Ritonavir

Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications ( 4 ) ] .

Other Agents Alpha 1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Contraindicated due to potential hypotension [see Contraindications (4) ].

7 DRUG INTERACTIONS Concomitant use of PDE5 inhibitors with alpha adrenergic antagonists, including alfuzosin hydrochloride extended-release tablets, can potentially cause symptomatic hypotension (5.4 , 7.4) 7.1 CYP3A4 Inhibitors Alfuzosin hydrochloride extended-release tablets are contraindicated for use with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, or ritonavir, since alfuzosin blood levels are increased [see Contraindications (4) , Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ] .

( 7.1 ) Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. Strong Inhibitors of CYP3A (except ritonavir) Clinical implication Concomitant use of alprazolam with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see Clinical Pharmacology (12.3) ]. Prevention or management Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4) , Warnings and Precautions (5.5) ].

Strong Inhibitors of CYP3A (except ritonavir) Clinical implication Concomitant use of alprazolam with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see CLINICAL PHARMACOLOGY (12.3)]. Prevention or management Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.5)]. Examples Carbamazepine, phenytoin Ritonavir Clinical implication Interactions involving ritonavir and alprazolam are complex and time dependent.

Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to ritonavir or to the class of protease inhibitors [see Contraindications (4) ] . # refers to interaction with apalutamide.

Lipid-modifying agents HMG-CoA Reductase Inhibitor: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4) ]. Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If ritonavir is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co- administration with atorvastatin and rosuvastatin.

In combination with tipranavir or other protease inhibitors, significantly increases atorvastatin levels and myopathy risk.

7 DRUG INTERACTIONS • Avanafil can potentiate the hypotensive effect of nitrates, alpha-blockers, antihypertensives, and alcohol ( 7.1 ) • CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, erythromycin) increase avanafil exposure ( 7.2 ) 7.1 Potential for Pharmacodynamic Interactions with Avanafil Nitrates Administration of avanafil to patients who are using any form of organic nitrate, is contraindicated. Other potent inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir and telithromycin) would be expected to have similar effects. HIV Protease inhibitor — Ritonavir (600 mg twice daily), a strong CYP3A4 inhibitor, which also inhibits CYP2C9, increased avanafil 50 mg single-dose C max and AUC equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 9 hours in healthy volunteers.

Strong CYP3A4 inhibitor that significantly increases fluticasone propionate plasma exposure and reduces serum cortisol, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression.

CYP3A4 inhibitor that can increase systemic budesonide concentrations. Avoid use.

Strong CYP3A4 inhibitor causing significant increases in colchicine plasma levels.

Anticipated significant increase in saxagliptin plasma concentrations. Do not coadminister with dapagliflozin and saxagliptin.

Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications ( 4 ) ] . A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy - Liver Enzyme Elevation Co-administration of VIORELE ® with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated, due to potential for ALT elevations (see WARNINGS , RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).

Strong CYP3A4 inhibitor; rare reports of serious adverse events including vasospasm leading to cerebral ischemia and ischemia of extremities.

7.2 Effects of Other Drugs on Dronedarone Ketoconazole and Other Potent CYP3A Inhibitors Concomitant use of ketoconazole as well as other potent CYP3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to dronedarone is significantly increased [see Contraindications (4) , Clinical Pharmacology (12.3) ] .

Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications ( 4 ) ] . Avoid co-administration of encorafenib or ivosidenib with NORVIR due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with NORVIR cannot be avoided, modify dose as recommended in encorafenib USPI.

Strong CYP3A4 inhibitor. Should not be coadministered with everolimus.

Strong CYP3A4 inhibitor; co-administration with everolimus is not recommended.

Strong CYP3A4 inhibitor; concomitant use is contraindicated due to increased risk of myopathy and rhabdomyolysis.

Strong CYP3A4 inhibitor; concomitant use is contraindicated due to increased risk of hypotension and syncope.

Strong CYP3A4 inhibitor significantly increases plasma fluticasone propionate exposure and reduces serum cortisol concentrations, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.

Strong CYP3A4 inhibitor significantly increases fluticasone propionate exposure and reduces serum cortisol. Postmarketing reports of systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.

Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications ( 4 ) ] . Avoid use of neratinib, venetoclax or ibrutinib with NORVIR.

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

Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications ( 4 ) ] . Avoid co-administration of encorafenib or ivosidenib with NORVIR due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of ivosidenib with NORVIR cannot be avoided, reduce ivosidenib dose to 250 mg once daily.

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine). In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine). 7.3 Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy – Liver Enzyme Elevation Co-administration of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations [see Warning and Precautions (5.4) ] .

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and nonnucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine). In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine). 7.3 Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy – Liver Enzyme Elevation Co-administration of Simpesse with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations [see Warning and Precautions (5.4) ] .

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. Concomitant use of moderate CYP3A4 inhibitors (such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) has not been studied, but concomitant use with lomitapide is contraindicated since lomitapide exposure will likely increase significantly in the presence of these inhibitors.

Lipid-modifying agents HMG-CoA Reductase Inhibitor: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4) ].

Strong CYP3A4 inhibitor that increases lurasidone exposure; concomitant use is contraindicated.

Strong CYP3A4 inhibitor increases macitentan exposure. Avoid co-administration; use other PAH treatment options.

Strong CYP3A4 inhibitor that increases exposure to both macitentan and tadalafil. Avoid concomitant use.

HIV protease inhibitor and strong CYP 3A4 inhibitor; should not be co-administered due to risk of vasospasm leading to cerebral ischemia and/or ischemia of extremities.

HIV protease inhibitor and strong CYP 3A4 inhibitor; rare reports of serious adverse events with ergot alkaloids including vasospasm leading to cerebral ischemia and ischemia of extremities.

Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications (4) ] . Sedative/hypnotics: Parenteral midazolam ↑ midazolam Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications ( 4 ) ] . Avoid use of neratinib, venetoclax or ibrutinib with NORVIR.

Co-administered with atazanavir; nevirapine is contraindicated with this combination due to decreased atazanavir exposure and increased nevirapine levels.

Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications ( 4 ) ] . A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Co-administration of Tarina Fe 1/20 EQ with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations (see WARNINGS, Risk of Liver Enzyme Elevations with concomitant Hepatitis C Treatment ).

Concomitant Use with HCV Combination Therapy - Liver Enzyme Elevation Co-administration of norethindrone acetate and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations (see Warnings , RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ).

Do not co-administer with HCV combination therapy containing ombitasvir/paritaprevir/ritonavir due to potential for ALT elevations.

CYP3A4 inhibitor may increase codeine plasma concentrations and morphine levels, potentially causing fatal respiratory depression. Avoid use; if necessary, monitor frequently.

CYP2D6 and CYP3A4 inhibitor; simultaneous use with both CYP2D6 and CYP3A4 inhibitors should be avoided due to increased risk of proarrhythmia.

Increased quinine plasma levels have been observed when used concomitantly. Concomitant administration should be avoided.

( 7.2 ) 7.1 Effects of Other Drugs on Ranolazine Strong CYP3A Inhibitors Do not use ranolazine with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir [see Contraindications (4) , Clinical Pharmacology (12.3) ].

Protease inhibitor and strong CYP3A4/P-gp inhibitor that increases sirolimus concentrations. Avoid concomitant use.

As component of ritonavir-boosted saquinavir, concomitant use contraindicated due to severe hepatocellular toxicity.

Combined P-gp and strong CYP3A inhibitor that increases rivaroxaban exposure and may increase bleeding risk. Avoid concomitant administration.

Lipid-modifying agents HMG-CoA Reductase Inhibitor: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications ( 4 ) ] . Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.

7 DRUG INTERACTIONS Sildenafil citrate can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives ( 4.1 , 5.5 , 7.1 , 7.2 , 7.3 , 12.2 ) With concomitant use of alpha blockers, initiate sildenafil citrate at 25 mg dose ( 2.3 ) CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin): Increase sildenafil citrate exposure ( 2.4 , 7.4 , 12.3 ) Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period ( 2.4 , 5.6 ) Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg ( 2.4 , 7.4 ) 7.1 Nitrates Administration of sildenafil tablets with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. 7.4 Ritonavir and other CYP3A4 Inhibitors Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC).

7 DRUG INTERACTIONS • Sildenafil can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives ( 4.1 , 5.5 , 7.1 , 7.2 , 7.3 , 12.2 ) • With concomitant use of alpha blockers, initiate sildenafil at 25 mg dose ( 2.3 ) • CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin): Increase sildenafil exposure ( 2.4 , 7.4 , 12.3 ) o Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period ( 2.4 , 5.6 ) o Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg ( 2.4 , 7.4 ) 7.1 Nitrates Administration of sildenafil with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. 7.4 Ritonavir and other CYP3A4 inhibitors Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC).

Strong CYP3A4 inhibitor that may cause significant increase in silodosin plasma concentrations. Concomitant administration is contraindicated.

Lipid-modifying agents HMG-CoA Reductase Inhibitor: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications ( 4 ) ] .

Strong CYP3A inhibitor; concomitant use not recommended due to increased suvorexant exposure.

Strong CYP3A inhibitor that substantially increases ticagrelor exposure, increasing risk of dyspnea, bleeding, and other adverse events.

( 4 , 5.4 , 7 ) 7.1 Potential for APTIVUS/ritonavir to Affect Other Drugs APTIVUS co-administered with ritonavir at the recommended dose is a net inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Thus, co-administration of APTIVUS/ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated [see Contraindications (4) ] . Clinically significant drug-drug interactions of APTIVUS co-administered with ritonavir are summarized in Table 4 below.

Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications (4) ] .

In vivo studies Do not use vardenafil orally disintegrating tablet with moderate and strong CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of vardenafil is increased in their presence [see Warnings and Precautions (5) and Dosage and Administration ( 2.4 )] . [See Dosage and Administration (2.4) and Warnings and Precautions ( 5 ).] Ritonavir (600 mg b.i.d.) co-administered with vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil C max . The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly strong CYP3A4 inhibitor, which also inhibits CYP2C9.

Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3) ] Drug/Drug Class (Mechanism of Interaction by the Drug) Voriconazole Plasma Exposure (C max and AUC τ after 200 mg every 12 hours) Recommendations for Voriconazole Dosage Adjustment/Comments Rifampin and Rifabutin (CYP450 Induction) Significantly Reduced Contraindicated Efavirenz (400 mg every 24 hours) (CYP450 Induction) Significantly Reduced Contraindicated High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction) Significantly Reduced Contraindicated Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole Carbamazepine (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Phenytoin (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every12 hours Letermovir (CYP2C9/2C19 Induction) Reduced If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole. Frequent monitoring for adverse reactions and toxicity related to voriconazole A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3) ] Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (C max and AUC τ ) Recommendations for Drug Dosage Adjustment/Comments Sirolimus (CYP3A4 Inhibition) Significantly Increased Contraindicated Rifabutin (CYP3A4 Inhibition) Significantly Increased Contraindicated Efavirenz (400 mg every 24 hours) (CYP3A4 Inhibition) Significantly Increased Contraindicated High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir C max or AUC τ Contraindicated because of significant reduction of voriconazole C max and AUC τ Low-dose Ritonavir (100 mg every 12 hours) Slight Decrease in Ritonavir C max and AUC τ Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C max and AUC τ ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes Ergot Alkaloids (CYP450 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Contraindicated Naloxegol (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Contraindicated Tolvaptan (CYP3A4 Inhibition) Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan Contraindicated Venetoclax (CYP3A4 Inhibition) Not studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

ketoconazole), and protease inhibitors(e.g., ritonavir), may result in an increase in codeine plasma concentrations , with subsequently greater metabolism by CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of acetaminophen and codeine phosphate tablets is achieved (see WARNINGS ).

Strong CYP3A4 inhibitor that may increase DM1 exposure and toxicity. Concomitant use should be avoided or KADCYLA treatment delayed.

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) . Intervention : Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin.

CYP2D6 inhibitor that increases amphetamine exposure and risk of serotonin syndrome.

CYP2D6 inhibitor that increases amphetamine exposure and serotonin syndrome risk.

Combined P-gp and strong CYP3A4 inhibitor that increases apixaban exposure and bleeding risk. Reduce apixaban dose by 50% or avoid coadministration.

Intervention Avoid concomitant use of aprepitant Examples Moderate inhibitor: diltiazem Strong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir Strong CYP3A4 Inducers Clinical Impact Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of aprepitant [see Clinical Pharmacology ( 12.3 )].

Co-administration increases atazanavir concentration. See complete prescribing information for atazanavir for dosing details.

These recommendations are based either on observed drug interactions in studies of cobicistat, atazanavir, or atazanavir coadministered with ritonavir or predicted drug interactions based on the expected magnitude of interaction and potential for serious events or loss of therapeutic effect of EVOTAZ [see Contraindications (4) , Warnings and Precautions (5.8) , and Clinical Pharmacology (12.3) ] . ritonavir or products containing ritonavir ↑ atazanavir Coadministration of EVOTAZ and ritonavir or ritonavir-containing regimens is not recommended due to similar effects of cobicistat and ritonavir on CYP3A [see Warnings and Precautions (5.9) ] . Switching from atazanavir coadministered with ritonavir to EVOTAZ: Maintain bosentan dose.

CYP3A4 inhibitor increases hydrocodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

Strong CYP3A4 inhibitor may increase corticosteroid exposure and risk of systemic side effects; monitor closely.

CYP3A4 inhibitor that increases buprenorphine plasma concentration, resulting in increased or prolonged opioid effects and respiratory depression risk.

CYP3A4 inhibitor (protease inhibitor) that increases buprenorphine plasma concentration, resulting in increased or prolonged opioid effects.

CYP3A4 inhibitor that can increase plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects and respiratory depression.

CYP3A4 inhibitor may increase codeine plasma concentrations and morphine levels, potentially causing fatal respiratory depression, particularly when added after stable dosing.

CYP3A4 inhibitor may increase codeine plasma concentrations and morphine levels, potentially causing fatal respiratory depression, particularly when added after stable dosing.

Strong CYP3A inhibitor may increase plasma concentrations of cabazitaxel. Avoid coadministration or consider 25% dose reduction.

Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) while taking COMETRIQ or reduce the dosage of COMETRIQ if concomitant use with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )] . Monitor patients for increased toxicity when MRP2 inhibitors (e.g., abacavir, adefovir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, saquinavir, and tenofovir) are co-administered with COMETRIQ [see Clinical Pharmacology ( 12.3 )] .

Prevention or Management Avoid co-administration of potent ENT1, CNT3, or BCRP transporter inhibitors (e.g., ritonavir, eltrombopag, curcumin, cyclosporine, dilazep, nifedipine, nimodipine, cilostazol, sulindac, dipyridamole, or reserpine) during the 4 to 5 day cladribine treatment cycles.

ketoconazole), or protease inhibitors (e.g., ritonavir), may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of TUXARIN ER is achieved [ see Warnings and Precautions (5.8) ].

Protease inhibitor and CYP3A4 inhibitor that increases codeine and morphine levels, potentially causing fatal respiratory depression.

Darifenacin systemic exposure is increased with potent CYP3A4 inhibitors; daily dose should not exceed 7.5 mg when co-administered with ritonavir.

Co-administered ritonavir is a CYP3A, CYP2D6, and P-gp inhibitor that alters darunavir concentrations. Darunavir and ritonavir are both metabolized by CYP3A.

CYP2D6 inhibitor increases dextroamphetamine exposure and serotonin syndrome risk. Use lower doses and monitor.

CYP2D6 inhibitor that increases amphetamine exposure and risk of serotonin syndrome. Initiate with lower doses and monitor for serotonin syndrome.

CYP2D6 inhibitor that increases dextroamphetamine exposure and risk of serotonin syndrome. Initiate with lower doses and monitor for serotonin syndrome symptoms.

Digoxin AUC increased 86%. Monitor serum digoxin concentrations and consider dose reduction.

Enzyme inducer that elevates glucuronosyltransferase levels and increases valproate clearance. Increased monitoring and dosage adjustment indicated.

Protease inhibitor and potent CYP3A4 inhibitor that may increase docetaxel exposure. Concomitant use should be avoided; if unavoidable, dose reduction and close toxicity monitoring required.

Protease inhibitor and potent CYP3A4 inhibitor that may increase docetaxel exposure. Concomitant use should be avoided; if unavoidable, close monitoring and dose reduction considered.

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.

Coadministration of TRUVADA with certain HIV-1 protease inhibitors including ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity.

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 CYP3A4 inhibitor expected to increase eszopiclone exposure and effects similarly to ketoconazole. Dose reduction needed.

CYP3A4 inhibitor that increases fentanyl plasma concentration, resulting in increased or prolonged opioid effects, respiratory depression, and sedation.

Protease inhibitor and CYP3A4 inhibitor that increases fentanyl plasma concentration, resulting in increased or prolonged opioid effects and respiratory depression.

CYP3A4 inhibitor; concomitant use can increase plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, respiratory depression, and sedation.

Co-administration increases amprenavir concentration. See complete prescribing information for fosamprenavir for dosing details.

Potent CYP3A4 inhibitor that increases amprenavir concentrations and alters drug interaction profile; also inhibits CYP2D6 leading to clinically significant interactions with CYP2D6 substrates.

Intervention Avoid concomitant use of fosaprepitant Examples Moderate inhibitor: diltiazemStrong inhibitors:ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir Strong CYP3A4Inducers Clinical Impact Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of fosaprepitant [see Clinical Pharmacology (12.3) ] .

Intervention Avoid concomitant use of FOCINVEZ Examples Moderate inhibitor: diltiazem Strong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir Strong CYP3A4 Inducers Clinical Impact Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of FOCINVEZ [see Clinical Pharmacology (12.3)] .

Abnormal renal function observed during concurrent use with foscarnet and ritonavir.

CYP3A4 inhibitor that increases hydrocodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

Protease inhibitor CYP3A4 inhibitor that increases hydrocodone plasma concentration, resulting in increased or prolonged opioid effects and potential respiratory depression.

Protease inhibitor and CYP3A4 inhibitor that can increase hydrocodone plasma concentration and prolong opioid effects.

Protease inhibitor and CYP3A4 inhibitor that can increase hydrocodone plasma concentration, resulting in increased or prolonged opioid effects.

Protease inhibitor and CYP3A4 inhibitor that increases hydrocodone plasma concentration, resulting in increased or prolonged opioid effects.

Protease inhibitor and CYP3A4 inhibitor that can increase plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects.

Co-administration increases indinavir concentration. Appropriate doses for this combination with respect to efficacy and safety have not been established.

Strong CYP3A4 inhibitor may cause increased plasma concentration of triamcinolone acetonide and adverse reactions.

P-glycoprotein inhibitor increases loperamide plasma concentrations 2- to 3-fold with potential for enhanced CNS adverse reactions.

Strong CYP3A4 inhibitor may increase plasma concentration of triamcinolone leading to adverse reactions.

Concomitant use can increase meperidine plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression.

Protease inhibitor that increases methadone plasma concentration, resulting in increased opioid effects and potential fatal overdose.

Protease inhibitor and CYP3A4 inhibitor that increases methadone plasma concentration, resulting in increased opioid effects and risk of fatal overdose.

Potent CYP3A4 inhibitor may cause intense and prolonged sedation and respiratory depression due to decreased midazolam plasma clearance.

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) ] .

CYP3A inhibitor that may increase nifedipine exposure. Careful monitoring and dose adjustment necessary; consider lowest dose.

Strong CYP3A4 inhibitor that significantly increases nimodipine plasma concentration and blood pressure lowering effect. Concomitant administration should generally be avoided.

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

Ritonavir-containing products : See prescribing information for specific drugs. 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) ] .

Strong CYP3A4 inhibitor that also inhibits OATP1B; avoid concomitant use as it significantly increases FOUNDAYO plasma concentrations and risk of adverse reactions.

Protease inhibitor and CYP3A4 inhibitor that increases oxycodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

Protease inhibitor and CYP3A4 inhibitor that increases plasma concentration of oxycodone, resulting in increased or prolonged opioid effects.

Protease inhibitor and CYP3A4 inhibitor that increases oxycodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

CYP3A4 inhibitor that increases oxycodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

Protease inhibitor and CYP3A4 inhibitor that increases oxycodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

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

Strong CYP3A inhibitor increases paricalcitol exposure. Dose adjustment may be necessary; monitor intact PTH and serum calcium closely.

ketoconazole), or protease inhibitors (e.g., ritonavir), may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Promethazine and Phenylephrine HCl and Codeine Phosphate Oral Solution is achieved [see Warnings and Precautions (5.9) ] .

Dual CYP2D6 and CYP3A4 inhibitor that increases propafenone plasma levels, potentially causing cardiac arrhythmias and proarrhythmia risk.

Strong CYP3A4 inhibitor significantly increases quetiapine exposure; reduce quetiapine dose to one sixth of original dose.

Strong CYP3A4 inhibitor that increases quetiapine exposure; quetiapine dose should be reduced to one sixth of original dose.

Increases quinine plasma levels. Concomitant administration should be avoided.

Ritonavir increases rifabutin and desacetyl-rifabutin concentrations. Dose adjustment of rifabutin and increased monitoring for adverse reactions warranted.

HIV protease inhibitor and strong CYP/P-gp/BCRP inhibitor increases riociguat exposure and may result in hypotension. Consider starting dose of 0.5 mg three times daily and monitor for hypotension.

Ritonavir (in combination with atazanavir or lopinavir) increases rosuvastatin exposure up to 3-fold. Limit rosuvastatin calcium dose to 10 mg once daily.

Strong CYP3A4 inhibitor may increase salmeterol exposure and risk of cardiovascular effects including QTc prolongation, palpitations, and tachycardia.

7 DRUG INTERACTIONS When co-administering ritonavir with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions. HIV-1 Protease Inhibitor: saquinavir ↑ saquinavir See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir. Saquinavir/ritonavir in combination with rifampin is not recommended due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.

Strong CYP3A4/5 inhibitor anticipated to significantly increase saxagliptin plasma concentrations. Limit saxagliptin dosage to 2.5 mg.

Strong CYP3A4/5 inhibitor anticipated to significantly increase saxagliptin plasma concentrations. Dose limitation required.

Protease inhibitor and CYP3A4 inhibitor that increases sufentanil plasma concentration, resulting in increased or prolonged opioid effects and risk of respiratory depression.

CYP3A4 inhibitor that increases sufentanil plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

Strong CYP3A Inhibitors 3 : Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).

Strong CYP3A Inhibitors : Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).

CYP3A4 inhibitor that increases tadalafil exposure, requiring dose adjustment: no more than 10 mg every 72 hours for as-needed use or 2.5 mg for once-daily use.

Avoid coadministration of strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) and strong CYP3A4 inducers (e.g., rifampin, phenytoin) with thiotepa due to the potential effects on efficacy and toxicity [see Clinical Pharmacology (12.2) ] . Avoid coadministration of strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) and strong CYP3A4 inducers (e.g., rifampin, phenytoin) with thiotepa due to the potential effects on efficacy and toxicity [see Clinical Pharmacology (12.2) ] .

Potent CYP3A4 inhibitor that may increase tolterodine systemic exposure. Dose reduction to 2 mg once daily recommended.

Strong CYP3A4 inhibitor that increases toremifene steady-state concentration and should be avoided.

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.

ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol[see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase[see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures, serotonin syndrome, and/or potentially fatal respiratory depression.

Ritonavir increases trazodone AUC 2.4-fold, half-life 2.2-fold, with adverse effects including nausea, hypotension, and syncope.

Strong CYP3A4 inhibitor causing increased triamcinolone plasma concentration and adverse reactions.

CYP3A4 inhibitor causing elevation of verapamil plasma levels, resulting in hypotension and bradyarrhythmias.

P-glycoprotein inhibitor that increases afatinib exposure. Reduce GILOTRIF dose by 10 mg per day if not tolerated.

ritonavir): Use with caution. Caution should be exercised when considering the co-administration of AIRSUPRA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.11) ] .

Strong CYP3A4 inhibitor may increase plasma concentrations of amlodipine to a greater extent. Monitor for symptoms of hypotension and edema.

• Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. Caution should be exercised when considering the coadministration of BREYNA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.9) ] .

7 DRUG INTERACTIONS Strong Cytochrome P450 3A4 Inhibitors (e.g., ritonavir): Use with caution. Caution should be exercised when considering the coadministration of budesonide inhalation suspension with long- term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions ( 5.12 ), Clinical Pharmacology ( 12.3 )].

CYP3A4 inhibitor increases buprenorphine plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

CYP3A4 inhibitor increases buprenorphine plasma concentration, resulting in increased or prolonged opioid effects.

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.

CYP3A4 inhibitor may alter serum levels of calcifediol by inhibiting vitamin D metabolism enzymes. Dose adjustment and monitoring of serum 25-hydroxyvitamin D, PTH, and calcium may be required.

UGT enzyme inducer decreases canagliflozin exposure which may reduce effectiveness of INVOKANA. Dosage adjustment may be required.

UGT enzyme inducer that decreases canagliflozin exposure and may reduce effectiveness. May require canagliflozin dose increase.

Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine Use With Caution No Dose Adjustment Atazanavir : Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] . Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] . Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) Use With Caution No Dose Adjustment Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3) ] .

CYP3A4 inhibitor may increase plasma concentrations of estrogens and may result in side effects.

HIV protease inhibitor that inhibits CYP3A4 and may increase cyclosporine concentrations. Care should be exercised; dosage monitoring required.

Potent CYP3A4 inhibitor; darifenacin daily dose should not exceed 7.5 mg when co-administered.

Antiarrhythmics: disopyramide, lidocaine, mexiletine ↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.

Elevates glucuronosyltransferase levels, increasing valproate clearance and potentially decreasing valproate concentrations.

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 inhibitors: Fosamprenavir/ritonavir a Tipranavir/ritonavir a ↓Dolutegravir Adjust dose of TIVICAY to twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients.

Caution should be exercised when concomitantly administering CARDURA XL with a strong CYP 3A4 inhibitor, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole [see Clinical Pharmacology (12.3) ] .

Monitor for potentially increased dronabinol-related adverse reactions when dronabinol capsules are co-administered with inhibitors of CYP2C9 (e.g., amiodarone, fluconazole) and inhibitors of CYP3A4 enzymes (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, erythromycin, grapefruit juice).

Elevates hepatic glucuronosyltransferase levels, increasing clearance of valproate. Monitoring of valproate concentrations recommended.

7 DRUG INTERACTIONS Use with caution in patients taking potent, chronic cytochrome P450 (CYP)3A4 enzyme inhibitors (e.g., ritonavir). Because of the potential for drug-drug interactions, use caution when prescribing dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) [see Clinical Pharmacology (12.3)] .

Because of the potential for drug-drug interactions, use caution when prescribing a dutasteride-containing product, including dutasteride and tamsulosin hydrochloride capsules, to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) [see Clinical Pharmacology ( 12.3 ) ] .

Additional ritonavir dosing may be required when coadministered with efavirenz and certain protease inhibitors.

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. Monitor patients receiving emtricitabine and tenofovir disoproxil fumarate concomitantly with HARVONI® (ledipasvir/sofosbuvir) without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination for adverse reactions associated with TDF.

CYP3A4 inhibitor that may increase plasma concentrations of estradiol and may result in side effects.

CYP3A4 inhibitor may increase estradiol acetate plasma concentration and result in side effects.

CYP3A4 inhibitor that may increase plasma concentrations of estrogens and may result in adverse reactions.

CYP3A4 inhibitor that may increase plasma concentrations of estrogens and result in adverse reactions.

CYP3A4 inhibitor may increase plasma concentrations of estrogen or progestin, resulting in adverse reactions.

CYP3A4 inhibitor that may increase estradiol plasma concentrations and result in adverse reactions.

CYP3A4 inhibitor that may increase estradiol plasma concentrations and result in adverse reactions.

CYP3A4 inhibitor that may increase plasma concentrations of estradiol valerate and result in side effects.

CYP3A4 inhibitor that may increase plasma concentrations of estrogens and result in side effects.

CYP3A4 inhibitor may increase plasma concentrations of estrogens and result in side effects.

HIV protease inhibitor that may decrease plasma concentrations of etonogestrel.

• Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. Caution should be exercised when considering the coadministration of budesonide and formoterol fumarate dihydrate with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.9) ] .

Drugs That Affect Phenytoin Concentrations Interacting Agent Examples Drugs that may increase phenytoin serum levels Antiepileptic drugs Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate Azoles Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole Antineoplastic agents Capecitabine, fluorouracil Antidepressants Fluoxetine, fluvoxamine, sertraline Gastric acid reducing agents H 2 antagonists (cimetidine), omeprazole Sulfonamides Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim Other Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin Drugs that may decrease phenytoin serum levels Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agents Fosamprenavir, nelfinavir, ritonavir Antiepileptic drugs Carbamazepine, vigabatrin Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. 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. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.

Kinase Inhibitors: fostamatinib (also see anticancer agents above ) ↑ fostamatinib metabolite R406 Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.

Combined CYP3A4 and CYP2D6 inhibitor that increases haloperidol plasma concentrations; monitor for increased adverse effects including QTc prolongation.

CYP3A4 and CYP2D6 inhibitor that increases haloperidol plasma concentrations, raising risk of adverse events including QTc prolongation.

CYP3A4 inhibitor may increase serum hydrocortisone concentrations and risk of adverse reactions; may require dose decrease.

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

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.

Cobicistat Elvitegravir (ritonavir-boosted) Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir (unboosted) a Monitor for adverse reactions. Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavira Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions. For, cobicistat, elvitegravir, indinavir, ombitasvir/paritaprevir/ ritonavir with or without dasabuvir, ritonavir, and saquinavir, see also Table 1.

Potent CYP3A4 inhibitor that may increase ketoconazole bioavailability. Should be used with caution and patients monitored for signs of increased pharmacologic effects.

7 DRUG INTERACTIONS • Atazanavir: Atazanavir should be coadministered with ritonavir when coadministered with CIMDUO. ( 7.2 ) • HIV-1 Protease Inhibitors: Monitor for evidence of tenofovir toxicity when CIMDUO is coadministrated with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. When coadministered with CIMDUO, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg.

Lopinavir/ritonavir decreases lamotrigine concentration approximately 50%.

HIV Antiretrovirals: Regimens containing tenofovir DF without an HIV protease inhibitor/ ritonavir or cobicistat ↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients receiving HARVONI concomitantly with a regimen containing tenofovir DF without an HIV protease inhibitor/ritonavir or cobicistat. 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. tipranavir/ritonavir ↓ ledipasvir ↓ sofosbuvir Coadministration of HARVONI with tipranavir/ritonavir is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI.

Ritonavir increased plasma AUC of cetirizine by ~42%, with increased half-life (53%) and decreased clearance (29%).

HIV protease inhibitor may significantly decrease plasma concentrations of estrogen and/or progestin.

β-Blockers: metoprolol, timolol ↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended.

Potent CYP2D6 inhibitor may increase metoprolol plasma concentration, decreasing cardioselectivity.

Potent CYP2D6 inhibitor may increase plasma concentration of metoprolol; caution should be exercised.

Strong CYP3A inhibitor may increase mirtazapine plasma concentration. May require dose decrease.

Caution should be exercised when considering the co-administration of mometasone furoate nasal spray with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Clinical Pharmacology (12.3) ] .

Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. Caution should be exercised when considering the coadministration of ASMANEX HFA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) ] .

Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. Caution should be exercised when considering the coadministration of DULERA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3) ] .

Caution should be exercised when considering the coadministration of mometasone furoate monohydrate nasal spray with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Clinical Pharmacology (12.3) ] .

Moderate (e.g., fluconazole, atazanavir, aprepitant, diltiazem, erythromycin) and Strong (e.g., itraconazole, ketoconazole, clarithromycin, ritonavir, saquinavir) CYP3A Inhibitors Clinical Impact Increase in plasma naldemedine concentrations [see Clinical Pharmacology (12.3) ] Intervention Monitor for potential naldemedine-related adverse reactions [see Adverse Reactions (6.1) ] .

HIV protease inhibitor that may decrease plasma concentrations of estrogen and/or progestin.

Significant decrease in systemic concentrations of norethindrone may occur.

HIV protease inhibitor may significantly decrease plasma concentrations of estrogen and/or progestin.

CYP3A4 inhibitor (protease inhibitor) that increases oliceridine plasma concentration and prolonged opioid adverse reactions. Caution advised with possible less frequent dosing needed.

CYP3A4 inhibitor may decrease clearance of oxycodone, leading to increased plasma concentrations and prolonged opioid effects.

Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4. Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.

Phenytoin Decreased paroxetine exposure Fosamprenavir/Ritonavir Decreased plasma concentration of paroxetine Cimetidine Increased plasma concentration of paroxetine Use caution if co-administering paroxetine capsules with other drugs that inhibit CYP2D6 (e.g., quinidine).

Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agents Fosamprenavir, nelfinavir, ritonavir Antiepileptic drugs Carbamazepine, vigabatrin Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. 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, lamotrigine, topiramate, oxcarbazepine, lacosamide 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. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.

Interacting Agent Examples Drugs that may increase phenytoin serum levels Antiepileptic drugs Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate Azoles Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole Antineoplastic agents Capecitabine, fluorouracil Antidepressants Fluoxetine, fluvoxamine, sertraline Gastric acid reducing agents H2 antagonists (cimetidine), omeprazole Sulfonamides Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole- trimethoprim Other Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin Drugs that may decrease phenytoin serum levels Antacids a Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agents Fosamprenavir, nelfinavir, ritonavir Antiepileptic drugs Carbamazepine, vigabatrin Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. 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 a Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide 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. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.

Anti-HIV Drugs that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Ritonavir and atazanavir are CYP3A4 substrates and posaconazole increased plasma concentrations of these drugs [see Clinical Pharmacology (12.3) ]. Prevention or Management Ritonavir and Atazanavir Monitor frequently for adverse reactions and toxicity of ritonavir and atazanavir during concomitant use.

Combined with darunavir, increases pravastatin exposure (↑81% AUC). Increased risk of myopathy.

Concomitant administration of a Moderate CYP 3A inducer, such as efavirenz, should be avoided unless the benefit outweighs the risks [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) .] 7.2 CYP450 Inhibitors Concomitant administration of drugs that decrease the activity of drug metabolizing liver enzymes (CYP450 inhibitors), for example, cimetidine, ketoconazole, itraconazole, erythromycin, and ritonavir may increase plasma concentrations of praziquantel.

induce barbiturates, phenytoin, carbamazepine, rifampin inhibit ketoconazole, itraconazole, ritonavir, indinavir, macrolide antibiotics such as erythromycin indinavir, erythromycin Ketoconazole Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.

CYP2D6 and CYP1A2 substrate/inhibitor that may increase blood levels and/or toxicity of propranolol.

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

When coadministered with tenofovir disoproxil fumarate, use atazanavir given with ritonavir. 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.

β-Blockers: metoprolol, timolol ↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended.

Potent CYP3A4 inhibitor that increases tolterodine systemic exposure. Dose reduction to 2 mg once daily recommended.

CYP3A4 inhibitor causing elevation of verapamil plasma levels. Patients should be monitored for drug interactions.

Ritonavir elevates glucuronosyltransferase levels and may increase the clearance of valproate.

May increase valproate clearance by elevating hepatic glucuronosyltransferase levels. Increased monitoring of valproate concentrations indicated.

Ritonavir is an inhibitor of hepatic efflux transporter MRP2, which may increase systemic exposure to valsartan.

Co-administration of ritonavir (efflux transporter inhibitor) may increase systemic exposure to valsartan.

Co-administration with micafungin did not alter micafungin pharmacokinetics.

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.

Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

7 DRUG INTERACTIONS When co-administering ritonavir with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions. Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Ritonavir or Concomitant Drug Clinical Comment HIV-Antiviral Agents HIV-1 Protease Inhibitor: atazanavir darunavir fosamprenavir ↑ amprenavir ↑ atazanavir ↑ darunavir See the complete prescribing information for fosamprenavir, atazanavir, darunavir for details on co-administration with ritonavir.

Use of atazanavir without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When atazanavir with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 ( 12.3 )]. The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when atazanavir is coadministered with ritonavir.

Intervention: • Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with ATORVALIQ is not recommended. • In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with ATORVALIQ. • In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed ATORVALIQ 20 mg.

Other Inhibitors and Inducers of CYP3A4 Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism.

Other inhibitors and inducers of CYP3A4: Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism.

Rilpivirine Based on drug interaction study results, the following drugs can be coadministered with rilpivirine (non-antiretrovirals and cabotegravir) or given after discontinuation of rilpivirine (antiretrovirals and non-antiretrovirals): acetaminophen, atorvastatin, cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, sildenafil, tenofovir alafenamide, and tenofovir disoproxil fumarate [see Clinical Pharmacology ( 12.3 )] .

Anticonvulsants: carbamazepine, clonazepam, ethosuximide ↑ anticonvulsants A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

Use of TYBOST with lopinavir is not recommended because lopinavir is co-formulated with ritonavir. In addition to the drug interactions noted in Table 7 , TYBOST is not recommended for use in combination with fixed-dose combination tablets that contain cobicistat, lopinavir/ritonavir or regimens containing ritonavir, or in combination with more than one antiretroviral agent that requires pharmacokinetic enhancement [see Warnings and Precautions (5.4) ]. Switching from ritonavir to TYBOST coadministered with atazanavir or darunavir: Maintain bosentan dose.

Drug Interactions: Pharmacokinetic Parameters for Colchicine Tablets in the Presence of the Coadministered Drug Coadministered Drug Dose of Coadministered Drug (mg) Dose of Colchicine Tablets (mg) N % Change in Colchicine Concentrations from Baseline (Range: Min – Max) C max AUC 0-t Cyclosporine 100 mg single dose 0.6 mg single dose 23 270.0 (62.0 to 606.9) 259.0 (75.8 to 511.9) Clarithromycin 250 mg twice daily, 7 days 0.6 mg single dose 23 227.2 (65.7 to 591.1) 281.5 (88.7 to 851.6) Ketoconazole 200 mg twice daily, 5 days 0.6 mg single dose 24 101.7 (19.6 to 219.0) 212.2 (76.7 to 419.6) Ritonavir 100 mg twice daily, 5 days 0.6 mg single dose 18 184.4 (79.2 to 447.4) 296.0 (53.8 to 924.4) Verapamil 240 mg daily, 5 days 0.6 mg single dose 24 40.1 (-47.1 to 149.5) 103.3 (-9.8 to 217.2) Diltiazem 240 mg daily, 7 days 0.6 mg single dose 20 44.2 (-46.0 to 318.3) 93.4 (-30.2 to 338.6) Azithromycin 500 mg x 1 day, then 250 mg x 4 days 0.6 mg single dose 21 21.6 (-41.7 to 222.0) 57.1 (-24.3 to 241.1) Grapefruit juice 240 mL twice daily, 4 days 0.6 mg single dose 21 -2.55 (-53.4 to 55.0) -2.36 (-46.4 to 62.2) Estrogen-containing oral contraceptives: In healthy female volunteers given ethinyl estradiol and norethindrone (Ortho-Novum ® 1/35) coadministered with colchicine tablets (0.6 mg twice daily × 14 days), hormone concentrations are not affected.

7 DRUG INTERACTIONS Co-administration of darunavir/ritonavir with other drugs can alter the concentrations of other drugs and other drugs may alter the concentrations of darunavir. ( 4 , 5.5 , 7 , 12.3 ) 7.1 Potential for Darunavir/ritonavir to Affect Other Drugs Darunavir co-administered with ritonavir is an inhibitor of CYP3A, CYP2D6, and P-gp. Co-administration of darunavir and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 or are transported by P-gp may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events.

Switching from darunavir co-administered with ritonavir to PREZCOBIX in patients on bosentan : Maintain bosentan dose. Patients switching from darunavir co-administered with ritonavir to PREZCOBIX : Maintain tadalafil dose.

Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs. Switching from darunavir co-administered with ritonavir to SYMTUZA in patients on bosentan: Maintain bosentan dose. Patients switching from darunavir co-administered with ritonavir to SYMTUZA: Maintain tadalafil dose.

The concomitant use of deferasirox with strong UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in deferasirox efficacy due to a possible decrease in deferasirox concentration.

Co-administration with other drugs which strongly inhibit CYP 3A4 (e.g., itraconazole, clarithromycin, ritonavir, cobicistat-containing products) may lead to increased plasma concentrations of corticosteroids and potentially increase the risk for systemic corticosteroid side effects.

Co-administration with other drugs which strongly inhibit CYP 3A4 (e.g., itraconazole, clarithromycin, ritonavir, cobicistat-containing products) may lead to increased plasma concentrations of corticosteroids and potentially increase the risk for systemic corticosteroid side effects.

Ritonavir-containing products : See prescribing information.

Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.

No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, and methadone [see Clinical Pharmacology (12.3) ].

No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, or methadone [see Clinical Pharmacology (12.3) ] .

7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Yaz with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.5 )] .

7.3 Concomitant Use of HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Tydemy with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.5 )] .

7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Beyaz with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.5 )] .

( 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. Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with either atazanavir or atazanavir and ritonavir is not recommended. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with efavirenz, emtricitabine and tenofovir disoproxil fumarate.

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).

Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration ↓=Decrease Clinical Comment ↑= Increase Antiretroviral Agents: Protease Inhibitors (PI) tipranavir/ritonavir ↓ TAF Coadministration with DESCOVY is not recommended. 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.

7.17 Ritonavir Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram. However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram.

7.17 Ritonavir Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram. However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram.

Increased concentrations of saquinavir For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in Cmax by 75%, and in Cmin by 106%, following multiple dosing of saquinavir/ritonavir (1,000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15.

Ritonavir-containing products: see prescribing information for specific drugs Voriconazole Clinical Impact: Increased exposure of esomeprazole [see Clinical Pharmacology (12.3) ].

Ritonavir-containing products: see prescribing information for specific drugs Voriconazole Clinical Impact: Increased exposure of esomeprazole [see Clinical Pharmacology ( 12.3 )].

Ritonavir-containing products : see prescribing information for specific drugs Voriconazole Clinical Impact: Increased exposure of esomeprazole [see Clinical Pharmacology (12.3) ].

Increased concentrations of saquinavir For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in C max by 75%, and in C min by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily coadministered days 11 to 15.

Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.

Anticonvulsants: carbamazepine, clonazepam, ethosuximide ↑ anticonvulsants A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Kelnor with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see WARNINGS, Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment ).

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]). 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer etonogestrel and ethinyl estradiol vaginal ring with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations.

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]). 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer etonogestrel and ethinyl estradiol vaginal ring with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations.

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.

Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.

7.5 Drugs without Clinically Significant Interactions with RUKOBIA Based on drug interaction study results, the following drugs can be coadministered with RUKOBIA without a dose adjustment: atazanavir/ritonavir, buprenorphine/naloxone, cobicistat, darunavir/cobicistat, darunavir/ritonavir with and without etravirine, etravirine, famotidine, maraviroc, methadone, norethindrone, raltegravir, ritonavir, rifabutin with and without ritonavir, tenofovir disoproxil fumarate [see Clinical Pharmacology ( 12.3 )] .

Hepatitis C direct acting antiviral: glecaprevir/pibrentasvir simeprevir ↑ glecaprevir ↑ pibrentasvir ↑ simeprevir It is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir, or simeprevir.

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

Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%. Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%. (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%. Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.

Ritonavir-containing products : See prescribing information.

Ritonavir-containing products : See prescribing information. Ritonavir Etravirine Ritonavir, Etravirine : (see Ritonavir and Etravirine under "Drugs That Affect Clarithromycin Tablets" in the table below). Ritonavir (in patients with decreased renal function) Ritonavir : Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium .

atazanavir/ritonavir ↑ lenacapavir (atazanavir/cobicistat, atazanavir/ritonavir) Concomitant administration of efavirenz, nevirapine, or tipranavir/ritonavir may result in loss of therapeutic effect and development of resistance. efavirenz nevirapine tipranavir/ritonavir ↓ lenacapavir (efavirenz, nevirapine, tipranavir/ritonavir) Concomitant administration with atazanavir/cobicistat, atazanavir/ritonavir, efavirenz, nevirapine, or tipranavir/ritonavir is not recommended.

Examples Antivirals (e.g., ritonavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, saquinavir) Glucocorticoid and progesterone receptor antagonists (e.g., mifepristone) Strong CYP3A4 Inducers Clinical Impact May decrease plasma concentrations of levoketoconazole and reduce the efficacy of RECORLEV Prevention or Management Administration of strong enzyme inducers of CYP3A4 with RECORLEV is not recommended.

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.

7 DRUG INTERACTIONS • Coadministration with CYP3A inhibitors, including protease inhibitors (except tipranavir/ritonavir), will increase the concentration of maraviroc.

Co-administration of other strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin, cobicistat-containing products) with triamcinolone acetonide injectable suspension may cause increased plasma concentration of triamcinolone leading to adverse reactions (see ADVERSE REACTIONS ). During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving triamcinolone acetonide and strong CYP3A4 inhibitors (e.g., ritonavir) (see WARNINGS, Endocrine and PRECAUTIONS, Endocrine ).

Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone ↑ glucocorticoids Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

Antialcoholics: disulfiram/ metronidazole Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

CYP2C19 and CYP3A4 Inducer Co-administration of micafungin with rifampin and ritonavir did not alter the pharmacokinetics of micafungin.

Ritonavir ↑ nelfinavir ↔ ritonavir Concentrations of nelfinavir were increased when coadministered with ritonavir. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir.

( 4 , 5.1 , 7 , 12.3 ) 7.1 Potential for PAXLOVID to Affect Other Drugs PAXLOVID (nirmatrelvir co-packaged with ritonavir) is a strong inhibitor of CYP3A, and an inhibitor of CYP2D6, P-gp and OATP1B1. 7.2 Potential for Other Drugs to Affect PAXLOVID Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce PAXLOVID therapeutic effect [see Contraindications (4) and Drug Interactions (7.3) Table 2 ] . The healthcare provider should consult other appropriate resources such as the prescribing information for the interacting drug for comprehensive information on dosing or monitoring with concomitant use of a strong CYP3A inhibitor such as ritonavir.

7 DRUG INTERACTIONS When co-administering NORVIR with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions. Co-administration of NORVIR can alter the concentrations of other drugs. The potential for drug-drug interactions must be considered prior to and during therapy ( 4 , 5.1 , 7 , 12.3 ) 7.1 Potential for NORVIR to Affect Other Drugs Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A.

Ritonavir-containing products: see prescribing information for specific drugs.

Ritonavir-containing products: See prescribing information for specific drugs.

Ritonavir-containing products : see prescribing information for specific drugs.

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.

Fosamprenavir/Ritonavir Clinical Impact Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine.

Fosamprenavir/Ritonavir Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine.

Hepatitis C direct acting antiviral: glecaprevir/pibrentasvir simeprevir ↑ glecaprevir ↑ pibrentasvir ↑ simeprevir It is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir, or simeprevir.

Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see Clinical Pharmacology ( 12.3 )] . Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.

Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone ↑ glucocorticoids Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.

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.

Integrase Inhibitor: raltegravir ↓ raltegravir The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.

HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with coadministration of low-dose ritonavir) or Unboosted (i.e., without coadministration of low-dose ritonavir) darunavir/ritonavir *† ↑ rilpivirine ↔ boosted darunavir Concomitant use of rilpivirine tablets with darunavir/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 darunavir/ritonavir. 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).

HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with coadministration of low-dose ritonavir) or Unboosted (i.e., without coadministration of low-dose ritonavir) darunavir/ritonavir ↑ rilpivirine ↔ boosted darunavir Concomitant use of EDURANT or EDURANT PED with darunavir/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 darunavir/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).

7 DRUG INTERACTIONS When co-administering ritonavir with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions. Co-administration of ritonavir can alter the concentrations of other drugs. ( 4 , 5.1 , 7 , 12.3 ) 7.1 Potential for Ritonavir to Affect Other Drugs Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A.

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). In contrast, significant increases in systemic exposure of estrogen and/or progestin have been noted when CHCs are co-administered with certain other HIV protease inhibitors (eg, indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (eg, etravirine). 7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer ANNOVERA with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Contraindications (4) and Warnings and Precautions (5.3) ] .

Hepatitis C direct acting antiviral: glecaprevir/pibrentasvir simeprevir ↑ glecaprevir ↑ pibrentasvir ↑ simeprevir It is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir, or simeprevir.

HIV Protease Inhibitors: tipranavir/ritonavir ↓ sofosbuvir ↓ GS-331007 Coadministration of SOVALDI with tipranavir/ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. 7.2 Drugs without Clinically Significant Interactions with SOVALDI Based on drug interaction studies conducted with SOVALDI, no clinically significant drug interactions have been either observed or are expected when SOVALDI is combined with the following drugs [see Clinical Pharmacology (12.3) ]: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, oral contraceptives, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

tipranavir/ritonavir ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended. 7.4 Drugs without Clinically Significant Interactions with VOSEVI Based on drug interaction studies conducted with the components of VOSEVI (sofosbuvir, velpatasvir, and/or voxilaprevir) or VOSEVI, no clinically significant drug interactions have been observed with the following drugs [see Clinical Pharmacology (12.3) ]: VOSEVI: cobicistat, darunavir, elvitegravir, emtricitabine, ethinyl estradiol/norgestimate, gemfibrozil, rilpivirine, ritonavir, tenofovir alafenamide, voriconazole Sofosbuvir/velpatasvir: dolutegravir, ketoconazole, raltegravir Sofosbuvir: methadone, tacrolimus

However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent.

ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.7)] .

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.

Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone ↑ glucocorticoids Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

[See Dosage and Administration (2.4) and Warnings and Precautions (5.2) .] Ritonavir (600 mg b.i.d.) co-administered with vardenafil hydrochloride tablets 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13­ fold increase in vardenafil C max . The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly strong CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours.

tipranavir/ritonavir ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended. 7.4 Drugs without Clinically Significant Interactions with EPCLUSA Based on drug interaction studies conducted with the components of EPCLUSA (sofosbuvir or velpatasvir) or EPCLUSA, no clinically significant drug interactions have been observed or are expected with the following drugs [see Clinical Pharmacology (12.3) ]: EPCLUSA: atazanavir/ritonavir, buprenorphine/naloxone, cyclosporine, darunavir/ritonavir, dolutegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, methadone, naltrexone, raltegravir, or rilpivirine.

See saquinavir prescribing information for instructions when saquinavir (with or without ritonavir) is co-administered with clarithromycin. Ritonavir (CYP3A inhibitor) Use of VOQUEZNA TRIPLE PAK with ritonavir is not recommended in patients with decreased renal function. See saquinavir prescribing information for instructions when saquinavir (with or without ritonavir) is co-administered with clarithromycin.

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 .