, AUC, and Cmin of a single 50 mg dose of elbasvir by 1.29-, 1.80, and 1.89-fold, respectively (n=7).

MANAGEMENT: Concomitant use of elbasvir with potent CYP450 3A4 inhibitors should generally be avoided.

References (3)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2016) "Product Information. Zepatier (elbasvir-grazoprevir)." Merck & Co., Inc

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Moderate

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)
  1. (2001) "Product Information. Viread (tenofovir)." Gilead Sciences
  2. 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
  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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Kapadia J, Shah S, Desai C, et al. (2013) "Tenofovir induced Fanconi syndrome: a possible pharmacokinetic interaction." Indian J Pharmacol, 45, p. 191-2

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Moderate

lopinavir elbasvir

Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and elbasvir / grazoprevir

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of elbasvir, which is a substrate of the isoenzyme. In 10 study subjects, administration of elbasvir (50 mg once daily) with the potent CYP450 3A4 inhibitors atazanavir/ritonavir (300 mg/100 mg once daily) increased elbasvir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 4.15-fold, 4.76-fold and 6.45-fold, respectively, compared to elbasvir alone. Likewise, administration with lopinavir/ritonavir 400 mg/100 mg twice daily increased elbasvir Cmax, AUC, and Cmin by 2.87-, 3.71-, and 4.58-fold, respectively (n=10), while administration with darunavir/ritonavir 600 mg/100 mg twice daily increased elbasvir Cmax, AUC, and Cmin by 1.67-, 1.66-, and 1.82-fold, respectively (n=10). Another potent CYP450 3A4 inhibitor, ketoconazole (400 mg once daily), increased the Cmax, AUC, and Cmin of a single 50 mg dose of elbasvir by 1.29-, 1.80, and 1.89-fold, respectively (n=7).

MANAGEMENT: Concomitant use of elbasvir with potent CYP450 3A4 inhibitors should generally be avoided.

References (3)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2016) "Product Information. Zepatier (elbasvir-grazoprevir)." Merck & Co., Inc

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Drug and food interactions

Moderate

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)
  1. (2001) "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical

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Moderate

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)
  1. (2001) "Product Information. Kaletra (lopinavir-ritonavir)." Abbott Pharmaceutical

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Minor

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)
  1. (2001) "Product Information. Viread (tenofovir)." Gilead Sciences

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Minor

grazoprevir food

Applies to: elbasvir / grazoprevir

Food does not appear to have clinically significant effects on the pharmacokinetics of elbasvir and grazoprevir. When a single 50 mg-100 mg dose of elbasvir-grazoprevir was administered to healthy study subjects with a high-fat meal (900 kcal; 500 kcal from fat), elbasvir peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 15% and 11%, respectively, while grazoprevir Cmax and AUC increased by 2.8- and 1.5-fold, respectively, compared to administration under fasting conditions. According to the product labeling, elbasvir-grazoprevir may be administered with or without food.

References (1)
  1. (2016) "Product Information. Zepatier (elbasvir-grazoprevir)." Merck & Co., Inc

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Therapeutic duplication warnings

Therapeutic duplication is the use of more than one medicine from the same drug category or therapeutic class to treat the same condition. This can be intentional in cases where drugs with similar actions are used together for demonstrated therapeutic benefit. It can also be unintentional in cases where a patient has been treated by more than one doctor, or had prescriptions filled at more than one pharmacy, and can have potentially adverse consequences.

Duplication

Protease inhibitors

Therapeutic duplication

The recommended maximum number of medicines in the 'protease inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'protease inhibitors' category:

  • elbasvir/grazoprevir
  • emtricitabine/lopinavir/ritonavir/tenofovir disoproxil

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.


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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.