Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV

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Drug-Drug Interactions

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

Last Updated: October 17, 2017; Last Reviewed: October 17, 2017

Table 18b. 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 18c, 19a, and 19b. Recommendations for managing a particular drug interaction may differ depending on whether a new ARV drug is being initiated in a patient on a stable concomitant medication or if a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of drug interactions are difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly.

Note: Delavirdine (DLV) is not included in this table. Please refer to the DLV Food and Drug Administration package insert for information regarding drug interactions.

Table 18b. 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
Apixaban EFV, ETR, NVP ↓ apixaban possible Consider alternative therapy.
Betrixaban EFV, NVP, RPV ↔ betrixaban expected No dose adjustment necessary.
ETR ↑ betrixaban possible Consider alternative therapy. If coadministration is necessary, reduce betrixaban initial dose to 80 mg, followed by 40 mg daily. Monitor for betrixaban toxicity.
Clopidogrel ETR ↓ activation of clopidogrel possible ETR may prevent metabolism of clopidogrel (inactive) to its active metabolite. Avoid coadministration, if possible.
NVP, RPV ↔ clopidogrel expected No dose adjustment necessary.
Dabigatran EFV, NVP, RPV ↔ dabigatran expected No dose adjustment necessary.
ETR ↑ dabigatran possible Consider alternative therapy. If coadministration is necessary, monitor for dabigatran toxicity.
Edoxaban EFV, NVP, RPV ↔ edoxaban expected No dose adjustment necessary.
ETR ↑ edoxaban possible Consider alternative therapy. If coadministration is necessary, monitor for edoxaban toxicity.
Prasugrel EFV, ETR, NVP, RPV ↔ prasugrel expected No dose adjustment necessary.
Rivaroxaban EFV, ETR, NVP ↓ rivaroxaban possible Consider alternative therapy.
Ticagrelor EFV, ETR, NVP ↓ ticagrelor expected Consider alternative therapy.
Warfarin EFV, ETR, NVP ↑ or ↓ warfarin possible Monitor INR and adjust warfarin dose accordingly.
Anticonvulsants
Carbamazepine, Phenobarbital, Phenytoin EFV Carbamazepine + EFV:
  • Carbamazepine AUC ↓ 27%
  • EFV AUC ↓ 36%

Phenytoin + 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.
Eslicarbazepine EFV, ETR, NVP, RPV ↓ NNRTI possible Monitor virologic outcomes and consider monitoring plasma concentrations of ARVs, or consider alternative anticonvulsant or ARV drug.
Oxcarbazepine RPV ↓ RPV possible Contraindicated. Do not coadminister. Consider alternative anticonvulsant.
Ethosuximide, Lacosamide, Tiagabine, Zonisamide ETR, EFV ↓ anticonvulsant possible Monitor seizure control and plasma concentrations of anticonvulsants (when available).
Lamotrigine EFV ↓ lamotrigine possible Monitor seizure control and plasma concentrations of lamotrigine.
Antidepressants
Bupropion EFV, NVP Bupropion AUC ↓ 55%

↓ bupropion possible
Titrate bupropion dose based on clinical response.
Citalopram, Escitalopram EFV, ETR, NVP ↓ antidepressant possible Titrate antidepressant dose based on clinical response.
Fluoxetine, Fluvoxamine EFV, ETR, NVP, RPV ↔ antidepressant expected No dose adjustment necessary.
Paroxetine EFV, ETR, NVP, RPV ↔ paroxetine observed with EFV or ETR

↔ expected with NVP or RPV
No dose adjustment necessary.
Nefazodone EFV, ETR, NVP ↓ nefazodone expected

↑ NNRTI possible
Monitor the antidepressant effect and titrate dose as necessary. Monitor for ARV-related adverse events.
RPV ↑ RPV possible
Sertraline EFV Sertraline AUC ↓ 39% Titrate sertraline dose based on clinical response.
Trazodone EFV, ETR, NVP ↓ trazodone possible Monitor the therapeutic effect of trazodone and titrate dose as necessary.
Antifungals
Fluconazole EFV ↔ fluconazole or EFV No dose adjustment necessary.
ETR ETR AUC ↑ 86% No dose 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 dose adjustment necessary.
Isavuconazole EFV, ETR, NVP ↓ isavuconazole possible Dose adjustments for isavuconazole may be necessary. Consider monitoring isavuconazole level and antifungal response.
RPV ↑ RPV possible No dose adjustment necessary.
Itraconazole EFV Itraconazole and OH-itraconazole AUC, Cmax, and Cmin ↓ 35%–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 AUC ↓ 61%

↑ NVP possible
Avoid this combination if possible. If coadministered, monitor itraconazole concentration and adjust dose accordingly.
RPV ↑ RPV possible No dose adjustment necessary.
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, NVP, RPV ↑ NNRTI possible Monitor for NNRTI toxicities.
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 dose 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 ↑ RPV possible No dose adjustment necessary.
Antihyperglycemics
Canagliflozin, Dapagliflozin, Empagliflozin, Sitagliptin EFV, ETR, NVP, RPV ↔ antihyperglycemic expected No dose adjustment necessary.
Linagliptin, Saxagliptin EFV, ETR, NVP ↓ antihyperglycemic possible Monitor glycemic control.
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%–72%

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

Lumefantrine:
  • Study results are conflicting. Lumefantrine AUC ↓ 25%– 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 dose recommendation. Consider alternative drug for malaria prophylaxis, if possible.
Antimycobacterials
Bedaquiline EFV, ETR ↓ bedaquiline possible Do not coadminister.
NVP ↔ bedaquiline AUC No dose 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%

NVP AUC ↑ 26%
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 an 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 dose adjustment necessary. Use with caution.
RPV Rifabutin + 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%–58% Do not coadminister.
RPV RPV AUC ↓ 80% Contraindicated. Do not coadminister.
Rifapentine EFV ↔ EFV concentrations No dose adjustment necessary.
ETR, NVP ↓ NNRTI possible Do not coadminister.
RPV ↓ RPV expected Contradindicated.
Antipneumocystis and Antitoxoplasmosis Drugs
Atovaquone EFV Atovaquone AUC ↓ 44%–47% Consider alternative agent for PCP or toxoplasmosis treatment or use alternative ARV drug. If used in combination, monitor therapeutic efficacy of atovaquone.
Antipsychotics
Olanzapine EFV ↓ olanzapine possible Monitor effect of olanzapine.
ETR, NVP, RPV ↔ olanzapine expected No dose adjustment necessary.
Pimozide EFV ↑ pimozide possible Coadministration is not recommended. Consider alternative antipsychotic.
ETR, NVP ↓ pimozide possible Monitor effect of pimozide.
Lurasidone, Quetiapine, Thioridazine EFV, ETR, NVP ↓ antipsychotic possible Monitor effect of antipsychotic.
Benzodiazepines
Alprazolam EFV, ETR, NVP ↓ alprazolam possible Monitor for therapeutic effectiveness of alprazolam.
Diazepam EFV, NVP ↓ diazepam possible Monitor for therapeutic effectiveness of diazepam.
ETR ↑ diazepam possible Decreased dose of diazepam may be necessary. Monitor for diazepam toxicity.
Lorazepam EFV Lorazepam Cmax ↑ 16%, AUC ↔ No dose 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, ETR, 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, and 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 120 mg once daily + EFV 600 mg daily compared to daclatasvir 60 mg alone: daclatasvir Cmin ↓ 17%, AUC ↑ 37% The recommended dose is daclatasvir 90 mg once daily.
RPV No data No dose adjustment necessary.
Dasabuvir + Paritaprevir/ Ombitasivir/ RTV EFV No data Contraindicated.
ETR, NVP ↓ DAAs possible Do not coadminister.
RPV RPV AUC ↑ 150%–225% Do not coadminister, due to 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 dose adjustment necessary.
Glecaprevir/ Pibrentasvir EFV ↓ glecaprevir and pibrentasvir expected Do not coadminister.
NVP, ETR ↓ glecaprevir and pibrentasvir possible
RPV ↔ glecaprevir, pibrentasvir, and RPV AUC ↑ 84% No dose adjustment necessary.
Ledipasvir/ Sofosbuvir EFV Ledipasvir AUC, Cmin, and Cmax: all ↓ 34%

Sofosbuvir: no significant effect
No dose adjustment necessary.
ETR, NVP No significant effect expected
RPV Ledipasvir, sofosbuvir, and RPV ↔
Simeprevir EFV Simeprevir AUC ↓ 71%, Cmin ↓ 91%

↔ EFV
Do not coadminister.
ETR, NVP ↓ simeprevir expected Do not coadminister.
RPV ↔ simeprevir and RPV No dose adjustment necessary.
Sofosbuvir/ Velpatasvir EFV Velpatasvir AUC ↓ 43% , Cmax ↓ 37% and Cmin ↓ 47% Do not coadminister.
ETR, NVP ↓ velpatasvir expected Do not coadminister.
RPV No significant effect expected No dose adjustment necessary.
Sofosbuvir/ Velpatasvir/ Voxilaprevir EFV Velpatasvir AUC ↓ 43% , Cmax ↓37% and Cmin ↓47

↓ voxilaprevir expected
Do not coadminister.
ETR, NVP, ↓ voxilaprevir expected

↓ velpatasvir expected
Do not coadminister.
RPV No signficant effect expected No dose adjustment necessary.
Herbal Products
St. John’s Wort EFV, ETR, NVP, RPV ↓ NNRTI Contraindicated.
Hormonal Therapies
Hormonal Contraceptives EFV Ethinyl estradiol ↔

Levonorgestrel (metabolite of oral norgestimate) AUC ↓ 83%

Norelgestromin (metabolite of oral norgestimate) AUC ↓ 64%

Etonogestrel (metabolite of oral desogestrel) Cmin ↓ 61%

Etonogestrel (implant) AUC ↓ 63%–82%

Levonorgestrel (implant) AUC ↓ 47%
Use alternative or additional contraceptive methods.

Unintended pregnancies were observed in women who used EFV and levonorgestrel implant concomitantly.
DMPA: no significant change No dose adjustment necessary.
ETR Ethinyl estradiol AUC ↑ 22%

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

Norethindrone AUC ↓ 18%

Etonogestrel (metabolite of oral desogestrel) Cmin ↓ 22%
Based on clinical data demonstrating no change in effectiveness, no dose adjustment necessary.
Etonogestrel (implant): no significant change No dose adjustment necessary.
DMPA: no significant change No dose adjustment necessary.
Levonorgestrel (implant) AUC ↑ 35% No dose adjustment necessary.
RPV Ethinyl estradiol: no significant change

Norethindrone: no significant change
No dose adjustment necessary.
Levonorgestrel
For emergency contraception
EFV Levonorgestrel AUC ↓ 58% Effectiveness of emergency postcoital contraception may be diminished.
Menopausal Hormone Replacement Therapy EFV, ETR, NVP With estradiol or conjugated estrogen (equine and synthetic): ↓ estrogen possible

↓ medroxyprogesterone possible

↓ micronized progesterone possible

↓ drospirenone possible

See Hormonal Contraceptives for other progestin-NNRTI interactions
Monitor menopausal symptoms. The lowest dose of hormonal therapy should be used to achieve menopausal symptom relief.
Gender-Affirming Hormone Therapy EFV, ETR, NVP ↓ estradiol possible

↔ goserelin, leuprolide acetate, and spironolactone expected

↓ dutasteride and finasteride possible
Monitor feminizing effects of estrogen and antiandrogen therapy and adjust dosing as necessary.
EFV, ETR, NVP ↓ testosterone possible Monitor masculinizing effects of testosterone and adjust testosterone dose as necessary.
HMG-CoA Reductase Inhibitors
Atorvastatin EFV, ETR Atorvastatin AUC ↓ 32%–43% Adjust atorvastatin according to lipid responses, but do not exceed the maximum recommended dose.
NVP ↓ atorvastatin possible Adjust atorvastatin according to lipid responses, not to exceed the maximum recommended dose.
RPV Atorvastatin AUC ↔

Atorvastatin metabolites ↑ 23%–39%
No dose adjustment necessary.
Fluvastatin EFV, ETR ↑ fluvastatin possible Dose adjustments for fluvastatin may be necessary. Monitor for fluvastatin toxicity.
Lovastatin, Simvastatin EFV Simvastatin AUC ↓ 68%

Simvastatin active metabolite AUC ↓ 60%
Adjust simvastatin dose according to lipid responses, but do not 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, but do not 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 dose adjustment necessary.
ETR, NVP, RPV ↔ pitavastatin expected No dose adjustment necessary.
Pravastatin EFV Pravastatin AUC ↓ 44% Adjust statin dose according to lipid responses, but do not exceed the maximum recommended dose.
ETR ↓ pravastatin possible
Rosuvastatin EFV, ETR, NVP ↔ rosuvastatin expected No dose adjustment necessary.
Immunosuppressants
Cyclosporine, Everolimus, 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 or buccal
EFV Buprenorphine AUC ↓ 50%

Norbuprenorphineb AUC ↓ 71%
No dose adjustment recommended; monitor for withdrawal symptoms.
ETR Buprenorphine AUC ↓ 25% No dose adjustment necessary.
NVP No significant effect No dose 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 dose 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 dose adjustment necessary, but monitor for withdrawal symptoms.
PDE5 Inhibitors
Sildenafil ETR Sildenafil AUC ↓ 57% May need to increase sildenafil dose based on clinical effect.
EFV, NVP ↓ sildenafil possible
RPV ↔ sildenafil No dose adjustment necessary.
Avanafil, Tadalafil, Vardenafil EFV, ETR, NVP ↓ PDE5 inhibitor possible May need to increase PDE5 inhibitor 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; DMPA = depot medroxyprogesterone acetate; EFV = efavirenz; ETR = etravirine; 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; PI/r = protease inhibitor/ritonavir; PK = pharmacokinetic; PPI = proton pump inhibitor; RPV = rilpivirine; RTV = ritonavir

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