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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 23 

Table 15a. Drug Interactions between PIs* and Other Drugs (Updated January 10, 2011)

Page 1 of 8

*NFV and IDV are not included in this table. Please refer to the FDA package insert for information regarding NFV and IDV drug interactions.

This table provides information relating to pharmacokinetic interactions between PIs and non-ARV drugs. When information is available, 

interactions with boosted and unboosted PIs are listed separately. For interactions among ARV agents and for dosing recommendations, 

refer to Table 16a.

Concomitant Drug PI

Effect on PI or 

Concomitant Drug 

Concentrations

Dosing Recommendations and Clinical 

Comments

Acid Reducers

Antacids

ATV +/− RTV ↓ ATV expected when given 

simultaneously

Give ATV at least 2 hours before or 1 hour after antacids or 

buffered medications.

FPV APV AUC ↓ 18%; no significant 

change in APV Cmin

Give FPV simultaneously with or at least 2 hours before or 

1 hour after antacids.

TPV/r TPV AUC ↓ 27% Give TPV at least 2 hours before or 1 hour after antacids.

H2 receptor antagonists

RTV-boosted PIs

ATV/r ↓ ATV

H2 receptor antagonist dose should not exceed a dose 

equivalent to famotidine 40 mg BID in ART-naïve patients 

or 20 mg BID in ART-experienced patients.

Give ATV 300 mg + RTV 100 mg simultaneously with 

and/or >10 hours after the H2 receptor antagonist.

If using TDF and H2 receptor antagonist in ARTexperienced patients, use ATV 400 mg + RTV 100 mg.

DRV/r, LPV/r No significant effect

PIs without RTV

ATV ↓ ATV

H2 receptor antagonist single dose should not exceed a dose 

equivalent of famotidine 20 mg or total daily dose 

equivalent of famotidine 20 mg BID in ART-naïve patients.

Give ATV at least 2 hours before and at least 10 hours after 

the H2 receptor antagonist.

FPV APV AUC ↓ 30%; no significant 

change in APV Cmin

Give FPV at least 2 hours before H2 receptor antagonist if 

concomitant use is necessary. Consider boosting with RTV.

Proton pump inhibitors 

(PPIs)

ATV ↓ ATV

PPIs are not recommended in patients receiving 

unboosted ATV. In these patients, consider alternative 

acid-reducing agents, RTV boosting, or alternative PIs.

ATV/r ↓ ATV

PPIs should not exceed a dose equivalent to omeprazole 20 

mg daily in PI-naïve patients. PPIs should be administered 

at least 12 hours prior to ATV/r.

PPIs are not recommended in PI-experienced patients. 

DRV/r, TPV/r ↓ omeprazole

PI: no significant effect May need to increase omeprazole dose with TPV/r.

FPV +/– RTV, LPV/r No significant effect

SQV/r SQV AUC ↑ 82% Monitor for SQV toxicities.

Anticoagulants

Warfarin

ATV +/- RTV, DRV/r, 

FPV +/- RTV, LPV/r, SQV/r, 

TPV/r

↑ or ↓ warfarin possible

DRV/r ↓ S-warfarin AUC 21%

Monitor INR closely when stopping or starting PI and 

adjust warfarin dose accordingly.
January 10, 2011

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 24 

Concomitant Drug PI

Effect on PI or 

Concomitant Drug 

Concentrations

Dosing Recommendations and Clinical 

Comments

Anticonvulsants

Carbamazepine

RTV-boosted PIs

ATV/r, FPV/r, LPV/r, 

SQV/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.

PIs without RTV

ATV, FPV May ↓ PI levels substantially

Monitor anticonvulsant level and virologic response. 

Consider alternative anticonvulsant; RTV boosting for 

ATV and FPV; and/or monitoring PI level.

Lamotrigine LPV/r lamotrigine AUC ↓ 50%

LPV: no significant change

Titrate lamotrigine dose to effect. A similar interaction is 

possible with other RTV-boosted PIs.

Phenobarbital All PIs 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.

Phenytoin RTV-boosted PIs

ATV/r, DRV/r, 

SQV/r, TPV/r

↓ phenytoin possible

↓ PI possible

Consider alternative anticonvulsant or monitor levels of 

both drugs and assess virologic response. 

FPV/r phenytoin AUC ↓ 22%

APV AUC ↑ 20%

Monitor phenytoin level and adjust dose accordingly. No 

change in FPV/r dose recommended.

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.

PIs without RTV

ATV, FPV May ↓ PI levels substantially

Consider alternative anticonvulsant; RTV boosting for 

ATV and FPV; and/or monitoring PI level.

Monitor anticonvulsant level and virologic response.

Valproic acid (VPA) LPV/r ↓VPA possible 

LPV AUC ↑ 75%

Monitor VPA levels and response. Monitor for LPV-related 

toxicities.

Antidepressants

Bupropion

LPV/r bupropion AUC ↓ 57%

Titrate bupropion dose based on clinical response.

TPV/r bupropion AUC ↓ 46%

Paroxetine

DRV/r paroxetine AUC ↓ 39%

Titrate paroxetine dose based on clinical response.

FPV/r paroxetine AUC ↓ 58%

Sertraline DRV/r sertraline AUC ↓ 49% Titrate sertraline dose based on clinical response.

Trazodone

ATV +/- RTV, DRV/r, 

FPV +/- RTV, LPV/r, TPV/r 

RTV 200 mg BID (for 2 days) 

↑ trazodone AUC 240%

Use lowest dose of trazodone and monitor for CNS and 

cardiovascular adverse effects.

SQV/r ↑ trazodone expected Contraindicated. Do not coadminister.

Tricyclic 

antidepressants (TCAs)

 (amitriptyline,

 desipramine, 

 imipramine, 

 nortriptyline) 

All RTV-boosted PIs ↑ TCA expected Use lowest possible TCA dose and titrate based on clinical 

assessment and/or drug levels.

Table 15a. Drug Interactions between PIs and Other Drugs

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January 10, 2011

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Concomitant Drug PI

Effect on PI or 

Concomitant Drug 

Concentrations

Dosing Recommendations and Clinical 

Comments

Antifungals

Fluconazole 

RTV-boosted PIs

ATV/r No significant effect

SQV/r No data with RTV boosting

SQV (1,200 mg TID) AUC ↑ 50%

TPV/r TPV AUC ↑ 50%

Fluconazole >200 mg daily is not recommended. If highdose fluconazole is indicated, consider alternative PI or 

another class of ARV drug.

Itraconazole

RTV-boosted PIs

ATV/r, DRV/r, FPV/r, TPV/r ↑ itraconazole possible

↑ PI possible

Consider monitoring itraconazole level to guide dosage 

adjustments. High doses (>200 mg/day) are not 

recommended unless dosing is guided by drug levels.

LPV/r ↑ itraconazole Consider not exceeding 200 mg itraconazole daily or 

monitor itraconazole level.

SQV/r Bidirectional interaction has been 

observed

Dose not established, but decreased itraconazole dosage 

may be warranted. Consider monitoring itraconazole level. 

PIs without RTV

ATV, FPV ↑ itraconazole possible

↑ PI possible

Consider monitoring itraconazole level to guide dosage 

adjustments.

Posaconazole

ATV/r ATV AUC ↑ 146% Monitor for adverse effects of ATV. 

ATV ATV AUC ↑ 268% Monitor for adverse effects of ATV.

Voriconazole

RTV-boosted PIs

ATV/r, DRV/r,

FPV/r, LPV/r, 

SQV/r, TPV/r

RTV 400 mg BID ↓ voriconazole 

AUC 82% 

RTV 100 mg BID ↓ voriconazole 

AUC 39% 

Do not coadminister voriconazole and RTV unless benefit 

outweighs risk. If administered, consider monitoring 

voriconazole level.

PIs without RTV

ATV, FPV ↑ voriconazole possible

↑ PI possible Monitor for toxicities.

Anti-mycobacterials

Clarithromycin 

ATV +/− RTV clarithromycin AUC ↑ 94% May cause QTc prolongation. Reduce clarithromycin dose 

by 50%. Consider alternative therapy.

DRV/r, FPV/r, LPV/r, 

SQV/r, TPV/r

DRV/r ↑ clarithromycin AUC 57%

FPV/r ↑ clarithromycin possible

LPV/r ↑ clarithromycin expected

RTV 500 mg BID ↑ clarithromycin 

77%

SQV unboosted ↑ clarithromycin 

45%

TPV/r ↑ clarithromycin 19% and 

↓ active metabolite 97%

clarithromycin ↑ unboosted SQV 

177%

clarithromycin ↑ TPV 66%

Monitor for clarithromycin-related toxicities.

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. 

FPV APV AUC ↑ 18% No dose adjustment

Table 15a. Drug Interactions between PIs and Other Drugs

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January 10, 2011

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Concomitant Drug PI

Effect on PI or 

Concomitant Drug 

Concentrations

Dosing Recommendations and Clinical 

Comments

Rifabutin

RTV-boosted PIs

ATV +/– RTV

rifabutin (150 mg once daily) 

AUC ↑ 110% and metabolite 

AUC ↑ 2,101% compared with 

rifabutin 300 mg daily alone

Rifabutin 150 mg every other day or three times a week. 

Some experts recommend rifabutin 150 mg daily or 300 mg 

three times a week. Monitor for antimycobacterial activity. 

Therapeutic drug monitoring for rifabutin is recommended.

Rifabutin 150 mg three times a week in combination with 

LPV/r has resulted in inadequate rifabutin levels and has 

led to acquired rifamycin resistance in patients with HIVassociated TB. 

Pharmacokinetic data reported in this table are results from 

healthy volunteer studies.

DRV/r

rifabutin (150 mg every other day) 

and metabolite AUC ↑ 55% 

compared with rifabutin 300 mg 

once daily alone

FPV/r

rifabutin (150 mg every other day) 

and metabolite AUC ↑ 64% 

compared with rifabutin 300 mg 

once daily alone

LPV/r

rifabutin (150 mg once daily) and 

metabolite AUC ↑ 473% compared 

with rifabutin 300 mg daily alone

SQV/r ↑ rifabutin with unboosted SQV

TPV/r rifabutin (150 mg x 1 dose) and 

metabolite AUC ↑ 333%

PIs without RTV

FPV ↑ rifabutin AUC expected Rifabutin 150 mg daily or 300 mg three times a week 

Rifampin All PIs ↓ PI >75% approximately 

Do not coadminister rifampin and PIs. Additional RTV 

does not overcome this interaction and increases 

hepatotoxicity.

Benzodiazepines

Alprazolam

Diazepam All PIs

↑ benzodiazepine possible

RTV 200 mg BID for two days

↑ alprazolam half-life 222% and 

AUC 248% 

Consider alternative benzodiazepines such as lorazepam, 

oxazepam, or temazepam.

Lorazepam

Oxazepam

Temazepam

All PIs No data

Metabolism of these benzodiazepines via non-CYP450 

pathways decreases interaction potential compared with 

other benzodiazepines.

Midazolam All PIs

↑ midazolam expected

SQV/r ↑ midazolam (oral) AUC 

1,144% and Cmax 327%

Do not coadminister oral midazolam and PIs.

Parenteral midazolam can be used with caution as a single 

dose and can be given in a monitored situation for 

procedural sedation.

Triazolam All PIs

↑ triazolam expected

RTV 200 mg BID ↑ triazolam halflife 1,200% and AUC 2,000%

Do not coadminister triazolam and PIs.

Cardiac Medications

Bosentan All PIs

LPV/r ↑ bosentan 48-fold (Day 4) 

and 5-fold (Day 10)

↓ ATV expected

Do not coadminister bosentan and ATV without RTV.

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 prior to PI 

initiation and restart 10 days after PI initiation at 62.5 mg 

once daily or every other day.

Table 15a. Drug Interactions between PIs and Other Drugs

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January 10, 2011

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 27 

Concomitant Drug PI

Effect on PI or 

Concomitant Drug 

Concentrations

Dosing Recommendations and Clinical 

Comments

Digoxin

RTV, SQV/r

RTV 200 mg BID ↑ digoxin AUC 

29% and half-life 43%

SQV/r ↑ digoxin AUC 49%

Use with caution. Monitor digoxin levels. Digoxin dose 

may need to be decreased.

Dihydropyridine 

calcium channel 

blockers (CCBs)

All PIs ↑ dihydropyridine possible Use with caution. Titrate CCB dose and monitor closely. 

ECG monitoring is recommended when used with ATV. 

Diltiazem

ATV +/– RTV diltiazem AUC ↑ 125% Decrease diltiazem dose by 50%. ECG monitoring is 

recommended.

DRV/r, FPV +/– RTV, 

LPV/r, SQV/r, TPV/r

↑ diltiazem possible Use with caution. Adjust diltiazem according to clinical 

response and toxicities.

Corticosteroids

Dexamethasone All PIs ↓ PI levels possible Use systemic dexamethasone with caution or consider 

alternative corticosteroid for long-term use.

Fluticasone

(inhaled or intranasal) All RTV-boosted PIs RTV 100 mg BID ↑ fluticasone 

AUC 350-fold and ↑ Cmax 25-fold

Coadministration can result in adrenal insufficiency, 

including Cushing’s syndrome. Do not coadminister 

unless potential benefit outweighs risk of systemic 

corticosteroid adverse effects.

Prednisone LPV/r ↑ prednisolone AUC 31% No dosage adjustment necessary.

Herbal Products

St. John’s wort All PIs ↓ PI expected Do not coadminister.

Hormonal Contraceptives

Hormonal 

contraceptives

RTV-boosted PIs

ATV/r ↓ ethinyl estradiol

↑ norgestimate

Oral contraceptive should contain at least 35 mcg of ethinyl 

estradiol. Oral contraceptives containing progestins other 

than norethindrone or norgestimate have not been studied. 

DRV/r ethinyl estradiol AUC ↓ 44%

norethindrone AUC ↓ 14% Use alternative or additional method.

FPV/r ethinyl estradiol AUC ↓ 37%

norethindrone AUC ↓ 34% Use alternative or additional method.

LPV/r ethinyl estradiol AUC↓ 42%

norethindrone AUC ↓ 17% Use alternative or additional method.

SQV/r ↓ ethinyl estradiol Use alternative or additional method.

TPV/r

ethinyl estradiol AUC ↓ 48%

norethindrone: no significant 

change

Use alternative or additional method. 

PIs without RTV

ATV ethinyl estradiol AUC ↑ 48%

norethindrone AUC ↑ 110%

Oral contraceptive should contain no more than 30 mcg of 

ethinyl estradiol or use alternate method. Oral 

contraceptives containing less than 25 mcg of ethinyl 

estradiol or progestins other than norethindrone or 

norgestimate have not been studied.

FPV With APV: ↑ ethinyl estradiol and 

↑ norethindrone; ↓ APV 20% Use alternative method.

Table 15a. Drug Interactions between PIs and Other Drugs

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Concomitant Drug PI

Effect on PI or 

Concomitant Drug 

Concentrations

Dosing Recommendations and Clinical 

Comments

HMG-CoA Reductase Inhibitors

Atorvastatin All PIs

DRV/r + atorvastatin 10 mg similar 

to atorvastatin 40 mg alone;

FPV +/– RTV ↑ atorvastatin AUC 

130%–153%;

LPV/r ↑ atorvastatin AUC 488%;

SQV/r ↑ atorvastatin AUC 79%;

TPV/r ↑ atorvastatin AUC 836%

Use lowest possible starting dose with careful monitoring 

for toxicities or consider other HMG-CoA reductase 

inhibitors with less potential for interaction. 

Lovastatin All PIs Significant ↑ lovastatin expected Contraindicated. Do not coadminister.

Pitavastatin

ATV

pitavastatin AUC ↑ 31%; 

Cmax ↑ 60%

ATV: no significant effect

No dosage adjustment needed for ATV without RTV.

All RTV-boosted PIs ↑ pitavastatin possible

Do not coadminister due to possible increase in 

pitavastatin concentration and increased risk of 

rhabdomyolitis.

Pravastatin

DRV/r pravastatin AUC ↑ 81% Use lowest possible starting dose with careful monitoring. 

LPV/r pravastatin AUC ↑ 33% No dose adjustment necessary

SQV/r pravastatin AUC ↓ 47%–50% No dose adjustment necessary

Rosuvastatin

ATV/r rosuvastatin AUC ↑ 213% and 

Cmax ↑ 600% 

Use lowest possible starting dose with careful monitoring 

or consider other HMG-CoA reductase inhibitors with less 

potential for interaction.

DRV/r, FPV +/- RTV, SQV/r ↑ rosuvastatin possible

LPV/r rosuvastatin AUC ↑ 108% and 

Cmax ↑ 366%

TPV/r rosuvastatin AUC ↑ 26% and 

Cmax ↑ 123%

Simvastatin All PIs

Significant ↑ simvastatin level;

SQV/r 400 mg/400 mg BID 

↑ simvastatin AUC 3,059%

Contraindicated. Do not coadminister.

Narcotics/Treatment for Opioid Dependence

Buprenorphine

ATV

buprenorphine AUC ↑ 93% 

norbuprenorphine AUC ↑ 76%

↓ ATV possible

Do not coadminister buprenorphine with unboosted 

ATV.

Norbuprenorphine is an active metabolite of buprenorphine.

ATV/r buprenorphine AUC ↑ 66% 

norbuprenorphine AUC ↑ 105%

Monitor for sedation. Buprenorphine dose reduction may be 

necessary.

Norbuprenorphine is an active metabolite of buprenorphine.

DRV/r

buprenorphine: no significant effect

norbuprenorphine AUC ↑ 46% and 

Cmin ↑ 71%

No dose adjustment necessary. Clinical monitoring is 

recommended.

Norbuprenorphine is an active metabolite of buprenorphine.

LPV/r No significant effect No dose adjustment necessary

TPV/r

buprenorphine: no significant effect

norbuprenorphine AUC, Cmax, and 

Cmin ↓ 80%

TPV Cmin ↓ 19–40%

Consider monitoring TPV level.

Norbuprenorphine is an active metabolite of buprenorphine. 

Methadone

RTV-boosted PIs

ATV/r, DRV/r,

FPV/r, LPV/r,

SQV/r, TPV/r

ATV/r, DRV/r, FPV/r

↓ R-methadone AUC 16%−18%;

LPV/r ↓ methadone AUC 26%–

53%;

SQV/r 1,000/100 mg BID 

↓ R-methadone AUC 19%;

TPV/r ↓ R-methadone AUC 48%

Opioid withdrawal unlikely but may occur. No adjustment 

in methadone usually required but monitor for opioid 

withdrawal and increase methadone dose as clinically 

indicated.

(R-methadone is the active form of methadone.)

Table 15a. Drug Interactions between PIs and Other Drugs

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January 10, 2011

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Concomitant Drug PI

Effect on PI or 

Concomitant Drug 

Concentrations

Dosing Recommendations and Clinical 

Comments

Methadone (continued)

PIs without RTV

ATV No significant effect No dosage adjustment necessary.

FPV

No data with unboosted FPV

APV ↓ R-methadone Cmin 21%, 

AUC no significant change

Monitor and titrate methadone as clinically indicated. The 

interaction with FPV is presumed to be similar.

(R-methadone is the active form of methadone.)

Phosphodiesterase Type 5 (PDE5) Inhibitors

Sildenafil All PIs

DRV/r + sildenafil 25 mg similar to 

sildenafil 100mg alone;

RTV 500 mg BID ↑ sildenafil AUC 

1,000%;

SQV unboosted ↑ sildenafil AUC 

210%

For treatment of erectile dysfunction

Start with sildenafil 25 mg every 48 hours and monitor for 

adverse effects of sildenafil.

For treatment of pulmonary arterial hypertension

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 pulmonary arterial hypertension

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 prior to PI initiation, restart 7 days 

after PI initiation at 20 mg once daily, and increase to 40 

mg once daily based on tolerability.

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.

Miscellaneous Interactions

All PIs

Colchicine All PIs

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.

With FPV without RTV: 1.2 mg x 1 dose and no repeat dose 

for at least 3 days

For prophylaxis of gout flares

Colchicine 0.3 mg once daily or every other day

With FPV without RTV: colchicine 0.3 mg BID or 0.6 mg 

once daily or 0.3 mg once daily

For treatment of familial Mediterranean fever

Do not exceed colchicine 0.6 mg once daily or 0.3 mg BID. 

With FPV without RTV: Do not exceed 1.2 mg once daily 

or 0.6 mg BID.

Do not coadminister in patients with hepatic or renal 

impairment.

Salmeterol ↑ salmeterol possible

Do not coadminister because of potential increased risk of 

salmeterol-associated cardiovascular events, including QT 

prolongation, palpitations, and sinus tachycardia. 

ATV/r

LPV/r Atovaquone/proguanil

ATV/r ↓ atovaquone AUC 46% 

and ↓ proguanil AUC 41%

LPV/r ↓ atovaquone AUC 74% and 

↓ proguanil AUC 38%

No dosage recommendation. Consider alternative drug for 

malaria prophylaxis, if possible.

Table 15a. Drug Interactions between PIs and Other Drugs

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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 30 

Acronyms: APV = amprenavir, ARV = antiretroviral, ATV = atazanavir, ATV/r = atazanavir + ritonavir, AUC = area under the curve, 

BID = twice daily, CCB = calcium channel blocker, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration, 

CNS = central nervous system, CrCl = creatinine clearance, CYP = cytochrome P, DRV/r = darunavir + ritonavir, ECG = electrocardiogram, 

FDA = Food and Drug Administration, FPV = fosamprenavir (FPV is a prodrug of APV), FPV/r = fosamprenavir + ritonavir, IDV = indinavir, 

IDV/r = indinavir + ritonavir, INR = international normalized ratio, LPV = lopinavir, LPV/r = lopinavir + ritonavir, NFV = nelfinavir, 

PDE5 = phosphodiesterase type 5, PI = protease inhibitor, PPI = proton pump inhibitor, RTV = ritonavir, SQV = saquinavir, 

SQV/r = saquinavir + ritonavir, TB = tuberculosis, TCA = tricyclic antidepressant, TID = three times a day, TPV = tipranavir, 

TPV/r = tipranavir + ritonavir, VPA = valproic acid.

Table 15a. Drug Interactions between PIs and Other Drugs

Page 8 of 8