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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents

Drug Interactions

Drug Interactions between Non-Nucleoside Reverse Transcriptase Inhibitors and Other Drugs

(Last updated: July 14, 2016; last reviewed: July 14, 2016)

Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other Drugs

This table provides information relating to PK interactions between NNRTIs and non-ARV drugs. For interactions between ARV agents and for dosing recommendations, refer to Tables 19c, 20a and 20b.

Note: DLV is not included in this table. Please refer to the DLV FDA package insert for information regarding drug interactions.

Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other Drugs
Concomitant Drug Class/Name NNRTIa Effect on NNRTI and/or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments
Acid Reducers
Antacids RPV ↓ RPV expected when given simultaneously Give antacids at least 2 hours before or at least 4 hours after RPV.
H2-Receptor Antagonists RPV ↓ RPV Give H2-receptor antagonists at least 12 hours before or at least 4 hours after RPV.
PPIs RPV With omeprazole 20 mg daily:
  • RPV AUC ↓ 40%, Cmin ↓ 33%
 Contraindicated. Do not coadminister.
Anticoagulants/Antiplatelets
Warfarin EFV, NVP ↑ or ↓ warfarin possible Monitor INR and adjust warfarin dose accordingly.
ETR ↑ warfarin possible Monitor INR and adjust warfarin dose accordingly.
Clopidogrel ETR ↓ activation of clopidogrel possible ETR may prevent metabolism of clopidogrel (inactive) to its active metabolite. Avoid coadministration, if possible.
Anticonvulsants
Carbamazepine,
Phenobarbital,
Phenytoin		 EFV Carbamazepine plus EFV: 
  • Carbamazepine AUC ↓ 27%
  • EFV AUC ↓ 36%
Phenytoin plus EFV:
  • ↓ EFV
  • ↓ phenytoin possible
 Monitor anticonvulsant and EFV levels or, if possible, use alternative anticonvulsant to those listed.
ETR ↓ anticonvulsant and ETR possible Do not coadminister. Consider alternative anticonvulsant.
NVP ↓ anticonvulsant and NVP possible Monitor anticonvulsant and NVP levels and virologic responses or consider alternative anticonvulsant.
RPV ↓ RPV possible Contraindicated. Do not coadminister. Consider alternative anticonvulsant.
Oxcarbazepine RPV ↓ RPV possible Contraindicated. Do not coadminister. Consider alternative anticonvulsant.
Antidepressants
Bupropion EFV Bupropion AUC ↓ 55% Titrate bupropion dose based on clinical response.
Paroxetine EFV, ETR No significant effect No dosage adjustment necessary.
Sertraline EFV Sertraline AUC ↓ 39% Titrate sertraline dose based on clinical response.
Antifungals
Fluconazole EFV No significant effect No dosage adjustment necessary.
ETR ETR AUC ↑ 86% No dosage adjustment necessary. Use with caution.
NVP NVP AUC ↑ 110% Increased risk of hepatotoxicity possible with this combination. Monitor NVP toxicity or use alternative ARV agent.
RPV ↑ RPV possible No dosage adjustment necessary. Clinically monitor for breakthrough fungal infection.
Isavuconazole EFV, ETR, NVP ↓ isavuconazole possible Dose adjustments for isavuconazole may be necessary. Consider monitoring isavuconazole level and antifungal response.
RPV ↓ isavuconazole possible (likely to a lesser extent than with other NNRTIs)

↑ RPV possible 		No dosage adjustment necessary. Clinically monitor for breakthrough fungal infection.
Itraconazole EFV Itraconazole and OH-itraconazole AUC, Cmax, and Cmin ↓ 35% to 44% Failure to achieve therapeutic itraconazole concentrations has been reported. Avoid this combination if possible. If coadministered, closely monitor itraconazole concentration and adjust dose accordingly.
ETR ↓ itraconazole possible
↑ ETR possible		 Dose adjustments for itraconazole may be necessary. Monitor itraconazole level and antifungal response.
NVP ↓ itraconazole possible
↑ NVP possible		 Avoid combination if possible. If coadministered, monitor itraconazole concentration and adjust dose accordingly.
RPV ↓ itraconazole possible
↑ RPV possible 		No dosage adjustment necessary. Clinically monitor for breakthrough fungal infection.
Posaconazole EFV Posaconazole AUC ↓ 50%
↔ EFV		 Avoid concomitant use unless the benefit outweighs the risk. If coadministered, monitor posaconazole concentration and adjust dose accordingly.
ETR ↑ ETR possible No dosage adjustment necessary.
RPV ↓ posaconazole possible
↑ RPV possible 		No dosage adjustment necessary. Clinically monitor for breakthrough fungal infection.
Voriconazole EFV Voriconazole AUC ↓ 77%
EFV AUC ↑ 44%		 Contraindicated at standard doses.

Dose adjustment:
  • Voriconazole 400 mg BID, EFV 300 mg daily
ETR Voriconazole AUC ↑ 14%
ETR AUC ↑ 36%		 No dosage adjustment necessary; use with caution. Consider monitoring voriconazole level.
NVP ↓ voriconazole possible
↑ NVP possible		 Monitor for toxicity and antifungal response and/or voriconazole level.
RPV ↓ voriconazole possible
↑ RPV possible 		No dosage adjustment necessary. Clinically monitor for breakthrough fungal infection.
Antimalarials
Artemether/Lumefantrine
 EFV Artemether AUC ↓ 79%
DHA AUC ↓ 75%
Lumefantrine AUC ↓ 56%		 Consider alternative ARV or antimalarial drug. If used in combination, monitor closely for antimalarial efficacy and malaria recurrence.
ETR Artemether AUC ↓ 38%
DHA AUC ↓ 15%
Lumefantrine AUC ↓ 13%
ETR AUC ↑ 10%		 Clinical significance of the reduced antimalarial drug concentrations unknown. If used in combination with ETR, monitor closely for antimalarial efficacy.
NVP Artemether AUC ↓ 67% to 72%

DHA:
  • Study results are conflicting. AUC ↓ 37% in one study, no difference in another.


Lumefantrine:
  • Study results are conflicting. Lumefantrine AUC ↓ 25% to 58% in 2 studies but ↑ 56% in another.
 Clinical significance unknown. If used, monitor closely for antimalarial efficacy and lumefantrine toxicity.
Atovaquone/Proguanil EFV Atovaquone AUC ↓ 75%
Proguanil AUC ↓ 43%		 No dosage recommendation. Consider alternative drug for malaria prophylaxis, if possible.
Antimycobacterials
Bedaquiline
 EFV ↓ bedaquiline possible Not Recommended.
NVP ↔ bedaquiline AUC No dosage adjustment necessary.
Clarithromycin EFV Clarithromycin AUC ↓ 39% Monitor for effectiveness or consider alternative agent, such as azithromycin, for MAC prophylaxis and treatment.
ETR Clarithromycin AUC ↓ 39%

ETR AUC ↑ 42%		 Consider alternative agent, such as azithromycin, for MAC prophylaxis and treatment.
NVP Clarithromycin AUC ↓ 31% Monitor for effectiveness or use alternative agent, such as azithromycin, for MAC prophylaxis and treatment.
RPV ↔ clarithromycin expected
↑ RPV possible		 Consider alternative macrolide, such as azithromycin, for MAC prophylaxis and treatment.
Rifabutin EFV Rifabutin ↓ 38% Dose:
  • Rifabutin 450–600 mg/day; or
  • Rifabutin 600 mg 3 times/week if EFV is not coadministered with a PI.
ETR Rifabutin and metabolite AUC ↓ 17%

ETR AUC ↓ 37%		 If ETR is used with RTV-boosted PI, rifabutin should not be coadministered.

Dose:
  • Rifabutin 300 mg once daily if ETR is not coadministered with a PI/r.
NVP Rifabutin AUC ↑ 17% and metabolite AUC ↑ 24%

NVP Cmin ↓ 16%		 No dosage adjustment necessary. Use with caution.
RPV Rifabutin plus RPV 50 mg once daily compared to RPV 25 mg once daily alone:

↔ RPV AUC, Cmin 		Increase RPV dose to 50 mg once daily.
Rifampin EFV EFV AUC ↓ 26% Maintain EFV dose at 600 mg once daily and monitor for virologic response. Consider therapeutic drug monitoring.
ETR Significant ↓ ETR possible Do not coadminister.
NVP NVP ↓ 20% to 58% Do not coadminister.
RPV RPV AUC ↓ 80% Contraindicated. Do not coadminister.
Rifapentine EFV ↔ EFV concentrations No dosage adjustment necessary.
ETR, NVP, RPV ↓ NNRTI possible Do not coadminister.
Antipneumocystis and Antitoxoplasmosis Drugs
Atovaquone EFV Atovaquone AUC ↓ 44 to 47% Consider alternative agent for PCP or toxoplasmosis treatment or use alternative ARV drug.

If used in combination, monitor therapeutic efficacy of atovaquone.
Benzodiazepines
Alprazolam EFV, ETR, NVP, RPV No data Monitor for therapeutic effectiveness of alprazolam.
Diazepam ETR ↑ diazepam possible Decreased dose of diazepam may be necessary.
Lorazepam EFV Lorazepam Cmax ↑ 16%,
AUC ↔		 No dosage adjustment necessary.
Midazolam EFV Significant ↑ midazolam expected Do not coadminister with oral midazolam.
Parenteral midazolam can be used with caution as a single dose and can be given in a monitored situation for procedural sedation.
Triazolam EFV Significant ↑ triazolam expected Do not coadminister.
Cardiac Medications
Dihydropyridine CCBs EFV, NVP ↓ CCBs possible Titrate CCB dose based on clinical response.
Diltiazem
Verapamil		 EFV Diltiazem AUC ↓ 69%
↓ verapamil possible		 Titrate diltiazem or verapamil dose based on clinical response.
NVP ↓ diltiazem or verapamil possible
Corticosteroids
Dexamethasone EFV, ETR, NVP ↓ EFV, ETR, NVP possible Consider alternative corticosteroid for long-term use. If dexamethasone is used with NNRTI, monitor virologic response.
RPV Significant ↓ RPV possible Contraindicated with more than a single dose of dexamethasone.
Hepatitis C Direct Acting Antiviral Agents 
Daclatasvir EFV, ETR, NVP Daclatasvir Cmin ↓ 17%, following daclatasvir 120 mg once daily + EFV 600 mg daily Daclatasvir 90 mg once daily.
RPV No data No dosage adjustment necessary.
Dasabuvir plus Paritaprevir/Ombitasivir/ RTV EFV No data Contraindicated. Do not coadminister.
ETR, NVP ↓ DAAs possible Do not coadminister.
 RPV RPV AUC ↑ 150% to 225% Do not coadminister because of potential for QT interval prolongation with higher concentrations of RPV.
Elbasvir/Grazoprevir EFV Elbasvir AUC ↓ 54%
Grazoprevir AUC ↓83%

EFV ↔ by grazoprevir
EFV ↔ AUC by elbasvir 		Contraindicated.
ETR, NVP ↓ elbasvir, grazoprevir expected Do not coadminister.
RPV Elbasvir, grazoprevir and RPV ↔ No dosage adjustment necessary.
Ledipasvir/Sofosbuvir  EFV Ledipasvir AUC, Cmin, Cmax – all ↓ 34% 
Sofosbuvir: no significant effect		 No dosage adjustment necessary.
ETR, NVP, RPV  No significant effect expected
Simeprevir
 EFV Simeprevir AUC ↓ 71%, Cmin ↓ 91%
↔ EFV 		 Coadministration is not recommended.
ETR, NVP
 ↓ simeprevir expected
 Coadministration is not recommended.
RPV ↔ simeprevir and RPV
 No dosage adjustment necessary.
Herbal Products
St. John’s Wort EFV, ETR, NVP, RPV ↓ NNRTI Do not coadminister.
Hormonal Contraceptives
Hormonal Contraceptives EFV Ethinyl estradiol ↔

Levonorgestrel (oral) AUC ↓ 64%

Norelgestromin AUC ↓ 64%

Etonogestrel (implant) AUC ↓ 63%

Levonorgestrel (implant) AUC ↓ 48%

Use alternative or additional contraceptive methods. Norelgestromin and levonorgestrel are active metabolites of norgestimate.

Unintended pregnancies were observed in women who used EFV and levonorgestrel implant concomitantly.
ETR Ethinyl estradiol AUC ↑ 22%

Norethindrone: no significant effect		 No dosage adjustment necessary.
NVP Ethinyl estradiol AUC ↓ 29% Cmin ↓ 58%

Norethindrone AUC ↓ 18%

Etonogestrel (metabolite of oral desogestrel) ↓ 22%		 Consider alternative or additional contraceptive methods.
DMPA: no significant change No dosage adjustment necessary.
Levonorgestrel implant: AUC ↑ 30% No dosage adjustment necessary.
RPV Ethinyl estradiol: no significant change

Norethindrone: no significant change		 No dosage adjustment necessary.
Levonorgestrel
For emergency contraception		 EFV Levonorgestrel AUC ↓ 58% Effectiveness of emergency postcoital contraception may be diminished.
HMG-CoA Reductase Inhibitors
Atorvastatin EFV, ETR Atorvastatin AUC ↓ 32% to 43% Adjust atorvastatin according to lipid responses, not to exceed the maximum recommended dose.
RPV Atorvastatin AUC ↔
Atorvastatin metabolites ↑		 No dosage adjustment necessary.
Fluvastatin ETR ↑ fluvastatin possible Dose adjustments for fluvastatin may be necessary.
Lovastatin
Simvastatin		 EFV Simvastatin AUC ↓ 68% Adjust simvastatin dose according to lipid responses, not to exceed the maximum recommended dose. If EFV is used with a PI/r, simvastatin and lovastatin should be avoided.
ETR, NVP ↓ lovastatin possible
↓ simvastatin possible		 Adjust lovastatin or simvastatin dose according to lipid responses, not to exceed the maximum recommended dose. If ETR or NVP is used with a PI/r, simvastatin and lovastatin should be avoided.
Pitavastatin EFV Pitavastatin AUC ↓ 11%, Cmax ↑ 20% No dosage adjustment necessary.
ETR, NVP, RPV
 No data No significant effect expected. No dosage adjustment necessary.
Pravastatin
Rosuvastatin		 EFV Pravastatin AUC ↓ 44%
Rosuvatatin: no data		 Adjust statin dose according to lipid responses, not to exceed the maximum recommended dose.
ETR No significant effect expected No dosage adjustment necessary.
Immunosuppressants
Cyclosporine
Sirolimus
Tacrolimus		 EFV,
ETR,
NVP		 ↓ immunosuppressant possible Increase in immunosuppressant dose may be necessary. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with specialist as necessary.
Narcotics/Treatments for Opioid Dependence
Buprenorphine sublingual/buccal EFV Buprenorphine AUC ↓ 50%
Norbuprenorphineb AUC ↓ 71%		 No dosage adjustment recommended; monitor for withdrawal symptoms.
ETR Buprenorphine AUC ↓ 25% No dosage adjustment necessary.
NVP No significant effect No dosage adjustment necessary.
Buprenorphine
implant		 EFV, ETR, NVP No data Clinical monitoring is recommended if NNRTI is initiated after insertion of buprenorphine implant.
Methadone EFV Methadone AUC ↓ 52% Opioid withdrawal common; increased methadone dose often necessary.
ETR No significant effect No dosage adjustment necessary.
NVP Methadone AUC ↓ 37% to 51%
NVP: no significant effect		 Opioid withdrawal common; increased methadone dose often necessary.
RPV R-methadonec AUC ↓ 16% No dosage adjustment necessary, but monitor for withdrawal symptoms.
PDE5 Inhibitors
Avanafil EFV, ETR, NVP, RPV No data Coadministration is not recommended.
Sildenafil ETR Sildenafil AUC ↓ 57% May need to increase sildenafil dose based on clinical effect.
RPV ↔ sildenafil  No dosage adjustment necessary.
Tadalafil ETR ↓ tadalafil possible May need to increase tadalafil dose based on clinical effect.
Vardenafil ETR ↓ vardenafil possible May need to increase vardenafil dose based on clinical effect.

a Approved dose for RPV is 25 mg once daily. Most PK interaction studies were performed using 75 to 150 mg per dose.
b Norbuprenorphine is an active metabolite of buprenorphine.
c R-methadone is the active form of methadone.

Key to Symbols: ↑ = increase, ↓ = decrease, ↔ = no change

Key to Acronyms: ARV = antiretroviral; AUC = area under the curve; BID = twice daily; CCB = calcium channel blockers; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; DAAs = direct-acting antivirals; DHA = dihydroartemisinin; DLV = delavirdine; DMPA = depot medroxyprogesterone acetate; EFV = efavirenz; ETR = etravirine; FDA = Food and Drug Administration; HMG-CoA = hydroxy-methylglutaryl-coenzyme A; INR = international normalized ratio; MAC = Mycobacterium avium complex; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = nevirapine; OH-itraconazole = active metabolite of itraconazole; PCP = Pneumocystis jiroveci pneumonia; PDE5 = phosphodiesterase type 5; PI = protease inhibitor; PK = pharmacokinetic; PPI = proton pump inhibitor; RPV = rilpivirine; RTV = ritonavir

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