Common Drug Interactions with Protease Inhibitors

Updated: Sep 06, 2017
  • Author: Jason F Okulicz, MD, FACP, FIDSA; Chief Editor: Michelle R Salvaggio, MD, FACP  more...
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Overview

Overview

Potential for drug interactions should be considered when selecting antiretroviral therapy (ART) for patients with human immunodeficiency virus (HIV) infection. Drug interactions with antiretrovirals are commonly caused by the inhibition or induction of hepatic drug metabolism. [1, 2] Protease inhibitors in combination with other drugs may require dose adjustments or should be avoided because of potential drug interactions.

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Drug Interactions by Drug Category

Anticoagulants

Anticoagulants, including warfarin in combination with atazanavir (ATV) +/-ritonavir (RTV), darunavir (DRV)/RTV, fosamprenavir (FPV) +/- RTV, lopinavir/ritonavir (LPV/RTV), saquinavir (SQV)/RTV, and tipranavir (TPV)/RTV, may lead to increases or decreases in warfarin levels. [3, 4]

DRV/RTV may decrease the S-warfarin area under the curve (AUC) by 21%. [1]

The international normalized ratio (INR) should be closely monitored when initiating or discontinuing a protease inhibitor (PI); adjust warfarin doses as needed.

Rivaroxaban should be avoided with all PIs owing to increased risk of bleeding.

Antidepressants  [5, 6]

Antidepressants include drugs such as bupropion, paroxetine, sertraline, trazodone, and various tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline).

Bupropion in combination with either LPV/RTV or TPV/RTV will lead to decreased bupropion drug concentrations.

Paroxetine in combination with DRV/RTV or FPV/RTV will lead to decreased paroxetine drug levels.

Sertraline in combination with DRV/RTV will lead to decreased sertraline drug levels.

Give lowest dose of trazodone, and monitor for central nervous system and cardiovascular adverse effects when trazodone is used in combination with ATV +/- RTV, DRV/RTV, FPV +/- RTV, LPV/ RTV, or TPV/ RTV.

SQV/RTV in combination with trazodone is contraindicated.

RTV-boosted PIs in combination with tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline) will cause an increase in tricyclic antidepressant drug levels; use the lowest possible dose, and titrate as needed.

Antipsychotics

Coadministration of quetiapine with PIs is expected to increase quetiapine AUC; in patients receiving a PI, start quetiapine at the lowest dose, titrate up as needed, and monitor for adverse effects of quetiapine; in patients initiating a PI while on a stable dose of quetiapine, reduce quetiapine to one sixth of the original dose and closely monitor for quetiapine effectiveness and adverse effects

Antifungals  [7, 8]

Antifungal agents include fluconazole, itraconazole, posaconazole, and voriconazole.

Fluconazole increases tipranavir AUC by 50%; fluconazole >200 mg/day is not recommended; if high-dose fluconazole is indicated, consider an alternative PI or another class of antiretroviral agents.

When itraconazole and RTV-boosted PIs are given in combination, there is a potential for increased itraconazole or PI drug concentrations; high doses of itraconazole are not recommended (>200 mg/day) unless dosing is guided by drug levels.

LPV/RTV with itraconazole can lead to increased itraconazole drug levels; consider not exceeding 200 mg/day.

A bidirectional interaction has been observed between SQV/RTV and itraconazole; decreased itraconazole dosage may be needed; monitor itraconazole levels.

ATV or FPV in combination with itraconazole may increase itraconazole levels or PI levels.

Posaconazole can increase drug concentrations of ATV and ATV/RTV; monitor for ATV adverse effects.

Posaconazole should be avoided with FPV.

Do not coadminister voriconazole with RTV unless the benefits outweigh the risks; interaction applies to RTV-boosted PIs.

ATV or FPV in combination with voriconazole may lead to increased voriconazole or PI levels.

Benzodiazepines

Alprazolam or diazepam in combination with all PIs may increase benzodiazepine levels; use alternatives such as lorazepam, oxazepam, or temazepam, which have a decreased potential for interaction because of non-CYP450 metabolic pathways.

Avoid combination of midazolam or triazolam with PIs.

Antimycobacterials

Coadministration of bedaquiline with RTV-boosted PIs may result in increased AUC of bedaquiline; clinical significance unknown; use with caution if benefit outweighs the risk and monitor QTc prolongation and liver function tests.

ATV +/- RTV increases clarithromycin AUC; reduce the clarithromycin dose by 50% or consider alternative therapy; caution may cause QTc prolongation.

RTV-boosted PIs increase clarithromycin AUC; reduce the clarithromycin dose by 50% in patients with CrCl 30-60 mL/min; reduce by 75% in patients with CrCl <30 mL/min.

FPV in combination with clarithromycin requires no dose adjustment.

FPV may increase rifabutin levels; when coadministered with FPV, a dose reduction of rifabutin by ≥50% of the recommended dose is required (150 mg/day or 300 mg 3 times/wk); when coadministered with FPV/RTV, a dose reduction of rifabutin by ≥75% of the usual dose is recommended (maximum dose of 150 mg every other day or 3 times/wk).

SQV has been shown to increase rifabutin concentrations; rifabutin dose reduction of ≥75% of usual dose of 300 mg/day is recommended (ie, a maximum dose of 150 mg every other day or 3 times/wk).

Coadministration of TPV with rifabutin may increase concentrations of rifabutin and its metabolite; reduce rifabutin dose 75% (eg, 150 mg every other day).

Concomitant use of rifabutin and DRV in the presence of RTV can increase rifabutin plasma concentrations and decrease DRV plasma concentrations; administer rifabutin 150 mg once every other day when coadministered with DRV/RTV.

ATV increases rifabutin concentrations; rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times/wk) is recommended.

LPV/ RTV may increase serum rifabutin levels; therefore, dosage reduction of rifabutin by ≥75% of the usual dose of 300 mg/day is recommended (ie, a maximum dose of 150 mg every other day or 3 times/wk).

Rifampin and PIs should not be coadministered.

Cardiovascular agents

For patients receiving RTV for at least 10 days, start bosentan at 62.5 mg/day or every other day based on tolerability; for patients receiving bosentan, stop bosentan ≥36 hours before starting RTV; at least 10 days after starting RTV, resume bosentan at 62.5 mg/day or every other day; do not coadminister bosentan and ATV without RTV.

SQV/RTV or RTV can increase digoxin drug concentrations; monitor digoxin levels and use with caution.

All PIs may increase drug concentrations of dihydropyridine calcium channel blockers; electrocardiographic (ECG) monitoring is recommended with ATV.

When diltiazem is administered with ATV +/- RTV, decrease the diltiazem dose by 50%; ECG monitoring is recommended; use caution when diltiazem is coadministered with other PIs.

For antiarrhythmic drugs, amiodarone or dronedarone should not be coadministered with ATV +/- RTV, DRV/RTV, FPV +/- RTV, LPV/RTV, SQV/RTV, or TPV/RTV; flecainide or propafenone should not be used with FPV +/- RTV, SQV/RTV, or TPV/RTV; lidocaine and dofetilide should not be coadministered with SQV/RTV; quinidine should be avoided with SQV/RTV or TPR/RTV.

Herbal products

Coadministration of St. John’s wort and PIs is contraindicated; St. John’s wort can significantly decrease PI drug concentrations.

Anticonvulsants  [9, 10, 11]

In combination with RTV-boosted PIs (ATV/RTV, FPV/ RTV, LPV/ RTV, SQV/ RTV, TPV/ RTV), carbamazepine can decrease PI drug levels, which can result in antiretroviral treatment failure; carbamazepine levels may also be elevated; if coadministration cannot be avoided, close clinical monitoring is indicated; consider alternative therapy for carbamazepine.

Do not coadminister carbamazepine with unboosted ATV or FPV.

Carbamazepine in combination with DRV/RTV may decrease drug levels of DRV; DRV may increase carbamazepine drug levels; use caution if concomitant use cannot be avoided.

A combination of ATV or RTV with carbamazepine can lead to decreased PI drug concentrations; consider an alternative anticonvulsant.

LPV/RTV or ATV/RTV can decrease lamotrigine levels; lamotrigine dose increase may be required.

Phenobarbital decreases all PI drug levels; use alternative anticonvulsants, or monitor levels of both drugs.

Do not coadminister phenobarbital with LPV/RTV once daily, unboosted ATV, or unboosted FPV.

Phenytoin decreases levels of PIs; phenytoin levels may also be decreased, a dose increase may be needed when used with RTV.

Do not coadminister phenytoin with LPV/RTV once daily, unboosted ATV, or unboosted FPV.

LPV/RTV may decrease valproic acid (VPA) levels and increase LPV levels; monitor VPA levels; monitor virologic response and for LPV-related toxicities.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors  [12]

In combination with PIs, consider the lowest possible atorvastatin starting dose with careful monitoring for toxicities (myopathy, rhabdomyolysis), or consider other HMG-CoA reductase inhibitors.

Simvastatin and lovastatin are contraindicated with all PIs; avoid combination.

ATV may increase pitavastatin levels and LPV/r may decrease pitavastatin levels; no dosage adjustment necessary with coadministered PIs.

DRV/RTV in combination with pravastatin may lead to increased pravastatin levels; use the lowest possible starting dose and monitor closely.

No dose adjustments are needed with pravastatin and LPV/RTV or SQV/RTV.

Use the lowest rosuvastatin starting dose, or consider other HMG-CoA inhibitors with less potential for interactions in combination with PIs.

Phosphodiesterase type 5 (PDE5) inhibitors

For PIs in combination with sildenafil for the treatment of erectile dysfunction (ED), it is recommended to start with sildenafil 25 mg q48h; for sildenafil for treatment of pulmonary arterial hypertension (PAH), combination therapy is contraindicated.

For PIs in combination with tadalafil for the treatment of ED, it is recommended to start with tadalafil 5 mg (do not exceed a single dose of 10 mg q72h); for treatment of PAH (patients on a PI >7 days), start with tadalafil 20 mg/day and increase to 40 mg/day, based on tolerability; patients on tadalafil who require a PI, stop tadalafil >24 hours before PI initiation, restart 7 days after PI initiation at 20 mg/day, and increase to 40 mg/day, based on tolerability.

For PIs in combination with vardenafil, start with vardenafil 2.5 mg q72h and monitor for adverse effects of vardenafil.

Avanafil coadministration is not recommended with ATV +/- RTV, DRV/RTV, FPV/RTV, SQV/RTV, or LPV/RTV.

Antacids

Antacids can potentially decrease the drug concentrations of PIs.

ATV should be given at least 2 hours before or 1 hour after antacids or buffered medications.

FPV should be given simultaneously with, or at least 2 hours before or 1 hour after, antacids.

TPV should be given at least 2 hours before or 1 hour after antacids.

H2 receptor antagonists

H2 receptor antagonists include cimetidine, famotidine, nizatidine, and ranitidine.

H2 receptor antagonists can potentially decrease the drug concentration of RTV-boosted PI; doses should not exceed a dose equivalent of famotidine 40 mg BID in antiretroviral therapy (ART)–naive patients or 20 mg BID in ART-experienced patients.

ATV 300 mg plus RTV 100 mg can be given simultaneously with, and/or more than 10 hours after, the H2 receptor antagonist.

If using tenofovir (TDF) and an H2 receptor antagonist in ART-experienced patients, use ATV 400 mg plus RTV 100 mg.

There is no significant effect between H2 receptor antagonists and DRV/RTV and LPV/RTV.

If PIs such as ATV are used without RTV, they should be administered at least 2 hours before and at least 10 hours after the H2 receptor antagonist; 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-naive patients.

FPV without RTV should be given at least 2 hours before H2 receptor antagonist if concomitant use is needed; may consider RTV boosting.

Hepatitis C  direct-acting antivirals (DAAs)  [13, 14]

Drug interactions between HIV PIs and DAAs can result in alteration in drug levels of one or both classes, and coadministration may be contraindicated in certain circumstances.

Immunosuppressants  [15, 16]

Cyclosporine, sirolimus, and tacrolimus levels may be increased with coadministration with all PIs; therapeutic drug monitoring of immunosuppressant is recommended.

Narcotics

Oxycodone coadministration with LPV/RTV results in a 2.6-fold increase in oxycodone AUC; oxycodone dose reduction may be necessary and monitor for opioid-related adverse effects.

Methadone coadministration with boosted PIs may result in lower methadone levels; opioid withdrawal may occur but unlikely; dose adjustment of methadone not usually required but monitor for symptoms of opioid withdrawal.

Methadone use with unboosted ATV does not require dose adjustment.

Methadone coadministration with unboosted FPV may result in lower methadone levels; monitor and titrate methadone as clinically indicated.

Proton pump inhibitors (PPIs)

PPIs include omeprazole, pantoprazole, rabeprazole, esomeprazole, dexlansoprazole, and lansoprazole.

PPIs can potentially decrease the drug concentration of PIs; PPIs are not recommended in patients taking unboosted ATV.

When using ATV with RTV boosting, the PPIs should not exceed a dose equivalent of omeprazole 20 mg/day in PI-naive patients; PPIs should be given at least 12 hours prior to ATV/RTV.

PPIs are not recommended in patients who are PI experienced.

When DRV/RTV, TPV/RTV, FPV +/- RTV, and LPV/RTV are administered with PPIs, there is not a significant effect on the PI concentration.

When TPV/RTV is given, there may be a slight decrease in omeprazole concentration; consider adjusting omeprazole dose.

SQV/RTV in combination with PPIs may lead to an 82% increase in the AUC; it is important to monitor for SQV toxicities. [1]

Hormonal contraceptives

Oral contraceptives (OC) containing progestins other than norethindrone or norgestimate have not been studied; OC should contain at least 35 mcg of ethinyl estradiol.

RTV-boosted PIs can decrease ethinyl estradiol and norethindrone drug concentrations; use alternative or additional method.

ATV increases AUC of ethinyl estradiol and norethindrone; OC should contain no more than 30 mcg of ethinyl estradiol, or use alternative method; OC containing <25 mcg of ethinyl estradiol or progestins other than norethindrone or norgestimate have not been studied.

FPV with amprenavir (APV) increases drug concentrations of ethinyl estradiol and norethindrone; possible decreases in APV drug concentration by 20%; recommendation is to use alternative method.

Corticosteroids

Coadministration of inhaled beclomethasone with DRV/r may affect drug levels; RTV 100 mg BID increases 17-BMP AUC 2-fold and Cmax 1.6-fold; DRV 600 mg BIV plus RTV 100 mg BID decreases 17-BMP AUC 11% and Cmax 19%; no dosage adjustment necessary; significant interaction with other boosted PIs not expected.

Dexamethasone in combination with all PIs can decrease PI drug levels; use dexamethasone with caution, or consider an alternative corticosteroid for long-term use.

Fluticasone (inhaled or intranasal) or budesonide (inhaled or intranasal) should not be coadministered with RTV-boosted PIs unless the potential benefit outweighs the risk of systemic corticosteroid adverse effects (adrenal insufficiency, Cushing syndrome). [17]

Increased prednisolone levels possible when prednisone is coadministered with PIs; prednisone and LPV/RTV coadministration results in 31% increase in prednisolone AUC and a decrease in LPV levels; should not be coadministered unless the potential benefit of prednisone outweighs the risk of systemic corticosteroid adverse effects.

Local injections (including intra-articular, epidural, intra-orbital) of methylprednisolone, prednisolone, or triamcinolone coadministered with all RTV-boosted PIs is expected to increase glucocorticoid levels; coadministration may result in adrenal insufficiency, including Cushing syndrome; do not coadminister; consider alternative nonsteroidal therapies; if intra-articular corticosteroid therapy required, change to alternative non-CYP3A-modulating ART (eg, RAL, DTG).

Agents for gout

Do not coadminister colchicine and PIs in patients with hepatic or renal impairment.

In combination with PIs for treatment of gout flares, administer colchicine 0.6 mg for 1 dose, followed by 0.3 mg 1 hours later (do not repeat dose for at least 3 days); with FPV without RTV, give 1.2 mg for 1 dose and do not repeat dose for at least 3 days.

In combination with PIs for prophylaxis of gout flares, administer colchicine 0.3 mg once daily or every other day; with FPV without RTV, use colchicine 0.3 mg BID, 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.

Sympathomimetics

Coadministration of salmeterol with PIs is not recommended because of a potential increase in the risk of salmeterol-associated cardiovascular events, including QT prolongation, palpitations, and sinus tachycardia.

Antimalarials

Coadministration of artemether/lumefantrine with DRV/r or LPV/r decreases AUC of artemether and dihydroartemisinin and increases lumefantrine AUC; clinical significance is unknown; if used, monitor closely for antimalarial efficacy and lumefantrine toxicity.

Coadministration of atovaquone/proguanil with ATV/r or LPV/r decreases AUC of both atovaquone and proguanil; consider alternative drug for malaria prophylaxis, if possible.

Coadministration of mefloquine with RTV 200 mg BID reduces RTV AUC by 31% and Cmin by 43%; use with caution; effect on exposure of RTV-boosted PIs is unknown.

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