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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: May 1, 2014; last reviewed: May 1, 2014)

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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.

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

 

Table 18b. Drug Interactions between Non-Nucleoside Reverse Transcriptase Inhibitorsa and Other Drugs
Concomitant Drug Class/Name NNRTIa Effect on NNRTI 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 20mg daily, ↓ RPV AUC 40%, Cmin 33% Contraindicated. Do not co-administer.
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 co-administration, if possible.
Anticonvulsants
Carbamazepine
Phenobarbital
Phenytoin
EFV Carbamazepine plus EFV
Carbamazepine AUC ↓ 27%, and 
EFV AUC ↓ 36%

Phenytoin plus EFV:
↓ EFV, and 
↓ phenytoin possible
Monitor anticonvulsant and EFV levels or, if possible, use alternative anticonvulsant to those listed.
ETR ↓ anticonvulsant and ETR possible Do not co-administer. 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 co-administer. 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 (RPV 150 mg/day reduces ketoconazole exposure; no data on interaction with fluconazole).
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 co-administered, 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 co-administered, monitor itraconazole concentration and adjust dose accordingly.
RPV ↑ RPV possible No dosage adjustment necessary. Clinically monitor for breakthrough fungal infection. (RPV 150 mg/day reduces ketoconazole exposure; no data on interaction with itraconazole.)
Posaconazole EFV posaconazole AUC ↓ 50%
↔ EFV
Avoid concomitant use unless the benefit outweighs the risk. If co-administered, monitor posaconazole concentration and adjust dose accordingly.
ETR ↑ ETR possible No dosage adjustment necessary.
RPV ↑ RPV possible No dosage adjustment necessary. Clinically monitor for breakthrough fungal infection (RPV 150 mg/day reduces ketoconazole exposure; no data on interaction with posaconazole)
Voriconazole EFV voriconazole AUC ↓ 77%
EFV AUC ↑ 44%
Contraindicated at standard doses.
Dose: 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 ↑ RPV possible No dosage adjustment necessary. Clinically monitor for breakthrough fungal infection (RPV 150 mg/day reduces ketoconazole exposure; no data on interaction with voriconazole).
Antimalarials
Artemether/Lumefantrine
EFV artemether AUC ↓ 79%
DHA AUC ↓ 75%
lumefantrine AUC ↓ 56%
Clinical significance unknown. If used, monitor closely for anti-malarial efficacy.
ETR artemether AUC ↓ 38%
DHA AUC ↓ 15%
lumefantrine AUC ↓ 13%
ETR AUC ↑ 10%
Clinical significance unknown. If used, monitor closely for anti-malarial efficacy
NVP artemether AUC ↓ 72%
DHA AUC ↓ 37%
lumefantrine: no difference in one study, but AUC ↑ 55.6% in another study
Clinical significance unknown. If used, monitor closely for anti-malarial 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, 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 once daily or 600 mg 3times a week if EFV is not co-administered 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 co-administered.

Dose: rifabutin 300 mg once daily if ETR is not co-administered with an RTV-boosted PI.
NVP rifabutin AUC ↑ 17% and metabolite AUC ↑ 24%
NVP Cmin ↓ 16%
No dosage adjustment necessary. Use with caution.
RPV RPV AUC ↓ 46% Contraindicated. Do not co-administer.
Rifampin EFV EFV AUC ↓ 26% Maintain EFV dose at 600 mg once daily and monitor for virologic response. Consider therapeutic drug monitoring.

Some clinicians suggest EFV 800 mg dose in patients who weigh more than 60 kg.
ETR Significant ↓ ETR possible Do not co-administer.
NVP NVP ↓ 20% to 58% Do not co-administer.
RPV RPV AUC ↓ 80% Contraindicated. Do not co-administer.
Rifapentine EFV, ETR, NVP, RPV ↓ NNRTI expected Do not co-administer.
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 co-administer 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 co-administer.
Cardiac Medications
Dihydropyridine Calcium Channel Blockers 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 NS3/4A-PIs
Boceprevir EFV EFV AUC ↑ 20%

boceprevir AUC ↓ 19%,
Cmin ↓ 44%
Co-administration is not recommended.
ETR ETR AUC ↓ 23%

boceprevir AUC, Cmax ↑ 10%
No dosage adjustment necessary.
Simeprevir
EFV Simeprevir AUC ↓ 71%, Cmin ↓ 91%

EFV ↔
Co-administration is not recommended.
ETR, NVP
↓ simeprevir expected
Co-administration is not recommended.
RPV Simeprevir ↔ and RPV ↔
No dosage adjustment necessary.
Telaprevir EFV EFV AUC ↔

telaprevir AUC ↓ 26%, Cmin ↓ 47%

With TDF
EFV AUC ↓ 15% to 18%
Telaprevir AUC ↓ 18% to 20%
Increase telaprevir dose to 1125 mg q8h.
ETR ETR AUC ↔

telaprevir AUC ↓ 16%, Cmin ↓ 25%
No dosage recommendation.
Herbal Products
St. John’s Wort EFV, ETR, NVP, RPV ↓ NNRTI Do not co-administer.
Hormonal Contraceptives
Hormonal Contraceptives EFV ethinyl estradiol ↔

levonorgestrel AUC ↓ 83%

norelgestromin AUC ↓ 64%

↓ etonogestrel (implant) possible
Use alternative or additional contraceptive methods. Norelgestromin and levonorgestrel are active metabolites of norgestimate.
ETR ethinyl estradiol AUC ↑ 22%
norethindrone: no significant effect
No dosage adjustment necessary.
 
NVP
ethinyl estradiol AUC ↓ 20%
norethindrone AUC ↓ 19%
Use alternative or additional contraceptive methods.
DMPA: no significant change No dosage adjustment necessary
RPV ethinyl estradiol AUC ↑ 14%
norethindrone: no significant change
No dosage adjustment necessary
Levonorgestrel
(for emergency contraception)
EFV levonorgestrel AUC ↓ 58% Effectiveness of emergency post-coital 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 used with RTV-boosted PI, 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 used with RTV-boosted PI, 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/Treatment for Opioid Dependence
Buprenorphine 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.
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 Co-administration 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 Acronyms: ARV = antiretroviral; AUC = area under the curve; BID = twice daily; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; DHA = dihydroartemisinin; DLV = delavirdine; DMPA = depot medroxyprogesterone acetate; EFV = efavirenz; ETR = etravirine; FDA = Food and Drug Administration; INR = international normalized ratio; MAC = Mycobacterium avium complex; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; OH-clarithromycin = active metabolite of clarithromycin; PDE5 = phosphodiesterase type 5; PI = protease inhibitor; PPI = proton pump inhibitor; RPV = rilpivirine; RTV = ritonavir; TDF = tenofovir disoproxil fumarate

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