Liverpool HIV Interactions

Do Not Coadminister

Tenofovir-DF (TDF)

Elvitegravir/Cobicistat/ Emtricitabine/Tenofovir alafenamide (EVG/c/FTC/TAF)

Quality of Evidence: Very Low

Summary:

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Furthermore, Genvoya contains tenofovir alafenamide and should not be administered with tenofovir-DF.

Description:

Genvoya should not be co-administered with other antiretroviral medicinal products. Genvoya should not be administered concomitantly with medicinal products containing tenofovir disoproxil.
Genvoya Summary of Product Characteristics, Gilead Sciences International Ltd, November 2021.

Genvoya is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration of Genvoya with other antiretroviral medications for treatment of HIV-1 infection should be avoided. Do not use with drugs containing tenofovir disoproxil fumarate.
Genvoya US Prescribing Information, Gilead Sciences Inc, September 2021.

Viread should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
Viread Summary of Product Characteristics, Gilead Sciences Ltd, September 2016.

Do Not Coadminister

Emtricitabine (FTC)

Elvitegravir/Cobicistat/ Emtricitabine/Tenofovir alafenamide (EVG/c/FTC/TAF)

Quality of Evidence: Very Low

Summary:

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Furthermore, it must not be administered with additional emtricitabine.

Description:

Genvoya should not be co-administered with other antiretroviral medicinal products.
Genvoya Summary of Product Characteristics, Gilead Sciences International Ltd, November 2021.

Genvoya is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration of Genvoya with other antiretroviral medications for treatment of HIV-1 infection should be avoided.
Genvoya US Prescribing Information, Gilead Sciences Inc, September 2021.

Emtricitabine should not be taken with any other medicinal products containing emtricitabine.
Emtriva Summary of Product Characteristics, Gilead Sciences Ltd, April 2019.

Do Not Coadminister

Efavirenz (EFV)

Elvitegravir/Cobicistat/ Emtricitabine/Tenofovir alafenamide (EVG/c/FTC/TAF)

Quality of Evidence: Very Low

Summary:

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Genvoya should not be used in conjunction with non-nucleoside reverse transcriptase inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir and/or the coadministered antiretroviral products. When switching patients who are CYP2B6 poor metabolisers from an efavirenz containing regimen to Genvoya, there is a potential for lower elvitegravir exposure due to prolonged CYP3A induction by efavirenz. Monitoring of viral load is recommended for these patients during the first month after switching treatment to Genvoya.

Description:

Genvoya should not be co-administered with other antiretroviral medicinal products.
Genvoya Summary of Product Characteristics, Gilead Sciences International Ltd, November 2021.

Genvoya is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration of Genvoya with other antiretroviral medications for treatment of HIV-1 infection should be avoided.

Genvoya US Prescribing Information, Gilead Sciences Inc, September 2021.

Potential Interaction

Efavirenz (EFV)

Atorvastatin

Quality of Evidence: Low

Summary:

Coadministration of atorvastatin (10 mg once daily) and efavirenz (600 mg once daily) decreased atorvastatin Cmax (14%), AUC (43%) and Cmin (69%). Total active drug (including metabolites) decreased by 15% (Cmax), 32% (AUC) and 48% (Cmin). There was no change in efavirenz Cmax, AUC or Cmin. Given the decrease in exposure of total active drug, an increase in atorvastatin dose might be needed in presence of efavirenz. Monitor lipid values and adjust the atorvastatin dose based on the clinical response.

Description:

Coadministration of efavirenz (600 mg once daily) with atorvastatin (10 mg once daily) decreased the AUC and Cmax of atorvastatin by 43% and 12%, respectively; of 2-hydroxy atorvastatin by 35% and 13%, respectively; of 4-hydroxy atorvastatin by 4% and 47%, respectively; and of total active HMG-CoA reductase inhibitors by 34% and 20%, respectively. Coadministration did not affect efavirenz AUC or Cmax values. Cholesterol levels should be periodically monitored. Dosage adjustments of atorvastatin may be required (refer to the SmPC for atorvastatin). No dosage adjustment is necessary for efavirenz.

Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, May 2023.

Coadministration of atorvastatin (10 mg once daily for 4 days) and efavirenz (600 mg for 15 days) was studied in 14 subjects. There were decreases in atorvastatin Cmax, AUC and Cmin of 14%, 43% and 69%, respectively. Total active drug (including metabolites) decreased by 15% (Cmax), 32% (AUC) and 48% (Cmin). There was no change in efavirenz Cmax, AUC or Cmin. Consult the complete prescribing information for atorvastatin for guidance on individualising the dose.

Efavirenz US Prescribing Information, Aurobindo Pharma Limited, October 2021.

Coadministration of efavirenz (600 mg once daily) and atorvastatin (10 mg once daily) was studied in 14 HIV-negative subjects. Efavirenz reduced atorvastatin AUC0-24h by 43% (P<0.001) and the total active atorvastatin exposure by 34% (P=0.005). Atorvastatin had no effect on non-steady-state efavirenz concentrations. The reduced inhibition of HMG-CoA reductase activity may result in diminished antilipid efficacy at usual doses of atorvastatin.

Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study. Gerber JG, Rosenkranz SL, Fichtenbaum CJ, et al. J Acquir Immune Defic Syndr, 2005, 39(3): 307-12.

No Interaction Expected

Tenofovir-DF (TDF)

Emtricitabine (FTC)

Quality of Evidence: Low

Summary:

No significant interactions were observed between emtricitabine and tenofovir-DF. Coadministration of tenofovir-DF (300 mg once daily) and emtricitabine (200 mg once daily for 7 days) had no effect on tenofovir AUC, Cmax or Cmin. Emtricitabine AUC and Cmax were unaltered and there was a 20% increase in Cmin.

Description:

There are no clinically significant interactions when emtricitabine is co-administered with indinavir, zidovudine, stavudine, famciclovir or tenofovir disoproxil fumarate.
Emtriva Summary of Product Characteristics, Gilead Sciences Ltd, April 2019.

No significant interactions were observed between emtricitabine and tenofovir. Coadministration of emtricitabine (200 mg once daily for 7 days) and tenofovir (300 mg once daily for 7 days) was studied in 17 HIV-negative subjects. There was no change in emtricitabine AUC and Cmax and a 20% increase in Cmin. Tenofovir AUC, Cmax and Cmin were unaltered.
Emtriva Prescribing Information, Gilead Sciences Inc, December 2018.

There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was coadministered with emtricitabine.
Viread Summary of Product Characteristics, Gilead Sciences Ltd, September 2016.

Coadministration of tenofovir-DF (300 mg once daily) and emtricitabine (200 mg once daily for 7 days) was studied in 17 HIV-negative subjects. There was no change in tenofovir pharmacokinetic parameters. Emtricitabine AUC and Cmax were unaltered and there was a 20% increase in Cmin.
Viread Prescribing Information, Gilead Sciences International Inc, February 2016.

No Interaction Expected

Tenofovir-DF (TDF)

Atorvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as atorvastatin is metabolized by CYP3A4.

Description:

(See Summary)

No Interaction Expected

Emtricitabine (FTC)

Atorvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as atorvastatin is metabolized by CYP3A4.

Description:

(See Summary)

No Interaction Expected

Tenofovir-DF (TDF)

Rosuvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on the metabolism and clearance a clinically significant drug-drug interaction is unlikely as rosuvastatin is largely excreted unchanged via the faeces.

Description:

(See Summary)

No Interaction Expected

Emtricitabine (FTC)

Rosuvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on the metabolism and clearance a clinically significant drug-drug interaction is unlikely as rosuvastatin is largely excreted unchanged via the faeces.

Description:

(See Summary)

No Interaction Expected

Efavirenz (EFV)

Tenofovir-DF (TDF)

Quality of Evidence: Low

Summary:

Coadministration of tenofovir-DF (300 mg once daily) and efavirenz (600 mg once daily) had no effect on the Cmax, AUC or Cmin of either tenofovir or efavirenz.

Description:

Specific interaction studies have not been performed with efavirenz and NRTIs other than lamivudine, zidovudine, and tenofovir disoproxil fumarate. Clinically significant interactions are not expected since the NRTIs are metabolised via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways. No dosage adjustment is necessary for either medicinal product.

Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, May 2023.

Coadministration of tenofovir-DF (300 mg once daily) and efavirenz (600 mg once daily for 14 days) to 29 subjects resulted in no change in Cmax, AUC or Cmin of either tenofovir or efavirenz. No dosage adjustment is recommended when SUSTIVA is given with emtricitabine or tenofovir disoproxil fumarate.

Efavirenz US Prescribing Information, Aurobindo Pharma Limited, October 2021.

There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was coadministered with efavirenz.

Viread Summary of Product Characteristics, Gilead Sciences Ltd, September 2016.

No clinically significant drug interactions hace been observed between tenofovir-DF and efavirenz.

Viread Prescribing Information, Gilead Sciences International Inc, February 2016.

The interaction between tenofovir and efavirenz was assessed in TDM samples from groups of HIV+ patients receiving efavirenz (600 mg once daily) alone or with tenofovir (300 mg once daily). Samples were collected 0.5-23.9 h post dose in the control group (n=118) and the tenofovir group (n=126). There was no significant difference between the groups for the time post dose or efavirenz concentrations (2.34 µg/ml vs 2.22 µg/ml, control vs plus tenofovir).

Assessment of drug-drug interactions between tenofovir disoproxil fumarate and the nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz in HIV-infected patients. Droste JA, Kearney BP, Hekster YA, Burger DM. J Acquir Immune Defic Syndr, 2006, 41(1): 37-43.

Nine cases have been reported of patients stable on efavirenz therapy who developed neuropsychiatric disturbances following the introduction of tenofovir to their antiretroviral regimens. The patients had been stable on efavirenz-containing regimens for a median duration of 31 months (range 5-58) during which no efavirenz related CNS effects were reported. Moderate to severe neuropsychiatric events occurred within 48 h of starting tenofovir in 5 patients, with symptoms developing in the remaining 4 patients after 2 weeks to 24 months after initiation of tenofovir. Treatment was changed in 6/9 patients; 3 switched from tenofovir to nevirapine, 2 to from tenofovir to zidovudine and one discontinued treatment. All 6 patients exhibited marked improvement in CNS intolerance. Of the 3 patients who remained on efavirenz and tenofovir, one had spontaneous progressive improvement within 2 weeks, but two had chronic persistent sleeping disorders. Efavirenz plasma concentrations were available for 2 patients before tenofovir (1.35 and 2.09 µg/ml) and for 4 patients on tenofovir (1.30-1.95 µg/ml). The neuropsychiatric disorders could be either a consequence of an unexplained interaction between efavirenz and tenofovir, or an infrequent tenofovir-related side effect. Further studies are required to evaluate precisely the incidence of these symptoms, including the assessment of efavirenz binding sites or metabolites.

Neuropsychiatric adverse events after switching from an antiretroviral regimen containing efavirenz without tenofovir to an efavirenz regimen containing tenofovir: a report of nine cases. Allavena C, Le Moal G, Michau C, Chiffoleau A, Raffi F. Antivir Ther, 2006, 11(2): 263-5.

No Interaction Expected

Efavirenz (EFV)

Emtricitabine (FTC)

Quality of Evidence: Very Low

Summary:

Based on the results of in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low. The coadministration of emtricitabine, didanosine and efavirenz was studied in 9 treatment naive, HIV+ patients. When compared to historical data for each drug alone, the pharmacokinetics of emtricitabine were not affected, didanosine AUC and Cmax were higher than expected and efavirenz Cmax, Cmin and AUC were lower than expected. However, efavirenz concentrations may have been underestimated as dosing was delayed by 12 hours for ease of sampling.

Description:

In vitro, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation. Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.

Emtriva Summary of Product Characteristics, Gilead Sciences International Ltd, July 2011.

At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP 2C9, CYP2C19, CYP2D6 and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5'-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.

Emtriva Presrcibing Information, Gilead Sciences Inc, November 2011.

Specific interaction studies have not been performed with efavirenz and NRTIs other than lamivudine, zidovudine, and tenofovir disoproxil fumarate. Clinically significant interactions are not expected since the NRTIs are metabolised via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways. No dosage adjustment is necessary for either medicinal product.

Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, May 2023.

No dosage adjustment is recommended when efavirenz is given with emtricitabine.

Efavirenz US Prescribing Information, Aurobindo Pharma Limited, October 2021.

Emtricitabine + Didanosine
The coadministration of emtricitabine (200 mg once daily), didanosine (400 mg once daily for patients 60 kg and over; 250 mg once a daily for patients less than 60 kg) and efavirenz (600 mg once daily) was studied in 9 treatment naive, HIV+ patients. When compared to historical data for each drug alone, the pharmacokinetics of emtricitabine were not affected, didanosine AUC and Cmax were higher than expected and efavirenz Cmax, Cmin and AUC were lower than expected. The authors suggest the efavirenz concentrations may have been underestimated as they delayed dosing by 12 hours for ease of sampling.

Pharmacokinetics of emtricitabine, didanosine and efavirenz administered once-daily for the treatment of HIV-infected adults (pharmacokinetic substudy of the ANRS trial). Molina J-M, Peytavin G, Perusat S et al. HIV Medicine, 2004, 5: 99-104.

No Interaction Expected

Efavirenz (EFV)

Rosuvastatin

Quality of Evidence: Very Low

Summary:

This interaction has not been studied. No interaction is expected as rosuvastatin is largely excreted unchanged via the faeces. No dosage adjustment is necessary.

Description:

This interaction has not been studied. Rosuvastatin is largely excreted unchanged via the faeces, therefore interaction with efavirenz is not expected. No dosage adjustment is necessary for either medicinal product.

Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, May 2023.

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