Education grant to fund the project

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1 Education grant to fund the project

2 Author Rachel Therrien, Pharmacist at CHUM s (Centre hospitalier de l Université de Montréal) UHRESS (Unité hospitalière de recherche, d enseignement et de soins sur le sida). Acknowledgements My sincere thanks to everyone who contributed to writing and revising this document: Nathalie Gaudet, Pharmacist at the Centre de santé et de services sociaux du Nord de Lanaudière (CSSSNL); Léa Prince-Duthel, Pharmacist; Jean-Rémi Hoegy, pharmacy intern (France); Geneviève Duplain Cyr, Pharmacist at the CHUS (Centre hospitalier universitaire de Sherbrooke) SAMI (soins ambulatoires en maladies infectieuses) Clinic; Nathacha Beaulieu, Pharmacist (BCC section) and Marie-Claude Berthiaume (antiretroviral metabolism section). Release of liability While the author endeavours to keep up to date on the latest information, she would like to point out that developments in HIV treatment are constantly evolving. This document was designed as a reference only, and the author encourages readers to consult as many health professionals as necessary. Using the information contained in this document shall be at the reader s own risk. The author does not recommend or promote any of the treatments described in this work. Accordingly, she shall not be held liable for any damages, costs and consequences that may result from using this information, or for any errors that may appear in the text. Any decision on specific treatments should be made in consultation with a healthcare professional with the relevant experience. Copyright It is prohibited to reproduce, adapt or translate this work, in whole or in part, without the prior written consent of the copyright holders. January 2012 Website:

3 Foreword Antiretrovirals are known to often be responsible for drug interactions due to their pharmacokinetic properties and their ability to modify the absorption, metabolism and elimination of other drugs. This booklet explores the interactions between antiretrovirals and the various drugs used in cardiology. It was prepared in the aim of reviewing existing literature, initiating reflection and making recommendations based on available information. The document will serve as a basic tool to facilitate discussion among professionals in order to ensure the safest possible management of these drug interactions. We hope, therefore, to avoid the appearance of serious adverse effects, ensure optimal and effective treatment, and prevent treatment non-compliance that is, patients not taking the medications required to treat their HIV or heart disease. Antiretroviral therapy usually involves a combination of at least two classes of antiretrovirals. This document includes information on drug interactions with NNRTIs (non-nucleoside reverse transcriptase inhibitors), PIs (protease inhibitors), maraviroc and raltegravir. Legend The arrows indicate variation in the AUC (potential or observed ) of the associated drug (blue arrows) or antiretroviral (orange arrows). : No interaction is anticipated. : No interaction was observed. Potential increase in the plasma concentration of the associated drug or antiretroviral. A reduction in the dose may be necessary. Monitor the appearance of adverse effects. Observed increase in the plasma concentration of the associated drug or antiretroviral. A reduction in the dose may be necessary. Monitor the appearance of adverse effects. Potential decrease in the plasma concentration of the associated drug or antiretroviral. An increase in the dose may be necessary. Monitor clinical efficacy. Observed decrease in the plasma concentration of the associated drug or antiretroviral. An increase in the dose may be necessary. Monitor clinical efficacy. The background colour indicates the degree of interaction Green: No interaction or the interaction deemed not clinically significant. Yellow: Combination that requires close monitoring. Dose adjustments may be recommended. Orange: Avoid combination. If this is not possible, ensure close monitoring. Red: Combination contraindicated. Chose an alternative to using the associated drug or antiretroviral. Cardiology and HIV 3

4 Glossary Elimination half-life (T½): Time required for the plasma concentration of the drug to decrease by 50% Area under curve (AUC): Total drug exposure during the dosing interval; calculated by integrating repeated measures of the concentration over time following the drug s administration Maximum concentration (Cmax): The maximum or peak concentration in the dosing interval; generally occurs during the absorption phase Minimum concentration (Cmin): The minimum or trough concentration in the dosing interval CYP: Cytochrome NNRTI: Non-nucleoside reverse transcriptase inhibitor PI: Viral protease inhibitor UGT: Uridine diphosphate glucuronosyltransferase INR: International normalized ratio 4 Antiretrovirals and drug interactions

5 Table of contents Metabolism of antiretrovirals... 7 Anticoagulants Antiplatelets Angiotensin II type 1 receptor blockers (ARBs) Antiarrhythmics Beta blockers Calcium channel blockers (CCBs) Angiotensin converting enzyme inhibitors (ACEIs) Hypolipidemics (statins) Hypolipidemics (other) References... 81

6 6 Antiretrovirals and drug interactions

7 Metabolism of non-nucleoside reverse transcriptase inhibitors Substrates Phase I: CYP Phase II: UGT s/inducers Phase I: CYP Phase II: UGT Excretion Transporters Transporters Efavirenz (Sustiva, Atripla) 3A4 and 2B6 (major) Inactive hydroxylated metabolites P-gp (weak) 2C9, 2C19 and 3A4 (moderate) BCRP, MRP1, MRP2, MRP3 (weak) Urine: 14-34% as metabolites Feces: 16-61%, as unchanged drug Inducer 3A4 (strong) CYP2B6 and UGT (weak) T½: Single dose: hours Multiple doses: hours (induces its own metabolism) Etravirine (Intelence) 3A4, 2C9 and 2C19 (major) Main metabolites ~ 10% of etravirine activity against HIV P-gp 2C9 and 2C9 (moderate) P-gp (weak) Inducer 3A4 (strong) Urine: 1% Feces: 94%, up to 86% as unchanged drug T½: 41 hours (± 20 hours) Nevirapine (Viramune) 3A4 (major) 2B6 and 2D6 (minor) Inactive hydroxylated metabolites at 2B6 and 3A4 Inducer : 3A4 (strong) and 2B6 (potentially) 1A2, 2D6 and 3A4 (weak) BCRP, MRP1, MRP2 and MRP3 (weak) Urine: 81%, mainly as metabolites, and less than 3% as unchanged drug Feces: 10% T½: Single dose: 45 hours Multiple doses: hours (induces its own metabolism) Rilpivirine (Edurant, Complera) 3A4 (major) 2C19 (negligible) Inducer : 3A4 (weak) Urine: 6.1%, less than 1% as unchanged drug P-gp (negligible) Feces: 85%, with 25% as unchanged drug T½: hours Cardiology and HIV 7

8 Metabolism of viral protease inhibitors Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Atazanavir (Reyataz) 3A4 (major) Inactive metabolites BCRP, MRP1, MRP2 and P-gp 3A4 ((strong) 2C8 * (moderate) UGT1A1 (moderate) BCRP, MRP1, MRP2, OATP1B1, OATP1B3, OATP2B1, P-gp *Exercise caution if atazanavir without ritonavir is coadministered with other drugs whose metabolism strongly depends on CYP2C8 and have a narrow therapeutic index (e.g. paclitaxel, repaglinide). However, no clinically significant interaction is anticipated during coadministration of the atazanavir/ritonavir combination and CYP2C8 substrates Urine: 13%, with 7% of the total dose as unchanged drug Feces: 79%, with 20% of the total dose as unchanged drug T½: 7-8 hours without ritonavir, 9-18 hours with ritonavir Inducer Increases expression of P-gp and MRP1 Darunavir (Prezista) 3A4 (major) OATP1A2, OATP1B1 and P-gp 3A4 (strong), 2D6 (ritonavir effect) BCRP, MRP1, OATP 1B1, OATP 1B3, P-gp Urine: 14%, with 8% as unchanged drug Feces: 80%, with 41% as unchanged drug Inducer 2C9, 2C19 and 2C8 (ritonavir effect) T½: 15 hours (combined with ritonavir) Fosamprenavir (Telzir) Rapidly and almost completely converted to amprenavir by cellular phosphatases in the intestinal epithelium 3A4 (major) P-gp 3A4 (strong) BCRP, MRP1, OATP 1B1, OATP 1B3 and P-gp Inducer 3A4 (possible, net effect with ritonavir would be inhibition) Urine: 14% as metabolites, with about 1% as unchanged drug Feces: 75%, mainly as metabolites, less than 1% as unchanged drug T½: hours (with ritonavir) 8 Antiretrovirals and drug interactions

9 Metabolism of viral protease inhibitors Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Lopinavir/r (Kaletra) (see also ritonavir below) CYP3A4 (major) 13 metabolites identified, including 5 metabolites linked to the metabolism of ritonavir MRP1, MRP2, P-gp, OATP1A2, OATP1B1 3A4 and 2D6 (strong) BCRP, MPR2, OATP1A2, OATP1B1, OATP1B3, OATP2B1 and P-gp* Inducer 2C19 (strong) 1A2, 2C9 et UGT (moderate) Urine: 10%, with less than 3% as unchanged drug Feces: 83%, with 20% as unchanged drug T½: 5-6 hours P-gp* (moderate) * In vitro data suggest that lopinavir and ritonavir are P-gp inducers, whereas in vivo data show that the net effect of ritonavir is inhibition of P-gp and that the net effect of lopinavir is induction of P-gp during prolonged treatment. Nelfinavir (Viracept) 3A4 (major) 2C19 (major): Active metabolite M8 (activity comparable to nelfinavir) 2C9 and 2D6 (minor) 3A4 (strong) BCRP, MRP1,OATP1A2, OATP1B1, OATP2B1,OCT1, OCT2, P-gp Urine: 1-2% Feces: 98-99%, with 78% as metabolites and 22% as unchanged drug P-gp, MRP1, MRP2 Inducer 2C8, 2C9, 2B6, 2C19, 1A2 (potential) Increases expression of P-gp T½: hours Ritonavir (Norvir) 3A4 and 2D6 (major) 1A2 and 2B6 (minor) 3A4 and 2D6 (strong) Urine: 11%, with 4% as unchanged drug 5 metabolites, including a weak concentration of an active metabolite (M-2) P-gp, MRP1, MRP2 BCRP, OATP1A2, OATP1B, OATP1B3, MRP1, MRP2, OCT1, OCT2 and P-gp Inducer 2B6, 2C8, 2C9, 1A2, 2C19 (moderate) Feces: 86%, with 34% as unchanged drug T½:3-5 hours UGT (moderate) Cardiology and HIV 9

10 Metabolism of viral protease inhibitors Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Saquinavir (Invirase) 3A4 (major), significant first-pass effect in the liver Quickly metabolized into a range of mono- and inactive bi-hydroxylated components 3A4 (moderate) BCRP, MRP1, MRP2, OATP1A2, OATP1B1, OATP1B3, OATP2B1, OCT1, OCT2, P-gp Urine: 1-3% Feces: 81-88% T½: 7-12 hours (with ritonavir) MRP1, MRP2, OTP1A2, OATP1B1, OATP1B3, P-gp Tipranavir (Aptivus) 3A4 (major) P-gp 3A4 and 2D6 (strong) P-gp Urines: 4%, mainly as unchanged drug Feces: 82% Inducer 3A4 (strong) 2C19 and 1A2 (weak) T½: 6 hours with ritonavir P-gp (strong) There may be both an inhibition and induction effect with the tipranavir / ritonavir combination. The net effect is often inhibition, but this depends on the substrate. 10 Antiretrovirals and drug interactions

11 Metabolism of the integrase inhibitor Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Raltegravir (Isentress) UGT1A1 Urine: 32%, with 9% as unchanged drug Feces: 51% as unchanged drug T½: Biphasic Phase 1: 1 hour Phase 2: 9 hours Metabolism of the ccr5 inhibitor Substrates Phase I: CYP Phase II: UGT s/inducers Phase I: CYP Phase II: UGT Excretion Transporters Transporters Maraviroc (Celsentri) 3A4 (major) Inactive metabolites P-gp P-gp According to the product monograph, maraviroc could influence the bioavailability of some drugs transported by P-gp in the intestines. Clinical effect unknown to date. Urine: 20%, with 8% as unchanged drug In the presence of a CYP3A4 inhibitor, renal clearance of maraviroc could increase to 70% Feces: 76%, with 25% as unchanged drug T½: hours Cardiology and HIV 11

12 Metabolism of anticoagulants Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Acenocoumarol (Sintrom) Acenocoumarol is transformed by CYPs into two enantiomers, which produce an anticoagulant effect that is comparable to, or greater than, the effect of the R-enantiomer. S-enantiomer ( ): Metabolized by 2C9 Urine: 60% as metabolites Feces: 29%f as metabolites T½: 8-11 hours R-enantiomer (+): Metabolized by 1A2, 2C19 and 3A4 Apixaban (Eliquis) 3A4/5 (major) 1A2 and 2J2 (minor) 2C8, 2C9 and 2C19 (very minor) SULT 1A1: O-demethyltransferase sulfate (inactive metabolite) P-gp and BCRP According to preclinical studies, the potential for CYP450 inhibition is minimal Urine: 25-28%, with 22-24% as unchanged drug Feces: 56%, mainly as metabolites T½: 8-13 hours 25-30% of the dose is found as inactive metabolites The main metabolite is O-demethyl apixaban sulfate (inactive metabolite) Dabigatran etexilate (Pradax) Prodrug Low bioavailability due to its low solubility at phs greater than 3 and to the action of P-gp in enterocytes Metabolized in the liver to dabigatran, with hydrolysis catalyzed by an esterase Urine: 85% of the total dose Feces: 6%, mainly as unchanged drug T½: hours UGT: Conjugated into active acylglucuronides with 4 isomers, each representing less than 10% of the total quantity of dabigatran P-gp 12 Antiretrovirals and drug interactions

13 Metabolism of anticoagulants Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Rivaroxaban (Xarelto) 3A4 (major) 2J2 (minor) P-gp Urine: 33% as unchanged drug and 33% as inactive metabolites Feces: 33% as inactive metabolites T½: 5-13 hours Warfarine (Coumadin) Racemic mixture of R- and S-enantiomers S-enantiomer exhibits 2-5 times more anticoagulant activity than R-enantiomer 2C9 (moderate) 2C19 (weak) Urine: 92%, mainly as metabolites T½: hours 2C9 (major) 2C19, 2C8, 2C18, 1A2 and 3A4 (minor) CYP2C9: Primary pathway of S-warfarin metabolism. Slow metabolizers of CYP2C9 would require a lower dose of warfarin. Cardiology and HIV 13

14 Anticoagulants and Nnrtis Acenocoumarol (Sintrom) Apixaban (Eliquis) Dabigatran (Pradax) Rivaroxaban (Xarelto) Warfarine (Coumadin) Efavirenz (Sustiva, Atripla) Etravirine (Intelence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) Legend 1. Possible of the S-enantiomer of acenocoumarol due to CYP2C9 inhibition by efavirenz and etravirine. However, efavirenz and etravirine are CYP3A4 inducers and could the R-enantiomer of acenocoumarol. Actual clinical effect unknown. Recently a case involving the efavirenz/acenocoumarol combination was published. It showed that the dose of acenocoumarol had to be increased to maintain a therapeutic INR. Recommendation: Monitor INR. Monitor for signs and symptoms of efficacy and appearance of adverse effects associated with acenocoumarol (A). Adjust the dose as needed. 2. Although nevirapine and rilpivirine are weak CYP3A4 inducers, no significant clinical effect is expected due to other main metabolic pathways for acenocoumarol. Recommendation: Monitor the clinical efficacy (INR) and safety of acenocoumarol. 3. Possible in apixaban due to possible CYP3A4 induction. However, since apixaban has several metabolic pathways, it is not expected that NNRTIs would have a clinically significant effect on apixaban. One pharmacokinetic study with rifampicin, a potent CYP3A4 inducer, showed a 50% decrease of apixaban (deemed not significant by the author). Recommendation: No change in the dose is recommended since no clinically significant interaction is expected. Monitor clinical efficacy. 14 Antiretrovirals and drug interactions

15 Legend 4. Based on currently available information, no interaction is expected. 5. No clinically significant interaction expecteddue to the potentially weak inhibition effect of P-gp with etravirine. 6. Possible in plasma concentration of rivaroxaban due to CYP3A4 induction by efavirenz, etravirine and nevirapine. The induction effect of rilpivirine is probably not sufficient to cause a clinically significant interaction. Recommendation: Monitor the clinical efficacy of rivaroxaban. 7. INR observed (case report) with the combination of efavirenz and warfarin. After 22 days of efavirenz plus warfarin 5 mg, the patient was hospitalized for hematuria and an INR of 7. The dose of warfarin was decreased and a final dose of 1.25 mg was sufficient to obtain the desired INR. Efavirenz is an inhibitor of CYP2C9 and an inducer of CYP3A4. The net clinical effect is difficult to predict. In this case report, there is most likely an in the S-enantiomer of warfarin due to the inhibition of CYP2C9. Recommendation: Monitor INR. Monitor for signs and symptoms of efficacy and appearance of adverse effects associated with warfarin (B). Adjust the dose as needed. 8. Possible in INR with the combination of etravirine and warfarin, as observed with efavirenz, due to the potential inhibition of CYP2C9. See #7. Recommendation: Monitor INR. Monitor for signs and symptoms of efficacy and the appearance of adverse effects associated with warfarin (B). Adjust the dose as needed. 9. INR observed (case report) with the combination of nevirapine and warfarin. Nevirapine is a CYP3A4 inducer and could potentially increase the metabolism of warfarin and decrease its efficacy. Recommendation: The product monograph recommends monitoring the efficacy and safety of warfarin (B). Adjust dose if necessary. 10. No interaction is expected due to the weak induction effect of rilpivirine on CYP3A4. INR: International normalized ratio A. Adverse effects of acenocoumarol: Bleeding, hemorrhage, nausea, anemia B. Adverse effects of warfarin: Bleeding, hemorrhage, nausea, anemia, headache, skin necrosis Cardiology and HIV 15

16 Anticoagulants and PIs Acenocoumarol (Sintrom) Apixaban (Eliquis) Dabigatran (Pradax) Rivaroxaban (Xarelto) Warfarine (Coumadin) Atazanavir (Reyataz) Atazanavir/r (Reyataz) 1, Darunavir/r (Prezista) 1, Fosamprenavir/r (Telzir) 1, Lopinavir/r (Kaletra) 1, ,11 Nelfinavir (Viracept) 1, ,11 Saquinavir/r (Invirase) 1, Tipranavir/r (Aptivus) 1,2* 4* 6* 8* 10* R : Ritonavir (Norvir) 16 Antiretrovirals and drug interactions

17 Legend 1. Suspected in R-enantiomer due to CYP3A4 inhibition. Clinical effect unknown. Recommendation: Monitor INR. Monitor for signs and symptoms of efficacy and appearance of adverse effects associated with acenocoumarol (A). Adjust the dose as needed. 2. Suspected in R- and S-enantiomers of the active metabolite of acenocoumarol due to the potential induction of CYP2C9 and/or 1A2 with nelfinavir or the protease inhibitors associated with ritonavir. Recently, a case concerning the combination of atazanavir/ritonavir and acenocoumarol was published. It showed that the dose of acenocoumarol had to be increased to maintain a therapeutic INR. The patient was subsequently treated with raltegravir to stop the interaction. A case showing a significant decrease in the effect of acenocoumarol following the administration of a high dose (600 mg BID) of ritonavir had previously been reported. Recommendation: Monitor INR. Monitor for signs and symptoms of efficacy and appearance of adverse effects associated with acenocoumarol (A). Adjust the dose as needed. 3. Possible in apixaban due to possible CYP3A4 inhibition. However, since apixaban has several metabolic pathways, PIs are not expected to have a clinically significant effect on apixaban. One pharmacokinetic study with the potent CYP3A4 inhibitor ketoconazole showed a 100% (twofold) increase in apixaban, deemed not significant by the author. Recommendation: No change in the dose is recommended since no clinically significant interaction is expected. Monitor clinical efficacy and appearance of adverse effects associated with apixaban. 4. Possible or in apixaban due to the possible induction or inhibition of P-gp or CYP3A4. The net effect is difficult to predict. However, since apixaban has several metabolic pathways, PIs are not expected to have a clinically significant impact on apixaban. A pharmacokinetic study with rifampicin, a potent inducer of CYP3A4 and P-gp showed a 50% reduction in apixaban (deemed not significant by the author). A study with ketoconazole, a potent inhibitor of CYP3A4, showed a 100% (twofold) increase of apixaban (deemed not significant by the author). Recommendation: No change in the dose is recommended since no clinically significant interaction is expected. Monitor clinical efficacy and the appearance of adverse effects associated with apixaban. 5. Suspected in dabigatran due to the potential P-gp inhibition by protease inhibitors. The dabigatran monograph states that potent P-gp inhibitors could increase plasma concentrations of the latter. In fact, with amiodarone, ketoconazole, quinidine and verapamil, increases of % in dabigatran AUC were observed. A study with immediate-release verapamil demonstrated an of approximately 150% in the dabigatran AUC. When dabigatran is administered 2 hours before verapamil, an of only 20% is observed in the dabigatran AUC. It is hypothesized that dabigatran had sufficient time to be absorbed at 2 hours following administration. Recommendation: This combination is to be avoided since it has not yet been studied. Choose an alternative to using dabigatran or the protease inhibitor. If this combination cannot be avoided, follow the recommendations in the product monograph for verapamil - namely, a potent P-gp inhibitor. Cardiology and HIV 17

18 Legend A. Prevention of venous thromboembolism (VTE) in patients who have had a total hip or knee replacement: decrease the dose of dabigatran to 150 mg/day and administer 2 hours before the protease inhibitor. B. Atrial fibrillation: No dose adjustment is recommended and administer dabigatran 2 hours before the protease inhibitor. Monitor efficacy and the appearance of adverse effects associated with dabigatran (B). Suspect bleeding in the event of an unexplained drop in hemoglobin and/or hematocrit or a decrease in blood pressure. In patients experiencing bleeding, it may be useful to test activated partial thromboplastin time (APTT) in order to determine if there is an excessive anticoagulant effect. An APTT greater than 80 seconds at the end of the dosing interval (Cmin) of dabigatran is associated with an elevated risk of bleeding. 6. Possible or in dabigatran. The effect is difficult to predict. With nelfinavir or the combination of fosamprenavir/ ritonavir and tipranavir/ritonavir, a P-gp induction effect may be observed. There may, therefore, be a possible decrease in dabigatran. The combination with rifampicin, a significant P-gp inducer, was associated with a decrease of 67% in the dabigatran AUC. Recommendation: Avoid this combination. Monitor clinical efficacy and adverse effects associated with dabigatran (B). 7. Observed in rivaroxaban due to inhibition of CYP3A4 and/or P-gp. In a study involving a high dose of ritonavir (600 mg BID), there was an of 150% (2.5-fold) in rivaroxaban AUC. Recommendation: The product monograph recommends avoiding this combination. Choose an alternative to using dabigatran or the protease inhibitor. If this combination cannot be avoided, monitor clinical efficacy and adverse effects associated with rivaroxaban (C). 8. Possible or in rivaroxaban due to the inhibition or induction of CYP3A4 and/or P-gp with fosamprenavir/ ritonavir, nelfinavir and tipranavir/ritonavir. The net effect is difficult to predict. No pharmacokinetic studies have been conducted to date. Recommendation: The product monograph recommends avoiding this combination. Choose an alternative to using rivaroxaban or the protease inhibitor. If this combination cannot be avoided, monitor clinical efficacy and adverse effects associated with rivaroxaban (C). 9. No clinically significant interaction is anticipated, although a reduction in warfarin metabolism by CYP3A4 is possible. 10. Possible in the S-enantiomer of warfarin due to CYP2C9 induction by ritonavir or nelfinavir. In some case reports, increased dose of warfarin were necessary to maintain a therapeutic INR with ritonavir. An in warfarin can also be expected due to CYP3A4 inhibition. However, according to the reported cases, the clinical effect appears to be a decrease in the effect of warfarin. See also #11. Recommendation: Monitor INR. Monitor clinical efficacy and the appearance of adverse effects associated with warfarin (D). Adjust the dose as needed. Choose an alternative to using the protease inhibitor if it is difficult to obtain a therapeutic INR. 11. Observed of 21% in the S-warfarin AUC with the combination of warfarin and lopinavir/ritonavir, and with the combination of warfarin and darunavir/ritonavir. There have been cases where the warfarin dose had to be increased in order to maintain a therapeutic INR in the presence of lopinavir/ritonavir. 18 Antiretrovirals and drug interactions

19 INR: International normalized ratio A. Adverse effects of acenocoumarol: Hemorrhage that can present in the form of paralysis, paresthesia, headache, chest/abdominal/ joint pain, dizziness, shortness of breath, dyspepsia, difficulty swallowing or breathing, unexplained edema, weakness, hypotension, unexplained shock, hematoma, epistaxis, gingival bleeding B. Adverse effects of dabigatran: Bleeding (suspect bleeding if there is a drop in hemoglobin and/or hematocrit or hypotension), anemia, hematoma, hematuria, epistaxis, gastrointestinal disorders (abdominal pain, diarrhea, dyspepsia and nausea), gastrointestinal and urinary hemorrhage C. Adverse effects of rivaroxaban: Bleeding, hemorrhage, nausea, anemia D. Adverse effects of warfarin: Bleeding, hemorrhage, nausea, anemia, headache, skin necrosis * The combination of tipranavir/ritonavir has been associated with cases of intracranial hemorrhage. Use carefully with anticoagulants.

20 Anticoagulants and Maraviroc/Raltegravir Acenocoumarol (Sintrom) Apixaban (Eliquis) Dabigatran (Pradax) Rivaroxaban (Xarelto) Warfarine (Coumadin) Maraviroc (Celsentri) Raltegravir (Isentress) Legend 1. No interaction is anticipated. 2. Maraviroc is a potential P-gp inhibitor and, as such, may increase dabigatran and rivaroxaban. Clinical significance unknown. Recommendation: As a precautionary measure, administer dabigatran 2 hours before maraviroc. Monitor the clinical efficacy and safety of dabigatran and rivaroxaban. 20 Antiretrovirals and drug interactions

21 Metabolism of Antiplatelets Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Clopidogrel (Plavix) Prodrug Two main pathways: 1. Esterase hydrolysis (85%): Carboxylic acid derivative (inactive) 2B6 (moderate) 2C9 (weak) Urine : 50% Feces : 46% 2. Oxidation in two steps by CYP (15%): Primary oxidation to 2-oxo-clopidogrel, an intermediate metabolite, followed by a second oxidation to a thiol derivative of clopidogrel (active) T½: 8 hours 2C19 and 3A4 (major) 1A2, 2B6 and 2C9 (minor) Prasugrel (Effient) Prodrug Rapidly hydrolyzed in the intestine to thiolactone (inactive), an intermediate metabolite. This is then converted in a single step by CYPs to an active metabolite. 2B6 (weak) Urine: 68% as inactive metabolites Feces: 27%f as inactive metabolites 3A4 and 2B6 (major) 2C9 and 2C19 (minor) T½: 2-15 hours (mean: 7.4 hours) The active metabolite is then metabolized to two inactive compounds by S-methylation or conjugation with cysteine. Ticagrelor (Brilinta) 3A4 and 3A5: Active metabolite that is similar in activity to ticagrelor 3A4 (weak) Feces: Mainly as active metabolites P-gp P-gp (weak) Inducer 3A4 (weak) The inducing or inhibiting effect of ticagrelor on CYP3A4 depends on the associated drug (substrate). T½ of tigagreclor: 6.9 hours T½ of the active metabolite: 5.6 hours Ticlopidine (Ticlid) Prodrug The process of ticlopidine metabolism is not completely clear. It involves the formation of several metabolites (active and inactive) 2C19 et 2D6 (strong) 1A2, 2C9 et 2B6 (moderate) 2E1 and 3A4 (weak) Urine: 60% as metabolites Feces: 23%, with 33% as unchanged drug 2C9 and 2B6: 2-oxo-ticlopidine (active metabolite) 3A4: pyridinium metabolite Ticlopidine would inhibit its own metabolism T½: 4-5 days P-gp Cardiology and HIV 21

22 Antiplatelets and NNRTIs Clopidogrel (Plavix) Prasugrel (Effient) Ticagrelor (Brilinta) Ticlopidine (Ticlid) Efavirenz (Sustiva, Atripla) Etravirine (Intelence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) Legend 1. Possible in the formation of the active metabolite of clopidogrel due to CYP2C19 inhibition by efavirenz or etravirine. However, CYP3A4 induction could favour ( ) the formation of the active metabolite. To date, no case has been reported and no pharmacokinetic study conducted. Clinical significance unknown. In a study on omeprazole (CYP2C19 inhibitor), a decrease of more than 40% in the active metabolite of clopidogrel was observed, along with a decrease of more than 30% in the effect on platelet aggregation. Several studies have also reported a decrease in clinical efficacy. NB: The inhibition constant [Ki] of etravirine for CYP2C19 would be below that for omeprazole, but above that for pantoprazole. This suggests a possible inhibitory effect on CYP19, but less than that observed with omeprazole. Recommendation: Avoid combining clopidogrel with efavirenz or etravirine, if possible. Monitor clinical efficacy and the appearance of adverse effects associated with clopidogrel (A). Choose an alternative to using the NNRTI or clopidogrel, if deemed necessary. For example, use current data in the literature to determine if prasugrel is a good alternative. 22 Antiretrovirals and drug interactions

23 Legend 2. Possible in the plasma concentration of the active metabolite of clopidogrel due to CYP3A4 induction with nevirapine or rilpivirine. As rilpivirine is a weak CYP3A4 inducer, there may be no clinically significant effect on clopidogrel. Recommendation: Monitor for the appearance of adverse effects associated with clopidogrel (A). Adjust the dose or choose an alternative to the NNRTI or clopidogrel, if deemed necessary. 3. Possible in the plasma concentration of the active metabolite of prasugrel due to CYP3A4 induction. Clinical significance unknown. However, rifampicin, a powerful inducer of CYP3A and CYP2B6, as well as an inducer of CYP2C9, CYP2C19 and CYP2C8, does not significantly alter the pharmacokinetics of prasugrel nor inhibit platelet aggregation (which it induces). No studies or case reports with antiretrovirals have been reported to date. Recommendation: Monitor efficacy and the appearance of adverse effects associated with prasugrel (B). 4. Possible in ticagrelor and possible in its equally potent active metabolite. Clinical significance unknown. With rifampicin, a powerful CYP3A4 inducer, a decrease of 86% in ticagrelor and 46% in its active metabolite was observed. To date, no studies have been conducted on NNRTIs. Clinical significance unknown. Recommendation: If this combination is used, closely monitor the clinical efficacy and safety of ticagrelor (C). 5. Possible in the formation of the active metabolite of ticlopidine due to CYP2C9 inhibition by etravirine and efavirenz. Clinical significance unknown. Possible but probably non-significant increase in etravirine due to CYP2C19 inhibition by ticlopidine. Recommendation: Avoid this combination. Choose an alternative to using ticlopidine or the NNRTI, if deemed necessary. Monitor the clinical efficacy of ticlopidine. 6. According to the information available to date, no interaction is anticipated. A. Adverse effects of clopidogrel: Bleeding, bruising, dyspepsia, diarrhea/constipation, flu-like symptoms and headache B. Adverse effects of prasugrel: Unusual or persistent bleeding (nose, gums and vagina), easy bruising, anemia, weakness, constipation C. Adverse effects of ticagrelor: Bleeding (epistaxis, gastrointestinal/cutaneous hemorrhage), bruising, dyspnea, headache, dizziness, gastrointestinal effects (nausea, vomiting, dyspepsia, diarrhea or constipation), bradycardia Cardiology and HIV 23

24 Antiplatelets and PIs Clopidogrel (Plavix) Prasugrel (Effient) Ticagrélor (Brilinta) Ticlopidine (Ticlid) Atazanavir (Reyataz) Atazanavir/r (Reyataz) Darunavir/r (Prezista) Fosamprenavir/r (Telzir) Lopinavir/r (Kaletra) Nelfinavir (Viracept) Saquinavir/r (Invirase) Tipranavir/r (Aptivus) 2* 3* 4* 6* R : Ritonavir (Norvir) 24 Antiretrovirals and drug interactions

25 Legend 1. Possible in the formation of the active metabolite of clopidogrel due to CYP3A4 inhibition by atazanavir. To date, no case has been reported and no pharmacokinetic study conducted. Clinical significance unknown. In a study with erythromycin (CYP3A4 inhibitor), the following results were observed: baseline platelet aggregation of 93%, platelet aggregation of 42% with the addition of clopidogrel, and platelet aggregation of 55% when clopidogrel and erythromycin were administered together. The author concluded that the addition of a CYP3A4 inhibitor can potentially decrease the antiplatelet effect of clopidogrel. Moreover, although the findings vary from one study to another, several studies have also reported a loss of efficacy when atorvastatin (CYP3A4 inhibitor) is combined with clopidogrel. Recommendation: Avoid this combination if possible. Monitor the clinical efficacy of clopidogrel. Choose an alternative to using the viral protease inhibitor or clopidogrel, if deemed necessary. For example, use current data in the literature to determine if prasugrel is a good alternative. 2. Possible or in the formation of the active metabolite of clopidogrel due to CYP3A4 inhibition or 2C19 induction by nelfinavir or protease inhibitors combined with ritonavir. To date, no case has been reported and no pharmacokinetic study conducted. See #1 concerning potential CYP3A4 inhibition. Recommendation: Avoid this combination if possible. Monitor clinical efficacy and appearance of adverse effects associated with clopidogrel (A). Choose an alternative to using the protease inhibitor or clopidogrel, if deemed necessary. For example, use current data in the literature to determine if prasugrel is a good alternative. 3. Suspected in the formation of the active metabolite of prasugrel due to CYP3A4 inhibition. In the presence of ritonavir, there could potentially be an increase in the formation of the active metabolite of prasugrel due to a probable CYP2B6 induction. An in vitro study showed a decrease in the formation of the active metabolite when ritonavir is combined with prasugrel. A pharmacokinetic study is currently being conducted in HIV-positive subjects. However, the product monograph states that CYP3A4 inhibitors are not expected to have a significant effect on the metabolism of prasugrel. A study with ketoconazole, a potent CYP3A4 inhibitor, showed no significant effect on the formation of the active metabolite of prasugrel. Only a 34% decrease in Cmax was observed. Moreover, there was no change in the effect of prasugrel on platelets. Recommendation: Monitor clinical efficacy and appearance of adverse effects associated with of prasugrel (B), and stay up-to-date on new studies examining this interaction. 4. Possible in ticagrelor and possible in its equally potent active metabolite due to CYP3A4 inhibition. In a study with ketoconazole (potent inhibitor), a 140% increase in the ticagrelor AUC was observed, along with an 89% decrease in its active metabolite. The monograph states that combining ritonavir or another potent CYP3A4 inhibitor, such as atazanavir, with ticagrelor is contraindicated. Recommendation: As stated in the product monograph, do not combine ticagrelor with protease inhibitors. If this combination is used, closely monitor the clinical efficacy and safety of ticagrelor (C). 5. Based on currently available information, no clinically significant interaction is anticipated. Cardiology and HIV 25

26 Legend 6. Suspected in the formation of the active metabolite of ticlopidine due to CYP2C19 induction by ritonavir. Clinical significance unknown. To date, no case has been reported and no pharmacokinetic study conducted. Recommendation: Monitor the appearance of adverse effects associated with ticlopidine (D). Choose an alternative, if deemed necessary. * The combination of tipranavir/ritonavir has been associated with cases of intracranial hemorrhage. Use carefully with antiplatelets. A. Adverse effects of clopidogrel: Bleeding, bruising, dyspepsia, diarrhea/constipation, flu-like symptoms and headache B. Adverse effects of prasugrel: Unusual or persistent bleeding (nose, gums and vagina), easy bruising, anemia, weakness, constipation C. Adverse effects of ticagrelor: Bleeding (epistaxis, gastrointestinal/cutaneous hemorrhage), bruising, dyspnea, headache, dizziness, gastrointestinal effects (nausea, vomiting, dyspepsia, diarrhea or constipation), bradycardia D. Adverse effects of ticlopidine: Bleeding, bruising, gastrointestinal effects (diarrhea, nausea, dyspepsia, abdominal pain), rash, neutropenia, thrombocytopenia 26 Antiretrovirals and drug interactions

27 Antiplatelets and Maraviroc/Raltegravir Clopidogrel (Plavix) Prasugrel (Effient) Ticagrelor (Brilinta) Ticlopidine (Ticlid) Maraviroc (Celsentri) Raltegravir (Isentress) Legend 1. No interaction is anticipated. Cardiology and HIV 27

28

29 Metabolism of Angiotensin II type 1 receptor blockers (ARBs) Substrates Phase I: CYP Phase II: UGT s/inducers Phase I: CYP Phase II: UGT Excretion Transporters Transporters Candesartan (Atacand) Prodrug Hydrolyzed to candesartan during absorption in the gastrointestinal tract 2C9 and 2C8 (minor) 2C9 et 2C8 (weak) Urine: 60%, with 26% as candesartan Feces: 40% T½: 9 hours Eprosartan (Teveten) Not metabolized by cytochromes 2C9 et 2C8 (weak) Urine: 7%, mainly as unchanged drug Feces: 90% T½: 5-9 hours Irbesartan (Avapro, Avalide) 3A4 et 2C9 (minor) 2C9 et 2C8 (moderate) Urine: 20% Feces: 80% T½: hours Losartan (Cozaar, Hyzaar) 2C9 (major): Active metabolite, 40 times more active than losartan 3A4 (major): Inactive metabolite P-gp 2C9 et 2C8 (moderate) 2C19, 3A4 and 1A2 weak) Urine: 35% Feces : 60% T½: 2 hours; active metabolite: 6-9 hours Olmesartan (Olmetec) Prodrug OATP1B1 Hydrolyzed to its active metabolite in the gastrointestinal tract Urine: 35-50% as active metabolites Feces: 50-60% T½: 13 hours Telmisartan (Micardis) UGT 1A1 OATP1B3 2C19 (weak) Feces: 97% as unchanged drug T½: 24 hours Valsartan (Diovan, Tareg) OATP1B1 and MRP2 2C9 and/or 2C8 (weak) Urine: 13%, mainly as unchanged drug Feces: 83% T½: 6 hours Cardiology and HIV 29

30 Angiotensin II type 1 receptor blockers (ARBs) and NNTRIs Candesartan (Atacand) Eprosartan (Teveten) Irbesartan (Avapro, Avalide) Losartan (Cozaar, Hyzaar) Olmesartan (Olmetec) Telmisartan (Micardis) Valsartan (Diovan, Tareg) Efavirenz (Sustiva, Atripla) Etravirine (Intelence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) Legend 1. Based on currently available information, no clinically significant interaction is anticipated. 2. Possible or in losartan or its active metabolite due to potential CYP2C9 inhibition and possible CYP3A4 induction by efavirenz and etravirine. To date, no concrete information is available on this interaction. Recommendation: Monitor clinical efficacy and appearance of adverse effects, and adjust the dose if necessary. 3. Possible in losartan due to the potential CYP3A4 induction by nevirapine. However, 2C9 may increase the active metabolite of losartan. Interaction is probably not clinically significant. Recommendation: Monitor clinical efficacy and adjust the dose if necessary 4. As the CYP3A4 induction effect of rilpivirine is weak, no clinically significant interaction is anticipated. 30 Antiretrovirals and drug interactions

31 Angiotensin II type 1 receptor blockers (ARBs) and PIs Candesartan (Atacand) Eprosartan (Teveten) Irbesartan (Avapro, Avalide) Losartan (Cozaar, Hyzaar) Olmesartan (Olmetec) Telmisartan (Micardis) Valsartan (Diovan, Tareg) Atazanavir (Reyataz) Atazanavir/r (Reyataz) Darunavir/r (Prezista) Fosamprenavir/r (Telzir) Lopinavir/r (Kaletra) Nelfinavir (Viracept) Saquinavir/r (Invirase) Tipranavir/r (Aptivus) R : Ritonavir (Norvir) Cardiology and HIV 31

32 Legend 1. No clinical data. No clinically significant interaction is anticipated. 2. Possible in losartan due to the inhibition of 3A4/P-gp. Recommendation: Monitor clinical efficacy and appearance of adverse effects (A). 3. Possible in losartan due to the inhibition of CYP 3A4/P-gp and possible in the active metabolite of losartan in the presence of ritonavir due to potential CYP2C9 induction. Recommendation: Monitor clinical efficacy and adjust the dose if necessary (A). 4. Possible in olmesartan or telmisartan due to the potential inhibition of OATP1B1 or OATP1B3 by the viral protease inhibitors. To date, there are not concrete data on this interaction. Recommendation: Monitor clinical efficacy and appearance of adverse effects (B, C). 5. Possible in valsartan due to the potential OATP1B1 inhibition by the viral protease inhibitors. To date, there are not concrete data on this interaction. Recommendation: Monitor clinical efficacy and appearance of adverse effects (D). A. Adverse effects of losartan: Dizziness, vertigo, palpitations, headache, orthostatic hypotension, sleep disorders, drowsiness B. Adverse effects of olmesartan: Dizziness, vertigo, hypotension, angina pectoris, bronchitis, cough, pharyngitis, rhinitis, sinusitis, gastrointestinal effects, bone pain, hematuria, urinary tract infection, chest pain, fatigue, flu-like syndrome, peripheral oedema, elevated creatine phosphokinase, hypertriglyceridemia, hyperuricemia, elevated liver enzymes C. Adverse effects of telmisartan: Dizziness, hypotension, headache, flu-like symptoms, oedema, palpitations, insomnia, gastrointestinal disorder (abdominal pain, diarrhea, constipation, dyspepsia, nausea), arthralgia, myalgia, anxiety, rash D. Adverse effects of valsartan: Headache, vertigo, orthostatic hypotension, deterioration in renal function (rare cases), hyperkalemia 32 Antiretrovirals and drug interactions

33 Angiotensin II type 1 receptor blockers (ARBs) and Maraviroc/Raltegravir Candesartan (Atacand) Eprosartan (Teveten) Irbesartan (Avapro, Avalide) Losartan (Cozaar, Hyzaar) Olmesartan (Olmetec) Telmisartan (Micardis) Valsartan (Diovan, Tareg) Maraviroc (Celsentri) Raltegravir (Isentress) Legend 1. Maraviroc had a hypotensive effect (especially at high doses). Recommendation: Monitor effect on blood pressure and the occurrence of orthostatic hypotension. 2. No interaction is anticipated. Cardiology and HIV 33

34 Metabolism of Antiarrhythmics Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Adenosine (Adénocard) Enzymatic metabolism at the cellular level T½: Less than 10 seconds Amiodarone (Cordarone) Active metabolite Formation of N-desethylamiodarone (DHE) by 3A4 and 2C8 (major) 1A2, 2C19 and 2D6 (minor) P-gp 3A4, 2A6, 2C9 et 2D6 (moderate) 1A2, 2B6 and 2C19 (weak) P-gp Urine: Negligible, less than 1% Feces: Mainly T½: 1 week-3 months (mean: 53 hours) Digoxine (Lanoxin) P-gp and OATP4C1 Urine: 50-70% as unchanged drug T½: hours Disopyramide (Rythmodan) 3A4 (major) Urine: 80% as unchanged drug Feces: 10-15% as metabolites T½: 10-14,5 hours Dronedarone (Multaq) 3A4 (major): Active metabolite (N-debutyl) 3-10 times less active than dronedarone 3A4 (moderate) 2D6 (weak) Urine: 6% as metabolites Feces: 84% as metabolites P-gp and OAT T½: hours Esmolol (Brevibloc) Metabolized by red blood cell and/or tissue esterases Urine: 73-88% as metabolites, less than 2% as unchanged drug T½: 9 minutes Flecaïnide (Tambocor) 2D6 (major) 1A2 (minor) 2D6 (weak) Urine: 80-90% with 10-50% as unchanged drug or as metabolites T½: 14 hours 34 Antiretrovirals and drug interactions

35 Metabolism of Antiarrhythmics Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Ibutilide (Corvert) Significant hepatic metabolism. Formation of 8 metabolites, including 1 with weak activity. But according to the product monograph, low involvement of CYP450 Urine: 82%, with 7% as unchanged drug Feces: 19% T½: 2-12 hours (mean: 6 hours) Lidocaïne (Xylocaine) 2D6 and 3A4 (major) 2C9, 2B6, 2A6 and 1A2 (minor) Active metabolites: Monoethylglycinexylidide and glycinexylidide 1A2 (strong) 2D6 and 3A4 (moderate) Urine: 90%, mainly as metabolites and less than 10% as unchanged drug T½: hours P-gp Mexiletine (Mexitil) 1A2 and 2D6 (major) 1A2 (strong) Urine: 8-15% as unchanged drug T½: 8-15 hours (mean: 10 hours) Procaïnamide (Pronestyl) 2D6 (major) Active metabolite: N-acetylprocainamide (NAPA) by acetylation Urine: 30-60% as unchanged drug, and 50% as NAPA Feces: Less than 5% as unchanged drug T½: 4 hours Propafenone (Rythmol) Propafenone shows clinical activity (beta-blocker and class 1c) 2D6 (major): 5-hydroxypropafenone (class 1c active metabolite) 2D6 and 1A2 (weak) P-gp Urine: 20-40% as metabolites and less than 1% as unchanged drug Feces: as unchanged drug 1A2 and 3A4 (minor): N-depropylpropafenone (active metabolite) T½: 6 hours Quinidine (Biquin-Durule, Cardioquine) 3A4 (major) 2C9 and 2E1 (minor) P-gp 2D6 and 3A4 (strong) 2C9 (weak) P-gp, OCT, OATP Urine: 50%, with 15-25% as unchanged drug Feces: Less than 5% as metabolites T½: Approximately 6 hours Cardiology and HIV 35

36 36 Antiretrovirals and drug interactions

37 Antiarrhythmics and NNRTIs Adenosine (Adénocard) Amiodarone (Cordarone) Digoxine (Lanoxin) Disopyramide (Rythmodan) Dronedarone (Multaq) Esmolol (Brevibloc) Flecaïnide (Tambocor) Efavirenz (Sustiva, Atripla) Etravirine (Intelence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) 1,2 2,3 1,2 2,5 2,6 1,2 1,2 Ibutilide (Corvert) Lidocaïne (Xylocaine) Mexiletine (Méxitil) Procaïnamide (Pronestyl) Propafenone (Rhythmol) Quinidine Efavirenz (Sustiva, Atripla) Etravirine (Intelence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) 1,2 2,8 2,9 1,2 2,10 2,11 Cardiology and HIV 37

38 Legend There is little information in the literature on interactions between antiarrhythmics and antiretrovirals. Most of the information presented here is based on extrapolation of the metabolism data for each agent. 1. No clinically significant pharmacokinetic interaction is anticipated. 2. Rilpivirine has been associated with QT interval prolongation on ECG, which can increase the risk of cardiac arrhythmia. Data on the risk of pharmacodynamic interactions between rilpivirine and drugs that prolong the QT interval are limited, and caution should be exercised. Recommendation: The product monograph for rilpivirine recommends caution when combining rilpirvirine with other drugs with a known risk of torsades de pointes (see or in the presence of risk factors for dysrhythmia (e.g. QTc > 500 ms, heart failure, myocardial infarction, advanced age, hypokalemia, hypocalcemia, hypomagnesaemia, bradycardia, etc). 3. Suspected in amiodarone and suspected in its active metabolite due to potential CYP 3A4 induction by NNRTIs. Clinical significance is unknown. Amiodarone is a CYP3A4 inhibitor and could potentially increase NNRTI concentrations, although it is not likely that this increase is clinically significant. Recommendation: Monitor clinical efficacy and adjust the dose if necessary. 4. Possible in the concentration of digoxin when combined with etravirine due to possible P-gp inhibition. However, the clinical interaction is not expected to be significant and no digoxin dose adjustment is recommended. Recommendation: Monitor digoxin levels at steady state (3-7 days) and the appearance of adverse effects (A). 5. Suspected in disopyramide due to potential CYP3A4 induction by NNRTIs. Undocumented interaction and clinical significance is unknown. Recommendation: Monitor clinical efficacy and adjust the dose if necessary. 6. Suspected in drodenarone due to potential CYP3A4 induction by NNRTIs. Drodenarone is a moderate CYP3A4 inhibitor and could potentially increase NNRTI concentrations, although the clinical significance of these findings is unknown. Recommendation: Use with caution. Monitor clinical efficacy and adjust the dose if necessary. 7. Possible in flecainide when combined with etravirine, as reported in the product monograph for etravirine. Recommendation: The product monograph recommends caution when coadministering these drugs. Monitor clinical efficacy and adjust the dose if necessary. 8. Suspected in lidocaine due to potential CYP3A4 induction by NNRTIs. Clinical significance unknown. Lidocaine is a CYP3A4 inhibitor and could potentially increase NNRTI concentrations, although it is not likely that this increase is clinically significant. Recommendation: Monitor clinical efficacy and adjust the dose if necessary. 38 Antiretrovirals and drug interactions

39 Legend 9. Based on the information available on the metabolism of mexiletine, no interaction with NNRTIs is anticipated. 10. Suspected in propafenone due to potential CYP3A4 induction by NNRTIs. However, CYP3A4 would only be a minor pathway for propafenone. Clinical significance is unknown. Recommendation: Monitor clinical efficacy and adjust the dose if necessary. 11. Suspected in quinidine due to potential CYP3A4 induction by NNRTIs. Clinical significance is unknown. Quinidine is an inhibitor of CYP3A4 and could potentially increase NNRTI concentrations, although it is not likely that this increase is clinically significant. Recommendation: Monitor clinical efficacy and adjust the dose if necessary. A. Adverse effects of digoxin: Gastrointestinal effects (abdominal discomfort, nausea/vomiting, diarrhea, anorexia, dyspepsia), central nervous system effects, vision disorders, fatigue, headaches, bradycardia and rhythm disorders Cardiology and HIV 39

40 Antiarrhythmics and PIs Adenosine (Adénocard) Amiodarone (Cordarone) Digoxine (Lanoxin) Disopyramide (Rythmodan) Dronedarone (Multaq) Esmolol (Brevibloc) Flecaïnide (Tambocor) Atazanavir (Reyataz) 1,2 2,3 2,4 2,5 2,6 1,2 1,2 Atazanavir/r (Reyataz) 1,2 2,3 2,4 2,5 2,6 1,2 2,7 Darunavir/r (Prézista) 1,2 2,3 2,4b 2,5 2,6 1,2 2,7 Fosamprenavir/r (Telzir) 1,2 2,3 2,4 2,5 2,6 1,2 2,7 Lopinavir/r (Kaletra) 1,2 2,3 2,4c 2,5 2,6 1,2 2,7 Nelfinavir (Viracept) 1,2 2,3 2,4 2,5 2,6 1,2 1,2 Saquinavir/r (Invirase) 1,2 2,3 2,4d 2,5 2,6 1,2 2,7 Tipranavir/r (Aptivus) R : Ritonavir (Norvir) 1,2 2,3 2,4e 2,5 2,6 1,2 2,7 40 Antiretrovirals and drug interactions

41 Antiarrhythmics and PIs Ibutilide (Corvert) Lidocaïne (Xylocaine) Mexiletine (Méxitil) Procaïnamide (Pronestyl) Propafenone (Rhythmol) Quinidine Atazanavir (Reyataz) 2,8 2,9 1,2 1,2 2,12 2,13 Atazanavir/r (Reyataz) 2,8 2,9 2,10 2,11 2,12 2,13 Darunavir/r (Prezista) 2,8 2,9 2,10 2,11 2,12 2,13 Fosamprenavir/r (Telzir) 2,8 2,9 2,10 2,11 2,12 2,13 Lopinavir/r (Kaletra) 2,8 2,9 2,10 2,11 2,12 2,13 Nelfinavir (Viracept) 2,8 2,9 1,2 1,2 2,12 2,13 Saquinavir/r (Invirase) 2,8 2,9 2,10 2,11 2,12 2,13 Tipranavir/r (Aptivus) 2,8 2,9 2,10 2,11 2,12 2,13 Cardiology and HIV 41

42 Legend There is little information in the literature on interactions between antiarrhythmics and antiretrovirals. Most of the information presented here is based on extrapolation of the metabolism data for each agent. 1. No clinically significant pharmacokinetic interaction is anticipated. 2. Potential increased risk for QTc and PR interval prolongation. Increased PR or QTc interval prolongation on ECG, atrioventricular or bundle branch blocks, and rare cases of torsades de pointes with viral protease inhibitors have been observed in cohort studies and case reports. However, the benefits of using protease inhibitors exceed the risks associated with this effect. To avoid the risk of QT interval prolongation, it is recommended that no antiarrhythmic be coadministered with drugs that prolong the QT interval (see This is especially important for patients with high baseline QTc values or risk factors for dysrhythmia (patients with a conduction disorder; ischemic heart disease; cardiomyopathy; hypocalcemia, hypokalemia or refractory hypomagnesemia; bradycardia; an initial QT interval > 500 ms). The risk is even higher since PIs can decrease the metabolism of most antiarrhythmics. 3. Suspected in amiodarone and suspected in its active metabolite due to the potential inhibition of CYP3A4 or the inhibition of P-gp by PIs. Clinical significance is unknown. According to the product monograph for amiodarone, there is a reported case of an increase in serum concentrations of amiodarone when coadministered with indinavir. Amiodarone is a CYP3A4 inhibitor and could potentially increase PI concentrations, although it is not likely that this increase is clinically significant. Recommendation: Most product monographs recommend to avoid the combination of amiodarone and PIs. If this cannot be avoided, start at a low dose or decrease the dose if the patient is already taking amiodarone. Monitor efficacy and appearance of adverse effects (A), and adjust the dose if necessary. Monitor ECG. NB: Since the half-life of amiodarone is long and variable, the risk of interaction exists not only during concomitant treatment, but also after stopping amiodarone. 4. Suspected or documented in digoxin due to potential P-gp inhibition (decreased renal clearance) by viral protease inhibitors. a. 1.2-fold in digoxin AUC (oral route) and 1.9-fold in digoxin AUC (IV route) has been observed when ritonavir is administered alone. b. 1.4-fold in digoxin AUC with darunavir/ritonavir. c. 1.8-fold in digoxin AUC with lopinavir/ritonavir. d. 1.5-fold in digoxin AUC with saquinavir/ritonavir. e. 1.9-fold in digoxin AUC with tipranavir/ritonavir after the first dose of tipranavir/ritonavir, and then no effect after achieving a steady-state concentration of tipranavir/ritonavir. Recommendation: Start with a low dose or reduce the dose by half if the patient is already taking digoxin. Monitor efficacy and appearance of adverse effects (B), and adjust the dose if necessary. Monitor ECG. Monitor digoxin levels at steady state (3-7 days). 42 Antiretrovirals and drug interactions

43 Legend 5. Possible in disopyramide due to potential CYP3A4 inhibition by viral protease inhibitors. The product monograph states there is uncertainty regarding the CYP3A4 metabolism of disopyramide. However, there are reported cases in which coadministration with erythromycin (a powerful CYP3A4 inhibitor) triggered polymorphous ventricular tachycardia, QTc interval prolongation and an increase in disopyramide concentrations. Recommendation: Avoid this combination. If this is not possible, start at a low dose or decrease the dose if the patient is already taking disopyramide. Monitor efficacy and appearance of adverse effects (C), and adjust the dose if necessary. Monitor ECG. 6. Possible in dronedarone AUC in the presence of PIs due to 3A4 inhibition by the latter. Ketoconazole (a powerful 3A4 inhibitor) has been observed to result in a 17-fold increase in dronedarone AUC. A similar effect is expected with ritonavir and atazanavir. Although dronedarone is a CYP3A4 inhibitor, it is not expected to have a clinically significant effect on plasma concentrations of the viral protease inhibitor. Coadministration of dronedarone and ritonavir is contraindicated in the 2011 monograph, which also recommends dronedarone to be stopped if QTc 500 ms during treatment. Recommendation: Avoid this combination. If this is not possible, start at a low dose or decrease the dose if the patient is already taking dronedarone. Closely monitor efficacy and the appearance of adverse effects (D), and adjust the dose if necessary. ECG monitoring is desirable. 7. Possible in flecainide AUC in the presence of PIs combined with ritonavir due to potential CYP2D6 inhibition. Recommendation: Avoid this combination. If this is not possible, start at a low dose or decrease the dose if the patient is already taking flecainide. Monitor efficacy and appearance of adverse effects (E), and adjust the dose if necessary. ECG monitoring is desirable. 8. Since cytochrome P450 is not involved in the metabolism of ibutilide, no clinically significant interactions with the protease inhibitors are expected. The use of ibutilide is not recommended in patients with QTc interval > 440 ms. 9. Possible in lidocaine due to the potential inhibition of CYP3A4/CYP2D6 by PIs. Although lidocaine is a known CYP3A4 inhibitor, no significant effect on plasma concentrations of the viral protease inhibitor is expected. Recommendation: Avoid this combination. If this is not possible, start with a low dose of lidocaine. Monitor efficacy and appearance of adverse effects (F), and adjust the dose if necessary. ECG monitoring is desirable. 10. Possible in mexiletine in the presence of PIs combined with ritonavir due to potential CYP2D6 inhibition. Recommendation: Avoid this combination. If this is not possible, start with a low dose of mexiletine. Monitor efficacy and appearance of adverse effects (G), and adjust the dose if necessary. ECG monitoring is desirable. Cardiology and HIV 43

44 Legend 11. Possible in procainamide in the presence of PIs combined with ritonavir due to potential CYP2D6 inhibition. Recommendation: Avoid this combination. If this is not possible, start with a low dose of procainamide. Monitor efficacy and appearance of adverse effects (H), and adjust the dose if necessary. ECG monitoring is desirable. 12. Possible in propafenone AUC in the presence of PIs combined with ritonavir due to potential CYP2D6 inhibition. Possible in propafenone when coadministered with atazanavir and nelfinavir due to CYP3A4 inhibition. Recommendation: Avoid this combination. If this is not possible, start with a low dose of propafenone. Monitor efficacy and appearance of adverse effects (I), and adjust the dose if necessary. ECG monitoring is desirable. 13. Possible in quinidine AUC in the presence of PIs due to potential CYP3A4 inhibition. Recommendation: Avoid this combination. If this is not possible, start with a low dose of quinidine. Monitor efficacy and appearance of adverse effects (J), and adjust the dose if necessary. ECG monitoring is desirable. A. Adverse effects of amiodarone: Gastrointestinal effects (nausea/vomiting, anorexia and constipation), fatigue, central nervous system effects (coordination problems/ataxia/headache, dizziness/insomnia, etc.), hepatic anomalies, photosensitivity, hypo- and hyperthyroidism, altered sense of smell, muscle weakness, neuropathy, pulmonary fibrosis, corneal deposits/vision disorders, bluish-grey skin colour, bradycardia, conduction disorder B. Adverse effects of digoxin: Gastrointestinal effects (abdominal discomfort, nausea/vomiting, diarrhea, anorexia, dyspepsia), central nervous system effects, vision disorders, fatigue, headache, bradycardia and rhythm disorders C. Adverse effects of disopyramide: Anticholinergic effects (dry mouth, urinary retention, constipation, blurred vision, dry eyes), gastrointestinal effects (nausea/vomiting, altered taste, diarrhea, anorexia), dizziness, drowsiness, vertigo, pruritus, cardiac effects (hypotension, heart failure, edema), QRS and QTc interval prolongation, torsades de pointes D. Adverse effects of dronedarone: Gastrointestinal effects (nausea, vomiting, abdominal pain), fatigue, asthenia, bradycardia, skin rash and pruritus, QTc interval prolongation E. Adverse effects of flecainide: Dizziness, visual disorders, vertigo, dyspnea, nausea, palpitations, chest pain, edema, rhythm disorders, angina, proarrhythmic effects, headache, fatigue, asthenia, tremors, nervousness, paresthesia and skin rash F. Adverse effects of lidocaine: Dizziness; gastrointestinal effects (nausea, vomiting); drowsiness; hypo- or hypertension; difficulty talking; confusion; perioral numbness; tinnitus; little effect on PR interval, QRS and QT interval 44 Antiretrovirals and drug interactions

45 Legend G. Adverse effects of mexiletine: Abdominal discomfort, nausea/vomiting, light-headedness, nervousness, ataxia, headache, tremors, dizziness, vision disorders, nystagmus, confusion, staggering gait, seizures, hypotension, paresthesia, tinnitus, QRS and QTc interval prolongation. H. Adverse effects of procainamide: Anticholinergic effects, lupus erythematosus syndrome, depression, psychosis, QRS and QT interval prolongation, torsades de pointes. I. Adverse effects of propafenone: Dizziness, gastrointestinal effects (nausea/vomiting, altered taste, constipation), fatigue, vertigo, dyspnea, headaches, blurred vision, paresthesia, hypotension, bradycardia, negative inotropic effects, asthma, proarrhythmic effects. J. Adverse effects of quinidine: Diarrhea, nausea/vomiting, abdominal pain, anorexia, bitter taste, anticholinergic effects, headache, vision disorders, hearing disorders (tinnitus), hypersensitivity reaction (fever, rash and thrombocytopenia), rhythm disorders, QRS and QT interval prolongation, torsades de pointes (2-10%). Cardiology and HIV 45

46 Antiarrhythmics and Maraviroc/Raltegravir Adenosine (Adénocard) Amiodarone (Cordarone) Digoxine (Lanoxin) Disopyramide (Rythmodan) Dronedarone (Multaq) Esmolol (Brevibloc) Flecaïnide (Tambocor) Maraviroc (Celsentri) Raltegravir (Isentress) Ibutilide (Corvert) Lidocaïne (Xylocaine) Mexiletine (Méxitil) Procaïnamide (Pronestyl) Propafénone (Rhythmol) Quinidine Flecaïnide (Tambocor) Maraviroc (Celsentri) Raltegravir (Isentress) Legend 1. No interaction is anticipated. 2. Possible in the concentration of digoxin when combined with maraviroc due to possible P-gp inhibition. However, no significant clinical interaction is expected, and no digoxin dose adjustment is recommended. Recommendation: Monitor digoxin levels at steady state (3-7 days) and the appearance of adverse effects (A). A. Adverse effects of digoxin: Gastrointestinal effects (abdominal discomfort, nausea/vomiting, diarrhea, anorexia, dyspepsia), central nervous system effects, vision disorders, fatigue, headache, bradycardia and rhythm disorders 46 Antiretrovirals and drug interactions

47 Metabolism of Beta-blockers Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Acebutolol (Sectral) Substrate? Significant first-pass effect in the liver: Active metabolite (diacetol) 2D6 (weak) Urine: 30-40%f as diacetol Feces: 50-60% T½: 3-4 hours Bisoprolol (Monocor) 3A4 (major) 2D6 (minor) Urine: 50% as unchanged drug Feces: Less than 2% T½: 9-12 hours Carvedilol (Coreg) 2D6, 2C9 and 3A4 (major): Active metabolites, the effect of 4-hydroxyphenyl is approximately 13 times stronger than that of the parent compound P-gp Feces: Mainly T½: 7 à 10 hours 2E1 and 1A2 (minor) P-gp Labetalol (Trandate) 2D6 (minor) UGT 2D6 (weak) Urine: 55-60% as glucuronoconjugated metabolites and less than 5% as unchanged drug T½: 6-8 hours Metoprolol (Lopressor) 2D6 (major) 2C19 (minor) 2D6 (weak) Urine: 5-10% as unchanged drug T½: 3-7 hours Pindolol (Visken) 2D6 (major) 2D6 (weak) Urine: 35-40% as unchanged drug Feces: 6-9% T½: 3-4 hours Propranolol (Inderal) 1A2 and 2D6 (major) 3A4 and 2C19 (minor) Active and inactive metabolites 1A2 and 2D6 (weak): 4 hydroxypropanolol (active) P-gp Urine: 96-99% as metabolites, less than 1% as unchanged drug T½: 3-4 hours Timolol (Blocadren) 2D6 (major) 2D6 (weak) Urine: 15-20% as unchanged drug T½: 4-5 hours Cardiology and HIV 47

48 Beta-blockers and NNRTIs Acebutolol (Sectral) Bisoprolol (Monocor) Carvedilol (Coreg) Labetalol (Trandate) Metoprolol (Lopressor) Propranolol (Indéral) Pindolol (Visken) Timolol (Blocadren) Efavirenz (Sustiva, Atripla) Etravirine (Intelence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) 1,3 2,3 1,3 1,3 1,3 1,3 1,3 1,3 Legend There is little information in the literature on the interactions between beta-blockers and antiretrovirals. Most of the information presented here is based on extrapolation of the metabolism data for each agent. 1. Based on known metabolic pathways, no clinically significant interaction is expected. 2. Suspected in bisoprolol due to possible CYP3A4 induction. Recommendation: Monitor clinical efficacy, and adjust the dose if necessary. 3. Rilpivirine has been associated with QT interval prolongation on ECG, which can increase the risk of cardiac arrhythmia. Data on the risk of pharmacodynamic interactions between rilpivirine and drugs that prolong the QT interval are limited, and caution should be exercised. Recommendation: The product monograph recommends caution when coadministering rilpivirine with drugs that have a known risk of torsades de pointes (see or in the presence of risk factors for dysrhythmia (e.g. QTc > 500 ms, heart failure, myocardial infarction, advanced age, hypokalemia, hypocalcemia, hypomagnesemia, bradycardia, etc.). Note that atenolol (Tenormin), nadolol (Corgard) and sotalol (Sotacor) are not metabolized in the liver. They are eliminated entirely by the kidneys. No interaction between NNRTIs and these three betablockers is expected. 48 Antiretrovirals and drug interactions

49 Beta-blockers and PIs Acebutolol (Sectral) Bisoprolol (Monocor) Carvedilol (Coreg) Labetalol (Trandate) Metoprolol (Lopressor) Pindolol (Visken) Propranolol (Inderal) Timolol (Blocadren) Atazanavir (Reyataz) 1,2 1,2 1, Atazanavir/r (Reyataz) 1,2 1,2 1,2 2,4 1,2,6 1,2 2,4 1,2 Darunavir/r (Prezista) 1,2 1,2 1,2 2,4 1,2,6 1,2 2,4 1,2 Fosamprenavir/r (Telzir) 1,2 2,3 2,3 2,4 1,2,6 1,2 2,4 1,2 Lopinavir/r (Kaletra) 1,2 1,2 1,2 2,4 1,2,6 1,2 2,4 1,2 Nelfinavir (Viracept) 1,2 1,2 1,2 2, Saquinavir/r (Invirase) 1,2 1,2 1,2 2,4 1,2,6 1,2 2,4 1,2 Tipranavir/r (Aptivus) R : Ritonavir (Norvir) 1,2 2,3 2,3 2,4 1,2,6 1,2 2,4 1,2 Cardiology and HIV 49

50 Legend There is little information in the literature on the interactions between antiretrovirals and beta-blockers. Most of the information presented here is based on extrapolation of the metabolism data for each agent. 1. Suspected in the beta-blockers due to potential inhibition of the hepatic metabolism of beta-blockers (CYP2D6, CYP3A4 or P-gp) by ritonavir, atazanavir or nelfinavir. Recommendation: Start with a low dose or decrease the dose if the patient is already taking betablockers. Monitor blood pressure, heart rate and adverse effects associated with beta-blockers (A). Adjust the dose if necessary. 2. Risk of PR or QT interval prolongation. Increased PR or QT interval prolongation on ECG, atrioventricular or bundle branch blocks, and rare cases of torsades de pointes with viral protease inhibitors have been observed in cohort studies and case reports. However, the benefits of using protease inhibitors exceed the risk associated with this effect. Recommendation: Caution is recommended when coadministering PIs and other drugs at risk of causing torsades de pointes (see: in patients with conduction disorders, ischemic cardiac disease, cardiomyopathy, hypocalcemia/ hypokalemia/ refractory hypomagnesemia, bradycardia, a baseline QT interval > 500 ms, or in combination with other drugs that can increase the QT or PR interval. However, if coadministration cannot be avoided, do an ECG before and after initiating the drugs, if possible. 3. Possible or in beta-blocker due to the inhibition or induction effects with fosamprenavir/r and tipranavir/r. Recommendation: Monitor and adjust the dose if necessary. 4. Possible or in beta-blocker due to CYP2D6 inhibition, or to the induction of UGT (induction of labetalol metabolism) or CYP1A2 (induction of propranolol metabolism). The net effect is difficult to predict. Recommendation: Monitor and adjust the dose if necessary. 5. Possible in beta-blocker due to the possible induction of UGT conjugation with nelfinavir. Recommendation: Monitor and adjust the dose if necessary. 6. According to the product monograph, metoprolol is contraindicated when antiretroviral inhibitors of CYP2D6 are being administered. Note that atenolol (Tenormin), nadolol (Corgard) and sotalol (Sotacor) are not metabolized in the liver. They are eliminated entirely by the kidneys. No pharmacokinetic interaction is anticipated with PIs. However, there is a risk of PR or QT interval prolongation associated with these agents. A. Adverse effects of beta-blockers: Fatigue, insomnia, nightmares, dizziness, headache, gastrointestinal effects, arthralgia, asthenia, hypotension, bradycardia, peripheral edema, depression, hallucinations, bronchospasm, claudication, cold extremities 50 Antiretrovirals and drug interactions

51 Beta-blockers and Maraviroc/Raltegravir Acebutolol (Sectral) Bisoprolol (Monocor) Carvedilol (Coreg) Labetalol (Trandate) Metoprolol (Lopressor) Propranolol (Indéral) Pindolol (Visken) Timolol (Blocadren) Maraviroc (Celsentri) Raltegravir (Isentress) Legend There is little information in the literature on the interactions between beta-blockers and antiretrovirals. Most of the information presented here is based on extrapolation of the metabolism data for each agent. 1. Since maraviroc has been shown to have a hypotensive effect (especially at high doses), an additive effect can be expected. Recommendation: Monitor the effect on blood pressure and the occurrence of orthostatic hypotension. 2. No studies conducted to date. No clinically significant pharmacokinetic interaction is anticipated. Cardiology and HIV 51

52 52 Antiretrovirals and drug interactions

53 Metabolism of Calcium channel blockers (CCBs) Substrates Phase I: CYP Phase II: UGT s/inducers Phase I: CYP Phase II: UGT Excretion Transporters Transporters Amlodipine (Norvasc) 3A4 (major): Inactive metabolites 1A2 (moderate) 2A6, 2B6, 2C8, 2C9, 3A4 and 2D6 (weak) Urine: Mainly (60% as metabolites and less than 10% as unchanged drug) T½: hours Diltiazem (Cardizem, Tiazac) 3A4 (major) 2D6 and 2C9 (minor) 3A4 (moderate) Urine: 2-4% as unchanged drug and 6-7% as metabolites Desacetyl diltiazem (active metabolite with 25-50% the power of diltiazem) N-monodesmethyldiltiazem (active metabolite with 20% the power of diltiazem) 2D6 and 2C9 (weak) Feces T½: hours P-gp Felodipine (Renedil, Plendil) 3A4 (major) 2C8 (moderate) 2C9, 3A4 and 2D6 (weak) Urine: Mainly, with 70% as metabolites Feces: 10% T½: hours Nifedipine (Adalat) 3A4 (major) 2D6, 1A2 et 2A6 (minor) 1A2 (moderate) 2C9, 3A4 and 2D6 (weak) Urine: 60-80%, as metabolites Feces: Possibly by biliary elimination T½: 2-5 hours Nimodipine (Nimotop) 3A4 (major) Urine: 50%,f as metabolites Feces: 32% T½: 1-2 hours Verapamil (Isoptin) 3A4 (major) 1A2, 2B6, 2C9, 2C18, 2C8 and 2E1 (weak) P-gp 3A4 (moderate) 1A2, 2D6 and 2C9 (weak) P-gp Urine: Mainly, with 3-4% as unchanged drug T½: 3-7 hours Cardiology and HIV 53

54 Calcium channel blockers and PIs Dihydropyridines Phenylalkylamine Benzothiazepine Amlodipine (Norvasc) Nifedipine (Adalat) Nimodipine (Nimotop) Felodipine (Renedil, Plendil) Verapamil (Isoptin) Diltiazem (Cardizem, Tiazac) Atazanavir (Reyataz) ,4 1,4,5 Atazanavir/r (Reyataz) ,4 1,4 Darunavir/r (Prezista) ,4 1,4 Fosamprenavir/r (Telzir) ,4 1,4 Lopinavir/r (Kaletra) 1 1, ,4 1,4 Nelfinavir (Viracept) 1 1, ,4 1,4 Saquinavir/r (Invirase) ,4 1,4 Tipranavir/r (Aptivus) R : Ritonavir (Norvir) ,4 1,4 54 Antiretrovirals and drug interactions

55 Legend There is little information in the literature on the interactions between CCBs and antiretrovirals. Most of the information presented here is based on extrapolation of the metabolism data for each agent. 1. Suspected in CCB due to potential inhibition of the hepatic metabolism of CCBs (CYP3A4) by PIs. Use with caution. Although most CCBs are CYP3A4 inhibitors, a clinically significant increase in PI levels is expected. In a study on the coadministration of indinavir/ritonavir and amlodipine in HIV-negative subjects, an of 90% in amlodipine was observed. A study with indinavir/ritonavir and diltiazem showed an of 26.5% in diltiazem and an of 102% in desacetyldiltiazem, the active metabolite. No effect on indinavir was observed. Recommendation: Start with a low dose or decrease the dose if the patient is already taking CCBs. Monitor blood pressure, heart rate and adverse effects associated with CCBs (A). Adjust the dose according to clinical effect and the appearance of adverse effects. 2. There has been one reported case involving nelfinavir coadministered with long-acting nifedipine and atenolol. The patient, known for preexisting cardiac disease, developed symptomatic orthostatic hypotension, fatigue, dizziness and a complete heart block following the start of nifedipine. The nelfinavir was stopped and the symptoms disappeared within 24 hours. The symptoms subsequently reappeared when the nelfinavir was resumed. In another reported case involving the coadministration of lopinavir/ritonavir and long-acting nifedipine, the patient developed hypotension and progressive renal failure. The symptoms resolved after treatment was stopped. The same symptoms with edema returned several years later when coadministration of lopinavir/ritonavir and nifedipine was resumed. Recommendation: Start with a low dose or decrease the dose if the patient is already taking CCBs. Monitor blood pressure, heart rate and adverse effects associated with CCBs (A). Adjust the dose according to clinical effect and the appearance of adverse effects. 3. The product monograph states that nimodipine is contraindicated when antiretroviral inhibitors of CYP3A4 are being administered since the latter s metabolism depends entirely on CYP3A4. Recommendation: Avoid. If used, start with a low dose or decrease the dose if the patient is already taking CCBs. Monitor blood pressure, heart rate and adverse effects associated with CCBs (A). Adjust the dose according to clinical effect and the appearance of adverse effects. 4. Risk of PR or QT interval prolongation. Increased PR or QT interval prolongation on ECG, atrioventricular or bundle branch blocks, and rare cases of torsades de pointes with viral protease inhibitors have been observed in cohort studies and case reports. However, the benefits of using protease inhibitors exceed the risk associated with this effect. Recommendation: Caution is recommended when coadministering PIs and other drugs at risk of causing torsades de pointes (see: in patients with conduction disorder, ischemic cardiac disease, cardiomyopathy, hypocalcemia, refractory hypomagnesemia, bradycardia, a baseline QT interval > 500 ms, or in combination with other drugs that can increase the QT or PR interval. However, if coadministration cannot be avoided, do an ECG before and after combining the drugs, if possible. 5. Observed 2.25-fold in AUC and 2.42-fold in Cmin of diltiazem when combined with atazanavir. No clinically significant effect was observed with atazanavir. Recommendation: The product monograph for atazanavir suggests starting at 50% of the dose or decreasing the dose by 50% if the patient is already taking diltiazem. Close monitoring of the adverse effects associated with diltiazem (A) is required. A. Adverse effects associated with CCBs: Gastrointestinal effects, fatigue, hypotension, palpitations, tachycardia or bradycardia (diltiazem and verapamil), peripheral edema, dizziness, nervousness, vertigo, headache and drowsiness NB: Dihydropyridine CCBs are associated with hypotension and generally present no risk of PR or QT interval prolongation. However, the benzothiazepine and phenylalkylamine classed of CCBs, such as diltiazem and verapamil, can be associated with severe bradycardia, and PR and QT interval prolongation. Cardiology and HIV 55

56 Calcium channel blockers and NNRTIs Dihydropyridines Phenylalkylamine Benzothiazepine Amlodipine (Norvasc) Nifedipine (Adalat) Nimodipine (Nimotop) Felodipine (Renedil, Plendil) Verapamil (Isoptin) Diltiazem (Cardizem, Tiazac) Efavirenz (Sustiva) Etravirine (Intellence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) ,4 3,4 Legend There is little information in the literature on the interactions between CCBs and antiretrovirals. Most of the information presented here is based on extrapolation of the metabolism data for each agent. 1. Suspected in CCBs due to potential inhibition of the hepatic metabolism of CCBs (CYP3A4) by NNRTIs. Recommendation: Monitor clinical efficacy and adjust the dose if necessary. 2. Observed of 69% in diltiazem AUC. No clinically significant effect on efavirenz concentration was observed. Recommendation: Monitor the clinical efficacy of diltiazem and adjust the dose if necessary. 3. No clinically significant interaction is expected based on known metabolic pathways. 4. Rilpivirine has been associated with QT interval prolongation on ECG, which can increase the risk of cardiac arrhythmia. Data on the risk of pharmacodynamic interactions between rilpivirine and drugs that prolong the QT interval are limited and caution should be exercised. Recommendation: The product monograph recommends caution when coadministering rilpivirine with other drugs with a known risk of torsades de pointes (see or in the presence of risk factors for dysrhythmia (e.g. QTc > 500 ms, heart failure, myocardial infarction, advanced age, hypokalemia, hypocalcemia, hypomagnesemia, bradycardia, etc). 56 Antiretrovirals and drug interactions

57 Caqlcium channel blockers and Maraviroc/Raltegravir Dihydropyridines Phenylalkylamine Benzothiazepine Amlodipine (Norvasc) Nifedipine (Adalat) Nimodipine (Nimotop) Felodipine (Renedil, Plendil) Verapamil (Isoptin) Diltiazem (Cardizem, Tiazac) Maraviroc (Celsentri) 1,2 1,2 1,2 1,2 2,3 2,3 Raltegravir (Isentress) Legend 1. No studies conducted to date. No clinically significant pharmacokinetic interaction is anticipated. 2. Since maraviroc was shown to have a hypotensive effect (especially at high doses), an additive effect can be expected. Recommendation: Monitor the effect on blood pressure and the occurrence of orthostatic hypotension. 3. Adjusting the dose of maraviroc is recommended when coadministered with potent CYP3A4 inhibitors. Despite being moderate CYP3A4 inhibitors, diltiazem and verapamil are not reported in the product monograph to be potential inhibitors of maraviroc metabolism, hence no dose adjustment of maraviroc is suggested. Cardiology and HIV 57

58 Metabolism of Angiotensin-converting enzyme inhibitors (ACEIs) Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Benazepril (Lotensin) Prodrug Mainly hydrolyzed to benazeprilat (active metabolite) and glucuronide conjugates of benazepril and benazeprilat Urine: 20% as benazeprilat, and 12% as glycuroconjugated metabolites T½: hours Captopril (Capoten) 2D6 (major) Urine: Greater than 95%, with 40-50% as unchanged drug Cilazapril (Inhibace) Prodrug Metabolized to cilazaprilat (active metabolite) by esterification Urine: Mainly as cilazaprilat T½: hours Enalapril (Vasotec) Prodrug Mainly hydrolyzed to enalaprilat (active metabolite) 3A4 (minor) Urine: 60-80%, with 40% as enalaprilat Feces T½: 11 hours Fosinopril (Monopril) Prodrug Lisinopril (Zestril) 75% metabolized to fosinoprilat (active), and 20-30% as fosinoprilat by hydrolysis (active metabolite), glucuronide conjugates (inactive Not metabolized Urine: 50%, with 75% as fosinoprilat Feces: 50% T½: 12 hours Urine: Mainly as unchanged drug T½: hours Perindopril (Coversyl) Prodrug Metabolized to perindoprilat (active metabolite) in the liver by conjugation and hydrolysis Urine: Mainly, with 75% as perindoprilat and 4-12% as unchanged drug T½: 17 hours 58 Antiretrovirals and drug interactions

59 Metabolism of Angiotensin-converting enzyme inhibitors (ACEIs) Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Quinapril (Accupril) Prodrug Metabolized by hydrolysis to quinalaprilat (active metabolite) Urine: Mainly, 50-60% as quinalaprilat T½: 2-3 hours Ramipril (Altace) Prodrug Trandolapril (Mavik) Prodrug Metabolized by hydrolysis to ramiprilat (active metabolite) Significant first-pass effect in the liver Metabolized by hydrolysis to trandolaprilat (active metabolite) Urine: 60% as unchanged drug and as metabolites Feces: 40% as unchanged drug and as metabolites T½: hours Urine: 33%, with 46% as trandolaprilat Feces: 66%, with 57% as trandolaprilat T½: hours Cardiology and HIV 59

60 60 Antiretrovirals and drug interactions

61 ACEIs and NNRTIs Benazepril (Lotensin) Captopril (Capoten) Cilazapril (Inhibace) Enalapril (Vasotec) Fosinopril (Monopril) Efavirenz (Sustiva, Atripla) Etravirine (Intellence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) Lisinopril (Zestril) Perindopril (Coversyl) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Efavirenz (Sustiva, Atripla) Etravirine (Intellence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) No interaction is anticipated due to weak metabolism of CYP 3A4. Cardiology and HIV 61

62 ACEIs and PIs Benazepril (Lotensin) Captopril (Capoten) Cilazapril (Inhibace) Enalapril (Vasotec) Fosinopril (Monopril) Atazanavir (Reyataz) Atazanavir/r (Reyataz) Darunavir/r (Prezista) Fosamprenavir/r (Telzir) Lopinavir/r (Kaletra) Nelfinavir (Viracept) Saquinavir/r (Invirase) Tipranavir/r (Aptivus) R=Ritonavir (Norvir) 62 Antiretrovirals and drug interactions

63 ACEIs and PIs Lisinopril (Zestril) Perindopril (Coversyl) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Atazanavir (Reyataz) Atazanavir/r (Reyataz) Darunavir/r (Prezista) Fosamprenavir/r (Telzir) Lopinavir/r (Kaletra) Nelfinavir (Viracept) Saquinavir/r (Invirase) Tipranavir/r (Aptivus) Cardiology and HIV 63

64 Legend 1. No interaction anticipated for these agents based on what is known to date about their metabolism. No studies available in the current literature. 2. Possible in captopril AUC due to CYP2D6 inhibition when any PI is combined with ritonavir. No interactions reported to date. Recommendation: Monitor clinical efficacy and appearance of adverse effects associated with captopril (A). A. Adverse effects associated with captopril: Sleep disorders, dizziness, gastrointestinal effects, dry mouth, altered taste, palpitations, dry and irritative cough, pruritus and rash, alopecia, renal function disorders, fatigue and chest pain 64 Antiretrovirals and drug interactions

65 ACEIs and Maraviroc/Raltegravir Benazepril (Lotensin) Captopril (Capoten) Cilazapril (Inhibace) Enalapril (Vasotec) Fosinopril (Monopril) Maraviroc (Celsentri) Raltegravir (Isentress) Lisinopril (Zestril) Perindopril (Coversyl) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Maraviroc (Celsentri) Raltegravir (Isentress) Legend 1. Since maraviroc has be shown to have a hypotensive effect (especially at high doses), an additive effect can be expected. Recommendation: Monitor the effect on blood pressure and the occurrence of orthostatic hypotension. 2. No studies have been conducted to date. No clinically significant pharmacokinetic interaction is anticipated. Cardiology and HIV 65

66 Metabolism of Statins Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Atorvastatine (Lipitor) 3A4 (major), 2C8 (minor): Metabolized to the acid derivatives 2-hydroxy-atorvastatin and 4-hydroxy-atorvastatin (active). The active metabolites are responsible for approximately 70% of the inhibiting activity of circulating HMG-CoA reductase, 3A4 (weak) OATP1B1 P-gp Urine: Less than 1% Feces: Mainly T½: 14 hours OATP1B1 and P-gp Fluvastatine (Lescol) Made up of 2 enantiomers: 3R, 5S (active) and 5S, 3R (inactive) Significant first-pass effect in the liver 2C9 (major), 3A4, 2C8 and 2D6 (minor) 2C9 (moderate), 3A4, 2D6, 1A2, and 2C8 (weak) Urine: 5% Feces: 90% as metabolites T½: Less than 3 hours for the regular tablet, and 9 hours for the long-acting tablet OATP1B1 Lovastatine (Mevacor) Significant first-pass effect in the liver Hydrolyzed to beta hydroxy acid (active) 2C9 and 2D6, 3A4 (weak) P-gp Urine: 10% Feces: 80-85% T½: hours 3A4 (major) P-gp Pravastatine (Pravachol) Significant first-pass effect in the liver Metabolized to several metabolites The main metabolite is 3a-hydroxyiso- pravastatin (barely active, i.e % of the activity of the parent compound) 2C9, 2D6 and 3A4 (weak) Urine: 20%, with 8% as unchanged drug Feces: 70% T½: hours 3A4 (minor) UGT P-gp, OATP1B1 and OATP1B3 66 Antiretrovirals and drug interactions

67 Metabolism of Statins Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Rosuvastatine (Crestor) Weakly metabolized by CYPs. Approximately 10% of the rosuvastatin is found as metabolites in the bloodstream Feces: 90%, mainly as unchanged drug T½: 19 hours Rosuvastatin-lactone (inactive metabolite) observed after glucuronidation (UGT1A1, UGT1A3) Rosuvastatin accounts for 87% of the lipid-lowering activity 2C9 (minor, i.e. 10% is metabolized into N-desmethylrosuvastatin = 50% of the activity of rosuvastatin ) 2C19 and 3A4 (very minor) OATP1B1, OATP1B3, BCRP and MRP2 Simvastatine (Zocor) Metabolized to beta hydroxy acid (main active metabolite) Significant first-pass effect in the liver 3A4 (major) 2C8, 2C9 and 2D6 (weak) P-gp Urine: 13% Feces: 60% T½: 2 hours OATP1B1 Cardiology and HIV 67

68 Statins and NNRTIs Atorvastatine (Lipitor) Fluvastatine (Lescol) Lovastatine (Mevacor) Pravastatine (Pravachol) Rosuvastatine (Crestor) Simvastatine (Zocor) Efavirenz (Sustiva, Atripla) Etravirine (Intellence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) Antiretrovirals and drug interactions

69 Legend 1. Observed of 43% in atorvastatin AUC and observed of 34% in total active concentration (atorvastatin + active metabolite). No effect on efavirenz was observed. Recommendation: Monitor the clinical efficacy of atorvastatin, and adjust the dose if necessary. 2. Observed of 37% in atorvastatin AUC. No effect on etravirine was observed. Recommendation: Monitor the clinical efficacy of atorvastatin, and adjust the dose if necessary. 3. Possible in atorvastatin, lovastatin, simvastatin and pravastatin due to CYP3A4 induction by efavirenz, etravirine and nevirapine. Recommendation: Monitor the clinical efficacy of these statins and adjust the dose if necessary. 4. No effect on atorvastatin. Minimal in the active metabolite of atorvastatin. Moreover, a clinically significant improvement in lipid-lowering effect was observed. Recommendation: No dose adjustment of atorvastatin is recommended when combined with rilpivirine. 5. Suspected in fluvastatin due to possible CYP2C9 inhibition by efavirenz and etravirine. In a study with fluconazole (a CYP2C9 inhibitor), an of 44% in fluvastatin AUC was observed, along with an of 84% in T1/2. Recommendation: Monitor clinical efficacy and appearance of adverse effects (A). 6. No clinically significant interaction is expected based on the metabolism data for these agents. However, no pharmacokinetic study has been done to date. Recommendation: Monitor clinical efficacy, and adjust the dose if necessary. 7. Observed of 40% in pravastatin AUC. No effect on efavirenz was observed. Recommendation: Monitor clinical efficacy, and adjust the dose of pravastatin if necessary. 8. No clinically significant interaction is expected despite possible CYP2C9 inhibition by efavirenz or etravirine, since hepatic metabolism via the cytochromes would account for only 10% of the metabolism of rosuvastatin. In a study with fluconazole (a CYP2C9 inhibitor), only an of 14% was observed in rosuvastatin AUC. Recommendation: Monitor clinical efficacy and appearance of adverse effects (A), and adjust the dose if necessary. 9. Observed of 68% in simvastatin AUC. No effect on efavirenz was observed. Recommendation: Monitor clinical efficacy and adjust the dose if necessary A. Adverse effects associated with statins: Liver enzyme elevation, dyspepsia, muscle weakness, myalgia, muscle cramps, myopathy, rhabdomyolysis and myoglobinuria leading to renal failure Monitor: Increases in creatine phosphokinase (CPK), liver enzymes, muscle weakness or musculoskeletal pain. Advise patients to report all instances of unexplained muscle pain, sensitivity or weakness Cardiology and HIV 69

70 Statins and PIs Atorvastatine (Lipitor) Fluvastatine (Lescol) Lovastatine (Mevacor) Pravastatine (Pravachol) Rosuvastatine (Crestor) Simvastatine (Zocor) Atazanavir (Reyataz) Atazanavir/r (Reyataz) Darunavir/r (Prezista) Fosamprenavir/r (Telzir) Lopinavir/r (Kaletra) Nelfinavir (Viracept) Saquinavir/r (Invirase) Tipranavir/r (Aptivus) R: Ritonavir (Norvir) 70 Antiretrovirals and drug interactions

71 Legend 1. Possible in statin levels due to possible inhibition of CYP3A4 or transporters. Recommendation: Monitor clinical efficacy and appearance of adverse effects (A). 2. Observed of % ( 3-4 times) in atorvastatin AUC. In this study, a 10-mg dose of atorvastatin is equivalent to approximately 40 mg. No effect suspected on darunavir. Recommendation: Start with a low dose of atorvastatin (10 mg) or decrease the dose if the patient is already taking atorvastatin. Monitor clinical efficacy and appearance of adverse effects (A). 3. Observed of 153% in atorvastatin AUC. No effect on fosamprenavir was observed. Recommendation: See recommendation for #2. 4. Observed of 488% ( 5 times) in atorvastatin AUC. No effect on lopinavir/ritonavir was observed. Recommendation: Start with a low dose of atorvastatin (10 mg) or decrease the dose if the patient is already taking atorvastatin. Monitor clinical efficacy and appearance of adverse effects (A). 5. Observed of 74% in atorvastatin AUC. No effect on nelfinavir was observed. Recommendation: Start with a low dose of atorvastatin (10 mg) or decrease the dose if the patient is already taking atorvastatin. Monitor clinical efficacy and appearance of adverse effects (A). 6. Observed of 347% ( 4 times) in atorvastatin AUC, and of 79% in total active atorvastatin AUC. No effect on saquinavir was observed. Recommendation: Start with a low dose of atorvastatin (10 mg) or decrease the dose if the patient is already taking atorvastatin. Monitor clinical efficacy and appearance of adverse effects (A). 7. Observed of 840% ( 9 times) in atorvastatin AUC. No effect on tipranavir/ritonavir was observed. Recommendation: Avoid this combination or see recommendation for #2. 8. Fluvastatin is primarily metabolized via CYP2C9. Theoretically, coadministration with ritonavir could decrease fluvastatin levels. On the other hand, protease inhibitors can increase plasma concentrations of fluvastatin by inhibiting the transporters. However, these combinations have not been studied and actual effects are unknown. Recommendation: Monitor clinical efficacy and appearance of adverse effects. 9. Due to the significant first-pass effect of lovastatin and simvastatin in the liver via CYP3A4, coadministration of these drugs with PIs is contraindicated. See increases observed with simvastatin (#20 and 21). Cases of rhabdomyolysis have been reported. Recommendation: Avoid this combination. 10. Possible or in pravastatin. The effect on pravastatin is difficult to predict due to its metabolism and transporters. For example, an in pravastatin was observed with lopinavir/r and darunavir/r. On the other hand, pravastatin with saquinavir/r and nelfinavir. Recommendation: Start at a low dose, and monitor clinical efficacy and appearance of adverse effects (A). Cardiology and HIV 71

72 Legend 11. Observed of 81% in pravastatin AUC. 4 out of 14 patients showed a 200% increase in pravastatin AUC. No effect on darunavir suspected. Recommendation: Start at a low dose or decrease the dose if the patient is already taking pravastatin. Closely monitor clinical efficacy and appearance of adverse effects (A). 12. Observed of 33% in pravastatin AUC. No effect on lopinavir/ritonavir was observed. This interaction does not appear to be clinically significant. Recommendation: Due to very broad inter-patient variability with pravastatin, it would be prudent to start at a low dose, and to monitor clinical efficacy and appearance of adverse effects (A). 13. Observed of 47% in pravastatin AUC. No effect on nelfinavir was observed. Recommendation: Monitor clinical efficacy. A dose adjustment may be necessary. 14. Observed of 50% in pravastatin AUC. No effect on saquinavir was observed. Recommendation: Monitor clinical efficacy. A dose adjustment may be necessary. 15. Observed of 213% ( 3 times) in rosuvastatin AUC. No effect on atazanavir suspected. The mechanism proposed is inhibition of OATP1B1 transporters in the liver, and/or BCR P and MRP2 transporters in the intestine. Recommendation: Start at a low dose (5-10 mg) or decrease the dose if the patient is already taking rosuvastatin. Monitor clinical efficacy and appearance of adverse effects (A). 16. Observed 1.5-fold in rosuvastatin AUC, 2.4-fold in Cmax, and 1.4-fold in Cmin. Insignificant increase in T½ of rosuvastatin. No significant effect on darunavir/ritonavir was observed. The mechanism proposed was inhibition of the OATP1B1 transporter in the liver. Inhibition of MRP2 and BCRP transporters in the intestine was also suggested. No serious adverse effects were observed. However, the study lasted only 7 days. A partial decrease in the clinical efficacy of rosuvastatin was observed. It is hypothesized that very little or no rosuvastatin reaches its site of action in the hepatocytes. Hence, decreasing the dose of rosuvastatin in order to counteract the interaction is probably not an effective means of obtaining clinical efficacy or avoiding adverse effects. Other studies are needed in order to better understand this interaction and suggest a correct dose for coadministration with darunavir/r and rosuvastatin. Recommendation: If this combination is used, suggest starting at a dose of 5-10 mg of rosuvastatin, and monitoring clinical efficacy and appearance of adverse effects (A). 17. No change in rosuvastatin observed. No effect on fosamprenavir suspected. 18. Observed of 101% (2.1 times) in rosuvastatin AUC, and a 4.7-fold in Cmax of rosuvastatin. No effect on lopinavir/r was observed. 1 in 15 patients experienced symptomatic CK elevation ( 17 times normal). Another patient experienced an in liver enzymes to times the upper limit of normal. In this study, a decrease in the efficacy of rosuvastatin was observed. It is hypothesized that very little or no rosuvastatin reaches its site of action in the hepatocytes. Hence, decreasing the dose of rosuvastatin in order to counteract the interaction is probably not an effective means of obtaining clinical efficacy or avoiding adverse 72 Antiretrovirals and drug interactions

73 Legend effects. Other studies are needed in order to better understand this interaction and suggest a correct dose for coadministration with darunavir/r and rosuvastatin. Recommendation: If this combination is used, suggest starting at a dose of 5-10 mg of rosuvastatin, and monitoring clinical efficacy and appearance of adverse effects (A). One case of rhabdomyolysis with coadministration of lopinavir/ritonavir and rosuvastatin has recently been published. 19. Observed of 37% in rosuvastatin AUC. No effect on tipranavir suspected. Clinical significance unknown. Recommendation: Start at a low dose (5-10 mg) or decrease the dose if the patient is already taking rosuvastatin. Monitor clinical efficacy and appearance of adverse effects (A). 20. Observed of 505% in simvastatin AUC. No effect on nelfinavir was observed. One case of death was reported in a patient treated with nelfinavir and simvastatin. Recommendation: Avoid this combination. 21. Observed of 3059% in simvastatin AUC. No effect on saquinavir was observed. Recommendation: Avoid this combination. A. Adverse effects associated with statins: Elevated liver enzymes, dyspepsia, muscle weakness, myalgia, muscle cramps, myopathy, rhabdomyolysis and myoglobinuria leading to renal failure Monitor: Increases in creatine phosphokinase (CPK), liver enzymes, muscle weakness or musculoskeletal pain. Advise patients to report all instances of unexplained muscle pain, sensitivity or weakness Cardiology and HIV 73

74 Statins and Maraviroc/Raltegravir Atorvastatine (Lipitor) Fluvastatine (Lescol) Lovastatine (Mevacor) Pravastatine (Pravachol) Rosuvastatine (Crestor) Simvastatine (Zocor) Maraviroc (Celcentri) Raltegravir (Isentress) Legend 1. No clinically significant interaction is suspected. 2. No clinically significant interaction was observed. 74 Antiretrovirals and drug interactions

75 Metabolism of hypolipidemics (other than statins) Substrates Phase I: CYP Phase II: UGT Transporters s/inducers Phase I: CYP Phase II: UGT Transporters Excretion Acide nicotinique (Niacine, Niaspan) Significant first-pass effect in the liver Urine: 60-88% (as unchanged drug and as metabolites) Transformed into nicotinic acid (by conjugation), nicotinamide adenine dinucleotide and other metabolites T½: minutes Bezafibrate (Bezalip SR) Metabolized by hydroxylation and glucuronidation UGT, 3A4 (minor) Urine: 95% Feces: 3% T½: 1-2 hours Cholestyramine (Questran, Olestyr) Would not be absorbed Feces Colestipol (Colestid) Would not be absorbed Feces Ezetimibe (Ezetrol) SLCO1B1 Metabolized in the small intestine and liver by glucuronide conjugation to ezetimibe-glucuronide (active) Urine: 11% (9% as metabolites) Feces: 78% (69% in unchanged form) OATP1B1 T½: 22 hours Fenofibrate (Lipidil) Metabolized by esterases to fenofibric acid (active) 3A4 (minor) UGT (possibly) 2A6, 2C8, 2C9, 2C19 (weak) Urine: 60% (as metabolites) Feces: 25% T½: hours Gemfibrozil (Lopid) 3A4 (minor) UGT (possibly) 1A2 (moderate) 2C8, 2C9, 2C19 (strong) OATP1B1, OATP1B3, OATPC Urine: 70% (in conjugated form) Feces: 6% T½: 1.4 hours Cardiology and HIV 75

76 Hypolipidemics and NNRTIs Nicotinic acid (Niaspan) Bezafibrate (Bezalip SR) Cholestyramine (Questran) Colestipol (Colestid) Ezetimibe (Ezetrol) Fenofibrate (Lipidil) Gemfibrozil (Lopid) Efavirenz (Sustiva, Atripla) 1 1 1,2 1, Etravirine (Intellence) 1 1 1,2 1, Nevirapine (Viramune) 1 1 1,2 1, Rilpivirine (Edurant, Complera) 1 1 1,2 1, Legend 1. Due to the metabolism of these agents, no clinically significant interaction is expected. 2. Since cholestyramine may bind to other drugs given concomitantly, the product monograph recommends other drugs be taken at least one hour before, or four to six hours after, the taking of cholestyramine. 3. Given that the mechanism of action exhibited by colestipol is similar to that of cholestyramine, the same precautions should be followed for both drugs. See # Antiretrovirals and drug interactions

77 Hypolipidemics and PIs Nicotinic acid (Niaspan) Bezafibrate (Bezalip SR) Cholestyramine (Questran) Colestipol (Colestid) Ezetimibe (Ezetrol) Fenofibrate (Lipidil) Gemfibrozil (Lopid) Atazanavir (Reyataz) Atazanavir/r (Reyataz) Darunavir/r (Prezista) Fosamprenavir/r (Telzir) Lopinavir/r (Kaletra) Nelfinavir (Viracept) Saquinavir/r (Invirase) Tipranavir/r (Aptivus) R : Ritonavir (Norvir) Cardiology and HIV 77

78 Legend 1. No interaction is anticipated. 2. Possible in bezafibrate, fenofibrate and gemfibrozil when combined with nelfinavir or viral protease inhibitors combined with ritonavir, due to possible UGT induction. Recommendation: Monitor clinical efficacy, and adjust the dose if necessary. 3. Since cholestyramine may bind to other drugs administered concomitantly, the product monograph recommends other drugs be taken at least one hour before, or four to six hours after, cholestyramine. 4. Given that the mechanism of action of colestipol is similar to that of cholestyramine, the same precautions should be followed for both drugs. See #2. 5. Observed of 41% in gemfibrozil AUC. Clinical significance is unknown. Recommendation: Monitor clinical efficacy, and adjust the dose if necessary 78 Antiretrovirals and drug interactions

79 Hypolipidemics and Maraviroc/Raltegravir Nicotinic acid (Niaspan) Bezafibrate (Bezalip SR) Cholestyramine (Questran) Colestipol (Colestid) Ezetimibe (Ezetrol) Fenofibrate (Lipidil) Gemfibrozil (Lopid) Maraviroc (Celcentri) Raltegravir (Isentress) Legend 1. No clinically significant interaction is suspected. 2. No effect on raltegravir was observed. No effect on ezetimibe is suspected. 3. No study done to date. However, it is usually recommended to space out the taking of other drugs coadministered with cholestyramine or colestipol. Cardiology and HIV 79

80 80 Antiretrovirals and drug interactions

81 References The following sites were consulted Metabolism of antiretrovirals 1. Drug information : Metabolism/Transport effects, Pharmacodynamics/Kinetics. Uptodate 19.2 inc. Waltham, Massachusetts Disponible : com/contents/search (Consulté du 10 au 12 novembre 2011). 2. Lacy CF, Armstrong LL, et all. Drug Information Handbook, 17e édition, Boehringer Ingelheim. Monographie du fabricant : Aptivus. Version française. Burlington (Ontario).Mai p. 4. Bristol-Myers Squibb Canada. Monographie du fabricant : Reyataz. Version française. Montréal (Québec). Mai p. 5. Bristol-Myers Squibb Canada. Monographie du fabricant : Sustiva. Version française. Montréal (Québec).Novembre p. 6. Bristol-Myers Squibb Canada. Monographie du fabricant : Videx EC. Version française. Montréal (Québec).Mai p. 7. Choi MK, Song IS. Organic Cation Transporters and Their Pharmacokinetic and Pharmacodynamic Consequences. Drug Metab Pharmacokinet 2008 ; 23 : Corbett AH, Patterson KB, Tien HC, et al. Dose Separation Does Not Overcome the Pharmacokinetics Interaction between Fosamprenavir and Lopinavir/Ritonavir. Antimicrob Agents Chemother 2006 ; 50 : Cvetkovic RS, Goa KL. Lopinavir/Ritonavir: A Review of Its Use in the Management of HIV Infection. Drugs 2003 ; 63 : Dixit V, Hariparsad N, Li F, et al. Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease s in Human Hepatocytes : Implications for Predicting Clinical Drug Interactions. Drug Metab Dispos 2007 ; 35 : Foisy MM, Yakiwchuk EM, Hughes CA. Induction Effects of Ritonavir: Implications for Drug Interactions. Ann Pharmacother 2008;42: GiacominI KM, Huang S-M, Tweedie DJ et al. Membrane transporters in drug development. Nature Reviews Drug Discovery 2010; 9(issue 3): Gilead Sciences, Inc. Monographie du fabricant : Emtriva. Version française. Mississauga (Ontario). Janvier p. 14. Griffin L, Annaert P, et al. Influence of Drug Transport Proteins on the Pharmacokinetics and Drug Interactions of HIV Protease s. J Pharm Sci 2011; 100 (11) : Hariparsad N, Nallani SC, et al. Induction of CYP3A4 by efavirenz in primary human hepatocytes: comparison with rifampin and phenobarbital. J Clin Pharmacol 2004; 44: Hartkoom RC, Kwan WS, Shallcross V, et al. HIV Protease s Are Substrates For OATP1A2, OATP1B1 and OATP1B3 and Lopinavir Plasma Concentrations Are Influenced by SLCO1B1 Polymorphisms. Pharmacogenet Genomics 2010 ; 20 : Hoffman LaRoche. Monographie du fabricant : Invirase. Version française. Mississauga (Ontario). Novembre p. 18. Janssen Inc. Monographie du fabricant : Edura. Version française. Toronto (Ontario). Juillet p. 19. Janssen Inc. Monographie du fabricant : Intelence. Version française. Toronto (Ontario). Novembre p. 20. Janssen Inc. Monographie du fabricant : Prezista. Version française. Toronto (Ontario). Septembre p. 21. Kalliokoski A, Niemi M. Impact of OATP Transporters on Pharmacokinetics. Br J Pharmacol 2009 ; 158 : Kashuba AD, Tierney C, Downey GF, et al. Combining Fosamprenavir With Lopinavir/Ritonavir Substantially Reduces Amprenavir and Lopinavir Exposure: ACTG Protocol A5143 Results. AIDS 2005 ; 19 : Ka s h u b a A D. D r u g - D r u g I n t e ra c t i o n s a n d t h e Pharmacotherapy of HIV Infection. Top HIV Med 2005 ; 13 : Kharash ED, Bedynek PS, Walker A, et al. Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: II Ritonavir Effects on CYP3A and P-Glycoprotein Activities. Clin Pharmacol Ther 2008 ; 84 : Kharash ED, Mitchell D, Coles R, Blanco R. Rapid Clinical Induction of Hepatic Cytochrome P4502B6 Activity by Ritonavir. Antimicrob Agents Chemother 2008 ; 52 : Kis O, Robillard K, Chan GN, Bendayan R. The Complexities of Antiretroviral Drug-Drug Interactions: Role of ABC and SLC Transporters. Trends Pharmacol Sci 2009 ; 31 : Knox TA, Oleson L, von Moltke LL, et al. Ritonavir Greatly Impairs CYP3A Activity in HIV Infection With Chronic Viral Hepatitis. J Acquired Immune Defic Syndr 2008 ; 49 : Kusuhara H, Sugiyama Y. Pharmacokinetics Modeling of the Hepatobiliary Transport Mediated by Cooperation of Uptake and Efflux Transporters. Drug Metab Rev 2010 ; 42 : Laboratoires Abbott. Monographie du fabricant : Kaletra. Version française. St-Laurent (Québec). Août p. 30. Laboratoires Abbott. Monographie du fabricant : Norvir. Version anglaise. St-Laurent (Québec). Mai p. 31. Lim ML, Min SS, Sherene S, et al. Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction. J Acquir Immune Defic Syndr 2004; 36(5): Lin JH, Yamazaki M. Role of P-Glycoprotein in P h a r m a c o k i n e t i c s : C l i n i c a l I m p l i c a t i o n s. C l i n Pharmacokinet 2003 ; 42 : Long MC, King JR, Acosta EP. Pharmacologic aspects of new antiretroviral drugs. Current Infectious Disease Reports 2008; 10 : Marzolini C, Battegay M, Back D (ed) Chapter 3 : Mechanisms of drug interactions II : transport proteins. Drug interactions in infectious deseases, Springer Science + Business Media pp Mathias AA, West S, Hui J, Kearney BP. Dose-Response of Ritonavir on Hepatic CYP3A Activity and Elvitegravir Oral Exposure. Clin Pharmacol Ther 2009 ; 85 : McNicholl IR. Drug Interactions Among the Antiretrovirals. Curr Infect Dis Rep 2004; 6 : Cardiology and HIV 81

82 37. Merk Frosst Canada LTÉE. Monographie du fabricant : Isentress. Version fraçaise. Kirkland (Québec). Septembre p. 38. Nies AT, Schwab M, Keppler D. Interplay of Conjugating Enzymes With OATP Uptake Transporters and ABCC/MRP Efflux Pumps in the Elimination of Drugs. Expert Opin Drug Metab Toxicol 2008 ; 4 : Perloff MD, von Moltke LL, Fahey JM, et al. Induction of P-Glycoprotein Expression by HIV Protease s in Cell Culture. AIDS 2000 ; 14 : Perloff MD, von Moltke LL, Marchand JE, Greenblat DJ. Ritonavir Induces P-Glycoprotein Expression, Multidrug Resistance-Associated Protein (MRPI) Expression, and Drug Transporter-Mediated Activity in a Human Intestinal Cell Line. J Pharm Sci 2001 ; 90 : Rachel Therrien. Le petit guide des antirétroviraux. 6e édition. UHRESS du CHUM. Montréal p. 42. Robertson SM, Penzak SR, Pau A. Drug interactions in the management of HIV infection. Expert Opin Pharmacother 2007; 8(17): Rosa F. Yeh et al. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 Enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volonteers. J Aquir Immune Defic Syndr 2006; 42(1) : Shitara Y, Horie T, Sujiyama Y. Transporters as a Determinant of Drug Clearance and Tissue Distribution. Eur J Pharm Sci 2006 ; 27 : Shugarts S, Benet LZ. The Role of Transporters in the Pharmacokinetics of Orally Administered Drugs. Pharm Res 2009 ; 26 : Smith NF, Figg WD, Sparreboom A. Role of the Liver- Specific Transporters OATP1B1 and OATP1B3 in Governing Drug Elimination. Expert Opin Drug Metab Toxicol 2005; 1 : Smith PF, DiCenzo R, Morse GD. Clinical pharmacokinetics of nonnucleoside reverse transcriptase inhibitors. Clin Pharmacokinet 2001, 40: The international transporter consortium. Membrane transporters in drug development. Nature Reviews Drug Discovery 2010; 9 : ViiV Soins de santé Shire Canada. Monographie du fabricant : 3TC. Version française. Mississauga (Ontario). Août p. 50. ViiV Soins de santé ULC. Monographie du fabricant : Celsentri. Version française. Montréal (Québec). Août p. 51. ViiV Soins de santé ULC. Monographie du fabricant : Ziagen. Version française. Montréal (Québec). Avril p. 52. Vishnuvardan D, von Moltke LL, Richert C, Greenblat DJ. Lopinavir : Acute Exposure Inhibits P-Glycoprotein; Extended Exposure Induces P-Glycoprotein. AIDS 2003 ; 17 : Weemhoff JL, von Moltke LL, Richert C, et al. Apparent Mechanism-Based Inhibition of Human CYP3A in-vitro by Lopinavir. J Pharm Pharmacol 2003 ; 55 : Weiss J, Rose J, Storch CH, et al. Modulation of Human BCRP (ABCG2) Activity by Anti-HIV Drugs. J Antimicrob Chemother 2007 ; 59 : Yeh RF, Gaver VE, Patterson KB, et al. Lopinavir/Ritonavir Induces the Hepatic Activity of Cytochrome P450 Enzymes CYP2C9, CYP2C19, and CYP1A2 but Inhibits the Hepatic and Intestinal Activity of CYP3A As Measured by a Phenotyping Drug Cocktail in Healthy Volunteers. J Acquired Immune Defic Syndr 2006 ; 42 : Zhang L, Zhang Y, Huang SH. Scientific and Regulatory Perspectives on Metabolizing Enzyme-Transporter Interplay and Its Role in Drug Interactions : Challenges in Predicting Drug Interactions. Mol Pharm 2009; 6 : Zhang Y, Benet LZ. The Gut as a Barrier to Drug Absorption : Combined Role of Cytochrome P450 3A and P-Glycoprotein. Clin Pharmacokinet 2001 ; 40 : Anticoagulants 1. Bayer Inc. Monographi de produit, Xarelto. Toronto, On : Boehringer Ingelheim Canada limitée. Monographiede produit, Pradax. Burlington, On : Bonora S, Lanzafame M, D Avolio A, et al. Drug interactions between warfarin and efavirenz or lopinavir-ritonavir in clinical treatment. Clin Infect Dis 2008;46: Bristol-Myers Squibb Canada. Monographie de produit, Coumadin. Montréal, Qc : Darlington MR. Hypoprothrombinemia during concomitant therapy with warfarin and saquinavir [letter]. Ann Pharmacother 1997; 31: Dionisio D, Mininni S, Bartolozzi D, Esperti F, Vivarelli A, Leoncini F. Need for increased dose of warfarin in HIV patients taking nevirapine. AIDS 2001; 15: Frost C, Wang J, Nepal S, Schuster A, Zhang D, Yu Z et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. J Clin Pharmacol 2009; 49:1123. Abstract Fulco PP, Zingone MM, Higginson RT. Possible antiretroviral therapy warfarin drug interaction. Pharmacotherapy 2008; 28: Fulco PP, Zingone MM, Higgison RT. Possible antiretroviral therapy warfarin drug interaction. Pharmacotherapy 2008;28: Garcia B, De Juana P, Bermejo T, Gomez Rodrigo J, et al. Sequential interaction of ritonavir and nelfinavir with acenocoumarol [abstract 1069] 7th European Conference on Clinical Aspects and Treatment of HIV Infection. Lisbon, Portugal, October 23-27, Gatti G, Alessandrini A, Cemera M, et al. Influence of indinavir and ritonavir on warfarin anticoagulant activity. AIDS 1998; 12: Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165: Horn JR, Hansten PD. Dabigatran : a new oral anticoagulant. Pharmacy times 2010; 12(10) : Hughes CA, Freitas A, Miedzinski LJ. Interaction between lopinavir/ritonavir and warfarin. CMAJ 2007;177(4): Hughes CA, Freitas AJ, Miedzinski LJ. Interaction between lopinavir/ritonavir and warfarin. CMAJ 2007;177: Antiretrovirals and drug interactions

83 16. Knoell KR, Young TM, Cousins ES. Potential interaction involving warfarin and ritonavir. Ann Pharmacother 1998;32: Liedtke MD and Rathbun RC. Warfarin Antiretroviral Interactions. Ann Pharmacother 2009; 43: Liedtke MD, Rathbun RC. Drug interactions with antiretrovirals and warfarin. Expert Opin Drug Saf 2010;9: Llibre JM, Romeu J, Lopez E, and Sirera G. Severe interaction between ritonavir and acenocoumarol. Ann Pharmacother 2002;36: New drug : Xarelto (rivaroxaban). Pharmacist s Letter/ Prescriber s Letter 2008;24(11) : Newshan G, Tsang P. Ritonavir and warfarin interaction. AIDS 1999; 13: Pecora Fulco P., Zingone MM, Higginson RT. Possible antiretroviral therapy-warfarine drug interaction. Pharmacotherapy 2008;28(7): Pradax (dabigatran). Pharmacist s Letter/Prescriber s Letter 2011; 27(1) : Schöller-Gyure, M. et al. Effect of etravirine on cytochrome P450 isozymes assessed by Cooperstown 5+1 cocktail. 48th ICAAC Meeting, Washington, Drug Interaction Report. Abstract A Tagahashi H,Echizen H. Pharmacogenetics of warfarine elimination and its clinical implication. Clin Pharmacokit 2001;40: Vakkalagadda B, Frost C, Wang J, Nepal S, Schuster A, Zhang D et al. Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa. J Clin Pharamcol 2009; 49:1124. Abstract Welzen ME, van den Berk GE, Hamers R and, Burger DM. Interaction between antiretroviral drugs and acenocoumarol. Antiviral Ther, 2011, 16(2): Wong PC, Pinto DJP and Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb 2011; 31: Yeh R, Gaver V, Park J, et al. Lopinavir/ritonavir induces CYP2C9 and 2C19 activity, as measured by warfarin and omeprazole biomarkers in healthy human volunteers. 5th International Workshop on Clinical Pharmacology of HIV Therapy. Rome, Italy April 1-3, 2004 Abstract Antiplatelets 1. Altman R, Vidal HO. Battle of oral anticoagulants in the field of atrial fibrillation scrutinized from a clinical practice (the real world) perspective. J Thromb 2011, 9: Ancrenazl Y, Daali P, Fontana M, et al. Impact of Genetic Polymorphisms and Drug Drug Interactions on Clopidogrel and Prasugrel Response Variability. Current Drug Metabolism 2010; 11 ( 8) : AstraZeneca Canada Inc. Monographie de produit, Brilinta. Mississauga, On : Bates ER, Lau WC, Angiolillo DJ. Clopidogrel Drug interactions. Journal of the American College of Cardiology Vol. 57, No. 11, Close SL. Clopidogrel pharmacogenetics : metabolism and drug interactions. Drug Metab Drug Interact 2011; 26(2) : De Miguel A, Ibanez B, Badimon JJ. Clinical implications of clopidogrel resistance. Thromb Haemost 2008; 100: Eli Lilly Canada Inc. Monographie de produit, Effient. Toronto, On : Farid NA, Kurihara A, Wreighton SA. Metabolism and Disposition of the Thienopyridine Antiplatelet Drugs Ticlopidine, Clopidogrel, and Prasugrel in Humans. J Clin Pharmacol 2010;50: Kim KA, Parl PW, Park JY. Effect of CYP3A5*3 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects. Eur J Clin Pharmacol 2008; 64: Ko JW, Desta Z, et al. In vitro inhibition of the citochrome P450 system by the antiplatelet drug ticlopidine : potent effect on CYP 2C19 and 2D6. J Clin Pharmacol 2000; 49: Lau WC, Gurbel PA, et al. Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance. Circulation. 2004;109: Lau WC, Waskell LA, Watkins PB et al. Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation. A New Drug Drug Interaction. Circulation. 2003;107: Mega, JA, Close SL. Cytochrome P-450 Polymorphisms and Response to Clopidogrel. N Engl J Med 2009;360: Mylan Pharmaceuticals ULC. Monographie de produit, Mylan-Ticlopidine. Etobicoke, On : New Drug: Brilinta (Ticagrelor). Pharmacist a Letter/ Prescriber s Letter. July Nishiva Y, Hagihara K, et al. Mechanism-based inhibition of human cytochrome P450 2B6 by ticlopidine, clopidogrel, ans the thiolactone metabolite of prasugrel. Drug Metab Dispos 2009; 37: Sanofi-aventis Canada Inc. Monographie de produit, Plavix. Laval, Qc: Siller-Matula JM, Krumphuber J, et al. Pharmacokinetic, pharmacodynamic and clinical profil of novel antiplatelet drugs targeting vascular diseases. Br J Pharmacol 2010; 159 : Simon T, Verstuyft C, Mary-Krause M. Genetic D e t e r m i n a n t s o f Re s p o n s e t o C l o p i d o g r e l a n d Cardiovascular Events. N Engl J Med 2009;360: Small DS, Farid NA, Payne CD et al. Effect of Intrinsic and Extrinsic Factors on the Clinical Pharmacokinetics and Pharmacodynamics of Prasugrel. Clin Pharmacokinet 2010; 49 (12): Srinivasan M and Smith D. Drug interaction with antimycobacterial treatmentas a cause of clopidogrel resistance Med J 2008; 84; ARA 1. AstraZeneca Canada Inc, Monographie de produit, Atacand. Mississauga, On : Barreras A, Gurk-Turner C. Angiotensin II receptor blockers. Bayl Univ Med Cent 2003; 16(1) : Boehringer Ingelheim Canada Ltée. Monographie de Cardiology and HIV 83

84 produit, Micardis. Burlington, On : Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encoutered during HIV infection. Clin Pharmacokinet 2002; 41(14) : Laboratoires Abbott, Limitée. Monographie de produit, Teveten. St-Laurent, Qc : Merck Canada Inc. Monographie de produit, Olmetec. Kirkland, Qc : Merck Frosst Canada Ltée. Monographie de produit, Cozaar. Kirkland, Qc : Novartis Pharma Canada Inc. Monographie de produit, Diovan. Dorval, Qc : Sanofi-aventis Canada Inc. Monographie de produit, Avapro. Laval, Qc : Amini H, Ahmadiani A, Moazenzadeh M, Pharmacokinetics of Losartan and its Active Metabolite EXP3174 in Healthy Iranian Subjects. Clin Drug Invest 2004; 24 (10): Antiarrhythmics 1. Apotex Inc. Monographie de produit, Apo-Propafenone. Toronto, On : Astellas Pharma Canada Inc. Monographie de produit Adenocard injectable. Markham, On : AstraZeneca Canada Inc. Monographie de produit, Xylocaine en solutions parentérales. Mississauga, On : Charbit B, Gayat E, Voiriot P, et al. Effects of Protease s on Cardiac Conduction Velocity in Unselected HIV-Infected Patients. Clin Pharmacol Ther 2011 ; 90 : Cheng S, Keyes MJ, Larson MG, et al. Long-term Outcomes in Individuals with Prolonged PR Interval or First-Degree Atrioventricular Block. JAMA 2009; 301(24): Corporation Baxter. Monographie de produit, Brevibloc injectable. Mississauga, On : De Lannoy IA, Silverman M. The MDRI Gene Product, P-Glycoprotein, Mediates the Transport of the Cardiac Glycoside, Digoxin. Biochem Biophys Res Commun 1992 ; 189 : Ding R, Tayrouz Y, Riedel KD, et al. Substantial Pharmacokinetics Interaction Between Digoxin and Ritonavir in Healthy Volunteers. Clin Pharmacol Ther 2004; 76 : Drew BJ, Ackerman MJ, Funk M, et al. Prevention of Torsade de Pointes in Hospital Settings: A Scientific Statement From the American Heart Association and the American College of Cardiology Foundation. Circulation. 2010;121: Englund G, Hallberg P, Artursson P, et al. Association between the number of co-administered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring. BMC Med 2004;2(8): Grube S, Langguth P, et al. Biowaiver monographs for immediate release solid oral dosage forms: quinidine sulfate. J Pharm Sci 2009; 98: Haffajee CI, Love JC, et al. Clinical pharmacokinetics and efficacy of amiodarone for refractory tachyarrhythmias. Circulation 1983; 67: Jenkins AT, Oliphant C, Self TH. Amiodarone Drug Interactions. Consultant Live 2006 ; 46 (14). 14. Johnston A, Warrington S, Turner P. Flecainide pharmacokinetics in healthy volunteers : the influence of urinary ph. Br J Clin Pharmac 1985; 20 : Kaeser B, Wafa J, Riek M, et al. Effect of Saquinavir/ Ritonavir on the P-gp Activity in Healthy Volunteers Using Digoxin as a Probe. 46th Annual ICAAC. September 27-30, San Francisco. Abstract A Lessard E, Hamelin BA et all. Involvement of CYP2D6 activity in the N-oxidation of procainamide in man. Pharmacogenetics 1999; 9 (6) : Libersa CC, Brique SA, Motte KB, et al. Dramatic inhibition of amiodarone metabolism induced by grapefruit Juice. Br J Clin Pharmacol 2000; 49, Masereeuw R, Russel FGM. Therapeutic Implications of Renal Anionic Drug Transporters. Pharmacol Ther 2010 ; 126 : Maxwell DL, Gilmour-White SK, Hall MR. Digoxin Toxicity Due to Interaction of Digoxin With Erythromycin. BMI 1989 ; 298 : Noord CV, Eijgelsheim M, Stricker BH. Druf and non-drug associated QT interval prolongation. Br J Clin Pharmacol 2010; 70(1): Ohyama K, Kakajima M, et al. y effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: Prediction of in vivo drug interactions. Br J Clin Pharmacol 2000; 49: Penzak SR, Shen JM, Alfaro RM, et al. Ritonavir decreases the nonrenal clearance of digoxin in healthy volunteers with known MDR1 genotypes. Ther Drug Monitor 2004; 26(3): Pfizer Canada Inc. Monographie de produit, Corvert injectabl. Kirkland, Qc : Pharmascience Inc. Monographie de produit, Lanoxin. Montréal, Qc : Philips EJ, Rachlis AR, Ito S. Digoxin toxicity and ritonavir: a drug interaction mediated through p-glycoprotein? AIDS 2003, 17: Sanofi-aventis Canada Inc. Monographie de produit, Multaq. Laval, Qc : Sanofi-aventis Canada Inc. Monographie de produit, Rythmodan. Laval, Qc : Sanofi-Synthelabo. Monographie de produit, Cordarone. Kirkland, Qc : Schöller-Gyüre M, Kakuda TN, Van Solingen-Ristea RM, et al. No clinically relevant effect of etravirine (ETR; TMC125) on digoxin pharmacokinetics in HIV-negative volunteers 9th International Workshop on Clinical Pharmacology of HIV Therapy; 2008 : abstract P Soliman EZ, Lundgren JD, et all. Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations. AIDS 2011; 25 : Beta-blockers 1. Apotex Inc. Monographie de produit, Apo-Carvedilol. Weston, On: AstraZeneca Canada Inc. Monographie de produit, Tenormin. Mississauga, On : AstraZeneca UK limited, Pfizer Canada Inc. Monographie de produit, Indéral-La. Kirkland, Qc: Fux R, Mö rike K, Pröhmer AMT, et al. Impact of CYP2D6 genotype on adverse effects during treatment with 84 Antiretrovirals and drug interactions

85 metoprolol: A prospective clinical study. Clin Pharmacol Ther 2005; 78: Hingorani G, Jianhong W, et al. Human hepatic stability screening: a simplified higher throughoput assay and evaluation of different hepatocyte preparations. Biopharma. 6. Kirchheiner J, Heesch C, Bauer S, et al. Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2004;76(4): Lilja JJ, Raaska K et al. Effets of grapefruit juice on the pharmacokinetics of acebutolol. Br. J. Clin. Pharmacol. 2005; 60 : Mylan Pharmaceuticals ULC. Monographie de produit, Mylan-Sotalol. Etobicok, On : Novartis Pharma Canada Inc. Monographie de produit, Lopresor. Dorval, Qc: Paladin Labs Inc. Monographie de produit, Trandate. Montréal, Qc: Puech R. et al. Extreme bradycardia due to multiple drugdrug interaction in a patient with HIV post-exposure prophylaxis containing lopinavir-ritonavir. Br J Clin Pharmacol, 2011, 71(4): Sandoz Canada Inc. Monographie de produit, Labétalol injectable. Boucherville, Qc: Sanofi-aventis Canada Inc. Monographie de produit, Sectral. Laval, Qc : Zineh I, Beitelshees AL, Gaedigk A, et al. Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension. Clin Pharmacol Ther 2004; 76(6): Calcium channel blockers 1. Apotex Inc. Monographie de produit, Apo-Diltiaz TZ. Weston, On : AstraZeneca Canada Inc. Monographie de produit, Plendil. Mississauga, On : Baeza MT, Merino E, Boix V, et al. Nifedipine lopinavir/ ritonavir severe interaction: a case report. AIDS 2007; 21 (1) : Bayer Inc. Monographie de produit, Adalat XL. Toronto, On : Bayer Inc. Monographie de produit, Nimotop. Toronto, On : Izzedine H, Launay-Vacher V, Deray G, Hulot JS. Nelfinavir and felodipine: a cytochrome P450 3A4-mediated drug interaction. Clin Pharmacol Ther 2004; 75(4): Kaul S, et al. Pharmacokinetic interaction between efavirenz and diltiazem or itraconazole after multiple-dose administration in adult healthy subjects. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 2007, abstract Laboratoires Abbott Limitée. Monographie de produit, Isoptin SR. St-Laurent, Qc : Pfizer Canada Inc. Monographie de produit, Norvasc. Kirkland, Qc : Rossi DR, RathbunRc, Slater LN. Symptomatic orthostasis with extended-release nifedipine and protease inhibitors. Pharmacother 2002; 22 : ACEIs 1. Apotex Inc. Monographie de produit, Apo-Capto. Weston, On : AstraZeneca Canada Inc. Monographie de produit, Zestril. Mississauga, On : Bristol-Myers Squibb Canada Inc. Monographie de produit, Monopril. Montréal, Qc : Hoffmann-La Roche Limitée. Monographie de produit, Inhibace Plus. Mississauga, On : Laboratoires Abbott Limitée. Monographie de produit, Mavik. St-Laurent, Qc : M.C. de Parke, Davis & Company, Pfizer Canada Inc. Monographie de produit, Accupril. Kirkland, Qc : Merck Frosst Canada Ltée. Monographie de produit, Vasotec. Kirkland, Qc : Novartis Pharma Canada Inc. Monographie de produit, Lotensin. Dorval, Qc : Sanofi-aventis Canada Inc. Monographie de produit, Altace. Laval, Qc : Servier Canada Inc. Monographie de produit, Coversyl. Laval, Qc : Hypolipidemics 1. Aberg JA, Rosenkranz SL, Fichtenbaum CJ, et al. Pharmacokinetic interaction between nelfinavir and pravastatin in HIV-seronegative volunteers: ACTG Study A5108. AIDS 2006, 20: Aberg JA, Zackin RA, Brobst SW et al. A randomized trial of the efficacy and safety of fenofibrate versus pravastatine in HIV-infected subjects with lipid abnormalities : AIDS clinical trials group study AIDS Res Hum Retrovirus 2005;21:L Apotex Inc. Monographie de produit, Apo-Pravastatin. Weston, On : Aquilante, C. Kiser, J. Anderson, P. et al. DRV/R, pravastatin and pharmacogenetics: Influence of SL01B1 polymorphisms on pharmacokinetic variability in the drug-drug interaction between darunavir/ritonavir and pravastatin. Drug Interaction & Pharmacology Presentations at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, September Abstract A AstraZeneca Canada Inc. Monographie de produit, Crestor. Mississauga, On : Barry M, Belz G, Roll S, et al. Interaction of nelfinavir with atorvastatin and pravastatin in normal healthy volunteers. 5th International Congress on Drug Therapy in HIV Infection, October 2000, Glasgow, UK Abstract P260A. 7. Bertz R, Hsu A, Lam L, et al. Pharmacokinetic interactions between Kaletra (lopinavir/ritonavir or ABT-378/r) and other non-hiv drugs. 5th International Congress of Drug Therapy in HIV Infection. Glasgow, Scotland Abstract Bottaro EG, Cravello O, Scapellanto PG et al. Rosuvastatine for treatment of dyslipidemia in HIV-infected patients receiving highly active antiretroviral therapy. Enferm Infecc Microbiol Clin 2008 Jun-Jul;26(6): Burger D, Stroes E, Reiss P et al. Drug interactions between statins and antiretroviral agents. Current opinion in HIV and AIDS 2008;3: Cardiology and HIV 85

86 10. Busti AJ, Bain AM, et all. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol 2008; 51(6) : Carr TA, Andre AK, Bertz RJ, et al. Concomitant administration of ABT-378/ritonavir results in a clinically important pharmacokinetic interaction with atorvastatin but not pravastatin. 40th ICAAC, Toronto, September 2000, presentation Cheng CH, Miller C, Lowe C, et al. Rhabdomyolysis due to probable interaction between simvastatin and ritonavir [In Process Citation]. Am J Health Syst Pharm 2002 Apr 15;59(8): Davidson MH, Clark JA, et all. Statin safety : an appraisal from the adverse event reporting system. Am J Cardiol 2006; 97(suppl) : 32C-43C. 14. Dube MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003 Sep 1;37(5): Farnier M. Safety review of combination drugs for hyperlipidemia. Expert Opin Drug Saf 2011; 10 (3) : Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002 Mar 8;16(4): Gerber JG, Rosenkranz SL, Fichtenbaum CJ, et al. Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study. J Acquir Immune Defic Syndr 2005, 39(3): Hare CB, Vu MP, Grunfeld C, Lampiris HW. Simvastatinnelfinavir interaction implicated in rhabdomyolysis and death. Clin Infect Dis 2002, 35: e H e d m a n M, N e u vonen P J, N e u vonen M, e t a l. Pharmacokinetics and Pharmacodynamics of Pravastatin in Pediatric and Adolescent Cardiac Transplant Recipients on a Regimen of Triple Immunosuppression. Clin Pharmacol Ther 2004 ; 75 : Hoody D, et al. Drug-drug interaction between lopinavir/ ritonavir and rosuvastatin. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 2007, abstract Hsyu PH, Schultz-Smith MD, Lillibridge JH, et al. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001, 45: Huang L, Wang Y, Grimm S. ATP-Dependent Transport of Rosuvastatin in Membrane Vesicles Expressing Breast Cancer Resistance Protein. Drug Metab Dispos 2006 ; 34 : Ieiri I, Higuchi S, Sugiyama Y. Genetic Polymorphisms of uptake (OATP1B1, 1B3) and Efflux (MRP2, BCRP) Transporters: Implications for Inter-Individual Differences in the Pharmacokinetics and Pharmacodynamics of Statins and Other Clinically Relevant Drugs. Exper Opin Drug Metab Toxicol 2009 ; 5 : Jacobson TA. Comparative Pharmacokinetic Interaction Profiles of Pravastatin, Simvastatin and Atorvastatin When Coadministered Whit Cytochrome P450 s. Am J Cardiol 2004 ; 94 : Kalliokoski A, Niemi M. Impact of OATP Transporters on Pharmacokinetics. Br J Pharmacol 2009 ; 158 : Kiser JJ, Gerber JG, Predhomme JA, et al. Drug/Drug Interaction Between Lopinavir/Ritonavir and Rosuvastatin in Healthy Volunteers. J Acquired Immune Defic Syndr 2008 ; 47 : Kitamura S, Maeda K, Wang Y, Sugiyama Y. Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin. Drug Metab Dispos 2008 ; 36 : Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B Transporter Inhibition on the Pharmacokinetics of Atorvastatin in Healthy Volunteers. Clin Pharmacol Ther 2007 ; 81 : Lennernas H. Clinical Pharmacokinetics of Atorvastatin. Clin Pharmacokinet 2003 ; 42 : Martin PD, Warwick MJ, Dane AL, et al. Metabolism, Excretion and Pharmacokinetics of Rosuvastatin in Healthy Adult Male Volunteers. Clin Ther 2003 ; 25 : Merck Canada Inc. Monographie de produit, Mevacor. Kirkland, Qc : Merck Canada Inc. Monographie de produit, Zocor, Kirkland, Qc : Moyle GJ, Buss NE, Gazzard B. Pravastatin 40 mg qd does not alter protease inhibitor exposure or virological efficacy over 24 weeks therapy. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 2002, abstract 446-W 34. Neuvonen PJ, Niemi M, Backman JT. Drug Interactions With Lipid-Lowering Drugs: Mechanisms and Clinical Relevance. Clin Pharmacol Ther 2006 ; 80 : Noe J, Portmann R, Brun ME, Funk C. Substrate- Dependant Drug-Drug Interaction Between Gemfibrozil, Fluvastatin and Other Organic Anion-Transporting Peptide (OATP) Substrates on OATP1B1, OATP1B2, and OATP1B3. Drug Metab Dispos 2007 ; 35 : Novartis Pharma Canada Inc. Monographie de produit, Lescol. Dorval, Qc : Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M. SLCO1B1 Polymorphism Markedly Affects the Pharmacokinetics of Simvastatin Acid. Pharmacogenet Genomics 2006 ; 16 : Penzak SR, Chuck SK, and Stajich GV. Safety and efficacy of HMG-CoA reductase inhibitors for treatment of hyperlipidemia in patients with HIV infection. Pharmacother 2000; 20(9): Pfizer Ireland Pharmaceuticals. Monographie de produit, Lipitor. Kirkland, Qc : Pham PA, la Porte CJ, Lee LS, et al. Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother 2009, 53(10): Samineni D, Desai PB, Sallans L, Fichtenbaum CJ. Steadystate pharmacokinetic interactions of darunavir/ritonavir with lipid-lowering agent rosuvastatin. J Clin Pharmacol 2011, Epub ahead of print. 42. Schmidt GA, Hoehns JD, Purcel JL et al. Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvasttain, amiodarone, and atazanavir. J Am Board Fam Med 2007;20 : Scholler-Gyure M, Kakuda TN, De Smedt G, et al. Pharmacokinetic interaction between the non-nucleoside reverse transcriptase inhibitor TMC125 and atorvastatin 86 Antiretrovirals and drug interactions

87 in HIV-negative volunteers. 4th IAS Conference on HIV Pathogenesis, Treatment & Prevention, Sydney, July 2007, abstract WEPEA Sekar VJ, et al. Pharmacokinetic drug-drug interaction between the new HIV protease inhibitor darunavir (TMC114) and the lipid-lowering agent pravastatin. 8th International Workshop on Clinical Pharmacology of HIV Therapy, Budapest, April 2007, abstract Van der Lee M, Sankatsing R, Schippers E, et al. Pharmacokinetics and pharmacodynamics of combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected patients. Antiviriral Therapy 2007;12(7): Van Heeswijk R, et al. The pharmacokinetic interaction between atorvastatin and TMC278, a next generation nonnucleoside reverse transcriptase inhibitor, in HIV-negative volunteers. 11th European AIDS Conference, Madrid, October 2007, abstract P4.3/ Van Heeswijk R, Sabo JP, Cooper C, et al. The pharmacokinetic interactions between tipranavir/ritonavir 500/200 mg BID (TPV/r) and atorvastatin, antacid, and CYP3A4 in healthy adult volunteers. 5th International Workshop on Clinical Pharmacology of HIV Therapy. Rome, Italy April 1-3, 2004 Abstract Van Luin M, Colbers A, Van Ewijk-Beneken Kolmer E W J, e t a l. D r u g d r u g i n t e r a c t i o n s b e t w e e n raltegravir and pravastatin in healthy volunteers. 11th International Workshop on Clinical Pharmacology of HIV Therapy,Sorrento, April 2010, abstract Actavis Group PTC. Monographie de produit, Bezalip SR. Islande Busse, K., et al. Lopinavir/ritonavir significantly decreases gemfibrozil plasma concentrations in healthy volunteers. 48th ICAAC Meeting, Washington, Drug Interaction Report. Abstract A Fournier Pharma Inc. Monographie de produit, Lipidil Supra. St-Laurent, Qc: Jackson A, Moyle G, Watson V, et al. Variability in steady state raltegravir pharmacokinetics, impact of ezetimibe? 10th International Workshop on Clinical Pharmacology of HIV Therapy, Amsterdam, Avril Drug Interaction Report, Abstract P Klibanov OM, et al. The effect of ezetimibe on the steadystate trough levels of lopinavir/ritonavir. 8th International Workshop on Clinical Pharmacology of HIV Therapy, Budapest, April 2007, abstract Merck Canada Inc. Monographie de produit, Ezetrol. Kirkland, Qc : MM Thérapeutiques Inc. Monographie de produit, Olestyr. Montréal, Qc : Molto J, Valle M, Negredo E, Blanco A, Puig J, Miranda C, et al. The effect of ezetimibe on the steady-state pharmacokinetics of lopinavir. 7th International Workshop on Clinical Pharmacology of HIV Therapy Lisbon Abtract Oswald S, Scheuch E, Cascorbi I, Siegmund W. A LC-MS/ MS Method to Quantify the Novel Cholesterol Lowering Drug Ezetimibe in Human Serum, Urine and Feces in Healthy Subjects Genotyped for SCLO1B1. J Chromatogr Analyt Technol Biomed Life Sci 2006 ; 830 : Pfizer Canada Inc. Monographie de produit, Colestid. Kirkland, Qc : Sepracor Pharmaceuticals Inc. Monographie de produit, Niaspan FCT. Mississauga, On : Wa r n e r-lambert C o m p a ny, P f i z e r C a n a d a I n c. Monographie de produit, Lopid. Kirkland, Qc : Kanter CTMM, Keuter M, van der Lee MJ, et al. Rhabdomyolysis in an HIV-infected patient with impaired renal function concomitantly treated with rosuvastatin and lopinavir/ritonavir. Antiviral Ther, 2011, 16(3): Cardiology and HIV 87

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