Lopinavir

( 4 , 5.4 , 7 ) • HIV-1 protease inhibitors: Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with either lopinavir/ritonavir or darunavir and ritonavir increases tenofovir concentrations. Protease inhibitor: darunavir/ritonavir lopinavir/ritonavir ↑ tenofovir ↓ lopinavir ↑ tenofovir Monitor patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate concomitantly with ritonavir-boosted darunavir for TDF-associated adverse reactions. Do not use once daily administration of lopinavir/ritonavir.

Strong CYP3A4 inhibitor may increase systemic corticosteroid effects of fluticasone propionate.

CYP3A4 inhibitor may increase systemic exposure to irinotecan or SN-38. Do not administer unless no therapeutic alternatives.

Concomitant use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, voriconazole) with lomitapide is contraindicated.

Lopinavir/ ritonavir 400/100 mg twice a day for 20 days 150 mg once a day for 10 days Healthy subjects (14) ↑ AUC by 203% c ↓ C max by 112% Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Co-administration of rifabutin with cabotegravir/rilpivirine prolonged-release injectable suspension is contraindicated Ritonavir 500 mg twice a day for 10 days 150 mg once a day for 16 days Healthy subjects (5) ↑ AUC by 300%, ↑ C max by 150% ND Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination.

No drug interaction studies have been conducted with amlodipine besylate and atorvastatin calcium and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below: Amlodipine Increased Risk of Myopathy and Rhabdomyolysis ( 2 , 5.1 , 7.3 , 12.3 ) Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir Avoid atorvastatin Clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir,letermovir Do not exceed 20 mg atorvastatin daily Nelfinavir Do not exceed 40 mg atorvastatin daily Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine Consider the risk/benefit of concomitant use with atorvastatin Other Lipid-Lowering Medications: Increased risk of myopathy (7) . In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6 , 5.1 , 7 , 12.3 ) Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily • Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥ 1 g/day) of niacin increases the risk of adverse skeletal muscle effects. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium and the lowest dose necessary should be used.

Examples: cyclosporine, gemfibrozil, antiretrovirals (atazanavir, lopinavir, ritonavir, saquinavir, tipranavir), rifampin, eltrombopag Drugs that Cause Constipation Clinical Impact: Increased risk for constipation related adverse reactions and potential for constipation related serious adverse reactions Intervention: Avoid use with other drugs that may cause constipation (see below); loperamide may be used occasionally for acute management of severe diarrhea but avoid chronic use.

Avoid co-administering erlotinib with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin).

Avoid co-administering erlotinib tablets with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin).

Strong CYP3A inhibitor may increase mifepristone plasma concentrations; limit mifepristone dose to 900 mg per day when used together.

( 2.5 , 7.4 ) CYP2B6 Inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) may reduce efficacy by reducing bupropion exposure, avoid concomitant use. Inducers of CYP2B6: Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure and may reduce efficacy. Avoiding concomitant use with ritonavir, lopinavir, or efavirenz is recommended [see Clinical Pharmacology (12.3) ] .

Lopinavir/ritonavir decreases plasma concentrations of estrogen and progestin, potentially reducing contraceptive effectiveness.

HIV protease inhibitor (in combination with ritonavir) that may decrease plasma concentrations of norethindrone and ethinyl estradiol.

HIV protease inhibitor that may decrease plasma concentrations of estrogen and/or progestin, potentially reducing contraceptive effectiveness.

Avoid concomitant use of TALICIA with amprenavir, indinavir, lopinavir/ritonavir, saquinavir/ritonavir, ritonavir, tipranavir/ritonavir, fosamprenavir/ritonavir, or nelfinavir [see Warnings and Precautions (5.7) ] .

Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole).

Intervention: • Sofosbuvir/velpatasvir/voxilaprevir • Ledipasvir/sofosbuvir Avoid concomitant use with rosuvastatin • Simeprevir • Dasabuvir/ombitasvir/paritaprevir/ritonavir • Elbasvir/grazoprevir • Sofosbuvir/velpatasvir • Glecaprevir/pibrentasvir • Atazanavir/ritonavir • Lopinavir/ritonavir Initiate with rosuvastatin 5 mg once daily, and do not exceed a dose of rosuvastatin 10 mg once daily.

Lopinavir/ritonavir combination increases rosuvastatin exposure up to 3-fold. Limit rosuvastatin calcium dose to 10 mg once daily.

Avoid using strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS.

CYP2B6 inducer that decreases bupropion exposure; dose increase may be necessary but should not exceed maximum recommended dose.

Dose increase may be necessary as concomitant treatment decreases bupropion and hydroxybupropion exposure.

CYP2B6 inducer that decreases bupropion and hydroxybupropion exposure. Dosage increase of bupropion may be necessary but should not exceed maximum recommended dose.

CYP2B6 inducer that can decrease bupropion and hydroxybupropion exposure. Dose increase of bupropion may be necessary but should not exceed maximum recommended dose.

CYP2B6 inducer that may decrease bupropion and hydroxybupropion exposure. Dose increase may be necessary but should not exceed maximum recommended dose.

Use with TYBOST is not recommended because lopinavir is co-formulated with ritonavir.

Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) [ see Clinical Pharmacology (12.3)].

HIV protease inhibitor that may decrease plasma concentrations of estrogen and/or progestin, potentially diminishing contraceptive effectiveness.

lopinavir/ritonavir atazanavir/ritonavir darunavir/ritonavir ↑ tenofovir Monitor patients receiving TRUVADA concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir for TDF-associated adverse reactions.

HIV-1 Protease Inhibitors: atazanavirc lopinavir/ritonavirc atazanavir/ritonavirc darunavir/ritonavirc ↓ atazanavir ↑ tenofovir When coadministered with emtricitabine and tenofovir disoproxil fumarate, atazanavir 300 mg should be given with ritonavir 100 mg. Monitor patients receiving emtricitabine and tenofovir disoproxil fumarate concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir for TDF-associated adverse reactions.

Lopinavir/ritonavir 400 mg of lopinavir in combination with 100 mg of ritonavir. Caution is advised when CRESEMBA is coadministered with lopinavir/ritonavir There is a 96% increase in exposure of isavuconazole when coadministered with lopinavir/ritonavir [see Clinical Pharmacology ( 12.3 )] . The Effect of CRESEMBA on the Pharmacokinetics of Other Drugs Recommendation Comments Lopinavir/ritonavir 400 mg of lopinavir in combination with 100 mg of ritonavir.

( 7.2 ) • HIV-1 Protease Inhibitors: Monitor for evidence of tenofovir toxicity when CIMDUO is coadministrated with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations [see Clinical Pharmacology (12.3) ] . Patients receiving CIMDUO concomitantly with lopinavir/ritonavir, atazanavir and ritonavir, or darunavir and ritonavir should be monitored for tenofovir-associated adverse reactions.

Lopinavir/ritonavir decreases lamotrigine concentration approximately 50%.

Lopinavir/ritonavir, an HIV protease inhibitor, may significantly decrease plasma concentrations of estrogen and/or progestin.

HIV protease inhibitor (with ritonavir) may significantly decrease plasma concentrations of estrogen and/or progestin.

HIV protease inhibitor that may decrease plasma concentrations of estrogen and/or progestin when given with ritonavir.

HIV protease inhibitor (with ritonavir) that may decrease plasma concentrations of estrogen and/or progestin.

Significant decrease in systemic concentrations of norethindrone when combined with ritonavir; may reduce contraceptive efficacy.

HIV protease inhibitor (with ritonavir) that may decrease plasma concentrations of estrogen and/or progestin.

Strong CYP3A4 inhibitor that may increase midostaurin concentrations and risk of toxicity. Monitor for increased adverse reactions, especially during first week of administration.

HIV-1 Protease Inhibitors : atazanavir lopinavir/ritonavir atazanavir/ritonavir darunavir/ritonavir ↓ atazanavir ↑ tenofovir When coadministered with tenofovir disoproxil fumarate tablets, atazanavir 300 mg should be given with ritonavir 100 mg. Monitor patients receiving tenofovir disoproxil fumarate tablets concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir for tenofovir DF-associated adverse reactions.

Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir ( Table 6 ) [see Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 )] . Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.

• In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with ATORVALIQ. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.

Examples: efavirenz, nevirapine, etravirine, delavirdine Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects.

Examples: efavirenz, nevirapine, etravirine, delavirdine Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects.

Intervention: Patients who are on chronic buprenorphine sublingual tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen Examples: Efavirenz, nevirapine, etravirine, delavirdine Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects.

Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects.

Examples: efavirenz, nevirapine, etravirine, delavirdine Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects.

Table 1: Drug Interactions Drug class Outcome/effect Clinical comment Strong CYP3A4 Inhibitors † atazanavir clarithromycin darunavir/ritonavir indinavir itraconazole ketoconazole lopinavir/ritonavir nefazodone nelfinavir ritonavir saquinavir telithromycin tipranavir/ritonavir Significant increases in colchicine plasma levels [see Clinical Pharmacology (12.3)] .

lopinavir/ritonavir ↓ darunavir ↔ lopinavir Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and darunavir, with or without ritonavir.

lopinavir/ritonavir ↓ darunavir ↔ lopinavir Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and darunavir, with or without ritonavir.

Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir ( Table 8 ) [see Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 )] . Concomitant Drug Class: Drug Name Effect on Concentration of Dolutegravir and/or Concomitant Drug Clinical Comment HIV-1 Antiviral Agents Non-nucleoside reverse transcriptase inhibitor: Etravirine a ↓Dolutegravir Use of TIVICAY or TIVICAY PD with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.

Protease inhibitor: Lopinavir/ritonavir ↓ lopinavir * Lopinavir/ritonavir once daily dosing is not recommended when co-administered with efavirenz. The dose of lopinavir/ritonavir must be increased when co-administered with efavirenz. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when co-administered with efavirenz in adult and pediatric patients.

7.3 Protease Inhibitors HIV Protease Inhibitors: No dose adjustment is recommended when eltrombopag is co-administered with lopinavir/ritonavir (LPV/RTV).

7.3 Protease Inhibitors HIV Protease Inhibitors: No dose adjustment is recommended when PROMACTA is coadministered with lopinavir/ritonavir (LPV/RTV).

7.4 Drugs without Clinically Significant Interactions with DESCOVY Based on drug interaction studies conducted with the components of DESCOVY, no clinically significant drug interactions have been either observed or are expected when DESCOVY is combined with the following antiretroviral agents: atazanavir with ritonavir, atazanavir with cobicistat (in those weighing ≥35 kg), darunavir with ritonavir or cobicistat, dolutegravir, efavirenz, ledipasvir, lopinavir/ritonavir, maraviroc, nevirapine, raltegravir, rilpivirine, and sofosbuvir.

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of progestin have been noted in cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine, efavirenz] or increase [e.g., etravirine]).

Human immunodeficiency virus (HIV) / Hepatitis C Virus (HCV) protease inhibitors and non­-nucleoside reverse transcriptase inhibitors Significant changes in the plasma concentrations of the estrogen and /or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., efavirenz, nevirapine] or increase [e.g., etravirine]).

Human immunodeficiency virus (HIV) / Hepatitis C Virus (HCV) protease inhibitors and nonnucleoside reverse transcriptase inhibitors Significant changes in the plasma concentrations of the estrogen and /or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., efavirenz, nevirapine] or increase [e.g., etravirine]).

dolutegravir/darunavir/ritonavir ↓ dolutegravir ↔ etravirine The effect of etravirine on dolutegravir plasma concentrations was mitigated by co- administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. dolutegravir/lopinavir/ritonavir ↔ dolutegravir ↔ etravirine Dolutegravir should only be used with etravirine tablets when co- administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. HIV-antiviral agents: protease inhibitors (PIs) atazanavir (without ritonavir) atazanavir/ritonavir atazanavir/cobicistat darunavir/ritonavir darunavir/cobicistat fosamprenavir (without ritonavir) fosamprenavir/ritonavir indinavir (without ritonavir) lopinavir/ritonavir ↓ atazanavir ↓ atazanavir ↔ etravirine ↓ atazanavir ↓ cobicistat ↓ etravirine ↓ cobicistat darunavir: effect unknown ↑ amprenavir ↑ amprenavir ↓ indinavir ↓ etravirine Co-administration of etravirine tablets and atazanavir without low- dose ritonavir is not recommended.

HIV protease inhibitors: Lopinavir/ritonavir a ↓ Amprenavir ↓ Lopinavir An increased rate of adverse events has been observed.

Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide Antiplatelets Ticagrelor Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

Darunavir Lopinavir Ritonavir ↑ glecaprevir ↑ pibrentasvir Coadministration is not recommended.

Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%. (7, 12.3) · Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease lamotrigine exposure by approximately 50% and 32%, respectively.

Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.

Regimens containing tenofovir DF and an HIV protease inhibitor/ ritonavir or cobicistat atazanavir/ritonavir or cobicistat + emtricitabine/tenofovir DF darunavir/ritonavir or cobicistat + emtricitabine/tenofovir DF lopinavir/ritonavir + emtricitabine/tenofovir DF ↑ tenofovir The safety of increased tenofovir concentrations in the setting of HARVONI and an HIV protease inhibitor/ritonavir or cobicistat has not been established.

7 DRUG INTERACTIONS Co-administration of lopinavir and ritonavir can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of lopinavir. ( 4 , 5.1 , 7 , 12.3 ) 7.1 Potential for Lopinavir And Ritonavir to Affect Other Drugs Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with lopinavir and ritonavir.

Paradoxical Effects of Antiretroviral Agents on Methadone Hydrochloride Tablets Concurrent use of certain antiretroviral agents with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranavir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone.

Ritonavir and Ritonavir/Lopinavir Reduced plasma methadone levels have been observed after administration of ritonavir alone or ritonavir/lopinavir combination.

Lopinavir/Ritonavir* ↓Lopinavir Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors Significant changes (increase or decrease) in the plasma concentrations of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos) amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir], or increase [e.g., indinavir and atazanavir/ritonavir] HCV protease inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

7.7 Antiretroviral Drugs Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with antiretroviral drugs such as atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, and with the combinations lopinavir/ritonavir and emtricitabine/efavirenz/tenofovir disoproxil fumarate.

Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.

Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lacosamide, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Antiepileptic drugs a Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

Lopinavir/Ritonavir Co-administration of pretomanid with lopinavir/ritonavir did not affect the plasma concentrations of pretomanid [see Clinical Pharmacology (12.3) ] . Lopinavir/ritonavir can be co-administered with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid.

Lopinavir/ritonavir *† ↑ rilpivirine ↔ boosted lopinavir Concomitant use of rilpivirine tablets with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when rilpivirine tablets are coadministered with lopinavir/ritonavir.

Lopinavir/ritonavir ↑ rilpivirine ↔ boosted lopinavir Concomitant use of EDURANT or EDURANT PED with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT or EDURANT PED is coadministered with lopinavir/ritonavir.

Human Immunodeficiency Virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors : Significant decreases in systemic exposure of estrogen and/or progestin have been noted when CHCs are co-administered with some HIV protease inhibitors (eg, nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (eg, boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (eg, nevirapine).

Antiretrovirals: atazanavir lopinavir ↑ voxilaprevir Coadministration of VOSEVI with atazanavir- or lopinavir-containing regimens is not recommended.

Lopinavir ↓ Lopinavir Saquinavir ↓ Saquinavir Protease Inhibitors (co-administered with 100 mg of ritonavir): Atazanavir ↓ Atazanavir ↑ Tipranavir Virus Integrase Strand Transfer Inhibitors (INSTI): Raltegravir ↓ Raltegravir No dose adjustment is needed for 400 mg twice daily dosing regimen of raltegravir.

Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.3 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3.

Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.3 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3 .