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

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Drug-Drug Interactions

Drug Interactions between Protease Inhibitors and Other Drugs

Last Updated: November 5, 2018; Last Reviewed: October 25, 2018

Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs

This table provides known or predicted information regarding PK interactions between PIs and non-ARV drugs. When information is available, interactions for PK-boosted (with either RTV or COBI) and unboosted ATV are listed separately. The term “All PIs” refers to both unboosted ATV and PIs boosted with either RTV or COBI, except the PIs noted below. For interactions between ARV agents and for dosing recommendations, refer to Tables 19c, 20a, and 20b.

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

Note: FPV, IDV, NFV, and SQV are not included in this table. Please refer to the FDA product labels for FPV, IDV, NFV, and SQV for information regarding drug interactions with these PIs.

Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs
Concomitant Drug PI Effect on PI and/or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments
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/toxicity. Dose reduction may be necessary.
Tamsulosin All PIs ↑ tamsulosin expected Coadministration is not recommended. If coadministered, monitor for tamsulosin toxicities.
Terazosin All PIs ↔ or ↑ terazosin possible Initiate terazosin at lowest dose and titrate while monitoring for clinical response/toxicity. Dose reduction may be necessary.
Silodosin All PIs ↑ silodosin expected Contraindicated.
Acid Reducers
Antacids ATV, ATV/c, ATV/r When given simultaneously, ↓ ATV expected Give ATV at least 2 hours before or 1–2 hours after antacids or buffered medications.
TPV/r TPV AUC ↓ 27% Give TPV at least 2 hours before or 1 hour after antacids.
H2 Receptor Antagonists ATV (unboosted) ↓ ATV H2 receptor antagonist single dose 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 BID in PI-naive patients. Unboosted ATV plus famotidine should not be used in combination in PI-experienced patients.

Give ATV at least 2 hours before and at least 10 hours after the H2 receptor antagonist.
ATV/c, ATV/r ↓ ATV H2 receptor antagonist dose should not exceed a dose equivalent to famotidine 40 mg BID in ART-naive patients or famotidine 20 mg BID in ART-experienced patients.

Give ATV 300 mg plus (COBI 150 mg or RTV 100 mg) simultaneously with and/or ≥10 hours after the dose of H2 receptor antagonist.

If using TDF and H2 receptor antagonist in ART-experienced patients, use ATV 400 mg plus (COBI 150 mg or RTV 100 mg).
DRV/c, DRV/r, LPV/r ↔ demonstrated or expected No dose adjustment necessary.
PPIs ATV (unboosted) ↓ ATV PPIs are not recommended in patients receiving unboosted ATV. In these patients, consider alternative acid-reducing agents, RTV or COBI boosting, or alternative PIs.
ATV/c, ATV/r ↓ ATV PPIs 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.

PPIs are not recommended in PI-experienced patients.
DRV/c, LPV/r ↔ expected No dose adjustment necessary.
DRV/r Omeprazole AUC ↓ 42% No dose adjustment necessary. If there is a lack of symptomatic relief, increase dose to no more than omeprazole 40 mg daily.
TPV/r Omeprazole AUC ↓ 70% Coadministration is not recommended. If coadministration is necessary, dose increases of omeprazole may be considered based on clinical response.
Anticoagulants and Antiplatelets
Apixaban PI/c, PI/r ↑ apixaban expected Coadministration is not recommended in patients who require apixaban 2.5 mg twice daily.

In patients who require apixaban 5 mg or 10 mg twice daily, reduce apixaban dose by 50%.
Betrixaban ATV/c, ATV/r, LPV/r ↑ betrixaban expected Administer an initial single dose of betrixaban 80 mg followed by betrixaban 40 mg once daily.
DRV/c, DRV/r ↔ betrixaban expected No dose adjustment necessary.
TPV/r No data No dosing recommendations available at this time. Consider alternative ARV or warfarin.
Dabigatran ATV/c, ATV/r, LPV/r ↑ dabigatran expected

With COBI 150 mg Alone:
  • Dabigatran AUC ↑ 110% to 127%
Dabigatran dosing recommendation depends on indication and renal function. Refer to dabigatran dosing instructions for concomitant use with P-gp inhibitors in dabigatran prescribing information.
DRV/c, DRV/r ↔ dabigatran expected No dose adjustment necessary.
TPV/r No data No dosing recommendations available at this time. Consider alternative ARV or warfarin.
Edoxaban ATV/c, ATV/r, LPV/r ↑ edoxaban expected Stroke Prevention in Nonvalvular Atrial Fibrillation Indication:
  • No dose adjustment necessary.
Deep Venous Thrombosis and Pulmonary Embolism Indication:
  • Administer edoxaban 30 mg once daily.
DRV/c, DRV/r ↔ edoxaban expected No dose adjustment necessary.
TPV/r No data No dosing recommendations available at this time. Consider alternative ARV or warfarin.
Rivaroxaban PI/c, PI/r ↑ rivaroxaban expected Coadministration is not recommended.
Ticagrelor All PIs ↑ ticagrelor expected Coadministration is not recommended.
Vorapaxar All PIs ↑ vorapaxar expected Coadministration is not recommended.
Warfarin PI/r ↓ warfarin possible Monitor INR closely when stopping or starting PI/c 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/c No data
Anticonvulsants
Carbamazepine ATV (unboosted) May ↓ PI levels substantially Do not coadminister. Consider alternative anticonvulsant or ARV.
ATV/r, LPV/r, TPV/r ↑ carbamazepine possible

TPV/r ↑ carbamazepine AUC 26%

May ↓ PI levels substantially
Consider alternative anticonvulsant or monitor levels of both drugs and assess virologic response. Do not coadminister with LPV/r once daily.
DRV/r Carbamazepine AUC ↑ 45%

DRV: no significant change
Monitor anticonvulsant level and adjust dose accordingly.
PI/c ↑ carbamazepine possible

↓ cobicistat expected

↓ PI levels expected
Contraindicated.
Eslicarbazepine, Oxcarbazepine All PIs ↓ PI possible Consider alternative anticonvulsant or ARV. If coadministration is necessary, monitor for virologic response. Consider monitoring anticonvulsant and PI concentration.
Ethosuximide All PIs ↑ ethosuximide possible Clinically monitor for ethosuximide toxicities.
Lamotrigine ATV (unboosted) Lamotrigine: No effect No dose adjustment necessary.
ATV/r Lamotrigine AUC ↓ 32% A dose increase of lamotrigine may be needed; consider monitoring lamotrigine concentration or consider alternative anticonvulsant.
LPV/r Lamotrigine AUC ↓ 50%

LPV: No significant change
DRV/r, TPV/r ↓ lamotrigine possible
PI/c No data Monitor anticonvulsant level and adjust dose accordingly.
Phenobarbital PI/c ↓ cobicistat expected

↓ PI levels expected
Contraindicated.
ATV (unboosted), PI/r May ↓ PI levels substantially Consider alternative anticonvulsant or monitor levels of both drugs and assess virologic response.

Do not coadminister with LPV/r once daily or unboosted ATV.
Phenytoin ATV (unboosted) May ↓ PI levels substantially Do not coadminister. Consider alternative anticonvulsant or ATV/r.
ATV/r, DRV/r, TPV/r ↓ phenytoin possible

↓ PI possible
Consider alternative anticonvulsant or monitor levels of both drugs and assess virologic response.
LPV/r Phenytoin AUC ↓ 31%

LPV/r AUC ↓ 33%
Consider alternative anticonvulsant or monitor levels of both drugs and assess virologic response.

Do not coadminister with LPV/r once daily.
PI/c ↓ cobicistat expected

↓ PI levels expected
Contraindicated.
Valproic Acid (VPA) PI/c, PI/r ↓ or ↔ VPA possible

LPV AUC ↑ 75%
Monitor VPA levels and virologic response. Monitor for LPV-related toxicities.
Antidepressants, Anxiolytics, and Antipsychotics (also see Sedative/Hypnotics section below)
Aripiprazole PI/c, PI/r ↑ aripiprazole expected Administer 25% of the usual aripiprazole dose. Titrate dose based on clinical monitoring for efficacy/toxicity. Refer to aripiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
ATV (unboosted) ↑ aripiprazole expected Administer 50% of the usual aripiprazole dose. Titrate based on clinical monitoring for efficacy/toxicity. 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 PI/c, PI/r ↑ brexpiprazole expected Administer 25% of the usual brexpiprazole dose. Titrate based on clinical monitoring for efficacy/toxicity. Refer to brexipiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
ATV (unboosted) ↑ brexpiprazole expected Administer 50% of the usual brexpiprazole dose. Titrate based on clinical monitoring for efficacy/toxicity. Refer to brexpiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers.
Bupropion LPV/r Bupropion AUC ↓ 57% Titrate bupropion dose based on clinical response.
TPV/r Bupropion AUC ↓ 46%
ATV/r, DRV/r ↓ bupropion possible
PI/c ↔ bupropion expected No dose adjustment necessary.
Buspirone All PIs ↑ buspirone expected Use a low dose of buspirone with caution and titrate buspirone dose based on clinical response.
Cariprazine All PIs ↑ cariprazine expected Starting Cariprazine in a Patient 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 Already Receiving Cariprazine:
  • For patients receiving cariprazine 3 mg or cariprazine 6 mg daily, reduce 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, cariprazine dose may need to be increased.
Fluvoxamine All PIs ↑ fluvoxamine possible Titrate fluvoxamine dose based on clinical response.
Lurasidone PI/c, PI/r ↑ lurasidone expected Contraindicated.
ATV (unboosted) ↑ lurasidone expected Consider alternative therapy. If coadministration is necessary, reduce lurasidone dose by 50%.
Pimavanserin All PIs ↑ pimavanserin expected Reduce dose from pimavanserin 34 mg daily to pimavanserin 17 mg daily.
Pimozide All PIs ↑ pimozide expected Contraindicated.
Quetiapine All PIs ↑ quetiapine expected Starting Quetiapine in a Patient Receiving a PI:
  • Start quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine effectiveness and adverse effects.
Starting a PI in a Patient Receiving a Stable Dose of Quetiapine:
  • Reduce quetiapine dose to 1/6 of the original dose. Closely monitor for quetiapine effectiveness and adverse effects.
Trazodone All PIs RTV 200 mg BID (for 2 days) ↑ trazodone AUC 240% Use lowest dose of trazodone and monitor for CNS and CV adverse effects.
Tricyclic Antidepressants (TCA)
Amitriptyline, desipramine, doxepin, imipramine, nortriptyline
All PIs ↑ TCA expected Use lowest possible TCA dose and titrate based on clinical assessment and/or drug levels.
Other Antipsychotics
(CYP3A4 and/or CYP2D6 substrates)
PI/c, PI/r ↑ antipsychotic possible Titrate antipsychotic dose using the lowest initial dose, or adjust maintenance dose accordingly. Monitor for toxicities.
Other Selective Serotonin Reuptake Inhibitors (SSRIs)
(e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline)
DRV/r Paroxetine AUC ↓ 39%

Sertraline AUC ↓ 49%
Titrate SSRI dose based on clinical response.
ATV/r, LPV/r, TPV/r No data
PI/c Effects unknown Titrate SSRI dose using the lowest available initial or maintenance dose.
Antifungals
Fluconazole PI/c, ATV/r, DRV/r, LPV/r No significant effect observed or expected No dose adjustment necessary.
TPV/r TPV AUC ↑ 50% Fluconazole >200 mg daily is not recommended. If high-dose fluconazole is indicated, consider alternative ARV.
Isavuconazole LPV/r Isavuconazole AUC ↑ 96%

LPV AUC ↓ 27%

RTV AUC ↓ 31%
If coadministered, consider monitoring isavuconazole concentrations and toxicities and assessing virologic response.
All PIs except LPV/r ↑ isavuconazole possible

↑ or ↓ PI possible
If coadministered, consider monitoring isavuconazole concentrations and toxicities. Monitor for PI toxicity and virologic response.
Itraconazole All PIs ↑ itraconazole possible

↑ PI possible
Consider monitoring itraconazole level to guide dose adjustments. Doses >200 mg/day are not recommended with PI/r, ATV/c, or DRV/c unless dosing is guided by itraconazole levels.
Posaconazole ATV/r ATV AUC ↑ 146%

↑ posaconazole possible
If coadministered, monitor for PI adverse effects. Consider monitoring for posaconazole concentrations and toxicities.
ATV ATV AUC ↑ 268%

↑ posaconazole possible
ATV/c, DRV/c, DRV/r, LPV/r, TPV/r ↑ PI possible

↑ posaconazole possible
Voriconazole ATV (unboosted) ↑ voriconazole possible

↑ PI possible
Monitor for toxicities.
All PI/r RTV 100 mg BID ↓ voriconazole AUC 39% Do not coadminister voriconazole and RTV or COBI unless benefit outweighs risk. If coadministered, consider monitoring voriconazole concentration and adjust dose accordingly.
PI/c Effect on voriconazole unknown
Antihyperglycemics
Canagliflozin PI/r ↓ canagliflozin expected If a patient is already tolerating canagliflozin 100 mg daily, has an eGFR >60 mL/min/1.73m2, and requires additional glycemic control, consider increasing dose to canagliflozin 300 mg daily.
PI/c ↓ canagliflozin possible If used in combination, monitor glycemic control.
Saxagliptin All PIs ↑ saxagliptin expected Limit saxagliptin dose to 2.5 mg once daily.
Dapagliflozin/ Saxagliptin All PIs ↑ saxagliptin expected Do not coadminister, as this coformulated drug contains 5 mg of saxagliptin.
Antimalarials
Artemether/ Lumefantrine DRV/r Artemether AUC ↓ 16%

DHAa AUC ↓ 18%

Lumefantrine AUC ↑ 2.5-fold
Clinical significance unknown. If used, monitor closely for antimalarial efficacy and lumefantrine toxicity.
DRV/c ↑ lumefantrine expected

Effect on artemether unknown
LPV/r Artemether AUC ↓ 40%

DHA AUC ↓ 17%

Lumefantrine AUC ↑ 470%
Artesunate/ Mefloquine LPV/r Dihydroartemisinin AUC ↓ 49%

Mefloquine AUC ↓ 28%

↔ LPV
Clinical significance unknown. If used, monitor closely for antimalarial efficacy.
Atovaquone/ Proguanil ATV/r, LPV/r With ATV/r:
  • atovaquone AUC ↓ 46%
  • proguanil AUC ↓ 41%
  • With LPV/r:
  • atovaquone AUC ↓ 74%
  • proguanil AUC ↓ 38%
  • No dose recommendation. Consider alternative drug for malaria prophylaxis, if possible.
    Mefloquine RTV With RTV 200 mg BID:
    • RTV AUC ↓ 31% and Cmin ↓ 43%


    ↔ mefloquine
    Use with caution. Effect on exposure of RTV-boosted PIs is unknown.
    Antimycobacterials (for treatment of Mycobacterium tuberculosis and nontuberculosis mycobacterial infections)
    Bedaquiline All PIs With LPV/r:
    • Bedaquiline AUC ↑ 1.9-fold


    With other PI/r, ATV/c, or DRV/c:
    • ↑ bedaquiline possible
    Clinical significance unknown. Use with caution if benefit outweighs the risk. Monitor liver function and ECG for QTc prolongation.
    Clarithromycin ATV (unboosted) Clarithromycin AUC ↑ 94% May cause QTc prolongation. Reduce clarithromycin dose by 50%. Consider alternative therapy (e.g., azithromycin).
    All PIs ↑ clarithromycin expected

    DRV/r ↑ clarithromycin AUC 57%

    LPV/r ↑ clarithromycin expected

    RTV 500 mg BID ↑ clarithromycin 77%

    TPV/r ↑ clarithromycin 19%

    Clarithromycin ↑ TPV 66%
    Consider alternative macrolide (e.g., azithromycin).

    Monitor for clarithromycin-related toxicities or consider an alternative macrolide (e.g., azithromycin).

    Reduce clarithromycin dose by 50% in patients with CrCl 30-60 mL/min.

    Reduce clarithromycin dose by 75% in patients with CrCl <30 mL/min.
    Rifabutin ATV (unboosted) ↑ rifabutin AUC expected Rifabutin 150 mg once daily or 300 mg three times a week.

    Monitor for antimycobacterial activity and consider therapeutic drug monitoring.

    PK data reported 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%
    TPV/r Rifabutin AUC ↑ 190% and metabolite AUC ↑ 1,971%
    PI/c ↑ rifabutin expected
    Rifampin All PIs ↓ PI concentration by >75% Contraindicated. Additional RTV does not overcome this interaction and may increase hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
    Rifapentine All PIs ↓ PI expected Do not coadminister.
    Antipneumocystis and Antitoxoplasmosis Drug
    Atovaquone ATV/r ↔ atovaquone No dose adjustment necessary.
    Cardiac Medications
    Amiodarone TPV/r ↑ both amiodarone and PI possible Contraindicated.
    All PIs except TPV/r ↑ both amiodarone and PI possible Use with caution. Monitor for amiodarone toxicity and consider monitoring ECG and amiodarone drug levels.
    Antiarrhythmics
    (e.g., disopyramide, dofetilide, lidocaine, mexiletine, propafenone)
    ATV (unboosted) ↑ antiarrhythmic possible Consider alternative antiarrhythmics or ARV. If coadministered, monitor for antiarrhythmic toxicities.
    PI/c, PI/r ↑ antiarrhythmic possible Do not coadminister. Consider alternative antiarrhythmics or ARV.
    Dronedarone ATV (unboosted) ↑ dronedarone possible Do not coadminister.
    PI/c, PI/r ↑ dronedarone expected Contraindicated.
    Flecainide All PIs except TPV/r ↑ flecainide possible Do not coadminister.
    TPV/r ↑ flecainide expected Contraindicated.
    Propafenone All PIs except TPV/r ↑ propafenone possible Do not coadminister.
    TPV/r ↑ propafenone expected Contraindicated.
    Quinidine All PIs except TPV/r ↑ quinidine possible Do not coadminister.
    TPV/r ↑ quinidine expected Contraindicated.
    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 CYP450 enzymes (e.g., atenolol, labetalol, nadolol, sotalol).
    Bosentan All PIs 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 (CCBs), Except Diltiazem All PIs ↑ dihydropyridine possible

    ↑ verapamil possible
    Use with caution. Titrate CCB dose and monitor closely. ECG monitoring is recommended when CCB is used with ATV.
    Digoxin PI/c, PI/r RTV (200 mg BID) ↑ digoxin AUC 29% and half-life ↑ 43%

    DRV/r ↑ digoxin AUC 36%

    COBI ↑ digoxin Cmax 41% and ↔ AUC
    Use with caution. Monitor digoxin levels. Digoxin dose may need to be decreased. Titrate initial digoxin dose.
    Diltiazem ATV/c, ATV/r, ATV (unboosted) Unboosted ATV ↑ diltiazem AUC 125%

    Greater ↑ likely with ATV/c or ATV/r
    Decrease diltiazem dose by 50%. ECG monitoring is recommended.
    DRV/c, DRV/r, LPV/r, TPV/r ↑ diltiazem possible Use with caution. Adjust diltiazem according to clinical response and toxicities.
    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 BID ↑ 17-BMP AUC 2-fold
    No dose adjustment necessary.
    All PIs except DRV/r ↔ expected No dose adjustment necessary.
    Budesonide, Ciclesonide, Fluticasone, Mometasone
    Inhaled or intranasal
    All PIs ↑ glucocorticoids possible

    RTV 100 mg BID ↑ fluticasone AUC 350-fold
    Coadministration can result in adrenal insufficiency and Cushing’s syndrome. Do not coadminister unless potential benefits of inhaled or intranasal corticosteroid outweigh the risks of adverse effects associated with corticosteroids. Consider an alternative corticosteroid (e.g., beclomethasone).
    Betamethasone, Budesonide
    Systemic
    All PIs ↑ glucocorticoids possible

    ↓ PI possible
    Coadministration can result in adrenal insufficiency and Cushing’s syndrome. Do not coadminister unless potential benefits of systemic corticosteroid outweigh the risks of adverse effects associated with systemic corticosteroids.
    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 effects associated with systemic corticosteroids. If coadministered, monitor for adrenal insufficiency, Cushing’s syndrome, and other corticosteroid-associated toxicities.
    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.
    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 necessary.
    TPV/r No data No dosing recommendations available at this time.
    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.
    DRV DRV Cmin ↓ 43% to 48% Do not coadminister.
    LPV/r Paritaprevir AUC ↑ 117% Do not coadminister.
    ATV/c, DRV/c, TPV/r No data Do not coadminister.
    Elbasvir/ Grazoprevir ATV/r Elbasvir AUC ↑ 4.8-fold

    Grazoprevir AUC ↑ 10.6-fold

    ATV ↔ by elbasvir

    ATV AUC ↑ 43% by grazoprevir
    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, TPV/r ↑ grazoprevir expected
    Glecaprevir/ Pibrentasvir ATV (unboosted), ATV/c, ATV/r When Given with ATV/r 300 mg/100 mg Once Daily:
    • Glecaprevir AUC ↑ 6.5-fold
    • Pibrentasvir AUC ↑ 64%
    Contraindicated.
    DRV/c, DRV/r When Given with DRV/r 800 mg/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.
    TPV/r ↑ glecaprevir and pibrentasvir expected Do not coadminister.
    Ledipasvir/ Sofosbuvir ATV/r ATV AUC ↑ 33%

    Ledipasvir AUC ↑ 113%

    ↔ sofosbuvir
    No dose adjustment necessary.

    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 TDF toxicities. If coadministration is necessary, monitor for TDF-associated adverse reactions.
    DRV/r ↔ DRV expected

    ↔ ledipasvir/ sofosbuvir
    ATV (unboosted), ATV/c, DRV/c, LPV/r ↔ expected
    TPV/r ↓ ledipasvir and sofosbuvir expected Do not coadminister.
    Simeprevir All PIs Compared with Simeprevir 150 mg Alone, Simeprevir 50 mg plus DRV/r 800 mg/100 mg Daily:
    • Simeprevir AUC ↑ 159%
    RTV 100 mg BID ↑ simeprevir AUC 618%
    Do not coadminister.
    Sofosbuvir TPV/r ↓ sofosbuvir expected Do not coadminister.
    Sofosbuvir/ Velpatasvir ATV/r ↔ ATV/r

    ↔ sofosbuvir

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

    Sofosbuvir AUC ↓ 28%

    ↔ velpatasvir
    No dose adjustment necessary.
    ATV (unboosted), ATV/c, DRV/c, LPV/r ↔ sofosbuvir and velpatasvir expected No dose adjustment necessary.
    TPV/r ↓ sofosbuvir expected

    ↓ velpatasvir expected
    Do not coadminister.
    Sofosbuvir/ Velpatasvir/ Voxilaprevir ATV (unboosted), ATV/c, ATV/r When Given 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/r, DRV/c When Given with DRV/r:
    • Voxilaprevir AUC ↑ 2.4-fold
    • ↔ DRV/r, velpatasvir, and sofosbuvir
    No dose adjustment needed.
    TPV/r ↓ sofosbuvir expected

    ↓ velpatasvir expected

    Effect on voxilaprevir is unknown.
    Do not coadminister.
    Herbal Products
    St. John’s Wort All PIs ↓ PI expected Contraindicated.
    Hormonal Therapies
    Hormonal Contraceptives
    Oral
    ATV (unboosted) Ethinyl estradiol AUC ↑ 48%

    Norethindrone AUC ↑ 110%
    Prescribe oral contraceptive that contains no more than 30 mcg of ethinyl estradiolb or recommend alternative contraceptive method.

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

    Oral contraceptives containing progestins other than norethindrone or norgestimate have not been studied.
    ATV/c Drospirenone AUC ↑ 2.3-fold

    Ethinyl estradiol AUC ↓ 22%
    Contraindicated with drospirenone-containing hormonal contraceptive due to potential for hyperkalemia. Consider alternative or additional contraceptive method or alternative ARV drug.
    DRV/c Drospirenone AUC ↑ 1.6-fold

    Ethinyl estradiol AUC ↓ 30%
    Clinical monitoring is recommended due to the potential for hyperkalemia. Consider alternative or additional contraceptive method or alternative ARV.
    DRV/r, LPV/r, TPV/r Ethinyl estradiol AUC ↓ 37% to 55%

    Norethindrone AUC ↓ 14% to 34%

    With TPV/r:
    • ↔ norethindrone AUC
    Consider alternative or additional contraceptive method or alternative ARV drug.
    Depot MPA Injectable LPV/r MPA AUC ↑ 46%

    No significant change in Cmin
    No dose adjustment necessary.
    Etonogestrel-Releasing Subdermal Implant LPV/r Etonogestrel AUC ↑ 52% and Cmin ↑ 34% Use standard dose.
    All other PIs No data Consider alternative or additional contraceptive method or alternative ARV drug.
    Etonogestrel/ Ethinyl Estradiol Vaginal Ring ATV/r Ethinyl estradiol AUC ↓ 26%

    Etonogestrel AUC ↑ 79%
    Use standard dose.
    Transdermal Ethinyl Estradiol/ Norelgestromin LPV/r ↔ LPV

    Ethinyl estradiol AUC ↓ 45%, norelgestromin AUC ↑ 83%
    Use standard dose.
    All other PIs No data Consider alternative or additional contraceptive method or alternative ARV drug.
    Menopausal Hormone Replacement Therapy (HRT) All PIs ↓ estrogen possible with estradiol or conjugated estrogen (equine and synthetic) Adjust estrogen dosage as needed based on clinical effects.
    All PIs ↑ drospirenone possible

    ↑ medroxyprogesterone

    ↑ micronized progesterone

    See Hormonal Contraceptives for other progestin-PI interactions
    Adjust progestin/progesterone dosage as needed based on clinical effects. Because drospirenone is prescribed as a lower dose for menopausal HRT than the products used for hormonal contraceptives, it is not contraindicated with ATV/c products.
    Gender-Affirming Hormone Therapy All PIs ↓ estradiol possible Adjust estradiol dosage as needed based on clinical effects and endogenous hormone concentrations.
    All PIs ↔ finasteride, goserelin, leuprolide acetate, and spironolactone expected No dose adjustment necessary.
    All PIs ↑ dutasteride possible Adjust dutasteride dosage as needed based on clinical effects and endogenous hormone concentrations.
    All PIs ↓ testosterone possible Adjust testosterone dosage as needed based on clinical effects and endogenous hormone concentrations.
    HMG-CoA Reductase Inhibitors
    Atorvastatin ATV (unboosted), ATV/r ↑ atorvastatin possible Titrate atorvastatin dose carefully and use lowest dose necessary while monitoring for toxicities.
    ATV/c Atorvastatin AUC ↑ 9.2-fold and Cmax ↑ 18.9-fold Coadministration is not recommended.
    DRV/r DRV/r plus atorvastatin 10 mg similar to atorvastatin 40 mg administered alone Titrate atorvastatin dose carefully and use the lowest dose necessary while monitoring for toxicities. Do not exceed 20 mg atorvastatin daily.
    DRV/c Atorvastatin AUC ↑ 3.9-fold and Cmax ↑ 4.2-fold Titrate atorvastatin dose carefully and use lowest dose necessary while monitoring for toxicities. Do not exceed 20 mg atorvastatin daily.
    LPV/r Atorvastatin AUC ↑ 5.9-fold and Cmax ↑ 4.7-fold Titrate atorvastatin dose carefully and use lowest dose necessary while monitoring for toxicities. Do not exceed 20 mg atorvastatin daily.
    TPV/r Atorvastatin AUC ↑ 9.4-fold and Cmax ↑ 8.6-fold Do not coadminister.
    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 necessary.
    Pravastatin ATV/c, ATV/r No data Titrate pravastatin dose carefully while monitoring for toxicities.
    DRV/c, DRV/r With DRV/r:
    • Pravastatin AUC ↑ 81% following single dose of pravastatin
    • Pravastatin AUC ↑ 23% at steady state
    Titrate pravastatin dose carefully while monitoring for toxicities.
    LPV/r Pravastatin AUC ↑ 33% No dose adjustment necessary.
    Rosuvastatin ATV/r Rosuvastatin AUC ↑ 3-fold and Cmax ↑ 7-fold Titrate rosuvastatin dose carefully and use lowest dose necessary while monitoring for toxicities. Do not exceed rosuvastatin 10 mg daily.
    ATV/c Rosuvastatin AUC ↑ 3.4-fold and Cmax ↑ 10.6-fold
    DRV/c Rosuvastatin AUC ↑ 1.9-fold and Cmax ↑ 3.8-fold Titrate rosuvastatin dose carefully and use the lowest dose necessary while monitoring for toxicities. Do not exceed rosuvastatin 20 mg daily.
    DRV/r Rosuvastatin AUC ↑ 48% and Cmax ↑ 2.4-fold Titrate rosuvastatin dose carefully and use the lowest necessary dose while monitoring for toxicities.
    LPV/r Rosuvastatin AUC ↑ 2.1-fold and Cmax ↑ 4.7-fold Titrate rosuvastatin dose carefully and use the lowest necessary dose. Do not exceed rosuvastatin 10 mg daily.
    TPV/r Rosuvastatin AUC ↑ 26% and Cmax ↑ 2.2-fold No dose adjustment necessary.
    Simvastatin All PIs Significant ↑ simvastatin expected Contraindicated.
    Immunosuppressants
    Cyclosporine, Everolimus, 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 toxicities. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with specialist as necessary.
    Narcotics and Treatment for Opioid Dependence
    Buprenorphine
    Sublingual, buccal, or implant
    ATV (unboosted) Buprenorphine AUC ↑ 93%

    Norbuprenorphined AUC ↑ 76%

    ↓ ATV possible
    Do not coadminister.
    ATV/r Buprenorphine AUC ↑ 66%

    Norbuprenorphined AUC ↑ 105%
    Monitor for sedation and other signs or symptoms of over-medication. Buprenorphine dose reduction may be necessary. It may be necessary to remove implant and treat with a formulation that permits dose adjustments.
    DRV/r No significant effect on buprenorphine

    Norbuprenorphined AUC ↑ 46% and Cmin ↑ 71%
    No dose adjustment necessary. Clinical monitoring is recommended. When transferring buprenorphine from transmucosal delivery to implantation, monitor to ensure buprenorphine effect is adequate and not excessive.
    LPV/r No significant effect
    TPV/r No significant effect on buprenorphine

    Norbuprenorphined AUC, Cmax, and Cmin ↓ 80%

    TPV Cmin ↓ 19% to 40%
    Consider monitoring TPV level. When transferring buprenorphine from transmucosal delivery to implantation, monitor to ensure buprenorphine effect is adequate and not excessive.
    PI/c Effects unknown 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. Clinical monitoring is recommended.
    Fentanyl All PIs ↑ fentanyl possible Clinical monitoring is recommended, including for potentially fatal respiratory depression.
    Methadone ATV (unboosted) No significant effect No dose adjustment necessary.
    PI/c Effects unknown Titrate methadone dose using the lowest feasible initial dose. Dose adjustment of methadone may be needed. Clinical monitoring is recommended.
    All PI/r ATV/r and DRV/r ↓ R-methadonee AUC 16% to 18%

    LPV/r ↓ methadone AUC 26% to 53%

    TPV/r ↓ R-methadonee AUC 48%
    Opioid withdrawal is unlikely but may occur. Dosage adjustment of methadone is not usually required, but monitor for opioid withdrawal and increase methadone dose as clinically indicated.
    Oxycodone All PIs Oxycodone AUC ↑ 2.6-fold with LPV/r Monitor for opioid-related adverse effects. Oxycodone dose reduction may be necessary.
    Tramadol All PIs ↑ tramadol possible Tramadol dose reduction may be necessary. Monitor for tramadol toxicities and clinical response.
    PDE5 Inhibitors
    Avanafil All PIs except unboosted ATV RTV (600 mg BID for 5 days) ↑ avanafil AUC 13-fold and ↑ Cmax 2.4-fold Coadministration is not recommended.
    ATV (unboosted) No data Avanafil dose should not exceed 50 mg once every 24 hours.
    Sildenafil All PIs DRV/r plus sildenafil 25 mg similar to sildenafil 100 mg alone

    RTV 500 mg BID ↑ sildenafil AUC 1,000%
    For Treatment of Erectile Dysfunction:
    • Start with sildenafil 25 mg every 48 hours and monitor for adverse effects of sildenafil.


    For Treatment of PAH:
    • Contraindicated.
    Tadalafil All PIs RTV 200 mg BID ↑ tadalafil AUC 124%

    TPV/r (1st dose) ↑ tadalafil AUC 133%

    No significant effect on TPV/r steady state
    For Treatment of Erectile Dysfunction:
    • Start with tadalafil 5-mg dose and do not exceed a single dose of tadalafil 10 mg every 72 hours. Monitor for adverse effects 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 BID ↑ vardenafil AUC 49-fold Start with vardenafil 2.5 mg every 72 hours and monitor for adverse effects of vardenafil.
    Sedative/Hypnotics
    Alprazolam, Clonazepam, Diazepam All PIs ↑ benzodiazepine possible

    RTV (200 mg BID 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; thus, there is less interaction potential than with other benzodiazepines.
    Midazolam All PIs ↑ midazolam expected Oral midazolam is contraindicated with PIs.

    Parenteral midazolam can be used with caution when given as a single dose in a monitored situation for procedural sedation.
    Suvorexant All PIs ↑ suvorexant expected Coadministration is not recommended.
    Triazolam All PIs ↑ triazolam expected

    RTV (200 mg BID) ↑ triazolam half-life 1,200% and ↑ AUC 2,000%
    Contraindicated.
    Zolpidem PI/c, PI/r ↑ zolpidem possible Initiate zolpidem at a low dose. 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 BID ↑ 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:
    • Administer colchicine 0.3 mg once daily or every other day.
    For Treatment of Familial Mediterranean Fever:
    • Do not exceed colchicine 0.6 mg once daily or colchicine 0.3 mg BID.
    Do not coadminister in patients with hepatic or renal impairment.
    Dronabinol All PIs ↑ dronabinol possible Monitor for dronabinol-related adverse reactions.
    Eluxadoline All PIs ↑ eluxadoline expected Administer eluxadoline at a dose of 75 mg twice daily and monitor for eluxadoline-related adverse effects.
    Enzalutamide All PIs ↓ PI expected Contraindicated.
    Ergot Derivatives All PIs ↑ dihydroergotamine, ergotamine, methylergonovine expected Contraindicated.
    Flibanserin All PIs ↑ flibanserin expected Contraindicated.
    Irinotecan ATV (unboosted), ATV/c, ATV/r ↑ irinotecan expected Contraindicated.
    Mitotane All PIs ↓ PI expected Contraindicated.
    Salmeterol All PIs ↑ salmeterol possible Do not coadminister because of potential increased risk of salmeterol-associated CV events.
    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 (generic formulations may also be available): 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.
    c The following products contain at least 35 mcg of ethinyl estradiol combined with norethindrone or norgestimate (generic formulations may also be available): Brevicon; Femcon Fe; Modicon; Norinyl 1/35; Ortho-Cyclen; Ortho-Novum 1/35, 7/7/7; Ortho Tri-Cyclen; Ovcon 35; Tri-Norinyl.
    d Norbuprenorphine is an active metabolite of buprenorphine.
    e R-methadone is the active form of methadone.

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

    Key to Acronyms: 117-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; BID = twice daily; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; 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; FPV = fosamprenavir; HCV = hepatitis C virus; HRT = hormone replacement therapy; IDV = indinavir; INR = international normalized ratio; LPV = lopinavir; LPV/r = lopinavir/ritonavir; MPA = medroxyprogesterone acetate; NFV = nelfinavir; 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; SQV = saquinavir; TDF = tenofovir disoproxil fumarate; TPV = tipranavir; TPV/r = tipranavir/ritonavir

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