Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV
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.
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:
|
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:
Phenytoin + EFV:
|
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:
|
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:
Lumefantrine:
|
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:
|
ETR | Rifabutin and metabolite AUC ↓ 17%
ETR AUC ↓ 37% |
If ETR is used with an RTV-boosted PI, rifabutin should not be coadministered.
Dose:
|
|
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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