Print

Drug Interactions Between Protease Inhibitors and Other Drugs

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

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 toTables 19c, 20a, and 20b.

#1547 Pharmacokinetic enhancers - COBI
August 2015 - Feedback

Cobicistat (COBI) is only available within Australia as the co-formulated Stribild (EVG/cobi/ TDF/FTC). It does not have TGA approval for use as a pharmacological booster with other antiretroviral agents.

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 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%; 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

ATV unboosted

↓ 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 + RTV 100 mg simultaneously with and/or ≥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 ARTexperienced
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)

 

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

No dosage adjustment necessary.

DRV/c

No significant effect

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 CrCI > 50 mL/min.

Avoid concomitant if cr/CI < 50 mL/min.

Ticagrelor All PIs Avoid concomitant use

Vorapaxar

All PIs

 

Avoid concomitant use

Warfarin

PI/r

↓ warfarin possible

Monitor INR closely when stopping or starting PI 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.

Rivaroxaban

All PIs

↑ rivaroxaban

Avoid concomitant use

Anticonvulsants

Carbamazepine

 

ATV/r, FPV/r (unboosted)

May ↓ PI levels substantially

Do not co-administer. Consider alternative anticonvulsant or RTV boosting for ATV and FPV.

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 co-administer with LPV/r or FPV/r once daily.

DRV/r

carbamazepine AUC ↑ 45%
DRV: no significant change

Monitor anticonvulsant level and adjust dose accordingly.

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 another anticonvulsant.

 

LPV/r

Lamotrigine AUC ↓ 50%
LPV: no significant change

A dose increase of lamotrigine may be needed, consider monitoring lamotrigine concentration or consider another anticonvulsant.

PI/r (other than ATV/r or LPV/r)

 Lamotrigine possible>

A dose increase of lamotrigine may be needed, consider monitoring lamotrigine concentration or consider another anticonvulsant.

ATV/c, DRV/c No data

Monitor lamotrigine concentration or consider alternative anticonvulsant.

Ethosuximide

All PIs ↑ ethosuximide possible Clinically monitor for ethosuxamide toxicities.

Phenobarbital

All PIs

May ↓ PI levels substantially

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

Do not co-administer with LPV/r or FPV/r once daily, or unboosted ATV or FPV

Phenytoin

 

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

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 co-administer with LPV/r once daily.

ATV, FPV (unboosted)

May ↓ PI levels substantially

Do not co-administer. Consider alternative anticonvulsant or boosting either ATV or FPV.

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

escitalopramn <->

Titrate SSRI dose based on clinical response.

DRV/r

 

paroxetine AUC ↓ 39%
sertraline AUC ↓ 49%

 

FPV/r

paraxetine 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

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 co-administer.

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

No dosage adjustment necessary.

SQV/r

No data with RTV boosting
SQV (1200 mg TID) AUC ↑ 50%

No dosage adjustment necessary.

TPV/r

TPV AUC ↑ 50%

Fluconazole >200 mg daily is not recommended. If high-dose fluconazole is indicated, consider alternative PI or another class of ARV drug.

Itraconazole

All PIs

↑ itraconazole possible
↑ PI possible

Consider monitoring itraconazole level to guide dosage adjustments. High doses (>200 mg/day) are not recommended with RTV-boosted PIs, ATV/c, or DRV/c unless dose is guided by itraconazole levels.

Posaconazole

ATV/c

↑ ATV possible

Monitor for adverse effects of ATV.

ATV/r

ATV AUC ↑ 146%

Monitor for adverse effects of ATV.

ATV

ATV AUC ↑ 268%

Monitor for adverse effects of ATV.

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

All RTV-boosted PIs

RTV 400 mg BID ↓ voriconazole AUC 82%
RTV 100 mg BID ↓ voriconazole AUC 39%

Do not co-administer voriconazole and RTV or COBI unless benefit outweighs risk. If administered, consider monitoring voriconazole level and adjust dose accordingly.

ATV/c, DRV/r

Effects unknown

Do not co-administer voriconazole and RTV or COBI unless benefit outweighs riskIf administered, consider monitoring voriconazole level and adjust dose accordingly.

ATV, FPV (unboosted)

↑ voriconazole possible
↑ PI possible

Monitor for toxicities.

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

Clinical significance unknown. If used, monitor closely for antimalarial efficacy and lumefantrine toxicity.

LPV/r

artemether AUC ↓ 40%; DHA AUC ↓ 17%; lumefantrine AUC ↑ 470%

Clinical significance unknown. If used, monitor closely for anti-malarial efficacy and lumefantrine toxicity.

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 macroslide (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)

↑ ribabutin AUC expected

Ribabutin 150 mg daily or 300 mg three times a week

FPV (unboosted)

No data

Consider alternative ARV

ATV/r

Compared with rifabutin (300 mg daily) administered alone, when rifabutin (150 mg once daily) is administered with ATV/r, rifabutin AUC ↑ 110% and metabolite AUC ↑ 2101%

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/c, DRV/c

↑ ribabutin expected

DRV/r

Compared with rifabutin (300 mg once daily) administered alone, when rifabutin (150 mg every other day) is administered with DRV/r, rifabutin AUC not significantly changed and metabolite AUC ↑ 881%

FPV/r

Compared with rifabutin (300 mg once daily) administered alone, when rifabutin (150 mg every other day) is administered with FPV/r, rifabutin and metabolite AUC ↑ 64%.

LPV/r

Compared with rifabutin (300 mg daily) administered alone, when rifabutin (150 mg once daily) is administered 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 co-administer rifampin and PIs. Additional RTV does not overcome this interaction and increases hepatotoxicity. Consider rifabutin if a rifamycin is indicated.

Rifapentine

All PIs

↓ PI expected

Do not co-administer rifapentine and PIs. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.

Sedatives/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; 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 co-administer 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

Co-administration is not recommended

Triazolam

All PIs

↑ triazolam expected
RTV (200 mg BID) ↑ triazolam half-life 1200% and AUC 2000%

Do not co-administer triazolam and PIs.

Zolpidem

PI/r or ATV/c or DVR/c

↑ zolpidem possible

Initiate zolpidem at a low dose. Dose reduction may be necessary.

Cardiac Medications

Amiodarone

SQV/r, TPV/r

↑ both amiodarone and PI possible

Do not coadminister.

 

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 coadminister.

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 co-administer 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 before PI initiation and restart 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.

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.

Calcium Channel Blockers

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.

Diltiazem

ATV/r, ATV

Unboosted ATV ↑ diltiazem AUC 125%

Greater ↑ likely with ATV 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 plus 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

Co-administration can result in adrenal insufficiency, including Cushing’s syndrome. Do not co-administer 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

Co-administration can result in adrenal insufficiency, including Cushing’s syndrome. Do not co-administer unless potential benefits of inhaled or intranasal budesonide outweigh the risks of systemic corticosteroid adverse effects. Consider alternative therapy (e.g., beclomethasone).

Dexamethasone

Systemic

All PIs

↓ PI levels possible

Use systemic dexamethasone with caution or consider alternative corticosteroid for long-term use.

Prednisone

LPV/r
All PIs

↑ prednisolone AUC 31%

↑ prednisolone possible

Use with caution. Co-administration can result in adrenal insufficiency, including Cushing’s syndrome. Do not co-administer unless potential benefits of prednisone outweigh the risks of systemic corticosteroid adverse effects.

Methylprednisolone, Prednisolone, Triamcinolone 
(local injections, including intra-articular, epidural, intra-orbital)

All RTV- or BOCI-boosted PIs

↑ glucocorticoids expected

Co-administration can result in adrenal insufficiency, including Cushing’s syndrome. Do not co-administer. Consider alternative non-steroidal therapies. If intra-articular corticosteroid therapy required, change to alternative non-CYP3A-modulating ART (e.g., RAL, DTG).

Hepatitis C Direct-Acting Antiviral Agents

Boceprevir

ATV/r

ATV AUC ↓ 35%, Cmin ↓ 49%
RTV AUC ↓ 36%
boceprevir AUC ↔

Co-administration is not recommended.

ATV/c, DRV/c

Effects unknown 

Do not co-administer

DRV/r

DRV AUC ↓ 44%, Cmin ↓ 59%
RTV AUC ↓ 26%
boceprevir AUC ↓ 32%, Cmin ↓ 35%

Co-administration is not recommended.

LPV/r

LPV AUC ↓ 34%, Cmin ↓ 43%
RTV AUC ↓ 22%
boceprevir AUC ↓ 45%, Cmin ↓ 57%

Co-administration is not recommended.

Simeprevir

All PIs

DRV/r 800/100 mg daily plus simeprevir 50 mg: simeprevir AUC ↑ 159% compared with simeprevir 150 mg alone

RTV 100 mg BID ↑ simeprevir AUC 618%

Do not Co-administer

Dasabuvir + Paritaprevir/Ombitasvir/RTV

ATV

telaprevir AUC ↓ 20%

No dose adjustment necessary.

DRV

telaprevir AUC ↓ 35%
DRV AUC ↓ 40%

Do not Co-administer

LPV/r

telaprevir AUC ↓ 32%
APV AUC ↓ 47%

Do not Co-administer

ATV/c, DRV/c, FPV, SQV, TPV

No data

Do not Co-administer

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.

Herbal Products

St. John’s Wort

All PIs

↓ PI expected

Do not co-administer.

Hormonal Contraceptives

Hormonal Contraceptives (oral)

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

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

FPV

With APV: ↑ ethinyl estradiol and ↑ norethindrone Cmin;
APV Cmin ↓ 20%

Recommended 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/r, ATV

↑ atorvastatin possible

Titrate atorvastatin dose carefully and use lowest dose necessary.

DRV/r
FPV/r, FPV,
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 co-administer.

Lovastatin

All PIs

Significant ↑ lovastatin expected

Contraindicated. Do not co-administer.

Pitavastatin

All PIs

ATV ↑ pitavastatin AUC 31% and 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 efficiency and adverse effects.

DRV/c, DRV/r

With DVR/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/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.

ATV/c, DRV/c

↑ rosuvastatin possible

Titrate rosuvastatin dose carefully and use the lowest necessary dose while monitoring for toxicities. 

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 co-administer.

Immunosuppressants

Cyclosporine

Everolimus

Sirolimus

Tacrolimus

All PIs

↑ immunosuppressant possible

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/Treatment for Opioid Dependence

Buprenorphine

ATV (unboosted)

buprenorphine AUC ↑ 93%

norbuprenorphined AUC ↑ 76%
↓ ATV possible

Do not co-administer 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%–40%

Consider monitoring TPV level.

Oxycodone

LPV/r

oxycodone AUC ↑ 2.6-fold

Monitor for opioid-related adverse effects. Oxycodone dose reduction may be necessary.

Fentanyl 

All PIs 

 fentanyl possible

Clinical monitoring is recommended, including for potentially fatal respiratory depression. 

Methadone

ATV/c, DRV/c

Effects unknown

Titrate methadone dose usng the lowest feasible initial dose. Dose adjustment methadone may be nedded. Clinical monitoring is recommended.

RTV-boosted PIs

ATV/r, DRV/r, 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.

ATV (unboosted)

No significant effect

No dosage adjustment necessary.

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.

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

Co-administration 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 1000%

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, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.

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.

Miscellaneous Drugs

Colchicine

All PIs

RTV 100 mg BID colchicine AUC 296%, Cmax 184%

With all PIs: significant in colchicine AUC 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 co-administer 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): Ovcon 35, 50; Femcon Fe; Brevicon; Modicon; Ortho-Novum 1/35, 10/11, 7/7/7; Norinyl 1/35; Tri-Norinyl; Ortho-Cyclen; Ortho Tri-Cyclen.
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 Acronyms: 17-BMP = beclomethasone 17-monopropionate; APV = amprenavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = cobicist-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; DTG = dolutegravir; ECG = electrocardiogram; FDA = Food and Drug Administration; FPV = fosamprenavir; FPV/r = ritonavir-boosted fosamprenavir; IDV = indinavir; INR = international normalized ratio; LPV = lopinavir; LPV/r = ritonavir-boosted lopinavir; NFV = nelfinavir; PAH = pulmonary arterial hypertension; PDE5 = phosphodiesterase type 5; PI = protease inhibitor; PK = pharmacokinetic; PPI = proton pump inhibitor; RAL = raltegravir; RTV = ritonavir; SQV = saquinavir; SQV/r = ritonavir-boosted saquinavir; TDF = tenofovir disoproxil fumarate; TID = three times a day; TPV = tipranavir; TPV/r = ritonavir-boosted tipranavir; VPA = vaproic acid

Note: FPV is a pro-drug of APV

 

 

ASHM - Supporting the HIV, Viral Hepatitis and Sexual Health Workforce