skip navigation

Skip Nav

Clinical Guidelines Portal

Clinical Guidelines Portal

Table of Contents

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

Drug Interactions

Drug Interactions between Protease Inhibitors and Other Drugs

(Last updated: April 8, 2015; last reviewed: April 8, 2015)

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 specific pharmacologically-boosted (with either RTV or COBI) and unboosted PIs are listed separately. The term “All PIs” refers to both unboosted and pharmacologically-boosted PI products. For interactions between ARV agents and for dosing recommendations, refer to Tables 19c, 20a, and 20b.

Note: NFV and IDV are not included in this table. Please refer to the FDA product labels for NFV and IDV 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
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.
FPV APV AUC ↓ 18%;  ↔ 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

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 ART-naive 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 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

No significant effect shown or expected No dosage adjustment necessary.

FPV

(unboosted)

APV AUC ↓ 30%; no significant change in APV Cmin If concomitant use is necessary, give FPV at least 2 hours before H2 receptor antagonist. Consider boosting FPV with RTV.
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/r
omeprazole AUC ↓ 42%
No dosage adjustment necessary.
DRV/c No significant effect expected No dosage adjustment necessary
FPV, FPV/r, LPV/r No significant effect No dosage adjustment necessary.
SQV/r SQV AUC ↑ 82% Monitor for SQV toxicities.
TPV/r ↓ omeprazole May need to increase omeprazole dose.
Anticoagulants and Antiplatelets
Apixaban All PIs ↑ apixaban expected
Avoid concomitant use.
Dabigatran All RTV-boosted PIs, ATV/c, DRV/c ↑ dabigatran possible No dosage adjustment if CrCl > 50 mL/min. Avoid coadministration if CrCl < 50 mL/min.
Rivaroxaban All PIs  rivaroxaban
Avoid concomitant use.
Ticagrelor All PIs ↑ ticagrelor expected Avoid concomitant use.
Vorapaxar All PIs ↑ vorapaxar expected Avoid concomitant use.
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, FPV (unboosted) May ↓ PI levels substantially
Do not coadminister. Consider alternative anticonvulsant or ATV/r, ATV/c, or FPV/r.
ATV/c, ATV/r, DRV/c, 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 or FPV/r once daily.
DRV/r carbamazepine AUC ↑ 45%

DRV: no significant change
Monitor anticonvulsant level and adjust dose accordingly.
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

PI/r (other than ATV/r or LPV/r) ↓ lamotrigine possible 
ATV/c, DRV/c No data Monitor lamotrigine concentration or consider alternative anticonvulsant.
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 or FPV/r once daily, or unboosted ATV or FPV.
Phenytoin ATV, FPV (unboosted) May ↓ PI levels substantially
Do not coadminister. Consider alternative anticonvulsant or boosting either ATV or FPV.
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. 
 



ATV/c, DRV/c
Effect on phenytoin unknown

↓ PI possible
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.
Valproic Acid LPV/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.
Other Selective Serotonin Reuptake Inhibitors (SSRIs)
(e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline)

RTV escitalopram ↔ 



Titrate SSRI dose based on clinical response.

 
 
DVR/r

paroxetine AUC ↓ 39%


sertraline AUC ↓ 49%

FPV/r paroxetine AUC ↓ 55%
ATV/r, LPV/r, SQV/r, TPV/r
No data
ATV/c, DRV/c
Effects unknown Titrate SSRI dose using the lowest available initial or maintenance dose.
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 except SQV/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 
Amitriptyline, 
Desipramine, 
Doxepin,
Imipramine, 
Nortriptyline

All RTV-boosted PIs, ATV/c, DRV/c ↑ TCA expected
Use lowest possible TCA dose and titrate based on clinical assessment and/or drug levels.
Antifungals
Fluconazole ATV/c, ATV/r No significant effect observed or expected
No dosage adjustment necessary.
SQV/r No data with RTV boosting
No dosage adjustment necessary.
TPV/r TPV AUC ↑ 50% Fluconazole >200 mg daily is not recommended. If high-dose fluconazole is indicated, consider alternative ARV.
Itraconazole All PIs

↑ itraconazole possible


↑ PI possible

Consider monitoring itraconazole level to guide dosage adjustments. Doses >200 mg/day are not recommended with RTV-boosted PIs, ATV/c, or DRV/c unless dosing is guided by itraconazole levels.
 
Posaconazole
ATV/c ↑ ATV possible Monitor for adverse effects of ATV.
ATV/r ATV AUC ↑ 146%
ATV ATV AUC ↑ 268%
FPV With FPV 700 mg BID (without RTV): posaconazole AUC ↓ 23%, APV AUC similar to that with FPV 1400 mg BID

With FPV 1400 mg BID: ↑ APV expected
If coadministered, monitor posaconazole concentrations. 
DRV/c,
DRV/r,
FPV/r,
LPV/r,
SQV/r,
TPV/r

↑ PI possible


↑ posaconazole possible

If coadministered, consider monitoring posaconazole concentrations. Monitor for PI adverse effects.
Voriconazole ATV, FPV 
(unboosted)

↑ voriconazole possible


↑ PI possible

Monitor for toxicities.
All RTV-boosted PIs
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 
Antimalarials
Artemether/Lumefantrine 
 
DRV/r artemether AUC ↓ 16%

DHAa AUC ↓ 18% 

lumefantrine AUC ↑ 2.5-fold


Clinical significance unknown. If used, monitor closely for anti-malarial efficacy and lumefantrine toxicity.
DRV/c ↑ lumefantrine expected

effect on artemether unknown
LPV/r

artemether AUC ↓ 40%


DHA AUC ↓ 17%


lumefantrine AUC ↑ 470%

Atovaquone/Proguanil
ATV/r, LPV/r
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.
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 non-tuberculosis mycobacterial infections)
Bedaquiline All RTV-boosted PIs, ATV/c, DRV/c 
With LPV/r: bedaquiline AUC ↑ 22%, Cmax

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/r, ATV clarithromycin AUC ↑ 94% May cause QTc prolongation. Reduce clarithromycin dose by 50%. Consider alternative therapy (e.g., azithromycin).
ATV/c,
DRV/c

↑ clarithromycin expected
Consider alternative macrolide (e.g., azithromycin)
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% 

clarithromycin ↑ unboosted SQV 177%

clarithromycin ↑ TPV 66%
Monitor for clarithromycin-related toxicities or consider 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. 
FPV APV AUC ↑ 18% No dosage adjustment necessary.
Rifabutin

ATV

(unboosted)

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

FPV

(unboosted)

No data Consider alternative ARV.
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 HIV-infected patients than in the healthy study participants.

 
 
ATV/r
Compared with rifabutin (300 mg once daily) alone, rifabutin (150 mg once daily) with 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) with DRV/r, rifabutin AUC ↔ and metabolite AUC ↑ 881%
FPV/r Compared with rifabutin (300 mg once daily) alone, rifabutin (150 mg every other day) with FPV/r, rifabutin and metabolite AUC ↑ 64%.
LPV/r
Compared with rifabutin (300 mg daily) alone, rifabutin (150 mg once daily) with LPV/r, rifabutin and metabolite AUC ↑ 473%.
SQV/r ↑ rifabutin with unboosted SQV
TPV/r rifabutin and metabolite AUC ↑ 333%
Rifampin All PIs ↓ PI concentration by >75%  Do not coadminister rifampin and PIs. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
Rifapentine All PIs ↓ PI expected Do not co-administer.
Cardiac Medications
Amiodarone SQV/r,
TPV/r
↑ both amiodarone and PI possible Do not co-administer.
All PIs (except SQV/r, TPV/r) ↑ both amiodarone and PI possible Use with caution. Monitor for amiodarone toxicity and consider ECG and amiodarone drug level monitoring
Antiarrhythmics
(e.g., dofetilide, dronedarone, flecainide, lidocaine, propafenone, quinidine)
SQV/r ↑ antiarrhythmic possible Do not co-administer.
All PIs  ↑ antiarrhythmic possible Use with caution. Refer to Table 18 for contraindicated combinations.
Beta-blockers
(e.g., 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 10 days after PI initiation restart bosentan 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 used with ATV and SQV.
Digoxin PI/r, ATV/c, or DRV/c
RTV (200 mg BID) ↑ digoxin AUC 29% and ↑ half-life 43%

SQV/r ↑ digoxin AUC 49%

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 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, FPV/r, FPV, LPV/r, SQV/r, TPV/r
↑ diltiazem possible
Use with caution. Adjust diltiazem according to clinical response and toxicities.
Corticosteroids
Beclomethasone
Inhaled
DRV/r RTV 100 mg BID ↑ 17-BMP AUC 2-fold and ↑ Cmax 1.6-fold 

(DRV 600 mg + RTV 100 mg) BID ↓ 17-BMP AUC 11% and ↓ Cmax 19%
No dosage adjustment necessary. 

Significant interaction between beclomethasone (inhaled or intranasal) and other RTV-boosted PIs, ATV/c, or DRV/c is not expected.
Budesonide
Systemic
All PIs

↓ PI levels possible


↑ glucocorticoids

Coadministration can result in adrenal insufficiency and Cushing’s syndrome. Do not coadminister unless potential benefits of systemic budesonide outweigh the risks of systemic corticosteroid adverse effects.
Budesonide, Fluticasone, Mometasone
Inhaled or Intranasal
All RTV- or COBI-boosted PIs ↑ glucocorticoids possible

RTV 100 mg BID ↑ fluticasone AUC 350-fold and ↑ Cmax 25-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 alternative corticosteroid (e.g., beclomethasone).

Dexamethasone

Systemic

All PIs ↓ PI levels possible Use systemic dexamethasone with caution. Consider alternative corticosteroid for long-term use.
Prednisone

LPV/r

↑ prednisolone AUC 31%


Use with caution. Coadministration can result in adrenal insufficiency and Cushing’s syndrome. Do not coadminister unless potential benefits of prednisone outweigh the risks of systemic corticosteroid adverse effects.
All PIs ↑ prednisolone  possible
Methylprednisolone, Prednisolone, Triamcinolone 
(local injections, including intra-articular, epidural, intra-orbital)

All RTV- or COBI-boosted PIs
↑ glucocorticoids expected
Do not coadminister. Coadministration can result in adrenal insufficiency and Cushing’s syndrome.
Hepatitis C Direct-Acting Antiviral Agents 
Boceprevir ATV/r

ATV AUC ↓ 35%, Cmin ↓ 49%


boceprevir AUC ↔

Do not coadminister.
ATV/c, DRV/c
Effects unknown Do not coadminister.
DRV/r
DRV AUC ↓ 44%, Cmin ↓ 59%

boceprevir AUC ↓ 32%, Cmin ↓ 35%
Do not coadminister.
LVP/r LPV AUC ↓ 34%, Cmin ↓ 43%

boceprevir AUC ↓ 45%, Cmin ↓ 57%
 
Do not coadminister.
Dasabuvir + Paritaprevir/Ombitasvir/RTV
ATV 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.
LVP/r paritaprevir AUC ↑ 117% Do not coadminister.
ATV/c, DRV/c, FPV, SQV, TPV No data Do not coadminister.
Ledipasvir/Sofosbuvir ATV/r ATV AUC ↑ 33%

ledipasvir AUC ↑ 113%

sofosbuvir: no significant effect
 
No dosage 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: no significant effect expected

ledipasvir/sofosbuvir: no significant effect
ATV/c, DRV/c, FPV, FPV/r, LPV/r, SQV/r No significant effect 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 800/100 mg daily, simeprevir AUC ↑ 159% 

RTV 100 mg BID ↑ simeprevir AUC 618%
Do not coadminister.
Herbal Products
St. John’s Wort All PIs ↓ PI expected Do not co-administer.
Hormonal Contraceptives
 
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% 
Oral contraceptive should contain at least 35 mcg of ethinyl estradiol. 

Oral contraceptives containing progestins other than norethindrone or norgestimate have not been studied.b

ATV/c, DRV/c Effects unknown Recommend alternative or additional contraceptive method or alternative ARV drug.
DRV/r,
FPV/r,
LPV/r,
SQV/r,
TPV/r

ethinyl estradiol AUC ↓ 37% to 48%


norethindrone AUC ↓ 14% to 34%


With TPV/r: norethindrone AUC  

Recommend alternative or additional contraceptive method or alternative ARV drug. 
FPV With APV: ↑ ethinyl estradiol and ↑ norethindrone Cmin; APV Cmin ↓ 20% 
Recommend alternative contraceptive method or alternative ARV drug.
Etonogestrel-releasing subdermal implant LPV/r etonogestrel AUC ↑ 52% and Cmin ↑ 34%
Use standard dose.
All other PIs No data Recommend 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 Recommend alternative or additional contraceptive method or alternative ARV drug.
HMG-CoA Reductase Inhibitors
Atorvastatin ATV,
ATV/c,
ATV/r, 
DRV/c
↑ atorvastatin possible
Titrate atorvastatin dose carefully and use lowest dose necessary.

DRV/r 


  

FPV, FPV/r, 

  

SQV/r

DRV/r plus atorvastatin 10 mg similar to atorvastatin 40 mg administered alone

FPV +/– RTV ↑ atorvastatin AUC 130% to 153%

 

SQV/r ↑ atorvastatin AUC 79%

Titrate atorvastatin dose carefully and use the lowest necessary dose. Do not exceed 20 mg atorvastatin daily.
LPV/r LPV/r ↑ atorvastatin AUC 488%
Use with caution and use the lowest atorvastatin dose necessary.
TPV/r ↑ atorvastatin AUC 836%
Do not coadminister.
Lovastatin All PIs Significant ↑ lovastatin expected Contraindicated. Do not coadminister.
Pitavastatin All PIs ATV ↑ pitavastatin AUC 31%, Cmax ↑ 60%

ATV: no significant effect 

DRV/r: no significant effect 

LPV/r ↓ pitavastatin AUC 20%

LPV: no significant effect

No dose adjustment necessary.
 
 
Pravastatin
ATV/c, ATV/r
No data Use lowest starting dose of pravastatin and monitor for efficacy and adverse effects. 
DRV/c, DRV/r

With DRV/r, pravastatin AUC 

  • ↑ 81% following single dose of pravastatin
  • ↑ 23% at steady state
Use lowest possible starting dose of pravastatin with careful monitoring. 
LPV/r pravastatin AUC ↑ 33% No dose adjustment necessary.
SQV/r pravastatin AUC ↓ 47% to 50% No dose adjustment necessary.
Rosuvastatin ATV/c, DRV/c
↑ rosuvastatin possible
Titrate rosuvastatin dose carefully and use the lowest necessary dose while monitoring for toxicities.
ATV/r, LPV/r ATV/r ↑ rosuvastatin AUC 3-fold and Cmax ↑ 7-fold 

LPV/r ↑ rosuvastatin AUC 108% and Cmax ↑ 366%
Titrate rosuvastatin dose carefully and use the lowest necessary dose. Do not exceed 10 mg rosuvastatin daily.
DRV/r rosuvastatin AUC ↑ 48% and Cmax ↑ 139%
Titrate rosuvastatin dose carefully and use the lowest necessary dose while monitoring for toxicities.
FPV +/- RTV No significant effect on rosuvastatin No dosage adjustment necessary.
SQV/r No data available Titrate rosuvastatin dose carefully and use the lowest necessary dose while monitoring for toxicities.
TPV/r rosuvastatin AUC ↑ 26% and Cmax ↑ 123%
No dosage adjustment necessary.
Simvastatin All PIs Significant ↑ simvastatin level:
SQV/r 400 mg/400 mg BID
↑ simvastatin AUC 3059%
Contraindicated. Do not coadminister.
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 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. Buprenorphine dose reduction may be necessary.
ATV/c, DRV/c Effects unknown Titrate buprenorphine dose using the lowest initial dose. Dose adjustment of buprenorphine may be needed. Clinical monitoring is recommended. 
DRV/r buprenorphine: no significant effect

norbuprenorphined AUC ↑ 46% and Cmin ↑ 71%
No dosage adjustment necessary. Clinical monitoring is recommended.
FPV/r buprenorphine: no significant effect

norbuprenorphined AUC ↓ 15%
No dosage adjustment necessary. Clinical monitoring is recommended. 
LPV/r No significant effect 
No dosage adjustment necessary.
TPV/r buprenorphine: no significant effect

norbuprenorphined AUC, Cmax, and Cmin ↓ 80%

TPV Cmin ↓ 19% to 40%

Consider monitoring TPV level.
Fentanyl All PIs ↑ fentanyl possible
Clinical monitoring is recommended, including for potentially fatal respiratory depression.
Methadone ATV (unboosted) No significant effect
No dosage 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.

FPV

(unboosted)

No data with unboosted FPV

APV ↓ R-methadonee Cmin 21%, AUC no significant change
Monitor and titrate methadone as clinically indicated. The interaction with FPV is presumed to be similar to that with APV.
RTV-boosted PIs ATV/r, DRV/r, and FPV/r  
↓ R-methadonee AUC 16% to 18%

LPV/r ↓ methadone AUC 26% to 53%

SQV/r 1000/100 mg BID 
↓ R-methadonee AUC 19%

TPV/r ↓ R-methadonee AUC 48%

Opioid withdrawal 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 LPV/r oxycodone AUC ↑ 2.6-fold
Monitor for opioid-related adverse effects. Oxycodone dose reduction may be necessary.
Phosphodiesterase Type 5 (PDE5) Inhibitors
Avanafil All PIs except unboosted FPV RTV (600 mg BID for 5 days) ↑ avanafil AUC 13-fold, Cmax 2.4-fold
Coadministration is not recommended.
ATV, FPV (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%

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 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. 7 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 
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

SQV/r ↑ midazolam (oral) AUC 1144% and Cmax 327%
 
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%
Do not coadminister.
Zolpidem PI/r or ATV/c or DRV/c ↑ zolpidem possible
Initiate zolpidem at a low dose. Dose reduction may be necessary. 
Miscellaneous Drugs
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.
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 All PIs ↑ salmeterol possible Do not co-administer because of potential increased risk of salmeterol-associated cardiovascular 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; APV = amprenavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = cobicistat-boosted atazanavir; ATV/r = ritonavir-boosted atazanavir; 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; CYP = cytochrome P; DHA = dihydroartemisinin; DRV = darunavir; DRV/c = cobicistat-boosted darunavir; DRV/r = ritonavir-boosted darunavir; ECG = electrocardiogram; FPV = fosamprenavir; FPV/r = ritonavir-boosted fosamprenavir; HCV = hepatitis C virus; INR = international normalized ratio; LPV = lopinavir; LPV/r = ritonavir-boosted lopinavir; PAH = pulmonary arterial hypertension; PI = protease  inhibitor; PI/c = cobicistat-boosted protease inhibitor; PI/r = ritonavir-boosted protease inhibitor; PK = pharmacokinetic; PPI = proton pump inhibitor; QTc = QT corrected for heart rate; RTV = ritonavir; SQV = saquinavir; SQV/r = ritonavir-boosted saquinavir; TCA = tricyclic antidepressants; TDF = tenofovir disoproxil fumarate; TPV = tipranavir; TPV/r = ritonavir-boosted tipranavir; VPA = valproic acid

Note: FPV is a pro-drug of APV.

Back to Top