Updated
Reviewed
Jun. 03, 2021

Drug-Drug Interactions

Table 24a. Drug Interactions Between Protease Inhibitors and Other Drugs

This table provides information on the known or predicted interactions between protease inhibitors (PIs) and non- antiretroviral (ARV) drugs. When information is available, interactions for boosted atazanavir (ATV) (with either ritonavir [RTV] or cobicistat [COBI]) and unboosted ATV are listed separately. The term “all PIs” refers to both unboosted ATV and ATV, darunavir (DRV), and lopinavir (LPV) boosted with either RTV or COBI. This table does not include interactions for fosamprenavir, indinavir (IDV), nelfinavir (NFV), saquinavir (SQV), or tipranavir (TPV). For information regarding interactions between PIs and other ARV drugs, including dosing recommendations, refer to Tables 24c, 25a, and 25b.

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 whether 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. In cases where an interacting drug needs to be replaced with an alternative, providers should exercise their clinical judgement to select the most appropriate alternative medication to use.

Note: FPV, IDV, NFV, SQV, and TPV are no longer commonly used in clinical practice and are not included in this table. Please refer to the FDA product labels for these for information regarding drug interactions between these PIs and concomitant medications.

Table 24a. Drug Interactions Between Protease Inhibitors and Other Drugs
Concomitant Drug PI Effect on PI and/or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments
Acid Reducers
Antacids ATV, ATV/c, ATV/r When Given Simultaneously:
  • ↓ ATV expected
Administer ATV at least 2 hours before or 2 hours after antacids or buffered medications.
H2 Receptor Antagonists ATV (unboosted) When Given Simultaneously with Famotidine:
  • ATV AUC ↓ 41%
When Given 2 Hours Before and ≥10 Hours After H2RA:
  • ↔ ATV

A single dose of H2RA should not exceed a dose equivalent to famotidine 20 mg, and the total daily dose should not exceed a dose equivalent to famotidine 20 mg twice daily in PI-naive patients.

Give ATV with food at least 2 hours before and at least 10 hours after the H2RA.

Do not coadminister unboosted ATV plus H2RA in PI-experienced patients.

ATV/c, ATV/r ↓ ATV expected

H2RA dose should not exceed a dose equivalent to famotidine 40 mg twice daily in ART-naive patients or famotidine 20 mg twice daily in ART-experienced patients.

Give ATV 300 mg (plus COBI 150 mg or RTV 100 mg) with food simultaneously with and/or ≥10 hours after the dose of H2RA.

If using TDF and H2RA in ART-experienced patients, administer ATV 400 mg plus RTV 100 mg with food simultaneously with and/or ≥10 hours after the dose of H2RA. 

Do not coadminister ATV/c with TDF and H2RA in ART-experienced patients. 

DRV/c, DRV/r, LPV/r With Ranitidine:
  • ↔ DRV/r
↔ PI expected
No dose adjustment needed.
Proton Pump Inhibitors ATV (unboosted) With Omeprazole 40 mg:
  • ATV AUC ↓ 94%
Do not coadminister.
ATV/c, ATV/r With Omeprazole 40 mg:
  • ATV AUC ↓ 76%
When Omeprazole 20 mg is Given 12 Hours before ATV/c or ATV/r:
  • ATV AUC ↓ 42%

PPI dose should not exceed a dose equivalent to omeprazole 20 mg daily in PI-naive patients.

PPIs should be administered at least 12 hours before ATV/c or ATV/r.

Do not coadminister in PI-experienced patients.

DRV/c, LPV/r ↔ PI expected No dose adjustment needed.
DRV/r

↔ DRV/r

Omeprazole AUC ↓ 42%

Consider alternative ARV or acid reducer. If coadministered, monitor for omeprazole efficacy. If the patient does not experience symptomatic relief, increase the dose to no more than omeprazole 40 mg daily.
Alpha-Adrenergic Antagonists for Benign Prostatic Hyperplasia
Alfuzosin All PIs ↑ alfuzosin expected Contraindicated.
Doxazosin All PIs ↑ doxazosin possible Initiate doxazosin at lowest dose and titrate while monitoring for clinical response/adverse events. Dose reduction may be necessary.
Tamsulosin All PIs ↑ tamsulosin expected Do not coadminister, unless benefits outweigh risks. If coadministered, monitor for tamsulosin-related adverse events.
Terazosin All PIs ↔ or ↑ terazosin possible Initiate terazosin at lowest dose and titrate while monitoring for clinical response/adverse events. Dose reduction may be necessary.
Silodosin All PIs ↑ silodosin expected Contraindicated.
Antibacterials
Antimycobacterials
Bedaquiline All PIs With LPV/r:
  • Bedaquiline AUC ↑ 1.9-fold
With other PI/r, ATV/c, or DRV/c:
  • ↑ bedaquiline possible
Do not coadminister, unless benefits outweigh risks. Monitor liver function and ECG for QTc prolongation.
Rifabutin ATV (unboosted) ↑ rifabutin AUC expected

Recommended dose is rifabutin 150 mg once daily.

Monitor for antimycobacterial activity and consider therapeutic drug monitoring. Monitor for rifabutin-related adverse events, including neutropenia and uveitis. 

PK data in this table are results from healthy volunteer studies. Lower rifabutin exposure has been reported in patients with HIV than in healthy study participants.

ATV/r Compared with Rifabutin (300 mg Once Daily) Alone, Rifabutin (150 mg Once Daily) plus ATV/r:
  • Rifabutin AUC ↑ 110% and metabolite AUC ↑ 2,101%
DRV/r Compared with Rifabutin (300 mg Once Daily) Alone, Rifabutin (150 mg Every Other Day) plus DRV/r:
  • ↔ rifabutin AUC and metabolite AUC ↑ 881%
LPV/r Compared with Rifabutin (300 mg Daily) Alone, Rifabutin (150 mg Once Daily) plus LPV/r:
  • Rifabutin AUC ↑ 203% and metabolite AUC ↑ 375%
PI/c

↑ rifabutin expected

↓ COBI expected

Do not coadminister.
Rifampin All PIs ↓ PI concentration by >75% Contraindicated. Increasing the dose of RTV does not overcome this interaction and may increase hepatotoxicity. Increasing the COBI dose is not recommended. Consider rifabutin if a rifamycin is indicated.
Rifapentine All PIs ↓ PI expected Do not coadminister.
Macrolides
Azithromycin ATV (unboosted), ATV/c, ATV/r ↑ azithromycin possible No dose adjustment needed.
DRV/c, DRV/r ↔ azithromycin expected No dose adjustment needed.
Clarithromycin ATV (unboosted)

Clarithromycin AUC ↑ 94%

ATV ↑ 28%

Reduce clarithromycin dose by 50% or consider alternative ARV or azithromycin. Monitor for clarithromycin-related adverse events, including QTc prolongation.
ATV/r, PI/c

↑ Clarithromycin expected 

↑ ATV/r and PI/c expected

Consider alternative ARV or azithromycin. 
DRV/r, LPV/r

DRV/r ↑ clarithromycin AUC 57%

LPV/r ↑ clarithromycin expected

RTV 500 mg twice daily ↑ clarithromycin 77%

Consider alternative ARV or azithromycin.

If use of clarithromycin is necessary in a patient with impaired renal function, reduce clarithromycin dose by 50% in patients with CrCl 30 to 60 mL/min. In patients with CrCl <30 mL/min, reduce clarithromycin dose by 75%. 

Monitor for clarithromycin-related adverse events, including QTc prolongation.

Erythromycin All PIs

↑ erythromycin expected

↑ PIs expected

Consider alternative ARV or use azithromycin.
Anticoagulants
Apixaban ATV (unboosted) ↑ apixaban possible  No data available for dose recommendation. Consider alternative ARV or anticoagulant.
PI/c, PI/r ↑ apixaban expected

Do not coadminister in patients who require apixaban 2.5 mg twice daily.

In Patients Requiring Apixaban 5 mg or 10 mg Twice Daily:

  • Reduce apixaban dose by 50%.
Dabigatran ATV (unboosted), DRV/c, DRV/r, LPV/r No data No data available for dose recommendation. Consider alternative ARV or anticoagulant.
ATV/c, ATV/r

With COBI 150 mg Alone:

Dabigatran AUC ↑ 110% to 127%

↑ dabigatran expected

Dabigatran dosing recommendation depends on indication and renal function. Refer to dabigatran prescribing information for dosing instructions when using dabigatran concomitantly with P-glycoprotein inhibitors.
Edoxaban ATV (unboosted), DRV/c, DRV/r, LPV/r No data No data available for dose recommendation. Consider alternative ARV or anticoagulant.
ATV/r, ATV/c  ↑ edoxaban expected Stroke Prevention in Nonvalvular Atrial Fibrillation Indication:
  • No dose adjustment needed.
Deep Venous Thrombosis and Pulmonary Embolism Indication:
  • Administer edoxaban 30 mg once daily.
Rivaroxaban ATV (unboosted) ↑ rivaroxaban possible  No data available for dose recommendation. Consider alternative ARV or anticoagulant.
PI/c, PI/r ↑ rivaroxaban expected Do not coadminister.
Warfarin PI/c No data

Monitor INR closely when stopping or starting PI/c or PI/r and adjust warfarin dose accordingly.

If switching between RTV and COBI, the effect of COBI on warfarin is not expected to be equivalent to RTV’s effect on warfarin.

PI/r ↓ warfarin possible
Anticonvulsants
Carbamazepine ATV (unboosted) May ↓ PI concentrations substantially Do not coadminister.
ATV/r, LPV/r

↑ carbamazepine possible

May ↓ PI concentrations substantially

Consider alternative ARV or anticonvulsant. If coadministration is necessary, consider monitoring concentrations of both drugs and assess virologic response. Carbamazepine dose reduction may be necessary.

Do not coadminister with LPV/r once daily.

DRV/r

Carbamazepine AUC ↑ 45%

↔ DRV

Monitor anticonvulsant concentration and adjust dose accordingly.
PI/c

↑ carbamazepine possible

↓ cobicistat expected

↓ PI expected

Contraindicated. 
Eslicarbazepine All PIs ↓ PI possible Consider alternative ARV or anticonvulsant. If coadministration is necessary, monitor for virologic response. Consider monitoring anticonvulsant and PI concentrations.
Ethosuximide All PIs ↑ ethosuximide possible Monitor for ethosuximide-related adverse events.
Lamotrigine ATV (unboosted) ↔ lamotrigine No dose adjustment needed.
ATV/r Lamotrigine AUC ↓ 32% A dose increase of lamotrigine may be needed; monitor lamotrigine concentration or consider alternative ARV or anticonvulsant.
LPV/r

Lamotrigine AUC ↓ 50%

↔ LPV

DRV/r ↓ lamotrigine possible
PI/c No data Monitor anticonvulsant concentration and adjust dose accordingly.
Oxcarbazepine All PIs ↓ PI possible Consider alternative ARV or anticonvulsant. If coadministration necessary, monitor for virologic response. Consider monitoring anticonvulsant and PI concentrations.
Phenobarbital ATV (unboosted) ↓ ATV expected Do not coadminister.
ATV/r, DRV/r

↓ phenytoin possible

↓ PI possible

Consider alternative anticonvulsant. If coadministration is necessary, consider monitoring concentrations of both drugs and assessing virologic response.
LPV/r

↓ phenytoin possible

↓ LPV/r possible

Do not coadminister with LPV/r once daily.

Consider alternative anticonvulsant. If coadministration necessary, consider monitoring concentrations of both drugs and assessing virologic response.

PI/c

↓ cobicistat expected

↓ PI expected

Contraindicated.
Phenytoin ATV (unboosted) ↓ ATV expected Do not coadminister.
ATV/r, DRV/r

↓ phenytoin possible

↓ PI possible

Consider alternative anticonvulsant. If coadministration is necessary, consider monitoring concentrations of both drugs and assessing virologic response.
LPV/r

Phenytoin AUC ↓ 31%

LPV/r AUC ↓ 33%

Do not coadminister with LPV/r once daily.

Consider alternative anticonvulsant or monitor concentrations of both drugs and assess virologic response.

PI/c

↓ cobicistat expected

↓ PI expected

Contraindicated.
Valproic Acid All PIs

↓ or ↔ VPA possible

LPV AUC ↑ 38%

No data for other PIs

Monitor VPA concentrations and monitor for PI tolerability.
Antidepressants, Anxiolytics, and Antipsychotics
Also see Sedative/Hypnotics section below
Bupropion ATV (unboosted) ↔ bupropion expected No dose adjustment needed.
ATV/r, DRV/r ↓ bupropion possible Titrate bupropion dose based on clinical response.
LPV/r Bupropion AUC ↓ 57%
PI/c ↔ bupropion expected No dose adjustment needed.
Buspirone All PIs ↑ buspirone expected Administer lowest dose of buspirone with caution and titrate buspirone dose based on clinical response. Dose reduction may be necessary. Monitor for buspirone-related adverse events.
Nefazodone All PIs

↑ nefazodone expected

↑ PI possible

Monitor for nefazodone-related adverse events and PI tolerability.
Trazodone All PIs RTV 200 mg twice daily (for 2 days) ↑ trazodone AUC 240% Administer lowest dose of trazodone and monitor for CNS and CV adverse events.
Tricyclic Antidepressants
Amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine
All PIs ↑ TCA expected Administer lowest possible TCA dose and titrate based on clinical assessment and/or drug concentrations. Monitor for TCA-related adverse events. 
Selective Serotonin Reuptake Inhibitors
(e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)
DRV/r

Paroxetine AUC ↓ 39%

Sertraline AUC ↓ 49%

Titrate SSRI dose based on clinical response.
All PIs except DRV/r No data Titrate SSRI dose using the lowest available initial or maintenance dose.
Antipsychotics
Aripiprazole ATV (unboosted) ↑ aripiprazole expected Administer 50% of the usual aripiprazole dose. Titrate dose based on clinical monitoring for efficacy/adverse events. Refer to aripiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
PI/c, PI/r ↑ aripiprazole expected Administer 25% of the usual aripiprazole dose. Titrate dose based on clinical monitoring for efficacy/adverse events. Refer to aripiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
Brexpiprazole ATV (unboosted) ↑ brexpiprazole expected Administer 50% of the usual brexpiprazole dose. Titrate dose based on clinical monitoring for efficacy/adverse events. Refer to brexpiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
PI/c, PI/r ↑ brexpiprazole expected Administer 25% of the usual brexpiprazole dose. Titrate the dose based on clinical monitoring for efficacy/adverse events. Refer to brexpiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
Cariprazine All PIs ↑ cariprazine expected Starting Cariprazine in a Patient Who Is Already Receiving a PI:
  • Administer cariprazine 1.5 mg on Day 1 and Day 3, with no dose given on Day 2. From Day 4 onward, administer cariprazine 1.5 mg daily. Dose can be increased to a maximum dose of cariprazine 3 mg daily. If the PI is withdrawn, cariprazine dose may need to be increased.
Starting a PI in a Patient Who Is Already Receiving Cariprazine:
  • For patients receiving cariprazine 3 mg or cariprazine 6 mg daily, reduce the dose by half. For patients taking cariprazine 4.5 mg daily, the dose should be reduced to cariprazine 1.5 mg or cariprazine 3 mg daily. For patients taking cariprazine 1.5 mg daily, change to cariprazine 1.5 mg every other day. If PI is withdrawn, the cariprazine dose may need to be increased.
Iloperidone All PIs ↑ iloperidone expected Decrease iloperidone dose by 50%.
Lumateperone All PIs ↑ lumateperone expected Do not coadminister.
Lurasidone ATV (unboosted) ↑ lurasidone expected

Consider alternative ARV or antipsychotic. If coadministration is necessary and atazanavir is added to lurasidone therapy, reduce lurasidone dose by 50%.

If co-administration is necessary and lurasidone is added to atazanavir therapy, the recommended starting dose of lurasidone is 20 mg daily and the maximum recommended dose is 80 mg daily.

PI/c, PI/r ↑ lurasidone expected Contraindicated.
Olanzapine ATV (unboosted), PI/c ↔ olanzapine expected No dose adjustment needed.
PI/r ↓ olanzapine possible Monitor for therapeutic effectiveness of olanzapine.
Other Antipsychotics
CYP3A4 and/or CYP2D6 substrates (e.g., clozapine, perphenazine, risperidone, thioridazine)
PI/c, PI/r ↑ antipsychotic possible Titrate the antipsychotic dose using the lowest initial dose or adjust the maintenance dose accordingly. Monitor for adverse events, including QTc prolongation. 
Pimavanserin ATV (unboosted) No data No data available for dose recommendation. Consider alternative ARV or antipsychotic.
LPV/r ↑ pimavanserin expected Do not coadminister, due to risk for QTc prolongation.
All other PIs ↑ pimavanserin expected Reduce pimavanserin dose to 10 mg once daily.
Pimozide All PIs ↑ pimozide expected Contraindicated.
Quetiapine All PIs ↑ quetiapine expected Starting Quetiapine in a Patient Receiving a PI:
  • Initiate quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine effectiveness and adverse events, including QTc prolongation.
Starting a PI in a Patient Receiving a Stable Dose of Quetiapine:
  • Consider alternative ARV. If co-administered, reduce quetiapine dose to 1/6 of the current dose. Closely monitor for quetiapine effectiveness and adverse events, including QTc prolongation.
Ziprasidone LPV/r ↑ ziprasidone expected Do not coadminister, because of the risk for QTc prolongation.
All other PIs ↑ ziprasidone expected Monitor for ziprasidone-related adverse events, including QTc prolongation.
Antifungals
Fluconazole All PIs

↔ PI expected

↔ fluconazole expected

No dose adjustment needed.
Isavuconazole LPV/r

Isavuconazole AUC ↑ 96%

LPV AUC ↓ 27%

RTV AUC ↓ 31%

If coadministered, monitor isavuconazole concentrations and adverse events. Monitor for virologic response.
All PIs except LPV/r

↑ isavuconazole expected

↑ PI possible

If coadministered, monitor isavuconazole concentrations and monitor for isavuconazole-related adverse events. Monitor for PI tolerability.
Itraconazole ATV (unboosted)

↑ itraconazole expected

Dose based on itraconazole concentrations and monitor for itraconazole-related adverse events.
PI/r, PI/c

↑ itraconazole possible

↑ PI expected

Itraconazole doses >200 mg/day are not recommended unless dosing is guided by itraconazole concentrations.
Posaconazole ATV

ATV AUC ↑ 268%

↑ or ↓ posaconazole possible

If coadministered, monitor posaconazole concentrations and monitor for posaconazole-related or PI-related adverse events.
ATV/r

ATV AUC ↑ 146%

↑ posaconazole possible

All other PIs

↑ PI expected

↑ posaconazole possible

Voriconazole ATV (unboosted)

↑ or ↓ PI possible

↑ or ↓ voriconazole possible

If coadministered, monitor voriconazole concentrations and monitor for voriconazole-related or PI-related adverse events.
PI/c No data Do not coadminister voriconazole and RTV or COBI unless benefits outweigh risks. If coadministered, monitor voriconazole concentration and adjust dose accordingly.
PI/r RTV 100 mg twice daily ↓ voriconazole AUC 39%
Antimalarials
Artemether/Lumefantrine ATV (unboosted), PI/c

↑ lumefantrine expected

No data for artemether

Clinical significance unknown. If coadministered, monitor closely for antimalarial efficacy and lumefantrine-related adverse events, including QTc prolongation.
DRV/r

Artemether AUC ↓ 16%

DHAa AUC ↓ 18%

Lumefantrine AUC ↑ 175%

↔ DRV

LPV/r

Artemether AUC ↓ 40%

DHA AUC ↓ 45%

Lumefantrine AUC ↑ 4.8-fold

↔ LPV

Atovaquone/Proguanil ATV/r, LPV/r With ATV/r:
  • Atovaquone AUC ↓ 46%
  • Proguanil AUC ↓ 41%
With LPV/r:
  • Atovaquone AUC ↓ 74%
  • Proguanil AUC ↓ 38%
Clinical significance unknown. Consider alternative ARV or malaria prophylaxis.
Mefloquine All PIs With RTV 200 mg Twice Daily:
  • RTV AUC ↓ 31% and Cmin ↓ 43%
  • ↔ mefloquine
With ATV (unboosted), PI/c, or PI/r:
  • No data
  • ↑ mefloquine possible
Clinical significance unknown. Consider alternative ARV or antimalarial drug. If coadministered, monitor for mefloquine-related adverse events, including psychiatric symptoms and QTc prolongation. Monitor virologic response. 
Antiplatelets
Clopidogrel All boosted PIs Clopidogrel active metabolite AUC ↓ 69% in persons with HIV compared to healthy volunteers without HIV.   Impaired platelet inhibition observed in persons with HIV. Do not coadminister.
Prasugrel All boosted PIs Prasugrel active metabolite AUC ↓ 52% in persons with HIV compared to healthy volunteers without HIV.  Adequate platelet inhibition observed in persons with HIV. No dose adjustment needed. 
Ticagrelor All PIs ↑ ticagrelor expected Do not coadminister.
Vorapaxar All PIs ↑ vorapaxar expected Do not coadminister.
Antipneumocystis and Antitoxoplasmosis Drug
Atovaquone
Oral suspension
ATV/r ↔ atovaquone No dose adjustment needed.
All other PIs ↔ atovaquone expected No dose adjustment needed.
Beta-Agonists, Long-Acting Inhaled
Arformoterol, Formoterol ATV (unboosted), ATV/c, ATV/r ↑ arformoterol possible No dose adjustment needed.
DRV/c, DRV/r, LPV/r ↔ arformoterol expected No dose adjustment needed.
Indacaterol All PIs With RTV 300 mg Twice Daily:
  • Indacaterol AUC ↑ 1.7-fold
No dose adjustment needed in patients receiving indacaterol 75 mcg daily.
Olodaterol All PIs ↑ olodaterol expected No dose adjustment needed.
Salmeterol All PIs ↑ salmeterol possible Do not coadminister, due to potential increased risk of salmeterol-related CV events.
Cardiac Medications
Amiodarone ATV/r

↑ amiodarone possible

↑ PI possible

Contraindicated.
All other PIs

↑ amiodarone possible

↑ PI possible

Do not coadminister unless the benefits outweigh the risks. If coadministered, monitor for amiodarone-related adverse events and consider monitoring ECG and amiodarone drug concentration.
Antiarrhythmics
(e.g., disopyramide, dofetilide, lidocaine, mexiletine, propafenone)
ATV (unboosted) ↑ antiarrhythmic possible Consider alternative ARV or antiarrhythmics. If coadministered, monitor for antiarrhythmic-related adverse events.
PI/c, PI/r ↑ antiarrhythmic possible Do not coadminister.
Dronedarone ATV (unboosted) ↑ dronedarone possible Do not coadminister.
PI/c, PI/r ↑ dronedarone expected Contraindicated.
Flecainide All PIs ↑ flecainide possible Do not coadminister.
Propafenone All PIs ↑ propafenone possible Do not coadminister.
Quinidine ATV/r ↑ quinidine expected Contraindicated.
All other PIs ↑ quinidine possible Do not coadminister.
Beta-Blockers
(e.g., carvedilol, metoprolol, timolol)
All PIs ↑ beta-blockers possible

May need to decrease beta-blocker dose; adjust dose based on clinical response.

Consider using beta-blockers that are not metabolized by CYP2D6 enzymes (e.g., atenolol, labetalol, nadolol, sotalol).

Bosentan All PIs With LPV/r:
  • ↑ bosentan 48-fold (day 4) and ↑ 5 fold (day 10)
↓ ATV expected

Do not coadminister bosentan and unboosted ATV.

In Patients on a PI (Other than Unboosted ATV) >10 Days:

  • Start bosentan at 62.5 mg once daily or every other day.

In Patients on Bosentan Who Require a PI (Other Than Unboosted ATV):

  • Stop bosentan ≥36 hours before PI initiation and restart bosentan 10 days after PI initiation at 62.5 mg once daily or every other day.
When Switching Between COBI and RTV:
  • Maintain same bosentan dose.
Calcium Channel Blockers, Except Diltiazem All PIs

↑ dihydropyridine possible

↑ verapamil possible

Titrate CCB dose and monitor closely. ECG monitoring is recommended when CCB is used with ATV.
Digoxin PI/c, PI/r

RTV 200 mg twice daily ↑ digoxin AUC 29% and ↑ half-life 43%

DRV/r ↑ digoxin AUC 36%

COBI ↑ digoxin Cmax 41% and ↔ AUC

Monitor digoxin concentrations. Digoxin dose may need to be decreased. Titrate initial digoxin dose.
Diltiazem ATV (unboosted), ATV/c, ATV/r

Unboosted ATV ↑ diltiazem AUC 125%

Greater ↑ of diltiazem AUC is likely with ATV/c or ATV/r

Decrease diltiazem dose by at least 50%. If starting diltiazem, start with the lowest dose and titrate according to clinical response and adverse events. ECG monitoring is recommended.
DRV/c, DRV/r, LPV/r ↑ diltiazem possible Titrate diltiazem dose according to clinical response and adverse events.
Eplerenone PI/c, PI/r ↑ eplerenone expected Contraindicated.
Ranolazine ATV (unboosted) ↑ ranolazine possible Do not coadminister.
PI/c, PI/r ↑ ranolazine expected Contraindicated.
Ivabradine All PIs ↑ ivabradine expected Contraindicated.
Corticosteroids
Beclomethasone
Inhaled or intranasal
DRV/r

↔ 17-BMP (active metabolite) AUC

RTV 100 mg twice daily ↑ 17-BMP AUC 2-fold

No dose adjustment needed.
All PIs except DRV/r ↔ 17-BMP expected No dose adjustment needed.
Budesonide, Ciclesonide, Fluticasone, Mometasone
Inhaled or intranasal
All PIs

↑ glucocorticoids possible

RTV 100 mg twice daily ↑ fluticasone AUC 350-fold

Do not coadminister unless the potential benefits of inhaled or intranasal corticosteroid outweigh the risks of adverse events associated with corticosteroids. Coadministration can result in adrenal insufficiency and Cushing’s syndrome. Consider alternative inhaled/intranasal corticosteroid (e.g., beclomethasone).
Betamethasone, Budesonide
Systemic
All PIs ↑ glucocorticoids possible

↓ PI possible
Do not coadminister unless the potential benefits of systemic corticosteroid outweigh the risks of adverse events associated with systemic corticosteroids. Coadministration can result in adrenal insufficiency and Cushing’s syndrome.
Dexamethasone
Systemic
All PIs

↑ glucocorticoids possible

↓ PI possible

Consider alternative corticosteroid for long-term use. If coadministration is necessary, monitor virologic response to ART.
Prednisone, Prednisolone
Systemic
LPV/r ↑ prednisolone AUC 31% Coadministration may be considered if the potential benefits outweigh the risks of adverse events associated with systemic corticosteroids. If coadministered, monitor for adrenal insufficiency, Cushing’s syndrome, and other corticosteroid-related adverse events. 
All PIs ↑ prednisolone possible
Betamethasone, Methylprednisolone, Triamcinolone
Local injections, including intra-articular, epidural, or intra-orbital
All PIs ↑ glucocorticoids expected Do not coadminister. Coadministration can result in adrenal insufficiency and Cushing’s syndrome.
Glucose-Lowering Medications
Canagliflozin ATV (unboosted), PI/c ↔ canagliflozin No dose adjustment needed.
PI/r ↓ canagliflozin expected

If a patient is already tolerating canagliflozin 100 mg daily, increase canagliflozin dose to 200 mg daily.

If a patient is already tolerating canagliflozin 200 mg daily and requires additional glycemic control, management strategy is based on renal function.

In Patients with eGFR ≥60 mL/min/1.73 m2:

  • Canagliflozin dose may be increased to 300 mg daily.
In Patients with eGFR <60 mL/min/1.73 m2:
  • Consider adding another antihyperglycemic agent.
Saxagliptin All PIs ↑ saxagliptin expected Limit saxagliptin dose to 2.5 mg once daily.
Dapagliflozin/Saxagliptin All PIs ↑ saxagliptin expected Do not coadminister. Dapagliflozin is only available as a coformulated drug that contains 5 mg of saxagliptin. When coadministered with EVG/c, the dose of saxagliptin should not exceed 2.5 mg once daily; thus, this combination is not recommended.
Hepatitis C Direct-Acting Antiviral Agents
Daclatasvir ATV/c, ATV/r ↑ daclatasvir Decrease daclatasvir dose to 30 mg once daily.
ATV (unboosted), DRV/c, DRV/r, LPV/r ↔ daclatasvir No dose adjustment needed.
Dasabuvir plus Paritaprevir/Ombitasvir/ RTV ATV (unboosted) ↔ ATV ATV 300 mg alone, without COBI or additional RTV, should be given in the morning with dasabuvir plus paritaprevir/ombitasvir/RTV.
ATV/c, ATV/r No data

This HCV regimen contains RTV. If ATV is part of the ARV regimen, prescribe ATV 300 mg daily without COBI or RTV.

ATV should be administered in the morning, at the same time as ombitasvir/paritaprevir/RTV plus dasabuvir.

Resume RTV or COBI regimen when HCV therapy is completed.

DRV DRV Cmin ↓ 43% to 48% Do not coadminister.
LPV/r Paritaprevir AUC ↑ 117% Do not coadminister.
DRV/c No data Do not coadminister.
Elbasvir/Grazoprevir ATV/r

Elbasvir AUC ↑ 4.8-fold

Grazoprevir AUC ↑ 10.6-fold

Elbasvir ↔ ATV

Grazoprevir ↑ ATV AUC 43%

Contraindicated.

May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

DRV/r

Elbasvir AUC ↑ 66%

Grazoprevir AUC ↑ 7.5-fold

↔ DRV

LPV/r

Elbasvir AUC ↑ 3.7-fold

Grazoprevir AUC ↑ 12.9-fold

↔ LPV

ATV (unboosted), ATV/c, DRV/c ↑ grazoprevir expected
Glecaprevir/Pibrentasvir ATV (unboosted), ATV/c, ATV/r With (ATV 300 mg plus RTV 100 mg) Once Daily:
  • Glecaprevir AUC ↑ 6.5-fold
  • Pibrentasvir AUC ↑ 64%
Contraindicated.
DRV/c, DRV/r With (DRV 800 mg plus RTV 100 mg) Once Daily:
  • Glecaprevir AUC ↑ 5-fold
  • ↔ pibrentasvir
Do not coadminister.
LPV/r

Glecaprevir AUC ↑ 4-fold

Pibrentasvir ↑ 2.5-fold

Do not coadminister.
Ledipasvir/Sofosbuvir ATV/r

ATV AUC ↑ 33%

Ledipasvir AUC ↑ 113%

↔ sofosbuvir

No dose adjustment needed.

Coadministration of ledipasvir/sofosbuvir with TDF and a PI/r results in increased exposure to TDF. The safety of the increased TDF exposure has not been established. Consider alternative HCV or ARV drugs to avoid increased risk of TDF toxicities. If coadministration is necessary, monitor for TDF-related adverse events.

ATV (unboosted), ATV/c, DRV/c, DRV/r, LPV/r

↔ PI expected

↔ ledipasvir and sofosbuvir

Sofosbuvir/Velpatasvir ATV/r ↔ ATV/r

↔ sofosbuvir

Velpatasvir AUC ↑ 2.4-fold
No dose adjustment needed.
DRV/r

↔ DRV/r

Sofosbuvir AUC ↓ 28%

↔ velpatasvir

No dose adjustment needed.
ATV (unboosted), ATV/c, DRV/c, LPV/r ↔ sofosbuvir and velpatasvir expected No dose adjustment needed.
Sofosbuvir/Velpatasvir/Voxilaprevir ATV (unboosted), ATV/c, ATV/r With ATV/r:
  • Voxilaprevir AUC ↑ 4.3-fold
  • Velpatasvir AUC ↑ 93%
  • Sofosbuvir AUC ↑ 40%
Do not coadminister.
LPV/r ↑ voxilaprevir expected Do not coadminister.
DRV/c, DRV/r With DRV/r:
  • Voxilaprevir AUC ↑ 2.4-fold
  • ↔ DRV/r, velpatasvir, and sofosbuvir
No dose adjustment needed.
Herbal Products
St. John’s Wort All PIs ↓ PI expected Contraindicated.
Hormonal Therapies
Contraceptives – Injectable
Depot MPA
LPV/r MPA AUC ↑ 46% No dose adjustment needed.
All other PIs No data No dose adjustment needed.
Contraceptives – Oral ATV (unboosted) Ethinyl estradiol AUC ↑ 48%

Norethindrone AUC ↑ 110%

Prescribe an oral contraceptive that contains no more than 30 mcg of ethinyl estradiolb or use alternative ARV or contraceptive methods.

Oral contraceptives that contain less than 25 mcg of ethinyl estradiol or progestins other than norethindrone or norgestimate have not been studied.

ATV/c

Drosperinone AUC ↑ 130%

Ethinyl estradiol AUC ↓ 22%

Contraindicated with drospirenone-containing hormonal contraceptive due to potential for hyperkalemia. Use alternative ARV or contraceptive methods.

↔ ethinyl estradiol AUC and Cmin ↓ 25%

↔ levonorgestrel

No dose adjustment needed.
ATV/r

Ethinyl estradiol AUC ↓ 19% and Cmin ↓ 37%

Norgestimate AUC ↑ 85%

Norethindrone AUC ↑ 51% and Cmin ↑ 67%

Oral contraceptive should contain at least 35 mcg of ethinyl estradiol.c
DRV/c

Drospirenone AUC ↑ 58%

Ethinyl estradiol AUC ↓ 30%

Clinical monitoring is recommended because of the potential for hyperkalemia. Use alternative ARV or contraceptive methods.
DRV/r

Ethinyl estradiol AUC ↓ 44% and Cmin ↓ 62%

Norethindrone AUC ↓ 14% and Cmin ↓ 30%

When Used for Contraception:
  • Consider alternative ARV or contraceptive methods. If combined, consider using an oral contraceptive with at least 35 mcg of ethinyl estradiol.
When Used for Other Clinical Indications (e.g., Acne, Menstrual Cycle Regulation):
  • Monitor for clinical effectiveness of hormonal therapy.

LPV/r

Ethinyl estradiol AUC ↓ 42% and Cmin ↓ 32-58%

Norethindrone AUC ↓ 17% and Cmin ↓ 32%

↔ Cmin Etonogestrel (metabolite of oral desogestrel)

Consider using an oral contraceptive with at least 35 mcg of ethinyl estradiol.
Contraceptives – Subdermal Implant
Etonogestrel
LPV/r Etonogestrel AUC ↑ 52% and Cmin ↑ 34% No dose adjustment needed.
All other PIs ↑ etonogestrel expected 
Contraceptives – Subdermal Implant
Levonorgestrel
All PIs ↑ levonorgestrel expected No dose adjustment needed.
Contraceptives – Transdermal
Ethinyl Estradiol/Norelgestromin
LPV/r

↔ LPV

Ethinyl estradiol AUC ↓ 45%

Norelgestromin AUC ↑ 83%

No dose adjustment needed.
All other PIs No data
Contraceptives – Vaginal Ring
Etonogestrel/Ethinyl Estradiol
ATV/r

Ethinyl estradiol AUC ↓ 26%

Etonogestrel AUC ↑ 79%

No dose adjustment needed.
All other PIs No data
Contraceptives – Vaginal Ring
Segesterone/Ethinyl Estradiol
All PIs No data Use alternative ARV or contraceptive methods.
Emergency Contraceptives
Levonorgestrel (oral)
All PIs ↑ levonorgestrel expected  No dose adjustment needed.
Gender-Affirming Therapy PI/c  ↑ estradiol possible  Adjust estradiol dose as needed based on clinical effects and endogenous hormone concentrations.
PI/r ↓ or ↑ estradiol possible 
All PIs ↔ goserelin, leuprolide acetate, and spironolactone expected No dose adjustment needed.
All PIs

↑ dutasteride possible

↑ finasteride possible

Adjust dutasteride dose as needed based on clinical effects and endogenous hormone concentrations. No dose adjustment needed for finasteride.
All PIs ↑ testosterone possible Adjust testosterone dose as needed based on clinical effects and endogenous hormone concentrations.
Menopausal Replacement Therapy All PIs ↓ or ↑ estrogen possible with estradiol or conjugated estrogen (equine and synthetic) Adjust estrogen dose as needed based on clinical effects.
All PIs

↑ drospirenone possible

↑ medroxyprogesterone

↑ micronized progesterone

See the different Contraceptives entries for other progestin-PI interactions

Adjust progestin/progesterone dose as needed based on clinical effects. Drospirenone is not contraindicated with ATV/c products because it is prescribed at a lower dose for menopausal HRT than products used for hormonal contraceptives.
Immunosuppressants
Cyclosporine, Sirolimus, Tacrolimus All PIs ↑ immunosuppressant expected Initiate with an adjusted dose of immunosuppressant to account for potential increased concentrations of the immunosuppressant and monitor for immunosuppressant-related adverse events. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with a specialist as necessary.
Everolimus DRV/c, DRV/r ↑ immunosuppressant expected Do not coadminister.
All other PIs ↑ immunosuppressant expected Initiate with an adjusted dose of immunosuppressant to account for potential increased concentrations of the immunosuppressant and monitor for immunosuppressant-related adverse events. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with a specialist as necessary.
Lipid-Modifying Agents
Atorvastatin ATV (unboosted), ATV/r ↑ atorvastatin possible Administer the lowest effective atorvastatin dose while monitoring for adverse events.
ATV/c Atorvastatin AUC ↑ 9.2-fold and Cmax ↑ 18.9-fold Do not coadminister.
DRV/c Atorvastatin AUC ↑ 3.9-fold and Cmax ↑ 4.2-fold Administer the lowest effective atorvastatin dose while monitoring for adverse events. Do not exceed 20 mg atorvastatin daily.
DRV/r DRV/r plus atorvastatin 10 mg similar to atorvastatin 40 mg administered alone Administer the lowest effective atorvastatin dose while monitoring for adverse events. Do not exceed 20 mg atorvastatin daily.
LPV/r Atorvastatin AUC ↑ 5.9-fold and Cmax ↑ 4.7-fold Administer the lowest effective atorvastatin dose while monitoring for adverse events. Do not exceed 20 mg atorvastatin daily.
Lomitapide All PIs ↑ lomitapide expected Contraindicated.
Lovastatin All PIs Significant ↑ lovastatin expected Contraindicated.
Pitavastatin All PIs

With Unboosted ATV:

  • ↑ Pitavastatin AUC 31% and Cmax ↑ 60%
  • ↔ ATV

With DRV/r:

  • ↓ Pitavastatin AUC 26%
  • ↔ DRV/r

With LPV/r:

  • ↓ Pitavastatin AUC 20%
  • ↔ LPV
No dose adjustment needed.
Pravastatin Unboosted ATV, ATV/c, ATV/r No data Administer the lowest effective pravastatin dose while monitoring for adverse events.
DRV/c, DRV/r With DRV/r:
  • Pravastatin AUC ↑ 81% following single dose of pravastatin
Pravastatin AUC ↑ 23% at steady state
Administer the lowest effective pravastatin dose while monitoring for adverse events.
LPV/r Pravastatin AUC ↑ 33% No dose adjustment needed.
Rosuvastatin Unboosted ATV ↑ rosuvastatin expected Administer the lowest effective rosuvastatin dose while monitoring for adverse events. Do not exceed rosuvastatin 10 mg daily.
ATV/r Rosuvastatin AUC ↑ 3-fold and Cmax ↑ 7-fold
ATV/c Rosuvastatin AUC ↑ 3.4-fold and Cmax ↑ 10.6-fold
DRV/c Rosuvastatin AUC ↑ 1.9-fold and Cmax ↑ 3.8-fold Administer the lowest effective rosuvastatin dose while monitoring for adverse events. Do not exceed rosuvastatin 20 mg daily.
DRV/r Rosuvastatin AUC ↑ 48% and Cmax ↑ 2.4-fold Administer the lowest effective rosuvastatin dose while monitoring for adverse events.
LPV/r Rosuvastatin AUC ↑ 2.1-fold and Cmax ↑ 4.7-fold Administer the lowest effective rosuvastatin dose while monitoring for adverse events. Do not exceed rosuvastatin 10 mg daily.
Simvastatin All PIs Significant ↑ simvastatin expected Contraindicated.
Narcotics and Treatment for Opioid Dependence
Buprenorphine
Sublingual, buccal, or implant
ATV (unboosted)

Buprenorphine AUC ↑ 93%

Norbuprenorphine (active metabolite) AUC ↑ 76%

↓ ATV possible

Do not coadminister.
ATV/r

Buprenorphine AUC ↑ 66%

Norbuprenorphine (active metabolite) AUC ↑ 105%

Monitor for sedation and other signs or symptoms of overmedication. Buprenorphine dose reduction may be necessary. It may be necessary to remove implant and treat with a formulation that permits dose adjustments.
DRV/r

↔ buprenorphine

Norbuprenorphine (active metabolite) AUC ↑ 46% and Cmin ↑ 71%

No dose adjustment needed. Monitor for buprenorphine-related adverse events. When transferring buprenorphine from transmucosal delivery to implantation, monitor to ensure buprenorphine effect is adequate and not excessive.
LPV/r ↔ LPV/r
PI/c No data Titrate buprenorphine dose using the lowest initial dose. Dose adjustment of buprenorphine may be needed. It may be necessary to remove implant and treat with a formulation that permits dose adjustments. Monitor for buprenorphine-related adverse events.
Fentanyl All PIs ↑ fentanyl possible Monitor for fentanyl-related adverse events, including potentially fatal respiratory depression.
Lofexidine ATV (unboosted) ↔ lofexidine expected No dose adjustment needed.
PI/c, PI/r ↑ lofexidine possible Monitor for lofexidine-related adverse events, including symptoms of orthostasis and bradycardia.
Methadone ATV (unboosted) ↔ ATV No dose adjustment needed.
PI/c No data Titrate methadone dose using the lowest feasible initial dose. Dose adjustment of methadone may be needed. Monitor for methadone-related adverse events.
All PI/r

ATV/r and DRV/r ↓ R-methadoned AUC 16% to 18%

LPV/r ↓ methadone AUC 26% to 53%

Opioid withdrawal is unlikely, but may occur. Monitor for opioid withdrawal and increase methadone dose as clinically indicated.
Oxycodone All PIs

LPV/r ↑ oxycodone AUC 2.6-fold

Other PIs: ↑ oxycodone expected

Monitor for opioid-related adverse events, including potentially fatal respiratory depression. Oxycodone dose reduction may be necessary.
Tramadol All PIs

↑ tramadol expected

↓ M1 (active metabolite) possible

Tramadol dose adjustments may be necessary. Monitor for clinical response and tramadol-related adverse events.
PDE5 Inhibitors
Avanafil ATV (unboosted) No data Avanafil dose should not exceed 50 mg once every 24 hours.
PI/c, PI/r RTV 600 mg twice daily (for 5 days) ↑ avanafil AUC 13-fold and ↑ Cmax 2.4-fold Do not coadminister.
Sildenafil All PIs DRV/r plus sildenafil 25 mg similar to sildenafil 100 mg alone

RTV 500 mg twice daily ↑ sildenafil AUC 1,000%
For Treatment of Erectile Dysfunction:
  • Start with sildenafil 25 mg every 48 hours and monitor for adverse events of sildenafil.
Contraindicated for treatment of PAH.
Tadalafil All PIs RTV 200 mg twice daily ↑ tadalafil AUC 124% For Treatment of Erectile Dysfunction:
  • Start with tadalafil 5 mg and do not exceed a single dose of tadalafil 10 mg every 72 hours. Monitor for adverse events of tadalafil.
     
For Treatment of PAH:
In Patients on a PI >7 Days:
  • Start with tadalafil 20 mg once daily and increase to tadalafil 40 mg once daily based on tolerability.
In Patients on Tadalafil who Require a PI:
  • Stop tadalafil ≥24 hours before PI initiation. Seven days after PI initiation, restart tadalafil at 20 mg once daily and increase to tadalafil 40 mg once daily based on tolerability.
In Patients Switching between COBI and RTV:
  • Maintain tadalafil dose.
     
For Treatment of Benign Prostatic Hyperplasia:
  • Maximum recommended daily dose is tadalafil 2.5 mg per day.
Vardenafil All PIs RTV 600 mg twice daily ↑ vardenafil AUC 49-fold Start with vardenafil 2.5 mg every 72 hours and monitor for adverse events of vardenafil.
Sedative/Hypnotics
Alprazolam, Clonazepam, Diazepam All PIs

↑ benzodiazepine possible

RTV 200 mg twice daily (for 2 days) ↑ alprazolam half-life 222% and ↑ AUC 248%

Consider alternative benzodiazepines, such as lorazepam, oxazepam, or temazepam.
Lorazepam, Oxazepam, Temazepam All PIs No data These benzodiazepines are metabolized via non-CYP450 pathways and therefore have less interaction potential than other benzodiazepines.
Midazolam All PIs ↑ midazolam expected

Oral midazolam is contraindicated with PIs.

Parenteral midazolam can be used with caution when given in a monitored situation with appropriate medical management available in case of respiratory sedation and/or prolonged sedation. Consider dose reduction, especially if more than a single dose of midazolam is administered. 

Suvorexant All PIs ↑ suvorexant expected Do not coadminister.
Triazolam All PIs

↑ triazolam expected

RTV 200 mg twice daily ↑ triazolam half-life 1,200% and ↑ AUC 2,000%

Contraindicated.
Zolpidem PI/c, PI/r ↑ zolpidem possible Initiate zolpidem at a low dose and monitor for zolpidem-related adverse events. Dose reduction may be necessary.
Miscellaneous Drugs
Calcifediol All PIs ↑ calcifediol possible Dose adjustment of calcifediol may be required, and serum 25-hydroxyvitamin D, intact PTH, and serum calcium concentrations should be closely monitored.
Cisapride All PIs ↑ cisapride expected Contraindicated.
Colchicine All PIs RTV 100 mg twice daily ↑ colchicine AUC 296% and Cmax ↑ 184%

Significant ↑ colchicine expected with all PIs, with or without COBI or RTV
For Treatment of Gout Flares:
  • Administer a single dose of colchicine 0.6 mg, followed by colchicine 0.3 mg 1 hour later. Do not repeat dose for at least 3 days.
For Prophylaxis of Gout Flares:
  • If original dose was colchicine 0.6 mg twice daily, decrease to colchicine 0.3 mg once daily. If dose was 0.6 mg once daily, decrease to 0.3 mg every other day.
For Treatment of Familial Mediterranean Fever:
  • Do not exceed colchicine 0.6 mg once daily or colchicine 0.3 mg twice daily.
Contraindicated in patients with hepatic (Child-Pugh Score A, B or C) or renal impairment (CrCl <60 mL/min).
Dronabinol All PIs ↑ dronabinol possible Monitor for dronabinol-related adverse events.
Eluxadoline All PIs ↑ eluxadoline expected Administer eluxadoline at a dose of 75 mg twice daily and monitor for eluxadoline-related adverse events.
Ergot Derivatives All PIs ↑ dihydroergotamine, ergotamine, and methylergonovine expected Contraindicated.
Flibanserin All PIs ↑ flibanserin expected Contraindicated.
a DHA is an active metabolite of artemether.

b The following products contain no more than 30 mcg of ethinyl estradiol combined with norethindrone or norgestimate: Lo Minastrin Fe; Lo Loestrin Fe; Loestrin 1/20, 1.5/30; Loestrin Fe 1/20, 1.5/30; Loestrin 24 Fe; Minastrin 24 Fe; Ortho Tri-Cyclen Lo. Generic formulations may also be available.

c The following products contain at least 35 mcg of ethinyl estradiol combined with norethindrone or norgestimate: Brevicon; Femcon Fe; Modicon; Norinyl 1/35; Ortho-Cyclen; Ortho-Novum 1/35, 7/7/7; Ortho Tri-Cyclen; Ovcon 35; Tri-Norinyl. Generic formulations may also be available.

d R-methadone is the active form of methadone.

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

Key: 17-BMP = beclomethasone 17-monopropionate; ALT = alanine aminotransferase; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; AUC = area under the curve; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; CCB = calcium channel blocker; CNS = central nervous system; COBI = cobicistat; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P; DHA = dihydroartemisinin; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; FDA = Food and Drug Administration; FPV = fosamprenavir; H2RA = H2 receptor antagonist; HCV = hepatitis C virus; HRT = hormone replacement therapy; INR = international normalized ratio; LPV = lopinavir; LPV/r = lopinavir/ritonavir; MPA = medroxyprogesterone acetate; OATP = organic anion-transporting polypeptide; PAH = pulmonary arterial hypertension; PDE5 = Phosphodiesterase Type 5; PI = protease inhibitor; PI/c = protease inhibitor/cobicistat; PI/r = protease inhibitor/ritonavir; PK = pharmacokinetic; PPI = proton pump inhibitor; PTH = parathyroid hormone; QTc = QT corrected for heart rate; RTV = ritonavir; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; TDF = tenofovir disoproxil fumarate; VPA = valproic acid 

Drug-Drug Interactions

Table 24a. Drug Interactions Between Protease Inhibitors and Other Drugs

This table provides information on the known or predicted interactions between protease inhibitors (PIs) and non- antiretroviral (ARV) drugs. When information is available, interactions for boosted atazanavir (ATV) (with either ritonavir [RTV] or cobicistat [COBI]) and unboosted ATV are listed separately. The term “all PIs” refers to both unboosted ATV and ATV, darunavir (DRV), and lopinavir (LPV) boosted with either RTV or COBI. This table does not include interactions for fosamprenavir, indinavir (IDV), nelfinavir (NFV), saquinavir (SQV), or tipranavir (TPV). For information regarding interactions between PIs and other ARV drugs, including dosing recommendations, refer to Tables 24c, 25a, and 25b.

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 whether 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. In cases where an interacting drug needs to be replaced with an alternative, providers should exercise their clinical judgement to select the most appropriate alternative medication to use.

Note: FPV, IDV, NFV, SQV, and TPV are no longer commonly used in clinical practice and are not included in this table. Please refer to the FDA product labels for these for information regarding drug interactions between these PIs and concomitant medications.

Table 24a. Drug Interactions Between Protease Inhibitors and Other Drugs
Concomitant Drug PI Effect on PI and/or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments
Acid Reducers
Antacids ATV, ATV/c, ATV/r When Given Simultaneously:
  • ↓ ATV expected
Administer ATV at least 2 hours before or 2 hours after antacids or buffered medications.
H2 Receptor Antagonists ATV (unboosted) When Given Simultaneously with Famotidine:
  • ATV AUC ↓ 41%
When Given 2 Hours Before and ≥10 Hours After H2RA:
  • ↔ ATV

A single dose of H2RA should not exceed a dose equivalent to famotidine 20 mg, and the total daily dose should not exceed a dose equivalent to famotidine 20 mg twice daily in PI-naive patients.

Give ATV with food at least 2 hours before and at least 10 hours after the H2RA.

Do not coadminister unboosted ATV plus H2RA in PI-experienced patients.

ATV/c, ATV/r ↓ ATV expected

H2RA dose should not exceed a dose equivalent to famotidine 40 mg twice daily in ART-naive patients or famotidine 20 mg twice daily in ART-experienced patients.

Give ATV 300 mg (plus COBI 150 mg or RTV 100 mg) with food simultaneously with and/or ≥10 hours after the dose of H2RA.

If using TDF and H2RA in ART-experienced patients, administer ATV 400 mg plus RTV 100 mg with food simultaneously with and/or ≥10 hours after the dose of H2RA. 

Do not coadminister ATV/c with TDF and H2RA in ART-experienced patients. 

DRV/c, DRV/r, LPV/r With Ranitidine:
  • ↔ DRV/r
↔ PI expected
No dose adjustment needed.
Proton Pump Inhibitors ATV (unboosted) With Omeprazole 40 mg:
  • ATV AUC ↓ 94%
Do not coadminister.
ATV/c, ATV/r With Omeprazole 40 mg:
  • ATV AUC ↓ 76%
When Omeprazole 20 mg is Given 12 Hours before ATV/c or ATV/r:
  • ATV AUC ↓ 42%

PPI dose should not exceed a dose equivalent to omeprazole 20 mg daily in PI-naive patients.

PPIs should be administered at least 12 hours before ATV/c or ATV/r.

Do not coadminister in PI-experienced patients.

DRV/c, LPV/r ↔ PI expected No dose adjustment needed.
DRV/r

↔ DRV/r

Omeprazole AUC ↓ 42%

Consider alternative ARV or acid reducer. If coadministered, monitor for omeprazole efficacy. If the patient does not experience symptomatic relief, increase the dose to no more than omeprazole 40 mg daily.
Alpha-Adrenergic Antagonists for Benign Prostatic Hyperplasia
Alfuzosin All PIs ↑ alfuzosin expected Contraindicated.
Doxazosin All PIs ↑ doxazosin possible Initiate doxazosin at lowest dose and titrate while monitoring for clinical response/adverse events. Dose reduction may be necessary.
Tamsulosin All PIs ↑ tamsulosin expected Do not coadminister, unless benefits outweigh risks. If coadministered, monitor for tamsulosin-related adverse events.
Terazosin All PIs ↔ or ↑ terazosin possible Initiate terazosin at lowest dose and titrate while monitoring for clinical response/adverse events. Dose reduction may be necessary.
Silodosin All PIs ↑ silodosin expected Contraindicated.
Antibacterials
Antimycobacterials
Bedaquiline All PIs With LPV/r:
  • Bedaquiline AUC ↑ 1.9-fold
With other PI/r, ATV/c, or DRV/c:
  • ↑ bedaquiline possible
Do not coadminister, unless benefits outweigh risks. Monitor liver function and ECG for QTc prolongation.
Rifabutin ATV (unboosted) ↑ rifabutin AUC expected

Recommended dose is rifabutin 150 mg once daily.

Monitor for antimycobacterial activity and consider therapeutic drug monitoring. Monitor for rifabutin-related adverse events, including neutropenia and uveitis. 

PK data in this table are results from healthy volunteer studies. Lower rifabutin exposure has been reported in patients with HIV than in healthy study participants.

ATV/r Compared with Rifabutin (300 mg Once Daily) Alone, Rifabutin (150 mg Once Daily) plus ATV/r:
  • Rifabutin AUC ↑ 110% and metabolite AUC ↑ 2,101%
DRV/r Compared with Rifabutin (300 mg Once Daily) Alone, Rifabutin (150 mg Every Other Day) plus DRV/r:
  • ↔ rifabutin AUC and metabolite AUC ↑ 881%
LPV/r Compared with Rifabutin (300 mg Daily) Alone, Rifabutin (150 mg Once Daily) plus LPV/r:
  • Rifabutin AUC ↑ 203% and metabolite AUC ↑ 375%
PI/c

↑ rifabutin expected

↓ COBI expected

Do not coadminister.
Rifampin All PIs ↓ PI concentration by >75% Contraindicated. Increasing the dose of RTV does not overcome this interaction and may increase hepatotoxicity. Increasing the COBI dose is not recommended. Consider rifabutin if a rifamycin is indicated.
Rifapentine All PIs ↓ PI expected Do not coadminister.
Macrolides
Azithromycin ATV (unboosted), ATV/c, ATV/r ↑ azithromycin possible No dose adjustment needed.
DRV/c, DRV/r ↔ azithromycin expected No dose adjustment needed.
Clarithromycin ATV (unboosted)

Clarithromycin AUC ↑ 94%

ATV ↑ 28%

Reduce clarithromycin dose by 50% or consider alternative ARV or azithromycin. Monitor for clarithromycin-related adverse events, including QTc prolongation.
ATV/r, PI/c

↑ Clarithromycin expected 

↑ ATV/r and PI/c expected

Consider alternative ARV or azithromycin. 
DRV/r, LPV/r

DRV/r ↑ clarithromycin AUC 57%

LPV/r ↑ clarithromycin expected

RTV 500 mg twice daily ↑ clarithromycin 77%

Consider alternative ARV or azithromycin.

If use of clarithromycin is necessary in a patient with impaired renal function, reduce clarithromycin dose by 50% in patients with CrCl 30 to 60 mL/min. In patients with CrCl <30 mL/min, reduce clarithromycin dose by 75%. 

Monitor for clarithromycin-related adverse events, including QTc prolongation.

Erythromycin All PIs

↑ erythromycin expected

↑ PIs expected

Consider alternative ARV or use azithromycin.
Anticoagulants
Apixaban ATV (unboosted) ↑ apixaban possible  No data available for dose recommendation. Consider alternative ARV or anticoagulant.
PI/c, PI/r ↑ apixaban expected

Do not coadminister in patients who require apixaban 2.5 mg twice daily.

In Patients Requiring Apixaban 5 mg or 10 mg Twice Daily:

  • Reduce apixaban dose by 50%.
Dabigatran ATV (unboosted), DRV/c, DRV/r, LPV/r No data No data available for dose recommendation. Consider alternative ARV or anticoagulant.
ATV/c, ATV/r

With COBI 150 mg Alone:

Dabigatran AUC ↑ 110% to 127%

↑ dabigatran expected

Dabigatran dosing recommendation depends on indication and renal function. Refer to dabigatran prescribing information for dosing instructions when using dabigatran concomitantly with P-glycoprotein inhibitors.
Edoxaban ATV (unboosted), DRV/c, DRV/r, LPV/r No data No data available for dose recommendation. Consider alternative ARV or anticoagulant.
ATV/r, ATV/c  ↑ edoxaban expected Stroke Prevention in Nonvalvular Atrial Fibrillation Indication:
  • No dose adjustment needed.
Deep Venous Thrombosis and Pulmonary Embolism Indication:
  • Administer edoxaban 30 mg once daily.
Rivaroxaban ATV (unboosted) ↑ rivaroxaban possible  No data available for dose recommendation. Consider alternative ARV or anticoagulant.
PI/c, PI/r ↑ rivaroxaban expected Do not coadminister.
Warfarin PI/c No data

Monitor INR closely when stopping or starting PI/c or PI/r and adjust warfarin dose accordingly.

If switching between RTV and COBI, the effect of COBI on warfarin is not expected to be equivalent to RTV’s effect on warfarin.

PI/r ↓ warfarin possible
Anticonvulsants
Carbamazepine ATV (unboosted) May ↓ PI concentrations substantially Do not coadminister.
ATV/r, LPV/r

↑ carbamazepine possible

May ↓ PI concentrations substantially

Consider alternative ARV or anticonvulsant. If coadministration is necessary, consider monitoring concentrations of both drugs and assess virologic response. Carbamazepine dose reduction may be necessary.

Do not coadminister with LPV/r once daily.

DRV/r

Carbamazepine AUC ↑ 45%

↔ DRV

Monitor anticonvulsant concentration and adjust dose accordingly.
PI/c

↑ carbamazepine possible

↓ cobicistat expected

↓ PI expected

Contraindicated. 
Eslicarbazepine All PIs ↓ PI possible Consider alternative ARV or anticonvulsant. If coadministration is necessary, monitor for virologic response. Consider monitoring anticonvulsant and PI concentrations.
Ethosuximide All PIs ↑ ethosuximide possible Monitor for ethosuximide-related adverse events.
Lamotrigine ATV (unboosted) ↔ lamotrigine No dose adjustment needed.
ATV/r Lamotrigine AUC ↓ 32% A dose increase of lamotrigine may be needed; monitor lamotrigine concentration or consider alternative ARV or anticonvulsant.
LPV/r

Lamotrigine AUC ↓ 50%

↔ LPV

DRV/r ↓ lamotrigine possible
PI/c No data Monitor anticonvulsant concentration and adjust dose accordingly.
Oxcarbazepine All PIs ↓ PI possible Consider alternative ARV or anticonvulsant. If coadministration necessary, monitor for virologic response. Consider monitoring anticonvulsant and PI concentrations.
Phenobarbital ATV (unboosted) ↓ ATV expected Do not coadminister.
ATV/r, DRV/r

↓ phenytoin possible

↓ PI possible

Consider alternative anticonvulsant. If coadministration is necessary, consider monitoring concentrations of both drugs and assessing virologic response.
LPV/r

↓ phenytoin possible

↓ LPV/r possible

Do not coadminister with LPV/r once daily.

Consider alternative anticonvulsant. If coadministration necessary, consider monitoring concentrations of both drugs and assessing virologic response.

PI/c

↓ cobicistat expected

↓ PI expected

Contraindicated.
Phenytoin ATV (unboosted) ↓ ATV expected Do not coadminister.
ATV/r, DRV/r

↓ phenytoin possible

↓ PI possible

Consider alternative anticonvulsant. If coadministration is necessary, consider monitoring concentrations of both drugs and assessing virologic response.
LPV/r

Phenytoin AUC ↓ 31%

LPV/r AUC ↓ 33%

Do not coadminister with LPV/r once daily.

Consider alternative anticonvulsant or monitor concentrations of both drugs and assess virologic response.

PI/c

↓ cobicistat expected

↓ PI expected

Contraindicated.
Valproic Acid All PIs

↓ or ↔ VPA possible

LPV AUC ↑ 38%

No data for other PIs

Monitor VPA concentrations and monitor for PI tolerability.
Antidepressants, Anxiolytics, and Antipsychotics
Also see Sedative/Hypnotics section below
Bupropion ATV (unboosted) ↔ bupropion expected No dose adjustment needed.
ATV/r, DRV/r ↓ bupropion possible Titrate bupropion dose based on clinical response.
LPV/r Bupropion AUC ↓ 57%
PI/c ↔ bupropion expected No dose adjustment needed.
Buspirone All PIs ↑ buspirone expected Administer lowest dose of buspirone with caution and titrate buspirone dose based on clinical response. Dose reduction may be necessary. Monitor for buspirone-related adverse events.
Nefazodone All PIs

↑ nefazodone expected

↑ PI possible

Monitor for nefazodone-related adverse events and PI tolerability.
Trazodone All PIs RTV 200 mg twice daily (for 2 days) ↑ trazodone AUC 240% Administer lowest dose of trazodone and monitor for CNS and CV adverse events.
Tricyclic Antidepressants
Amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine
All PIs ↑ TCA expected Administer lowest possible TCA dose and titrate based on clinical assessment and/or drug concentrations. Monitor for TCA-related adverse events. 
Selective Serotonin Reuptake Inhibitors
(e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)
DRV/r

Paroxetine AUC ↓ 39%

Sertraline AUC ↓ 49%

Titrate SSRI dose based on clinical response.
All PIs except DRV/r No data Titrate SSRI dose using the lowest available initial or maintenance dose.
Antipsychotics
Aripiprazole ATV (unboosted) ↑ aripiprazole expected Administer 50% of the usual aripiprazole dose. Titrate dose based on clinical monitoring for efficacy/adverse events. Refer to aripiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
PI/c, PI/r ↑ aripiprazole expected Administer 25% of the usual aripiprazole dose. Titrate dose based on clinical monitoring for efficacy/adverse events. Refer to aripiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
Brexpiprazole ATV (unboosted) ↑ brexpiprazole expected Administer 50% of the usual brexpiprazole dose. Titrate dose based on clinical monitoring for efficacy/adverse events. Refer to brexpiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
PI/c, PI/r ↑ brexpiprazole expected Administer 25% of the usual brexpiprazole dose. Titrate the dose based on clinical monitoring for efficacy/adverse events. Refer to brexpiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
Cariprazine All PIs ↑ cariprazine expected Starting Cariprazine in a Patient Who Is Already Receiving a PI:
  • Administer cariprazine 1.5 mg on Day 1 and Day 3, with no dose given on Day 2. From Day 4 onward, administer cariprazine 1.5 mg daily. Dose can be increased to a maximum dose of cariprazine 3 mg daily. If the PI is withdrawn, cariprazine dose may need to be increased.
Starting a PI in a Patient Who Is Already Receiving Cariprazine:
  • For patients receiving cariprazine 3 mg or cariprazine 6 mg daily, reduce the dose by half. For patients taking cariprazine 4.5 mg daily, the dose should be reduced to cariprazine 1.5 mg or cariprazine 3 mg daily. For patients taking cariprazine 1.5 mg daily, change to cariprazine 1.5 mg every other day. If PI is withdrawn, the cariprazine dose may need to be increased.
Iloperidone All PIs ↑ iloperidone expected Decrease iloperidone dose by 50%.
Lumateperone All PIs ↑ lumateperone expected Do not coadminister.
Lurasidone ATV (unboosted) ↑ lurasidone expected

Consider alternative ARV or antipsychotic. If coadministration is necessary and atazanavir is added to lurasidone therapy, reduce lurasidone dose by 50%.

If co-administration is necessary and lurasidone is added to atazanavir therapy, the recommended starting dose of lurasidone is 20 mg daily and the maximum recommended dose is 80 mg daily.

PI/c, PI/r ↑ lurasidone expected Contraindicated.
Olanzapine ATV (unboosted), PI/c ↔ olanzapine expected No dose adjustment needed.
PI/r ↓ olanzapine possible Monitor for therapeutic effectiveness of olanzapine.
Other Antipsychotics
CYP3A4 and/or CYP2D6 substrates (e.g., clozapine, perphenazine, risperidone, thioridazine)
PI/c, PI/r ↑ antipsychotic possible Titrate the antipsychotic dose using the lowest initial dose or adjust the maintenance dose accordingly. Monitor for adverse events, including QTc prolongation. 
Pimavanserin ATV (unboosted) No data No data available for dose recommendation. Consider alternative ARV or antipsychotic.
LPV/r ↑ pimavanserin expected Do not coadminister, due to risk for QTc prolongation.
All other PIs ↑ pimavanserin expected Reduce pimavanserin dose to 10 mg once daily.
Pimozide All PIs ↑ pimozide expected Contraindicated.
Quetiapine All PIs ↑ quetiapine expected Starting Quetiapine in a Patient Receiving a PI:
  • Initiate quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine effectiveness and adverse events, including QTc prolongation.
Starting a PI in a Patient Receiving a Stable Dose of Quetiapine:
  • Consider alternative ARV. If co-administered, reduce quetiapine dose to 1/6 of the current dose. Closely monitor for quetiapine effectiveness and adverse events, including QTc prolongation.
Ziprasidone LPV/r ↑ ziprasidone expected Do not coadminister, because of the risk for QTc prolongation.
All PIs except LPV/r ↑ ziprasidone expected Monitor for ziprasidone-related adverse events, including QTc prolongation.
Antifungals
Fluconazole All PIs

↔ PI expected

↔ fluconazole expected

No dose adjustment needed.
Isavuconazole LPV/r

Isavuconazole AUC ↑ 96%

LPV AUC ↓ 27%

RTV AUC ↓ 31%

If coadministered, monitor isavuconazole concentrations and adverse events. Monitor for virologic response.
All PIs except LPV/r

↑ isavuconazole expected

↑ PI possible

If coadministered, monitor isavuconazole concentrations and monitor for isavuconazole-related adverse events. Monitor for PI tolerability.
Itraconazole ATV (unboosted)

↑ itraconazole expected

Dose based on itraconazole concentrations and monitor for itraconazole-related adverse events.
PI/r, PI/c

↑ itraconazole possible

↑ PI expected

Itraconazole doses >200 mg/day are not recommended unless dosing is guided by itraconazole concentrations.
Posaconazole ATV

ATV AUC ↑ 268%

↑ or ↓ posaconazole possible

If coadministered, monitor posaconazole concentrations and monitor for posaconazole-related or PI-related adverse events.
ATV/r

ATV AUC ↑ 146%

↑ posaconazole possible

All other PIs

↑ PI expected

↑ posaconazole possible

Voriconazole ATV (unboosted)

↑ or ↓ PI possible

↑ or ↓ voriconazole possible

If coadministered, monitor voriconazole concentrations and monitor for voriconazole-related or PI-related adverse events.
PI/c No data Do not coadminister voriconazole and RTV or COBI unless benefits outweigh risks. If coadministered, monitor voriconazole concentration and adjust dose accordingly.
PI/r RTV 100 mg twice daily ↓ voriconazole AUC 39%
Antimalarials
Artemether/Lumefantrine ATV (unboosted), PI/c

↑ lumefantrine expected

No data for artemether

Clinical significance unknown. If coadministered, monitor closely for antimalarial efficacy and lumefantrine-related adverse events, including QTc prolongation.
RV/r

Artemether AUC ↓ 16%

DHAa AUC ↓ 18%

Lumefantrine AUC ↑ 175%

↔ DRV

LPV/r

Artemether AUC ↓ 40%

DHA AUC ↓ 45%

Lumefantrine AUC ↑ 4.8-fold

↔ LPV

Atovaquone/Proguanil ATV/r, LPV/r With ATV/r:
  • Atovaquone AUC ↓ 46%
  • Proguanil AUC ↓ 41%
With LPV/r:
  • Atovaquone AUC ↓ 74%
  • Proguanil AUC ↓ 38%
Clinical significance unknown. Consider alternative ARV or malaria prophylaxis.
Mefloquine All PIs With RTV 200 mg Twice Daily:
  • RTV AUC ↓ 31% and Cmin ↓ 43%
  • ↔ mefloquine
With ATV (unboosted), PI/c, or PI/r:
  • No data
  • ↑ mefloquine possible
Clinical significance unknown. Consider alternative ARV or antimalarial drug. If coadministered, monitor for mefloquine-related adverse events, including psychiatric symptoms and QTc prolongation. Monitor virologic response. 
Antiplatelets
Clopidogrel All PIs Clopidogrel active metabolite AUC ↓ 69% in persons with HIV compared to healthy volunteers without HIV.   Impaired platelet inhibition observed in persons with HIV. Do not coadminister.
Prasugrel All PIs Prasugrel active metabolite AUC ↓ 52% in persons with HIV compared to healthy volunteers without HIV.  Adequate platelet inhibition observed in persons with HIV. No dose adjustment needed. 
Ticagrelor All PIs ↑ ticagrelor expected Do not coadminister.
Vorapaxar All PIs ↑ vorapaxar expected Do not coadminister.
Antipneumocystis and Antitoxoplasmosis Drug
Atovaquone
Oral suspension
ATV/r ↔ atovaquone No dose adjustment needed.
All other PIs ↔ atovaquone expected No dose adjustment needed.
Beta-Agonists, Long-Acting Inhaled
Arformoterol, Formoterol ATV (unboosted), ATV/c, ATV/r ↑ arformoterol possible No dose adjustment needed.
DRV/c, DRV/r, LPV/r ↔ arformoterol expected No dose adjustment needed.
Indacaterol All PIs With RTV 300 mg Twice Daily:
  • Indacaterol AUC ↑ 1.7-fold
No dose adjustment needed in patients receiving indacaterol 75 mcg daily.
Olodaterol All PIs ↑ olodaterol expected No dose adjustment needed.
Salmeterol All PIs ↑ salmeterol possible Do not coadminister, due to potential increased risk of salmeterol-related CV events.
Cardiac Medications
Amiodarone ATV/r

↑ amiodarone possible

↑ PI possible

Contraindicated.
All other PIs

↑ amiodarone possible

↑ PI possible

Do not coadminister unless the benefits outweigh the risks. If coadministered, monitor for amiodarone-related adverse events and consider monitoring ECG and amiodarone drug concentration.
Antiarrhythmics
(e.g., disopyramide, dofetilide, lidocaine, mexiletine, propafenone)
ATV (unboosted) ↑ antiarrhythmic possible Consider alternative ARV or antiarrhythmics. If coadministered, monitor for antiarrhythmic-related adverse events.
PI/c, PI/r ↑ antiarrhythmic possible Do not coadminister.
Dronedarone ATV (unboosted) ↑ dronedarone possible Do not coadminister.
PI/c, PI/r ↑ dronedarone expected Contraindicated.
Flecainide All PIs ↑ flecainide possible Do not coadminister.
Propafenone All PIs ↑ propafenone possible Do not coadminister.
Quinidine ATV/r ↑ quinidine expected Contraindicated.
All other PIs ↑ quinidine possible Do not coadminister.
Beta-Blockers
(e.g., carvedilol, metoprolol, timolol)
All PIs ↑ beta-blockers possible

May need to decrease beta-blocker dose; adjust dose based on clinical response.

Consider using beta-blockers that are not metabolized by CYP2D6 enzymes (e.g., atenolol, labetalol, nadolol, sotalol).

Bosentan All PIs With LPV/r:
  • ↑ bosentan 48-fold (day 4) and ↑ 5 fold (day 10)
↓ ATV expected

Do not coadminister bosentan and unboosted ATV.

In Patients on a PI (Other than Unboosted ATV) >10 Days:

  • Start bosentan at 62.5 mg once daily or every other day.

In Patients on Bosentan who Require a PI (Other than Unboosted ATV):

  • Stop bosentan ≥36 hours before PI initiation and restart bosentan 10 days after PI initiation at 62.5 mg once daily or every other day.
When Switching Between COBI and RTV:
  • Maintain same bosentan dose.
Calcium Channel Blockers, Except Diltiazem All PIs

↑ dihydropyridine possible

↑ verapamil possible

Titrate CCB dose and monitor closely. ECG monitoring is recommended when CCB is used with ATV.
Digoxin PI/c, PI/r

RTV 200 mg twice daily ↑ digoxin AUC 29% and ↑ half-life 43%

DRV/r ↑ digoxin AUC 36%

COBI ↑ digoxin Cmax 41% and ↔ AUC

Monitor digoxin concentrations. Digoxin dose may need to be decreased. Titrate initial digoxin dose.
Diltiazem ATV (unboosted), ATV/c, ATV/r

Unboosted ATV ↑ diltiazem AUC 125%

Greater ↑ of diltiazem AUC is likely with ATV/c or ATV/r

Decrease diltiazem dose by at least 50%. If starting diltiazem, start with the lowest dose and titrate according to clinical response and adverse events. ECG monitoring is recommended.
DRV/c, DRV/r, LPV/r ↑ diltiazem possible Titrate diltiazem dose according to clinical response and adverse events.
Eplerenone PI/c, PI/r ↑ eplerenone expected Contraindicated.
Ranolazine ATV (unboosted) ↑ ranolazine possible Do not coadminister.
PI/c, PI/r ↑ ranolazine expected Contraindicated.
Ivabradine All PIs ↑ ivabradine expected Contraindicated.
Corticosteroids
Beclomethasone
Inhaled or intranasal
DRV/r

↔ 17-BMP (active metabolite) AUC

RTV 100 mg twice daily ↑ 17-BMP AUC 2-fold

No dose adjustment needed.
All PIs except DRV/r ↔ 17-BMP expected No dose adjustment needed.
Budesonide, Ciclesonide, Fluticasone, Mometasone
Inhaled or intranasal
All PIs

↑ glucocorticoids possible

RTV 100 mg twice daily ↑ fluticasone AUC 350-fold

Do not coadminister unless the potential benefits of inhaled or intranasal corticosteroid outweigh the risks of adverse events associated with corticosteroids. Coadministration can result in adrenal insufficiency and Cushing’s syndrome. Consider alternative inhaled/intranasal corticosteroid (e.g., beclomethasone).
Betamethasone, Budesonide
Systemic
All PIs ↑ glucocorticoids possible

↓ PI possible
Do not coadminister unless the potential benefits of systemic corticosteroid outweigh the risks of adverse events associated with systemic corticosteroids. Coadministration can result in adrenal insufficiency and Cushing’s syndrome.
Dexamethasone
Systemic
All PIs

↑ glucocorticoids possible

↓ PI possible

Consider alternative corticosteroid for long-term use. If coadministration is necessary, monitor virologic response to ART.
Prednisone, Prednisolone
Systemic
LPV/r ↑ prednisolone AUC 31% Coadministration may be considered if the potential benefits outweigh the risks of adverse events associated with systemic corticosteroids. If coadministered, monitor for adrenal insufficiency, Cushing’s syndrome, and other corticosteroid-related adverse events. 
All PIs ↑ prednisolone possible
Betamethasone, Methylprednisolone, Triamcinolone
Local injections, including intra-articular, epidural, or intra-orbital
All PIs ↑ glucocorticoids expected Do not coadminister. Coadministration can result in adrenal insufficiency and Cushing’s syndrome.
Glucose-Lowering Medications
Canagliflozin ATV (unboosted), PI/c ↔ canagliflozin No dose adjustment needed.
PI/r ↓ canagliflozin expected

If a patient is already tolerating canagliflozin 100 mg daily, increase canagliflozin dose to 200 mg daily.

If a patient is already tolerating canagliflozin 200 mg daily and requires additional glycemic control, management strategy is based on renal function.

In Patients with eGFR ≥60 mL/min/1.73 m2:

  • Canagliflozin dose may be increased to 300 mg daily.
In Patients with eGFR <60 mL/min/1.73 m2:
  • Consider adding another antihyperglycemic agent.
Saxagliptin All PIs ↑ saxagliptin expected Limit saxagliptin dose to 2.5 mg once daily.
Dapagliflozin/Saxagliptin All PIs ↑ saxagliptin expected Do not coadminister. Dapagliflozin is only available as a coformulated drug that contains 5 mg of saxagliptin. When coadministered with EVG/c, the dose of saxagliptin should not exceed 2.5 mg once daily; thus, this combination is not recommended.
Hepatitis C Direct-Acting Antiviral Agents
Daclatasvir ATV/c, ATV/r ↑ daclatasvir Decrease daclatasvir dose to 30 mg once daily.
ATV (unboosted), DRV/c, DRV/r, LPV/r ↔ daclatasvir No dose adjustment needed.
Dasabuvir plus Paritaprevir/Ombitasvir/ RTV ATV (unboosted) ↔ ATV ATV 300 mg alone, without COBI or additional RTV, should be given in the morning with dasabuvir plus paritaprevir/ombitasvir/RTV.
ATV/c, ATV/r No data

This HCV regimen contains RTV. If ATV is part of the ARV regimen, prescribe ATV 300 mg daily without COBI or RTV.

ATV should be administered in the morning, at the same time as ombitasvir/paritaprevir/RTV plus dasabuvir.

Resume RTV or COBI regimen when HCV therapy is completed.

DRV DRV Cmin ↓ 43% to 48% Do not coadminister.
LPV/r Paritaprevir AUC ↑ 117% Do not coadminister.
DRV/c No data Do not coadminister.
Elbasvir/Grazoprevir ATV/r

Elbasvir AUC ↑ 4.8-fold

Grazoprevir AUC ↑ 10.6-fold

Elbasvir ↔ ATV

Grazoprevir ↑ ATV AUC 43%

Contraindicated.

May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

DRV/r

Elbasvir AUC ↑ 66%

Grazoprevir AUC ↑ 7.5-fold

↔ DRV

LPV/r

Elbasvir AUC ↑ 3.7-fold

Grazoprevir AUC ↑ 12.9-fold

↔ LPV

ATV (unboosted), ATV/c, DRV/c ↑ grazoprevir expected
Glecaprevir/Pibrentasvir ATV (unboosted), ATV/c, ATV/r With (ATV 300 mg plus RTV 100 mg) Once Daily:
  • Glecaprevir AUC ↑ 6.5-fold
  • Pibrentasvir AUC ↑ 64%
Contraindicated.
DRV/c, DRV/r With (DRV 800 mg plus RTV 100 mg) Once Daily:
  • Glecaprevir AUC ↑ 5-fold
  • ↔ pibrentasvir
Do not coadminister.
LPV/r

Glecaprevir AUC ↑ 4-fold

Pibrentasvir ↑ 2.5-fold

Do not coadminister.
Ledipasvir/Sofosbuvir ATV/r

ATV AUC ↑ 33%

Ledipasvir AUC ↑ 113%

↔ sofosbuvir

No dose adjustment needed.

Coadministration of ledipasvir/sofosbuvir with TDF and a PI/r results in increased exposure to TDF. The safety of the increased TDF exposure has not been established. Consider alternative HCV or ARV drugs to avoid increased risk of TDF toxicities. If coadministration is necessary, monitor for TDF-related adverse events.

ATV (unboosted), ATV/c, DRV/c, DRV/r, LPV/r

↔ PI expected

↔ ledipasvir and sofosbuvir

Sofosbuvir/Velpatasvir ATV/r ↔ ATV/r

↔ sofosbuvir

Velpatasvir AUC ↑ 2.4-fold
No dose adjustment needed.
DRV/r

↔ DRV/r

Sofosbuvir AUC ↓ 28%

↔ velpatasvir

No dose adjustment needed.
ATV (unboosted), ATV/c, DRV/c, LPV/r ↔ sofosbuvir and velpatasvir expected No dose adjustment needed.
Sofosbuvir/Velpatasvir/Voxilaprevir ATV (unboosted), ATV/c, ATV/r With ATV/r:
  • Voxilaprevir AUC ↑ 4.3-fold
  • Velpatasvir AUC ↑ 93%
  • Sofosbuvir AUC ↑ 40%
Do not coadminister.
LPV/r ↑ voxilaprevir expected Do not coadminister.
DRV/c, DRV/r With DRV/r:
  • Voxilaprevir AUC ↑ 2.4-fold
  • ↔ DRV/r, velpatasvir, and sofosbuvir
No dose adjustment needed.
Herbal Products
St. John’s Wort All PIs ↓ PI expected Contraindicated.
Hormonal Therapies
Contraceptives – Injectable
Depot MPA
LPV/r MPA AUC ↑ 46% and ↔ Cmin No dose adjustment needed.
All other PIs No data No dose adjustment needed.
Contraceptives – Oral ATV (unboosted) Ethinyl estradiol AUC ↑ 48%

Norethindrone AUC ↑ 110%

Prescribe an oral contraceptive that contains no more than 30 mcg of ethinyl estradiolb or use alternative ARV or contraceptive methods.

Oral contraceptives that contain less than 25 mcg of ethinyl estradiol or progestins other than norethindrone or norgestimate have not been studied.

ATV/c

Drosperinone AUC ↑ 130%

Ethinyl estradiol AUC ↓ 22%

Contraindicated with drospirenone-containing hormonal contraceptive due to potential for hyperkalemia. Use alternative ARV or contraceptive methods.

↔ ethinyl estradiol AUC and Cmin ↓ 25%

↔ levonorgestrel

No dose adjustment needed.
ATV/r

Ethinyl estradiol AUC ↓ 19% and Cmin ↓ 37%

Norgestimate AUC ↑ 85%

Norethindrone AUC ↑ 51% and Cmin ↑ 67%

Oral contraceptive should contain at least 35 mcg of ethinyl estradiol.c
DRV/c

Drospirenone AUC ↑ 58%

Ethinyl estradiol AUC ↓ 30%

Clinical monitoring is recommended because of the potential for hyperkalemia. Use alternative ARV or contraceptive methods.
DRV/r

Ethinyl estradiol AUC ↓ 44% and Cmin ↓ 62%

Norethindrone AUC ↓ 14% and Cmin ↓ 30%

When Used for Contraception:
  • Consider alternative ARV or contraceptive methods. If combined, consider using an oral contraceptive with at least 35mcg of ethinyl estradiol.
When Used for Other Clinical Indications (e.g., Acne, Menstrual Cycle Regulation):
  • Monitor for clinical effectiveness of hormonal therapy.

LPV/r

Ethinyl estradiol AUC ↓ 42% and Cmin ↓ 32-58%

Norethindrone AUC ↓ 17% and Cmin ↓ 32%

↔ Cmin Etonogestrel (metabolite of oral desogestrel)

Consider using an oral contraceptive with at least 35mcg of ethinyl estradiol.
Contraceptives – Subdermal Implant
Etonogestrel
LPV/r Etonogestrel AUC ↑ 52% and Cmin ↑ 34% No dose adjustment needed.
All other PIs ↑ etonogestrel expected 
Contraceptives – Subdermal Implant
Levonorgestrel
All PIs ↑ levonorgestrel expected No dose adjustment needed.
Contraceptives – Transdermal
Ethinyl Estradiol/Norelgestromin
LPV/r

↔ LPV

Ethinyl estradiol AUC ↓ 45%

Norelgestromin AUC ↑ 83%

No dose adjustment needed.
All other PIs No data
Contraceptives – Vaginal Ring
Etonogestrel/Ethinyl Estradiol
ATV/r

Ethinyl estradiol AUC ↓ 26%

Etonogestrel AUC ↑ 79%

No dose adjustment needed.
All other PIs No data
Contraceptives – Vaginal Ring
Segesterone/Ethinyl Estradiol
All PIs No data Use alternative ARV or contraceptive methods.
Emergency Contraceptives
Levonorgestrel (oral)
All PIs ↑ levonorgestrel expected  No dose adjustment needed.
Gender-Affirming Therapy PI/c  ↑ estradiol possible  Adjust estradiol dose as needed based on clinical effects and endogenous hormone concentrations.
PI/r ↓ or ↑ estradiol possible 
All PIs ↔ goserelin, leuprolide acetate, and spironolactone expected No dose adjustment needed.
All PIs

↑ dutasteride possible

↑ finasteride possible

Adjust dutasteride dose as needed based on clinical effects and endogenous hormone concentrations. No dose adjustment needed for finasteride.
All PIs ↑ testosterone possible Adjust testosterone dose as needed based on clinical effects and endogenous hormone concentrations.
Menopausal Replacement Therapy All PIs ↓ or ↑ estrogen possible with estradiol or conjugated estrogen (equine and synthetic) Adjust estrogen dose as needed based on clinical effects.
All PIs

↑ drospirenone possible

↑ medroxyprogesterone

↑ micronized progesterone

See the different Contraceptives entries for other progestin-PI interactions

Adjust progestin/progesterone dose as needed based on clinical effects. Drospirenone is not contraindicated with ATV/c products because it is prescribed at a lower dose for menopausal HRT than products used for hormonal contraceptives.
Immunosuppressants
Cyclosporine, Sirolimus, Tacrolimus All PIs ↑ immunosuppressant expected Initiate with an adjusted dose of immunosuppressant to account for potential increased concentrations of the immunosuppressant and monitor for immunosuppressant-related adverse events. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with a specialist as necessary.
Everolimus DRV/c, DRV/r ↑ immunosuppressant expected Do not coadminister.
All other PIs ↑ immunosuppressant expected Initiate with an adjusted dose of immunosuppressant to account for potential increased concentrations of the immunosuppressant and monitor for immunosuppressant-related adverse events. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with a specialist as necessary.
Lipid-Modifying Agents
Atorvastatin ATV (unboosted), ATV/r ↑ atorvastatin possible Administer the lowest effective atorvastatin dose while monitoring for adverse events.
ATV/c Atorvastatin AUC ↑ 9.2-fold and Cmax ↑ 18.9-fold Do not coadminister.
DRV/c Atorvastatin AUC ↑ 3.9-fold and Cmax ↑ 4.2-fold Administer the lowest effective atorvastatin dose while monitoring for adverse events. Do not exceed 20 mg atorvastatin daily.
DRV/r DRV/r plus atorvastatin 10 mg similar to atorvastatin 40 mg administered alone Administer the lowest effective atorvastatin dose while monitoring for adverse events. Do not exceed 20 mg atorvastatin daily.
LPV/r Atorvastatin AUC ↑ 5.9-fold and Cmax ↑ 4.7-fold Administer the lowest effective atorvastatin dose while monitoring for adverse events. Do not exceed 20 mg atorvastatin daily.
Lomitapide All PIs ↑ lomitapide expected Contraindicated.
Lovastatin All PIs Significant ↑ lovastatin expected Contraindicated.
Pitavastatin All PIs

ATV ↑ pitavastatin AUC 31% and Cmax ↑ 60%

↔ ATV

DRV/r ↓ pitavastatin AUC 26%

↔ DRV/r

LPV/r ↓ pitavastatin AUC 20%

↔ LPV

No dose adjustment needed.
Pravastatin Unboosted ATV, ATV/c, ATV/r No data Administer the lowest effective pravastatin dose while monitoring for adverse events.
DRV/c, DRV/r With DRV/r:
  • Pravastatin AUC ↑ 81% following single dose of pravastatin
Pravastatin AUC ↑ 23% at steady state
Administer the lowest effective pravastatin dose while monitoring for adverse events.
LPV/r Pravastatin AUC ↑ 33% No dose adjustment needed.
Rosuvastatin Unboosted ATV ↑ rosuvastatin expected Administer the lowest effective rosuvastatin dose while monitoring for adverse events. Do not exceed rosuvastatin 10 mg daily.
  Rosuvastatin AUC ↑ 3-fold and Cmax ↑ 7-fold
ATV/c Rosuvastatin AUC ↑ 3.4-fold and Cmax ↑ 10.6-fold
DRV/c Rosuvastatin AUC ↑ 1.9-fold and Cmax ↑ 3.8-fold Administer the lowest effective rosuvastatin dose while monitoring for adverse events. Do not exceed rosuvastatin 20 mg daily.
DRV/r Rosuvastatin AUC ↑ 48% and Cmax ↑ 2.4-fold Administer the lowest effective rosuvastatin dose while monitoring for adverse events.
LPV/r Rosuvastatin AUC ↑ 2.1-fold and Cmax ↑ 4.7-fold Administer the lowest effective rosuvastatin dose while monitoring for adverse events. Do not exceed rosuvastatin 10 mg daily.
Simvastatin All PIs Significant ↑ simvastatin expected Contraindicated.
Narcotics and Treatment for Opioid Dependence
Buprenorphine
Sublingual, buccal, or implant
ATV (unboosted)

Buprenorphine AUC ↑ 93%

Norbuprenorphine (active metabolite) AUC ↑ 76%

↓ ATV possible

Do not coadminister.
ATV/r

Buprenorphine AUC ↑ 66%

Norbuprenorphine (active metabolite) AUC ↑ 105%

Monitor for sedation and other signs or symptoms of overmedication. Buprenorphine dose reduction may be necessary. It may be necessary to remove implant and treat with a formulation that permits dose adjustments.
DRV/r

↔ buprenorphine

Norbuprenorphine (active metabolite) AUC ↑ 46% and Cmin ↑ 71%

No dose adjustment needed. Monitor for buprenorphine-related adverse events. When transferring buprenorphine from transmucosal delivery to implantation, monitor to ensure buprenorphine effect is adequate and not excessive.
LPV/r ↔ LPV/r
PI/c No data Titrate buprenorphine dose using the lowest initial dose. Dose adjustment of buprenorphine may be needed. It may be necessary to remove implant and treat with a formulation that permits dose adjustments. Monitor for buprenorphine-related adverse events.
Fentanyl All PIs ↑ fentanyl possible Monitor for fentanyl-related adverse events, including potentially fatal respiratory depression.
Lofexidine ATV (unboosted) ↔ lofexidine expected No dose adjustment needed.
PI/c, PI/r ↑ lofexidine possible Monitor for lofexidine-related adverse events, including symptoms of orthostasis and bradycardia.
Methadone ATV (unboosted) ↔ ATV No dose adjustment needed.
PI/c No data Titrate methadone dose using the lowest feasible initial dose. Dose adjustment of methadone may be needed. Monitor for methadone-related adverse events.
All PI/r

ATV/r and DRV/r ↓ R-methadoned AUC 16% to 18%

LPV/r ↓ methadone AUC 26% to 53%

Opioid withdrawal is unlikely, but may occur. Monitor for opioid withdrawal and increase methadone dose as clinically indicated.
Oxycodone All PIs

LPV/r ↑ oxycodone AUC 2.6-fold

Other PIs: ↑ oxycodone expected

Monitor for opioid-related adverse events, including potentially fatal respiratory depression. Oxycodone dose reduction may be necessary.
Tramadol All PIs

↑ tramadol expected

↓ M1 (active metabolite) possible

Tramadol dose adjustments may be necessary. Monitor for clinical response and tramadol-related adverse events.
PDE5 Inhibitors
Avanafil ATV (unboosted) No data Avanafil dose should not exceed 50 mg once every 24 hours.
PI/c, PI/r RTV 600 mg twice daily (for 5 days) ↑ avanafil AUC 13-fold and ↑ Cmax 2.4-fold Do not coadminister.
Sildenafil All PIs DRV/r plus sildenafil 25 mg similar to sildenafil 100 mg alone

RTV 500 mg twice daily ↑ sildenafil AUC 1,000%
For Treatment of Erectile Dysfunction:
  • Start with sildenafil 25 mg every 48 hours and monitor for adverse events of sildenafil.
Contraindicated for treatment of PAH.
Tadalafil All PIs RTV 200 mg twice daily ↑ tadalafil AUC 124% For Treatment of Erectile Dysfunction:
  • Start with tadalafil 5 mg and do not exceed a single dose of tadalafil 10 mg every 72 hours. Monitor for adverse events of tadalafil.
     
For Treatment of PAH:
In Patients on a PI >7 Days:
  • Start with tadalafil 20 mg once daily and increase to tadalafil 40 mg once daily based on tolerability.
In Patients on Tadalafil who Require a PI:
  • Stop tadalafil ≥24 hours before PI initiation. Seven days after PI initiation, restart tadalafil at 20 mg once daily and increase to tadalafil 40 mg once daily based on tolerability.
In Patients Switching between COBI and RTV:
  • Maintain tadalafil dose.
     
For Treatment of Benign Prostatic Hyperplasia:
  • Maximum recommended daily dose is tadalafil 2.5 mg per day.
Vardenafil All PIs RTV 600 mg twice daily ↑ vardenafil AUC 49-fold Start with vardenafil 2.5 mg every 72 hours and monitor for adverse events of vardenafil.
Sedative/Hypnotics
Alprazolam, Clonazepam, Diazepam All PIs

↑ benzodiazepine possible

RTV 200 mg twice daily (for 2 days) ↑ alprazolam half-life 222% and ↑ AUC 248%

Consider alternative benzodiazepines, such as lorazepam, oxazepam, or temazepam.
Lorazepam, Oxazepam, Temazepam All PIs No data These benzodiazepines are metabolized via non-CYP450 pathways and therefore have less interaction potential than other benzodiazepines.
Midazolam All PIs ↑ midazolam expected

Oral midazolam is contraindicated with PIs.

Parenteral midazolam can be used with caution when given in a monitored situation with appropriate medical management available in case of respiratory sedation and/or prolonged sedation. Consider dose reduction, especially if more than a single dose of midazolam is administered. 

Suvorexant All PIs ↑ suvorexant expected Do not coadminister.
Triazolam All PIs

↑ triazolam expected

RTV 200 mg twice daily ↑ triazolam half-life 1,200% and ↑ AUC 2,000%

Contraindicated.
Zolpidem PI/c, PI/r ↑ zolpidem possible Initiate zolpidem at a low dose and monitor for zolpidem-related adverse events. Dose reduction may be necessary.
Miscellaneous Drugs
Calcifediol All PIs ↑ calcifediol possible Dose adjustment of calcifediol may be required, and serum 25-hydroxyvitamin D, intact PTH, and serum calcium concentrations should be closely monitored.
Cisapride All PIs ↑ cisapride expected Contraindicated.
Colchicine All PIs RTV 100 mg twice daily ↑ colchicine AUC 296% and Cmax ↑ 184%

Significant ↑ colchicine expected with all PIs, with or without COBI or RTV
For Treatment of Gout Flares:
  • Administer a single dose of colchicine 0.6 mg, followed by colchicine 0.3 mg 1 hour later. Do not repeat dose for at least 3 days.
For Prophylaxis of Gout Flares:
  • If original dose was colchicine 0.6 mg twice daily, decrease to colchicine 0.3 mg once daily. If dose was 0.6 mg once daily, decrease to 0.3 mg every other day.
For Treatment of Familial Mediterranean Fever:
  • Do not exceed colchicine 0.6 mg once daily or colchicine 0.3 mg twice daily.
Contraindicated in patients with hepatic (Child-Pugh Score A, B or C) or renal impairment (CrCl <60 mL/min).
Dronabinol All PIs ↑ dronabinol possible Monitor for dronabinol-related adverse events.
Eluxadoline All PIs ↑ eluxadoline expected Administer eluxadoline at a dose of 75 mg twice daily and monitor for eluxadoline-related adverse events.
Ergot Derivatives All PIs ↑ dihydroergotamine, ergotamine, and methylergonovine expected Contraindicated.
Flibanserin All PIs ↑ flibanserin expected Contraindicated.
a DHA is an active metabolite of artemether.

b The following products contain no more than 30 mcg of ethinyl estradiol combined with norethindrone or norgestimate: Lo Minastrin Fe; Lo Loestrin Fe; Loestrin 1/20, 1.5/30; Loestrin Fe 1/20, 1.5/30; Loestrin 24 Fe; Minastrin 24 Fe; Ortho Tri-Cyclen Lo. Generic formulations may also be available.

c The following products contain at least 35 mcg of ethinyl estradiol combined with norethindrone or norgestimate: Brevicon; Femcon Fe; Modicon; Norinyl 1/35; Ortho-Cyclen; Ortho-Novum 1/35, 7/7/7; Ortho Tri-Cyclen; Ovcon 35; Tri-Norinyl. Generic formulations may also be available.

d R-methadone is the active form of methadone.

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

Key: 17-BMP = beclomethasone 17-monopropionate; ALT = alanine aminotransferase; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; AUC = area under the curve; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; CCB = calcium channel blocker; CNS = central nervous system; COBI = cobicistat; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P; DHA = dihydroartemisinin; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; FDA = Food and Drug Administration; FPV = fosamprenavir; H2RA = H2 receptor antagonist; HCV = hepatitis C virus; HRT = hormone replacement therapy; INR = international normalized ratio; LPV = lopinavir; LPV/r = lopinavir/ritonavir; MPA = medroxyprogesterone acetate; OATP = organic anion-transporting polypeptide; PAH = pulmonary arterial hypertension; PDE5 = Phosphodiesterase Type 5; PI = protease inhibitor; PI/c = protease inhibitor/cobicistat; PI/r = protease inhibitor/ritonavir; PK = pharmacokinetic; PPI = proton pump inhibitor; PTH = parathyroid hormone; QTc = QT corrected for heart rate; RTV = ritonavir; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; TDF = tenofovir disoproxil fumarate; VPA = valproic acid 

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