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

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Drug-Drug Interactions

Drug Interactions between Protease Inhibitors and Other Drugs

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

Table 18a. 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 specific 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 18c, 19a, and 19b.

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

Note: Fosamprenavir (FPV), indinavir (IDV), nelfinavir (NFV), and saquinavir (SQV) are not included in this table. Please refer to the Food and Drug Administration product labels for FPV, IDV, NFV, and SQV for information regarding drug interactions with these PIs.

Table 18a. 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 Give ATV at least 2 hours before or 1 to 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 + 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 20 mg BID in ART-experienced patients.

Give ATV 300 mg + 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 + 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 omeprazole dose to no more than 40 mg daily if needed.
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. Consider alternative ARV or warfarin. If coadministration is necessary, reduce apixaban dose by 50% and monitor for apixaban toxicity.
Betrixaban PI/r ↑ or ↓ betrixaban possible Coadministration is not recommended. Consider alternative ARV or warfarin.
ATV/c, DRV/c ↑ betrixaban expected Coadministration is not recommended. Consider alternative ARV or warfarin.
Dabigatran PI/r With RTV 100 mg + dabigatran taken simultaneously: ↔ dabigatran

Dabigatran given 2 hours before RTV 100 mg: dabigatran AUC ↓ 29%
The extent of interaction of PI/r + dabigratran is unknown.

Consider alternative ARV or warfarin.

If coadministered, take dabigatran and PI/r simultaneously.
ATV/c, DRV/c With COBI 150 mg: dabigatran AUC ↑ 110%–127% Coadministration is not recommended. Consider alternative ARV or warfarin.
Edoxaban PI/r ↑ or ↓ edoxaban possible Coadministration is not recommended. Consider alternative ARV or warfarin.
ATV/c, DRV/c ↑ edoxaban expected Coadministration is not recommended. Consider alternative ARV or warfarin.
Rivaroxaban PI/c, PI/r ↑ rivaroxaban expected Coadministration is not recommended. Consider alternative ARV or warfarin.
Ticagrelor All PIs ↑ ticagrelor expected Coadministration is not recommended. Consider alternative ARV or warfarin.
Vorapaxar All PIs ↑ vorapaxar expected Coadministration is not recommended. Consider alternative ARV or warfarin.
Warfarin PI/r ↓ warfarin possible Monitor INR closely when stopping or starting PI/r and adjust warfarin dose accordingly.
ATV/c, DRV/c No data 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.
Anticonvulsants
Carbamazepine ATV (unboosted) May ↓ PI levels substantially Do not coadminister. Consider alternative anticonvulsant or ARV.
ATV/c, DRV/c ↓ cobicistat expected

↓ PI levels expected
Contraindicated.
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.
Oxcarbazepine, Eslicarbazepine 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 ethosuxamide 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
ATV/c, DRV/c No data Monitor lamotrigine concentration or consider alternative anticonvulsant.
Phenobarbital ATV/c, DRV/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.
ATV/c, DRV/c ↓ cobicistat expected

↓ PI levels expected
Contraindicated.
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.
Valproic Acid 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)
Bupropion LPV/r Bupropion AUC ↓ 57% Titrate bupropion dose based on clinical response.
TPV/r Bupropion AUC ↓ 46%
Buspirone All PIs ↑ buspirone expected Use a low dose of buspirone with caution and titrate buspirone dose based on clinical response.
Fluvoxamine All PIs ↑ or ↓ PI possible Consider alternative therapeutic agent.
Lurasidone PI/c, PI/r ↑ lurasidone expected Contraindicated.
ATV (unboosted) ↑ lurasidone expected Consider alternative therapy. If coadministration is necessary, reduce lurasidone dose by 50%.
Other Selective Serotonin Reuptake Inhibitors (SSRIs)
(e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline)
RTV Escitalopram ↔ Titrate SSRI dose based on clinical response.
DRV/r Paroxetine AUC ↓ 39%

Sertraline AUC ↓ 49%
ATV/r, LPV/r, TPV/r No data
ATV/c, DRV/c Effects unknown Titrate SSRI dose using the lowest available initial or maintenance dose.
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.
Other Antipsychotics
(e.g., perphenazine, risperidone, thioridazine)
PI/c, PI/r ↑ antipsychotic possible Titrate antipsychotic dose using the lowest initial dose, or adjust maintenance dose accordingly. Monitor for toxicities.
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
Amitriptyline, desipramine, doxepin, imipramine, nortriptyline
All PIs ↑ TCA expected Use lowest possible TCA dose and titrate based on clinical assessment and/or drug levels.
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 dosage 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 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 400 mg BID ↓ voriconazole AUC 82%

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.
ATV/c, DRV/c Effects 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 canagliflozin dose to 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%, 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 and monitor for QTc prolongation and liver function tests.
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 daily or 300 mg three times a week.
ATV/c, DRV/c ↑ rifabutin 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 the healthy study participants.
ATV/r

Compared with rifabutin (300 mg once daily) alone, rifabutin (150 mg once daily) + ATV/r:

  • rifabutin AUC ↑ 110% and metabolite AUC ↑ 2101%
DRV/r

Compared with rifabutin (300 mg once daily) alone, rifabutin (150 mg every other day) + DRV/r:

  • rifabutin AUC ↔ and metabolite AUC ↑ 881%
LPV/r

Compared with rifabutin (300 mg daily) alone, rifabutin (150 mg once daily) + LPV/r:

  • rifabutin and metabolite AUC ↑ 473%
TPV/r Rifabutin and metabolite AUC ↑ 333%
Rifampin All PIs ↓ PI concentration by >75% Contrainidcated. 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 ECG and amiodarone drug level monritoring.
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.
Flecanide All PIs except TPV/r ↑ flecainide possible Do not coadminister.
TPV/r ↑ flecanide 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/r, PI/c RTV (200 mg BID) ↑ digoxin AUC 29% and ↑ half-life 43%

DRV/r ↑ digoxin AUC 36%

COBI ↑ digoxin Cmax 41%, 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 systemic corticosteroid adverse effects. 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 systemic corticosteroid adverse effects.
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 systemic corticosteroid adverse effects. 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 + Paritaprevir/ Ombitasvir/ RTV ATV (unboosted) ATV ↔ ATV 300 mg alone, without COBI or additional RTV, should be given in the morning with dasabuvir + 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 300/100 mg Once Daily:
  • Glecaprevir AUC ↑ 6.5-fold
  • Pibrentasvir AUC ↑ 64%
Contraindicated.
DRV/c, DRV/r When Given with DRV/r 800/100 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 + DRV/r 800/100 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 adjument 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 estradiol 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.c
ATV/r Ethinyl estradiol AUC ↓ 19% and Cmin ↓ 37%

Norgestimate ↑ 85%

Norethindrone AUC ↑ 51% and Cmin ↑ 67%
Oral contraceptive should contain at least 35 mcg of ethinyl estradiol.b

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 drosperinone-containing hormonal contraceptive. Do not coadminister 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 Medroxyprogesterone Acetate (MPA) Injectable LPV/r MPA AUC ↑ 46%

Cmin: no significant change
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.
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 All PIs With estradiol or conjugated estrogen (equine and synthetic): ↓ estrogen possible 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, ATV/r ↑ atorvastatin possible Titrate atorvastatin dose carefully and use lowest dose necessary while monitoring for toxicities.
ATV/c Atorvastatin AUC ↑ 9.2-fold, Cmax ↑ 18.9-fold Coadministration is not recommended.
DRV/r DRV/r + 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, 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, 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, Cmax ↑ 8.6-fold Do not coadminister.
Lovastatin All PIs Significant ↑ lovastatin expected Contraindicated.
Pitavastatin All PIs ATV ↑ pitavastatin AUC 31%, 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
  • ↑ 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, Cmax ↑ 7-fold Titrate rosuvastatin dose carefully and use lowest dose necessary while monitoring for toxicities. Do not exceed 10 mg rosuvastatin daily.
ATV/c Rosuvastatin AUC ↑ 3.4-fold, Cmax ↑ 10.6-fold
DRV/c Rosuvastatin AUC ↑ 1.9-fold, Cmax ↑ 3.8-fold Titrate rosuvastatin dose carefully and use the lowest necessary dose while monitoring for toxicities. Do not exceed 20 mg rosuvastatin daily.
DRV/r Rosuvastatin AUC ↑ 48%, 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, Cmax ↑ 4.7-fold Titrate rosuvastatin dose carefully and use the lowest necessary dose. Do not exceed 10 mg rosuvastatin daily.
TPV/r Rosuvastatin AUC ↑ 26%, 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 buprenorphine with unboosted ATV.
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.
ATV/c, DRV/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.
DRV/r Buprenorphine: no significant effect

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

Norbuprenorphined AUC, Cmax, and Cmin ↓ 80%

TPV Cmin ↓ 19%–40%
Consider monitoring TPV level. When transferring buprenorphine from transmucosal to implantation, monitor to ensure buprenorphine effect is adequate and not excessive.
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.
ATV/c, DRV/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%–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 ATV/c, DRV/c ↑ tramadol possible Tramadol dose reduction may be necessary. Monitor for tramadol toxicities and clinical response.
Phosphodiesterase Type 5 (PDE5) Inhibitors
Avanafil All PIs except unboosted ATV RTV (600 mg BID for 5 days) ↑ avanafil AUC 13-fold, 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 + sildenafil 25 mg similar to sildenafil 100 mg alone

RTV 500 mg BID ↑ sildenafil AUC 1000%
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%

TPV/r steady state: no significant effect
For Treatment of Erectile Dysfunction:
  • Start with tadalafil 5-mg dose and do not exceed a single dose of 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 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 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 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 Do not coadminister oral midazolam and 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 1200% and AUC 2000%
Contraindicated.
Zolpidem PI/r, ATV/c, DRV/c ↑ zolpidem possible Initiate zolpidem at a low dose. Dose reduction may be necessary.
Miscellaneous Drugs
Alfuzosin All PIs ↑ alfuzosin expected Contraindicated.
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%, Cmax 184%

With all PIs with or without COBI or RTV: significant ↑ colchicine expected
For Treatment of Gout Flares:
  • Colchicine 0.6 mg x 1 dose, followed by 0.3 mg 1 hour later. Do not repeat dose for at least 3 days.

For Prophylaxis of Gout Flares:
  • 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 0.3 mg BID.
Do not coadminister in patients with hepatic or renal impairment.
Dronabinol All PIs ↑ dronabinol possible Monitor for increased 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.
Ergot Derivatives All PIs ↑ dihydroergotamine, ergotamine, methylergonovine expected Contraindicated.
Flibanserin All PIs ↑ flibanserin expected Contraindicated.
Irinotecan ATV, ATV/c, ATV/r ↑ irinotecan 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 at least 35 mcg of ethinyl estradiol combined with norethindrone or norgestimate (generic formulation 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.
c The following products contain no more than 30 mcg of ethinyl estradiol combined with norethindrone or norgestimate (generic formulation 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.
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: 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; BID = twice daily; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; CNS = central nervous system; COBI, c = 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; HCV = hepatitis C virus; HRT = hormone replacement therapy; INR = international normalized ratio; LPV = lopinavir; LPV/r = ritonavir-boosted lopinavir; MPA = medroxyprogesterone acetate; PAH = pulmonary arterial hypertension; 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, r = ritonavir; TCA = tricyclic antidepressant; TDF = tenofovir disoproxil fumarate; TPV = tipranavir; TPV/r = tipranavir/ritonavir; VPA = valproic acid

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