Common Drug Interactions with Protease Inhibitors

 Protease inhibitors (PIs) are an important class of antiretroviral therapy (ART) often administered in combination with two nucleosides or used as part of a nuceloside-sparing regimen. Potential for drug interactions should be considered when selecting 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]}  Failure to recognize these interactions may lead to loss of therapeutic effect or excess toxicity. Protease inhibitors in combination with other drugs may require dose adjustments or should be avoided because of these potential drug interactions.

Alpha-adrenergic antagonists for benign prostatic hyperplasia​

Alfuzosin and silodosin are contraindicated with all PIs because of expected elevation in blood levels of these alpha-adrenergic antagonists as well as cardiac arrythmias and risk forf QT prolongation.

Coadministration of tamsulosin with PIs is not recommended. If coadministration is required, monitoring for adverse effects related to tamsulosin is recommended.

Doxazosin and terazosin should be started at the lowest dose and titrated while monitoring for clinical response/toxicity.

Anticoagulants and antiplatelet agents

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 more potent warfarin enantiomer, 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.

PIs coadministered with direct-acting oral anticoagulants may result in an increased risk for bleeding events. A 50% dose reduction of apixaban is recommended with RTV-boosted or cobicistat (COBI)-boosted PIs. Do not coadminister RTV-boosted or COBI-boosted PIs with rivaroxaban or if requiring 2.5mg twice daily of apixaban. 

Dabigatran is largely dependent on metabolism by P-glycoprotein and renal elimination. A pharmacokinetic study determined that the AUC of dabigatran increased by 27% and 29% when administered with COBI and RTV, respectively.  ^[5]   The reader is directed to the dabigatran prescribing information for dosing recommendations with use of P-glycoprotein inhibitors.  ^[6]

No dose adjustment for prasugrel is required with any boosted PI regimen. Clopidogrel should not be coadministered with a boosted PI. A pharmacokinetic study demonstrated 69% and 52% AUC reduction of the active metabolites of clopidogrel and prasugrel, respectively with RTV-containing or COBI-containing regimens, however impaired platelet inhibition was observed in 44% of HIV-infected patients on clopidogrel whereas adequate platelet inhibition was observed in HIV-infected patients on prasugrel.  ^[7]  Ticagrelor and vorapaxar should be avoided with PIs owing to increased bleeding risk.

Antidepressants  ^{[8, 9]}

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

Bupropion in combination with RTV-boosted regimens will lead to decreased bupropion drug concentrations; bupropion dose should be adjusted based on clinical response. No dose adjustment is required for COBI-boosted regimens.

Selective serononin reuptake inhibitors (SSRIs, ie. Paroxetine or Sertraline) in combination with DRV/RTV and other PIs will lead to decreased SSRI drug levels. SSRI dose should be titrated to desired clinical response.

Give lowest dose of trazodone, and monitor for central nervous system and cardiovascular adverse effects when trazodone is used in combination with any PI-based regimen. SQV/RTV in combination with trazodone is contraindicated due to risk of serious arrhythmias from QTc-prolongation.

RTV-boosted or COBI-boosted PIs in combination with tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline, etc.) will cause an increase in tricyclic antidepressant drug levels; use the lowest possible dose, titrate as needed and monitor for adverse effects related to tricycline antidepressant use.

Antipsychotics

Dose adjustments of aripiprazole, brexpiprazole, cariprazine, iloperidone, and pimavanserin may be needed with certain PIs.

Lumateperone and pimozide are contraindicated with all PI-based regimens.

Lurasidone requires dose adjustments when used with unboosted atazanavir. If atazanavir is added to existing lurasidone therapy, reduce lurasidone dose by 50%. If lurasidose is added to existing atazanavir therapy, start lurasidone at 20mg daily and titrate to desired effect. Lurasidone is contraindicated with all boosted-PI regimens

Pimavanserin and ziprasidone are contraindicated with LPV/RTV due to QTc-prolonging effects.

Quetiapine coadministration with PIs is expected to increase quetiapine AUC. If quetiapine is added to existing PI therapy, start quetiapine at the lowest dose and titrate up as needed, while monitoring 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  ^{[10, 11, 12]}

Azole antifungal agents are of interest with PI-based regimens due to their ability to inhibit CYP enzymes. These include fluconazole, itraconazole, posaconazole, voriconazole and isavuconazole.

Fluconazole is primarily excreted unchanged renally, is minorly metabolized by CYP 3A4, and inhibits CYP 2C9 and 3A4 enzymes. Fluconazole increases tipranavir AUC by 50%; fluconazole >200 mg/day is not recommended; if higher doses of fluconazole are indicated, consider an alternative PI or another class of antiretroviral agents. Dose adjustments for fluconazole are not required for other PIs.

Isavuconazole is a substrate and moderate inhibitor of CYP 3A4. A pharmacokinetic study found a 96% increase in AUC when isavuconazole was administered with LPV/RTV. ^[13]  Isavuconazole concentrations and related adverse effects should be monitored while taken concomitantly.

Itraconazole undergoes extensive metabolism and acts as a P-glycoprotein and CYP 3A4 substrate and inhibitor. When itraconazole and RTV-boosted or COBI-boosted PIs are given in combination, there is a potential for increased itraconazole or PI drug concentrations; high doses of itraconazole (>200 mg/day) are not recommended unless dosing is guided by itraconazole drug levels.

Posaconazole is a substrate of UGT 1A4 and primarily inhibits CYP 3A4 enzymes. A pharmacokinetic study found that posaconazole increased atazanavir AUC 2.5-fold and 3.7-fold when administered with and without ritonavir, respectively. ^[14]  A similar interaction is expected with other protease inhibitors; posaconazole drug levels, and adverse effects related to both posaconazole and PIs, should be monitored.

Voriconazole is primarily metabolized hepatically and exhibits inhibitory activity against CYP 2C19, 2C9, and 3A4 enzymes. Furthermore, voriconazole metabolism is affected by genetic polymorphisms with CYP 2C19. A pharmacokinetic study assessing interactions of voriconazole and ATV/RTV demonstrated a 33% reduction and 460% increase in voriconazole levels in extensive and poor CYP 2C19 metabolizers, respectively.  ^[15] Voriconazole should not be administered with RTV-boosted or COBI-boosted regimens unless the benefits outweigh the risks; if coadministered, close monitoring of voriconazole drug levels is recommended with appropriate dose adjustments.

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

No dose adjustment is required when azithromycin is used concurrently with PIs.

Coadministration of bedaquiline with RTV-boosted PIs may result in increased AUC of bedaquiline; clinical significance unknown. Use with caution if the 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; use caution because this may cause QTc prolongation.

RTV-boosted PIs increase the 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.

Rifabutin concentrations are increased with PI use, with many pharmacokinetic studies demonstrating more than 2-fold increases in rifabutin AUC. Previous guidance recommended rifabutin dose reductions of >50-75%. However, these pharmacokinetic data are reported from healthy volunteers, and lower rifabutin exposure has been reported in patients with HIV. DHHS guidelines recommend a dose reduction of rifabutin to 150mg once daily, in addition to therapeutic drug monitoring of rifabutin concentration levels, and monitoring of rifabutin-related adverse effects (ie, uveitis and neutropenia).

Rifampin and PIs should not be coadministered; rifampin decreases PI concentrations by over 75%. If a rifamycin is indicated, rifabutin should be considered.

Rifapentine and PIs should not be coadministered.

Cardiovascular agents

Many commonly used antiarrhythmic agents are metabolized by CYP 3A4 and/or 2D6. ^[16]  Inhibition of these cytochromes by CYPs could potentially subject patients to adverse effects related to the antiarrhythmic. Amiodarone should not be administered unless benefits outweigh the risks, and provided that routine ECGs and close monitoring for adverse effects are available. Dronedarone, flecainide, propafenone, and quinidine should not be administered with any PI. Disopyramide, dotetilide, and lidocaine additionally should not be coadministered with a boosted-PI regimen.

Bosentan requires dose adjustments depending on whether the PI or bosentan is added to a pre-existing therapy. For patients receiving RTV or COBI-boosted PIs for at least 10 days, start bosentan at 62.5 mg/day or every other day based on tolerability. For patients receiving bosentan in whom a PI regimen is started, stop bosentan ≥36 hours before starting the PI and resume bosentan at 62.5 mg/day or every other day, beginning at least 10 days after starting the PI. Do not coadminister bosentan with unboosted ATV, due to concern for reduced drug concentrations of ATV.

RTV- or COBI-boosted PIs can increase digoxin drug concentrations; monitor digoxin levels and use with caution.

All PIs may increase drug concentrations of dihydropyridine calcium channel blockers (ie. diltiazem or verapamil); electrocardiographic (ECG) monitoring is recommended with ATV. When diltiazem is administered with ATV +/- RTV or COBI, decrease the diltiazem dose by 50%; ECG monitoring is recommended; use caution when diltiazem is coadministered with other PIs.

Eplerenone, ivabradine, and ranolazine should not be coadministered with PIs.

Herbal products

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

Anticonvulsants  ^{[17, 18, 19]}

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, once-daily LPV/r, or COBI-boosted PIs.

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.

Eslicarbazepine and oxcarbazepine may decrease all PI drug levels. Consider an alternative agent; if coadministration cannot be avoided, monitor virologic response and consider monitoring anticonvulsant concentrations.

RTV-boosted PIs (ie, LPV/RTV or ATV/RPV) can decrease lamotrigine levels; lamotrigine dose increase may be required. Limited data is available for COBI-boosted PIs; monitoring of anticonvulsant levels is recommended.

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, unboosted FPV, or COBI-boosted PIs.

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, unboosted FPV, or COBI-boosted PIs.

LPV/RTV may decrease valproic acid (VPA) levels and increase LPV levels. Limited data is available for other PIs. Monitoring of VPA levels, virologic response, and PI-related toxicities is recommended.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors  ^{[20, 21]}

In general, most HMG-CoA reductase inhibitors are subject to metabolism by hepatic CYP enzymes. Increased concentrations due to CYP inhibition may lead to muscle-related toxicities or rhabdomyolysis.

In combination with PIs, consider administerering the lowest possible effective atorvastatin dose with careful monitoring for toxicities, while not exceeding 20 mg/day. ATV/COBI should not be co-administered as this combination increases atorvastatin AUC approximately 9-fold.

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

Pitavastatin does not exhibit significant changes in levels with PIs as compared to other statins. Pitavastatin does not require dose adjustments with coadministered PIs. ATV may increase pitavastatin levels, while DRV/RTV and LPV/RTV may decrease pitavastatin levels.

Pravastatin should be given at the lowest effective dose if given with DRV/RTV or DRV/COBI as these PIs may significantly increase pravastatin levels. No dose adjustments are needed when coadministered with LPV/RTV.

Rosuvastatin should be started at the lowest effective dose, and maximal daily dose is dependent on the PI of choice. 20 mg/day should not be exceeded if taking DRV/COBI, and 10 mg/day should not be exceeded if taking a LPV/RTV or ATV-based regimen.

Phosphodiesterase type 5 (PDE5) inhibitors

Sildenafil should be started at 25 mg every 48 hours for the treatment of erectile dysfunction (ED). For treatment of pulmonary arterial hypertension (PAH), combination therapy is contraindicated.

Tadalafil should be started at 5 mg (not to exceed 10 mg in a single dose within 72 hours) for the treatment of ED. For treatment of PAH, dosing recommendations depend on which treatment is added to pre-existing therapy: If a PI has been used for >7 days, start with tadalafil 20 mg/day and increase to 40 mg/day based on tolerability; If tadalafil is added to pre-existing PI therapy, stop tadalafil >24 hours before PI initiation and restart 7 days after PI initiation at 20 mg/day (dose may be increased to 40 mg/day based on tolerability). For treatment of benign prostatic hyperplasia (BPH), the maximum daily dose should not exceed 2.5 mg/day.

Vardenafil should be started at 2.5 mg every 72 hours while monitoring for adverse effects related to vardenafil.

Avanafil coadministration is not recommended with any boosted-PI regimen. Avanafil should not exceed 50 mg/day if unboosted-ATV is used.

Antacids

Antacids can potentially decrease the drug concentrations of PIs.

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

H2 receptor antagonists

H₂ receptor antagonists include cimetidine, famotidine, and nizatidine.

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

Interactions are more significant when coadministered with ATV, as solubility and absorption decreases as gastric pH increases. Additionally, management depends on whether unboosted or boosted ATV is used.

• Unboosted ATV: ATV should be given either 2 hours before or 10 hours after the H ₂ receptor antagonist. In PI-naive patients, a single dose of famotidine should not exceed 20 mg (or equivalent for other H ₂ receptor antagonists) and the maximum daily dose should not exceed 40 mg/day (or equivalent for other H ₂ receptor antagonists). In PI-experienced patients, unboosted ATV and an H ₂ receptor antagonist should not be coadministered
• Boosted ATV: ATV 300 mg plus either RTV or COBI should be given at least 10 hours after the H ₂ receptor antagonist. In PI-experienced patients, famotidine should not exceed 20 mg twice daily. PI-experienced patients on tenofovir (TDF) should receive an increased dose of ATV (400 mg) plus RTV, while those on ATV/COBI and TDF should avoid H ₂ receptor antagonists.

FPV concentrations may be reduced if given concomitantly with H₂ receptor antagonist; may consider RTV boosting or separating 2 hours before the H₂ receptor antagonist.

Hepatitis C  direct-acting antivirals (DAAs)  ^{[22, 23]}

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

The following summary of interactions below is relevant to ATV, DRV or LPV-containing regimens:

• Daclatasvir: Daclatasvir should be reduced to 30 mg/day if given with boosted ATV. No adjustments are required if given with unboosted ATV, boosted DRV, or LPV/RTV.
• Dasabuvir plus Paritaprevir/Ombitasvir/RTV: If unboosted ATV is used, administer at the same time as dasabuvir plus paritaprevir/ombitasvir/RTV. A pharmacokinetic booster is already available as part of this hepatitis C regimen. DRV and LPV should not be coadministered.
• Elbasvir/grazoprevir: Significant elevations in grazoprevir levels may increase the risk for liver enzyme elevation and is contraindicated with ATV, DRV or LPV-containing regimens.
• Glecaprevir/pibrentasvir: Contraindicated with ATV-, DRV- or LPV-containing regimens.
• Ledipasvir/sofosbuvir: No dose adjustments are required, however caution is advised if a boosted PI regimen with TDF is coadministered with ledipasvir/sofosbuvir due to increased TDF exposure and the potential for higher risk of TDF-related adverse events.
• Sofosbuvir/velpatasvir: No dose adjustment is required.
• Sofosbuvir/velpatasvir/voxilaprevir: No dose adjustment is required with DRV-based regimens. Do not coadminister with ATV- or LPV-based regimens.

Immunosuppressants  ^{[24, 25, 26]}

Cyclosporine, everolimus sirolimus, and tacrolimus levels may be significantly increased with coadministration with all PIs, due to their affinity as substrates of CYP 3A4; therapeutic drug monitoring of immunosuppressant is recommended.

Narcotics

Oxycodone coadministration with LPV/RTV results in a 2.6-fold increase in oxycodone AUC and a similar interaction is expected with other opioids and PIs; oxycodone or opioid dose reduction may be necessary while monitoring 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 interactions are primarily significant with ATV, as increased gastric pH reduces absorption of ATV. Unboosted ATV should be avoided with PPIs due to significant reductions in ATV exposure. In PI-naive patients receiving ATV/RTV or ATV/COBI, a PPI at a max dose equivalent to omeprazole 20 mg/day may be given and should be administered at least 12 hours before the ATV-based regimen. Coadministration should be avoided in PI-experienced patients.

When DRV/RTV, TPV/RTV, FPV +/- RTV, and LPV/RTV are administered with PPIs, there is no 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.

Drosperinone-containing OCs are contraindicated with ATV/COBI and should be monitored closely if DRV/COBI are used, due to the potential for hyperkalemia from increased exposure to drosperinone. ^[27]

RTV-boosted PIs can decrease ethinyl estradiol and norethindrone drug concentrations; use alternative or additional method. If combination cannot be avoided, an OC containing at least 35 mcg of ethinyl estradiol should be used.

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 less than 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/RTV may affect drug levels; RTV 100 mg BID increases the active metabolite 17-BMP AUC 2-fold and C_max 1.6-fold; DRV 600 mg BIV plus RTV 100 mg BID decreases 17-BMP AUC 11% and C_max 19%; no dosage adjustment is necessary; significant interaction with other boosted PIs is not expected.

Dexamethasone in combination with all PIs can potentially decrease PI drug levels; use dexamethasone with caution, or consider an alternative corticosteroid for long-term use. If coadministration is required, monitoring virologic response closely is recommended.

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). ^[28]  A pharmacokinetic study demonstrated that the AUC of intranasal fluticasone increased 350-fold when coadministered with RTV 100 mg twice daily.

Increased prednisolone levels are possible when prednisolone is coadministered with PIs; prednisolone and LPV/RTV coadministration results in 31% increase in prednisolone AUC and a decrease in LPV levels; coadministration may be considered if the potential benefit of prednisone or prednisolone outweighs the risk for 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.

Colchicine dose for treatment of gout flares: Colchicine 0.6 mg for 1 dose, followed by 0.3 mg 1 hours later (do not repeat dose for at least 3 days); if taking FPV without RTV, give 1.2 mg for 1 dose and do not repeat dose for at least 3 days.

Colchicine dose for prophylaxis of gout flares when combined with PIs varies depending on the original intended dose:

• If the original colchicine dose was 0.6 mg twice daily: Decrease to 0.3 mg once daily
• If the original colchicine dose was 0.6 mg once daily: Decrease to 0.3 mg every other day.

Colchicine dose for familial Mediterranean fever: Do not exceed colchicine 0.6 mg once daily or 0.3 mg twice daily; if taking FPV without RTV, do not exceed 1.2 mg once daily or 0.6 mg BID.

Long-acting Inhaled Beta-Agonists

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

No dose adjustment is required for arformoterol, formoterol, indacaterol (75 mcg daily), or olodaterol when coadministered with unboosted or boosted ATV, DRV-containing regimens, or LPV/RTV.

Antimalarials

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

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

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