PsychotroPic and Vih January 2014

Transcription

1 Psychotropics and VIH January 2014

2 Author : Rachel Therrien, Pharmacist at CHUM s (Centre hospitalier de l Universite de Montreal) UHRESS (Unité hospitalière de recherche, d enseignement et de soins sur le sida). Collaborators Contributed to writing and revising this document: Geneviève Duplain Cyr, Pharmacist at the CHUS (Centre hospitalier universitaire de Sherbrooke) SAMI (soins ambulatoires en maladies infectieuses) Clinic. Benoît Rouleau, Pharmacist specialized in psychiatry at the Jewish General Hospital. Release of liability While the authors endeavours to keep up to date on the latest information, they would like to point out that developments in HIV treatment and in psychiatry are constantly evolving. For example, although not mentioned in the follow-up for antidepressants and antipsychotics, recent literature has documented the positive aspects of using plasma assay techniques for these agents (pharmacometrics). The use of pharmacometric techniques for antidepressants and antipsychotics could allow for dose adjustments in the context of a drug interaction. This document was designed as a reference only, and the authors encourage 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 authors do not recommend or promote any of the treatments described in this work. Accordingly, they 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 2014 Document available at : 2 Psychotropics and HIV

3 Foreword Antiretrovirals are known to often be responsible for drug interactions due to their pharmacodynamic 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 psychiatry. It was prepared with 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 psychiatric disorders. 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 s), PIs (protease s), maraviroc, raltegravir, and elvitegravir. Legend The arrows indicate variation in the AUC (potential or observed) of the associated drug (red arrows) or antiretroviral (blue arrows). The solid arrow refers to pharmacokinetics studies or reports of cases in the literature. The empty arrow refers to an extrapolation of the drug interaction based on the pharmakokinetics of both drugs: No interaction was observed. No interaction is anticipated. 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 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 decrease in the plasma concentration of the associated drug or antiretroviral. An increase in the dose may be necessary. Monitor clinical efficacy. Potential decrease in the plasma concentration of the associated drug or antiretroviral. An increase in the dose may be necessary. Monitor clinical efficacy. The background color indicates the degree of interaction Pink Grey Light blue Dark blue No interaction or interaction deemed not clinically significant. Combination that requires close monitoring. Dose adjustments may be recommended. Avoid combination. If this is not possible, carry out the required dose adjustments and ensure close monitoring. Combination contraindicated. Chose an alternative to using the associated drug or antiretroviral. No interaction Adjustement and/or follow-up Avoid Contraindicated Psychotropics 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 PI Viral protease SSRI Selective serotonin reuptake UGT Uridine diphosphate glucuronosyltransferase II Integrase s 4 Psychotropics and HIV

5 Table of content Foreword...3 Glossary...4 Metabolism of antiretrovirals Metabolism of non-nucleoside reverse transcriptase inhibitors (NNRTIs)...6 Metabolism of viral protease inhibitors (PIs)...7 Metabolism of integrase inhibitors (IIs)...10 Metabolism of the CCR5 inhibitor...10 Selective serotonin reuptake inhibitor (SSRI) Metabolism of SSRI...11 Tablea of interactions : SSRIs and NNRTIs...12 Table of interactions : SSRIs and PIs...15 Tablea of interactions : SSRIs and CCR5 or II inhibitors...19 Other antidepressants Metabolism of other antidepressants...20 Table of interactions other antidepressants and NNRTIs...21 Table of interactions other antidepressants and PIs...23 Table of interactions other antidepressants and CCR5 or II inhibitors...26 Antipsychotics Metabolism of antipsychotics...27 Table of interactions antipsychotics and NNRTIs...29 Table of interactions antipsychotics and PIs...31 Table of interactions antipsychotics and CCR5 or II inhibitors...37 References...38 Psychotropics and HIV 5

6 Metabolism of NNRTIs Substrates s/inducers Elimination Efavirenz (Sustiva, Atripla) 3A4 and 2B6 (major) Inactive hydroxlated metabolites P-gp (weak) 2C9, 2C19 and 3A4 (moderate) BCRP, MRP1, MRP2 and MRP3 (weak) Urine: 14% - 34% as metabolites Feces: 16% - 61%, mainly as unchanged drug Inducer 3A4 (strong) CYP 2B6 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 against HIV P-gp 2C9 and 2C19 (moderate) P-gp (weak) Inducer 3A4 (strong) Urine: 1% Feces: 94%, up to 86% as unchanged drug T½: 41 h (± 20 h) 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) Urine: 81%, mainly as metabolites, and less than 3% as unchanged drug Feces: 10% BCRP, MRP1, MRP2 and MRP3 (weak) T½: Single dose: 45 h Multiple doses: h (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: h 6 Psychotropics and HIV

7 Metabolism of PIs Substrates s/inducers Elimination Atazanavir (Reyataz) 3A4 (major) Inactive metabolites BCRP, MRP1, MRP2 and P-gp 3A4 (strong) 2C8 (moderate) * UGT1A1 (moderate) BCRP, MRP1, MRP2, OATP1B1, OATP1B3, OATP2B1 and 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). 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 h without ritonavir, 9-18 hours with ritonavir However, no clinically significant interaction is anticipated during coadministration of the atazanavir/ritonavir combination and CYP2C8 substrates. Inducer Increases expression of P-gp and MRP1 Darunavir (Prezista) 3A4 (major) OATP1A2, OATP1B1 and P-gp 3A4 (strong), 2D6 (ritonavir effect) MRP2, OATP1B1, OATP1B3 and P-gp Inducer 2C9, 2C19 and 2C8 (ritonavir effect) Urine: 14% with 8% as unchanged drug Feces: 80% with 41% as unchanged drug T½: 15 h (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% as metabolites, less than 1% as unchanged drug T½: h with ritonavir Psychotropics and HIV 7

8 Metabolism of PIs Substrates s/inducers Elimination Lopinavir/r (Kaletra) 3A4 (major) 13 metabolites identified, including 5 metabolites linked to the metabolism of ritonavir 3A4 and 2D6 (strong) BCRP, MPR2, OATP1A2, OATP1B1, OATP1B3, OATP2B1 and P-gp* Urine: 10% with less than 3% as unchanged drug Feces: 83% with 20% as unchanged drug) MRP1, MRP2, P-gp, OATP1A2 and OATP1B1 Inducer 2C19 (strong) 1A2, 2C9 and UGT (moderate) T½: 5 à 6 h 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 (minors) P-gp, MRP1 and MRP2 3A4 (strong) BCRP, MRP1, OATP1A2, OATP1B1, OATP2B1, OCT1, OCT2 and P-gp Inducer CYP 2C8, 2C9, 2B6, 2C19 and 1A2 (potential) Increases expression of P-gp Urine: 1% - 2% Feces: 98% - 99% with 78% as metabolites and 22% as unchanged drug T½: h Ritonavir (Norvir) 3A4 and 2D6 (majors) 1A2 and 2B6 (minors) 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 and MRP2 BCRP, OATP1A2, OATP1B1, OATP1B3, MRP1, MRP2, OCT1, OCT2 and P-gp Inducer 2B6, 2C8, 2C9, 1A2 and 2C19 (moderate) Feces: 86% with 34% as unchanged drug T½: 3-5 h UGT (moderate) 8 Psychotropics and HIV

9 Metabolism of PIs Substrates s/inducers Elimination Saquinavir (Invirase) 3A4 (major), significant first-pass effect in the liver Quickly metabolized into a range of mono or bi-inactive bi-hydroxylated components 3A4 (moderate) BCRP, MRP1, MRP2, OATP1A2, OATP1B1, OATP1B3, OATP2B1, OCT1, OCT2 and P-gp Urine: 1% - 3% Feces: 81% - 88% T½: 7-12 h with ritonavir MRP1, MRP2, OTP1A2, OATP1B1, OATP1B3 and 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 h with ritonavir P-gp (strong) There may be both an inhibition and an induction effect with the tipranavir / ritonavir combination. The net effect is often inhibition, but this depends on the substrate. Psychotropics and HIV 9

10 Metabolisme of IIs Substrates s/inducers Elimination Raltegravir (Isentress) UGT1A1 Urine: 32% with 9% as unchanged drug Feces: 51% as unchanged drug T½: biphasic Phase 1 : 1 h Phase 2 : 9 h Elvitegravir/ Cobicistat Elvitegravir 3A4 and then UGT1A1/3 Cobicistat 3A4 (major) and 2D6 (minor) 3A4 (strong), 2D6 (moderate) P-gp, BCRP, OATP1B1 and OATP1B3 Inducer 2C9 (moderate) Elvitegravir Urine: 6,7% Feces: 94,8% (hepatobiliary secretion) T½: 12.9 h Cobicistat Urine: 8,2% Feces: 86% (hepatobiliary secretion) T½: 3.5 h Dolutegravir (Tivicay) UGT1A1 (51%) CYP3A (21%) UGT1A9 (6%) UGT1A3 (3%) Transporters: P-gp, BCRP Metabolism of the CCR5 inhibitor Substrates s/inducers Elimination Maraviroc (Celsentri) 3A4 (major) 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: h 10 Psychotropics and HIV

11 Metabolism of SSRIs Substrates s/inducers Elimination Citalopram (Celexa) 2C19 and 3A4 (major) 2D6 (minor) Metabolite (with also an activity): demethylcitalopram 2D6 (very weak), 2C19 and 2C9 (negligible) Urine: 12% as citalopram T½: 37 h Escitalopram (Cipralex) 2C19 and 3A4 (major) 2D6 (minor) Metabolite (with also an activity): demethylcitalopram 2D6 (très weak), 2C9 and 2C19 (negligible) Urine: 8% as escitalopram and 8% as S-desmethylcitalopram T½: h Fluoxetine (Prozac) 2D6 (major), 2C9 and 2C19 (moderate) 1A2, 2B6, 2E1 and 3A4 (minor) Mainly metabolized to norfluoxetine (with activity similar to that of the parent compound) and several other metabolites. Non-linear pharmacokinetics. First-pass effect in the liver is significant but can be saturated. 2D6 (strong), 1A2 and 2C19 (moderate), 2B6, 2C9 and 3A4 (weak or moderate), P-gp Urine: 10% as norfluoxetine and 2.5-5% as fluoxetine T½ (fluoxetine): 4-6 days T½ (metabolites): 4-16 days Note: After stopping fluoxetine, it can take up to 1-2 months to eliminate fluoxetine and its metabolites Fluvoxamine (Luvox) 2D6 (major), 1A2 (minor) Metabolites with negligible activity Non-linear pharmacokinetics Significant first-pass effect in the liver 1A2 and 2C19 (strong), 3A4, 2C9 and 2D6 (moderate), P-gp Urine: 85% as metabolites and 2% as unchanged drug. T½: 9-28 h Paroxetine (Paxil) 2D6 (major), 1A2 and 3A4 (minor) Biphasic metabolism The metabolites have a negligible effect 2D6 (strong), 2B6 (moderate), 1A2, 2C19, 2C9 and 3A4 (weak), P-gp Urine: 64% (2% as unchanged drug) Feces: 36% T½: about 24 h First-pass effect in the liver is significant but can be saturated. Sertraline (Zoloft) 3A4 (major), 2D6, 2B6, 2C9, 2C19 (moderate), UGT2B7 Significant first-pass effect in the liver 2B6, 2C19, 2D6 and 3A4 (moderate) 1A2, 2C8 and 2C9 (weak) CYP450 inhibition is clinically significant at doses greater than 100 mg/day Urine: 40-45% as metabolites Feces: 40-45% T½: h Psychotropics and HIV 11

12 SSRIs and NNRTIs Citalopram (Celexa) Escitalopram (Cipralex) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Efavirenz (Sustiva, Atripla) 1,2 1,2 2,5 2,7 2,8 2,11 Etravirine (Intelence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) ,7 6 6 No interaction Adjustement and/or follow-up Avoid Contraindicated Legend 1. Possible or of the plasma concentration of citalopram or escitalopram. The metabolism of citalopram and escitalopram is primarily influenced by CYP2C19 inhibitors (see the FDA warning). Efavirenz and etravirine can inhibit CYP2C19 and potentially increase the plasma concentration of citalopram and escitalopram. The monograph states that citalopram in combination with omeprazole, a CYP2C19 inhibitor, reduces the rate of formation of demethylcitalopram (metabolite of citalopram) by 75-85%. Moreover, an increase of 107% in the AUC of citalopram was observed in individuals who were slow metabolizers of CYP2C19. However, efavirenz and etravirine can also induce CYP3A4 and potentially reduce the plasma concentration of citalopram and escitalopram. The net effect is difficult to predict. A pharmacokinetic modeling study predicts a decrease of 24% in the AUC of citalopram when combined with efavirenz. Moreover, two cases of exacerbation of panic attacks have been published concerning rifampicine (potent inducer of CYP3A4) combined with citalopram. FDA warning: Citalopram is associated with a risk of QTc prolongation, which may be responsible for torsade de pointes, ventricular tachycardia and sudden death. The FDA recommends a maximum citalopram dose of 40 mg per day (20 mg for escitalopram). Doses of more than 40 mg provide no additional benefit and are associated with a greater risk of QTc prolongation. 12 Psychotropics and HIV

13 SSRIs and NNRTIs Citalopram is not recommended for patients presenting with congenital QTc prolongation, bradycardia, hypokalemia or hypermagnesemia, recent myocardial infarction or decompensated heart failure. Furthermore, citalopram is not recommended for patients who are taking other drugs that could increase the QTc interval ( A maximum citalopram dose of 20 mg (10 mg for escitalopram) is recommended for individuals age 60 and over presenting with liver failure or known as slow metabolizers of CYP2C19, or who are taking a drug that could inhibit CYP2C19*. These factors are associated with an increase in the plasma concentration of citalopram, therefore a higher risk of QTc prolongation. Citalopram should be stopped if the patient has a persistent QTc increase of over 500 ms. Recommendation: Caution must be exercised when using citalopram with CYP2C19 inhibitors such as efavirenz and etravirine, especially in the presence of risk factors for QTc interval prolongation. In this case, there may also be induction of CYP3A4, hence the real clinical effect remains unknown. Use the smallest possible dose while respecting the recommendations mentioned above. Monitor electrolytes and/or ECG. Try to reduce all QTc prolongation risk factors. Advise patients to promptly contact a doctor if they have signs or symptoms associated with heart rhythm disorders (dizziness, palpitations, syncope). 2. Adverse effects of a psychiatric nature (such as anxiety, nervousness, sleep disorders and depression) are possible with efavirenz. Recommendation: If symptoms of a psychiatric nature present de novo, assess whether the efavirenz could be responsible for these symptoms before contemplating starting a psychotropic. A change in treatment could be considered. 3. Theoretical reduction in the effect of citalopram and escitalopram due to the potential CYP3A4 induction by nevirapine. In fact, two cases of exacerbation of panic attacks have been published concerning rifampicine (potent inducer of CYP3A4) combined with citalopram. Several cases have also been reported by the FDA. 4. No pharmacokinetic interaction is expected due to the weak effect of CYP3A4 induction by rilpivirine. However, caution must be exercised, since rilpivirine and citalopram or escitalopram are associated with a risk of QTc interval prolongation. Recommendation: See (in point 1) the FDA recommendations for preventive measures with citalopram and escitalopram, and the risk of QTc prolongation. 5. Clinical effect unknown. The potential effect is difficult to predict because fluoxetine is metabolized into an active metabolite with activity comparable to the parent drug. Moreover, it is metabolized by more than one CYP. For example, efavirenz could inhibit CYP2C19 and CYP2C9, and increase fluoxetine while decreasing norfluoxetine (activity comparable to fluoxetine). In addition, CYP2D6, if not inhibited by another drug, should continue the metabolism of fluoxetine. The clinical effect is thus unknown. A pharmacokinetic modeling study demonstrated an increase of 11% in the fluoxetine AUC due to the possible suspected inhibition of CYP2C9/2C19. Recommendation: Start fluoxetine at the lowest possible dose and increase gradually according to the patient s clinical response and tolerance. Psychotropics and HIV 13

14 SSRIs and NNRTIs 6. Caution must be exercised, since rilpivirine and psychotropic drugs are associated with a risk of QTc prolongation. Recommendation: Avoid or monitor closely in the presence of bradycardia, hypokalemia or hypermagnesemia, or when there is concurrent use of other drugs that could increase the QTc interval ( Monitor electrolytes and/or ECG. Try to reduce all QTc prolongation risk factors. 7. A weak increase in NNRTI plasma concentrations is possible due to the potential CYP3A4 inhibition by fluvoxamine. Probably without clinical consequence. In a cohort study, a reduction of approximately 35% was observed in the clearance of nevirapine when combined with fluvoxamine. Recommendation: No dose adjustment is recommended, since there is probably no clinical consequence. 8. The combination of paroxetine 20 mg QD and efavirenz 600 mg QD for 14 days showed no effect on the pharmacokinetics of these two drugs. Recommendation: No dose adjustment is necessary. 9. The combination of paroxetine 20 mg QD (x 7 days) and efavirenz 800 mg BID (x 14 days) showed no effect on the pharmacokinetics of these two drugs. Recommendation: No adjustment is required. 10. No pharmacokinetic interaction is expected. 11. The combination of sertraline 50 mg QD and efavirenz 600 mg QD reduced the Cmax, AUC and Cmin of sertraline by 29%, 39% and 46%, respectively. Moreover, a pharmacokinetic modeling study demonstrated a decrease of 41% in the sertraline AUC. Recommendation: Monitor the clinical efficacy of sertraline and adjust the dose as necessary. 12. Etravirine and nevirapine can increase the metabolism (via CYP3A4 induction) and reduce the plasma concentration of sertraline. Recommendation: Monitor the clinical efficacy of sertraline and adjust the dose as necessary. 14 Psychotropics and HIV

15 SSRIs and PIs Citalopram (Celexa) Escitalopram (Cipralex) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Atazanavir (Reyataz) Atazanavir/r (Reyataz) Darunavir/r (Prezista) Fosamprenavir/r (Telzir) Lopinavir/r (Kaletra) Nelfinavir (Viracept) Saquinavir/r (Invirase) Tipranavir/r (Aptivus) No interaction Adjustement and/or follow-up Avoid Contraindicated Psychotropics and HIV 15

16 SSRIs and PIs Legend 1. Possible of citalopram and escitalopram due to CYP3A4 inhibition by atazanavir and nelfinavir. In a study conducted on 18 healthy subjects, the combination of escitalopram 20 mg and ritonavir 600 mg showed no significant interaction. In another study, the concomitant administration of a single dose of citalopram 40 mg and a single dose of ketoconazole 200 mg (a potent CYP3A4 inhibitor) did not change the pharmacokinetic profile of citalopram. Recommendation: No dose adjustment is recommended. Monitor for the appearance of adverse effects and adjust the dose of citalopram or escitalopram, if deemed necessary. 2. Possible of citalopram or escitalopram due to CYP2C19 induction by ritonavir. Citalopram or escitalopram may also due to CYP3A4 inhibition by ritonavir. However, in a study conducted on 18 healthy subjects, the combination of escitalopram 20 mg and ritonavir 600 mg showed no significant interaction. In another study, the concomitant administration of a single dose of citalopram 40 mg and a single dose of ketoconazole 200 mg (a potent CYP3A4 inhibitor) did not change the pharmacokinetic profile of citalopram. A pharmacokinetic modeling study predicts a decrease of 20% in the citalopram AUC. Moreover, an increase of 107% in the AUC of citalopram was observed in individuals who were slow metabolizers of CYP2C19. An increase in citalopram was observed when combined with a CYP2C19 inhibitor (e.g., cimetidine, omeprazole). The monograph states that citalopram in combination with omeprazole reduces the rate of formation of demethylcitalopram (metabolite of citalopram) by 75-85%. Citalopram is associated with a risk of QTc prolongation, which may be responsible for torsade de pointes, ventricular tachycardia and sudden death. The FDA recommends a maximum citalopram dose of 40 mg per day (equivalent to 20 mg escitalopram). Doses of more than 40 mg provide no additional benefit and are associated with a greater risk of QTc prolongation. Citalopram is not recommended for patients presenting with congenital QTc prolongation, bradycardia, hypokalemia or hypermagnesemia, recent myocardial infarction or decompensated heart failure. Furthermore, citalopram is not recommended for patients who are taking other drugs that could increase the QTc interval ( A maximum citalopram dose of 20 mg is recommended for individuals age 60 and over presenting with liver failure or known as slow metabolizers of CYP2C19, or who are taking a drug that could inhibit CYP2C19*. These factors are associated with an increase in the plasma concentration of citalopram, therefore a higher risk of QTc prolongation. Citalopram should be stopped if the patient has a persistent QTc increase of over 500 ms. Recommendation: In a situation where the protease inhibitor inhibits CYP3A4 and the individual may be a slow metabolizer of CYP2C19, the two main metabolic routes for citalopram could be blocked (increased risk of QTc prolongation), particularly in individuals with risk factors (e.g., electrolyte imbalance, bradycardia). For these reasons, caution must be exercised when using citalopram with viral protease inhibitors, especially in the presence of risk factors for QTc interval prolongation. Also check the presence of CYP2C19 inhibitors* in concomitant treatment. Use the smallest possible dose while respecting the recommendations mentioned above. Monitor electrolytes and/or ECG. Try to reduce all QTc prolongation risk factors. 16 Psychotropics and HIV

17 SSRIs and PIs Advise patients to promptly contact a doctor if they have signs or symptoms associated with heart rhythm disorders (dizziness, palpitations, syncope or seizures). Patients must be warned not to end their treatment (nor modify the dose) without first consulting a health professional. Withdrawal symptoms (dizziness, feeling of agitation or anxiety, concentration difficulties, strange dreams, nausea or vomiting) can occur, especially if the stop is abrupt. Note that the pharmacokinetic modeling study indicates that the combination of ritonavir and citalopram would not be clinically significant. Recommendation: No dose adjustment is recommended. 3. No clinically significant interaction is expected. 4. Possible or in fluoxetine when combined with ritonavir-boosted protease inhibitors due to CYP2D6 inhibition or CYP2C9 induction. The effect is difficult to predict. A pharmacokinetic modeling study predicts a decrease of 43% in the fluoxetine AUC. Post-marketing, there have been reports of cardiac and neurological effects (confusion, mania, agitation, paranoia, anxiety, myoclonia, fever, diarrhea, nausea/vomiting and sweating) as well as serotonin syndromes with high doses of ritonavir. However, this interaction may be less significant with smaller doses of ritonavir, as currently used to boost viral protease inhibitors. Recommendation: Start the fluoxetine at a low dose and increase gradually according to the patient s tolerance 1 and clinical response. 5. Possible in fluvoxamine when combined with ritonavir-boosted protease inhibitors due to CYP2D6 inhibition. Recommendation: Start the fluvoxamine at a low dose and increase gradually according to the patient s tolerance 2 and clinical response. 6. Possible in paroxetine when combined with ritonavir-boosted protease inhibitors due to CYP2D6 inhibition. However, the interaction is difficult to predict, since a study with fosamprenavir/ritonavir and another with darunavir/ritonavir showed a reduction in the concentration of paroxetine. See 7 and 8. Recommendation: Start with a low dose of paroxetine and increase gradually according to the patient s tolerance 3 and clinical response. 7. of 39% and 37% was observed in the AUC and Cmin of paroxetine, respectively, when combined with darunavir/ritonavir. No effect observed on the plasma concentration of darunavir. Recommendation: Monitor the clinical efficacy of paroxetine and adjust the dose if necessary. 8. of 55% was observed in the AUC of paroxetine when combined with fosamprenavir/ritonavir. No effect observed on the plasma concentration of fosamprenavir. Recommendation: Monitor the clinical efficacy of paroxetine and adjust the dose if necessary. 9. Possible in sertraline due to CYP3A4 inhibition by atazanavir and nelfinavir. However, there appear to be several more significant metabolic routes. Probably without clinical consequence. Recommendation: Monitor the clinical efficacy and the appearance of adverse effects with sertraline 4 and adjust the dose accordingly. Psychotropics and HIV 17

18 SSRIs and PIs 10. Possible or in sertraline. Due to the numerous metabolic routes for sertraline, the potential pharmacokinetic interaction is difficult to predict. A pharmacokinetic modeling study demonstrated a decrease of 44% in the sertraline AUC. A decrease in sertraline was observed with the darunavir/ritonavir combination. (See 11.) Recommendation: Monitor the clinical efficacy and the appearance of adverse effects with sertraline 4 and adjust the dose accordingly. 11. of 49% was observed in the AUC and Cmin of sertraline when combined with darunavir/ritonavir. No effect observed on the concentration of darunavir. Recommendation: Monitor the clinical efficacy of sertraline and adjust the dose if necessary. 1. Adverse effects of fluoxetine: anxiety, nervousness, insomnia, headache, nausea, diarrhea, anorexia, asthenia, tremors, dry mouth, sexual problems. 2. Adverse effects of fluvoxamine: nausea, headache, drowsiness, weakness, dizziness, dry mouth, anorexia, sexual problems. 3. Adverse effects of paroxetine: nausea, drowsiness, dry mouth, headache, asthenia, constipation, dizziness, sexual problems, sweating, tremors. 4. Adverse effects of sertraline: nausea, dry mouth, diarrhea, dizziness. * List of drugs that could inhibit CYP2C19: armodafinil, esomeprazole, ethinylestradiol, estradiol, efavirenz, etravirine, felbamate, fluconazole, fluvoxamine, garlic, indomethacin, lansoprazole, moclobemide, modafinil, omeprazole, oxcarbamazepine, topiramate, probenecid and rabeprazole. 18 Psychotropics and HIV

19 SSRIs and CCR5 or II inhibitors Citalopram (Celexa) Escitalopram (Cipralex) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Dolutegravir (Tivicay) Elvitegravir/ cobicistat (Stribild) Maraviroc (Celsentri) Raltegravir (Isentress) No interaction Adjustement and/or follow-up Avoid Contraindicated Legend 1. No interaction is anticipated. 2. Possible in maraviroc due to the potential CYP3A4 inhibition by fluvoxamine. However, no adjustment is recommended. 3. Possible of antidepressants according to the Stribild monograph. As with ritonavir, cobicistat has the potential to inhibit CYP450. Additional studies will be required to determine the actual effect of Stribild on antidepressants. Psychotropics and HIV 19

20 Metabolism of other antidepressants Substrates s/inducers Elimination Bupropion (Wellbutrin, Zyban) 2B6 (major): contributes 90% to the formation of the metabolite hydroxybupropion (M3) having a comparable activity and an AUC 17 times greater than that of bupropion 2C19 (major): contributes 70-90% to the formation of the hydroxlated metabolites M4, M5 and M6 2D6 (moderate) Urine: 87% as metabolites Feces: 10% as metabolites T½: h T½ (metabolites): h Desvenlafaxine (Pristiq) Desvenlafaxine est le metabolite actif de la venlafaxine UGT (major) 3A4 (minor) 2D6 (weak) probably without risk of clinically significant interaction Urine: 45% as unchanged drug and 24% as metabolites T½: 11 h Duloxetine (Cymbalta) 1A2 (major), 2D6 (moderate) No active metabolite 2D6 (moderate) Urine: 70% Feces: 20% T½: 8-19 h Mirtazapine (Remeron) 2D6, 1A2 and 3A4 (major) and 2C9 (minor) Significant first-pass effect in the liver Formation of demethylmirtazapine (active) by demethylation Urine: 75% Feces: 15% as metabolites T½: 8-36 h Trazodone (Desyrel) 3A4 (major), 2D6 (minor) Metabolized into m chlorophenylpiperazine 3A4 (weak) Inducer P-gp Elimination Mainly in the urine T½: 4-9 h Venlafaxine (Effexor) 2D6 (major), 3A4, 2C9, 2C19 (minor) Significant first-pass effect in the liver CYP2D6: active metabolites with activity comparable to the parent drug: desvenlafaxine 2D6 (weak) Urine: 87% (5% as unchanged drug and the remainder in the form of metabolites, including 29% of unchanged ODV) T½: 3-7 h The desvenlafaxine is then metabolized by UGT T½ (metabolites): 9-13 h CYP3A4: formation of the metabolites N-desmethylvenlafaxine and O-desmethylvenlafaxine (ODV0) 20 Psychotropics and HIV

21 Other antidepressants and NNRTIs Bupropion (Wellbutrin) Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Mirtazapine (Remeron) Trazodone (Desyrel) Venlafaxine (Effexor) Efavirenz (Sustiva, Atripla) 1,2 2,6 2,3 2,8 2,9 10 Etravirine (Intelence) Nevirapine (Viramune) 3, Rilpivirine (Edurant, Complera) No interaction Adjustement and/or follow-up Avoid Contraindicated Legend 1. Observed of bupropion with efavirenz due to CYP2B6 induction. A decrease of 55% in the bupropion AUC was observed in a study conducted on 13 healthy volunteers with coadministration of efavirenz 600 mg QD (x 14 days) and a single dose of bupropion 150 mg. A reduction in the half-life of its active metabolite, hydroxybupropion, from 24 to 16 hours, was also observed. A publication on 11 HIV-positive subjects receiving bupropion mg QD with antiretrovirals such as efavirenz, ritonavir or nelfinavir for a median duration of 8 months reports no serious adverse effects, such as seizure. Recommendation: Monitor the clinical efficacy of bupropion and increase the dose if necessary. Consider the use of an alternative solution if efficacy is insufficient at the maximum dose of bupropion, since the risk of seizure increases when the daily dose exceeds 450 mg. However, the risk of seizure is judged by the experts to be very low. 2. Adverse effects of a psychiatric nature (such as anxiety, nervousness, sleep disorders and depression) are possible with efavirenz. Recommendation: Before contemplating starting a psychotropic, consider changing the antiretroviral treatment if symptoms of a psychiatric nature present de novo when taking efavirenz. 3. No clinically significant interaction is expected. Psychotropics and HIV 21

22 Other antidepressants and NNRTIs 4. Possible of bupropion due to the potential CYP2B6 induction by nevirapine. Recommendation: Monitor the clinical effect of bupropion and increase the dose if necessary. Consider the use of an alternative solution if efficacy is insufficient at the maximum dose of bupropion, since the risk of seizure increases when the daily dose exceeds 450 mg. 5. No clinically significant pharmacokinetic interaction is expected. However, since most psychotropics are associated with a potential risk of QTc prolongation, caution must be exercised in patients with risk factors for QTc prolongation (e.g., electrolyte imbalances, bradycardia, combination with other medications that prolong the QTc, presence of pharmacokinetic drug interactions, etc.). Recommendation: Ensure close monitoring with rilpivirine administered in combination with other drugs that could increase the QTc interval, specifically if the individual presents with other QTc prolongation risk factors. 6. Possible of desvenlafaxine. Desvenlafaxine is primarily metabolized by conjugation via UGT isoenzymes. Efavirenz, through its possible UGT induction effect, could reduce the plasma concentrations of desvenlafaxine. Recommendation: Monitor the clinical efficacy of venlafaxine and adjust the dose as necessary. 7. No clinically significant interactions expected, since there is marginal metabolism of desvenlafaxine by CYP3A4. 8. Possible in mirtazapine via CYP3A4 induction by NNRTIs. In fact, one case of exacerbation of panic attacks has been published concerning mirtazapine and rifampicine combined. Several cases have also been reported by the FDA for similar situations. A pharmacokinetic modeling study demonstrated a decrease of 48% in the mirtazapine AUC due to CYP3A4 induction. Recommendation: Monitor the clinical efficacy of mirtazapine and adjust the dose as necessary. 9. Possible in trazodone via CYP3A4 induction by NNRTIs. Recommendation: Monitor the clinical efficacy of trazodone and adjust the dose as necessary. 10. Due to the numerous metabolic routes for venlafaxine, no clinically significant interaction is expected. In fact, a pharmacokinetic modeling study demonstrated a decrease of 8% in the AUC of venlafaxine when combined with efavirenz. Recommendation: Monitor the clinical efficacy of venlafaxine and adjust the dose as necessary. 22 Psychotropics and HIV

23 Other antidepressants and PIs Bupropion (Wellbutrin) Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Mirtazapine (Remeron) Trazodone (Desyrel) Venlafaxine (Effexor) Atazanavir (Reyataz) Atazanavir/r (Reyataz) Darunavir/r (Prezista) Fosamprenavir/r (Telzir) Lopinavir/r (Kaletra) Nelfinavir (Viracept) Saquinavir/r (Invirase) Tipranavir/r (Aptivus) No interaction Adjustement and/or follow-up Avoid Contraindicated Legend 1. No clinically significant interaction is expected. Recommendation: No dose adjustment is recommended. 2. of approximately 20% was observed in the AUC and Cmin of bupropion when combined with a dose of ritonavir 100 mg PO BID. The reduction in bupropion was most marked ( of 66% AUC and of 62% Cmin) when combined with a dose of ritonavir 600 mg BID. The proposed mechanism is CYP2B6 induction. Psychotropics and HIV 23

24 Other antidepressants and PIs In a study whose goal was to show the effect of ritonavir induction (400 mg BID) on CYP2B6, it was shown that after three days ritonavir reduced bupropion by 15-20% and that this reduction was most marked ( of 30-40%) at steady state (2.5 weeks). An increase in oral clearance and a reduction in the bupropion half-life was also observed. A decrease in the AUC of the active metabolite, hydroxybupropion, and a reduction in the half-life were also observed. The induction effect was rapid (3 days) and lasted for approximately 14 days. See also lopinavir/ritonavir with a dose of ritonavir 100 mg BID (#3). Recommendation: No dose adjustment is recommended. Monitor the efficacy and the appearance of adverse effects with bupropion 1 and adjust the dose if necessary. Consider the use of an alternative solution if efficacy is insufficient at the maximum dose of bupropion (450 mg per day). 3. of 57% in the AUC of bupropion and of 50% in the AUC of the active metabolite of bupropion (hydroxybupropion) was observed when combined with lopinavir/ritonavir at steady state. No significant effect on the pharmacokinetics of lopinavir or ritonavir was observed. Recommendation: Monitor the clinical effect of bupropion and increase the dose if necessary. Consider the use of an alternative solution if efficacy is insufficient at the maximum dose of bupropion (450 mg per day). 4. of 50% in the AUC of bupropion and approximately 25% in the AUC of the active metabolite of bupropion (hydroxybupropion) was observed. Recommendation: Monitor the clinical effect of bupropion and increase the dose if necessary. Consider the use of an alternative solution if efficacy is insufficient at the maximum dose of bupropion (450 mg per day). 5. No significant pharmacokinetic interaction is expected. Desvenlafaxine is mainly conjugated (UGT) and weakly metabolized by CYP3A4. With ketoconazole 400 mg, an increase of 43% is observed in the AUC of desvenlafaxine, which is considered marginal according to the monograph. Recommendation: No dose adjustment is necessary. Conduct a follow-up of possible adverse effects of desvenlafaxine Suspected in the AUC of desvenlafaxine due to the possible UGT induction by ritonavir or nelfinavir. However, this interaction is theoretical and possibly clinically insignificant. Recommendation: Monitor the clinical effect of desvenlafaxine and increase the dose if necessary. 7. Suspected or in the AUC of duloxetine due to the induction and inhibition effect of ritonavir on CYP1A2 and CYP2D6. The clinical effect is difficult to predict. Paroxetine, which is a potent CYP2D6 inhibitor, increases the AUC of duloxetine by 60%. The monograph suggests exercising caution in the presence of CYP2D6 inhibitors. Recommendation: Monitor the clinical effect and the appearance of adverse effects with duloxetine 2 and adjust the dose if necessary. 8. Suspected in the AUC of mirtazapine due to the potential inhibition of CYP3A4 and/or CYP2D6. In fact, concomitant administration of mirtazapine (a single 30-mg dose) and ketoconazole, a potent inhibitor of CYP3A4 (200 mg BID x 6.5 days), increased the Cmax and AUC of mirtazapine by 40% and 50%, respectively. During concomitant use, two serious adverse effects were reported: one patient suffered a circulatory collapse or shock, and the other developed syncope. Both patients experienced brief loss of consciousness. Moreover, a pharmacokinetic study with mirtazapine (30 mg/day) and paroxetine (40 mg/day), a potent CYP2D6 inhibitor, revealed an increase in the plasma concentration of mirtazapine and its demethylated metabolite of about 18% and 25%. These increases were not considered to be clinically significant. However, among the side effects observed were exanthema (1 patient in 24), which required withdrawal 24 Psychotropics and HIV

25 Other antidepressants and PIs of the patient from the study. Increases in AST and ALT levels were reported by one of the participants, who subsequently had to be withdrawn from the study. This same participant also had elevated white blood cell and neutrophil counts and reduced lymphocyte and basophil numbers. A pharmacokinetic modeling study demonstrated an increase of 52% in the mirtarzapine AUC. Recommendation: Exercise caution. A dose adjustment may be necessary. Closely monitor the adverse effects associated with mirtazapine Suspected in the AUC of trazodone due to CYP3A4 and/or CYP2D6 inhibition. An increase of 140% in the AUC of trazodone was observed with high doses of ritonavir. Cases of patients presenting with symptoms such as nausea, dizziness, fatigue, performance disorders, hypertension and syncope have been reported. Recommendation: Monitor for the appearance of adverse effects with trazodone 4 and adjust the dose if necessary or select an alternative solution. 10. Trazodone would be contraindicated with saquinavir due to the increase in the risk of QTc interval prolongation. 11. Suspected in venlafaxine and its active metabolite. Particularly if the patient is a slow metabolizer of CYP2D6 or if there is another drug that inhibits CYP2D6. In a study with ketoconazole (a potent inhibitor of CYP3A4), a 21% increase in venlafaxine was observed in individuals who were rapid metabolizers of CYP2D6, and a 70% increase was observed in slow metabolizers. An increase of 23% and 33% of the active metabolite was also respectively observed in fast and slow metabolizers. Recommendation: Monitor for the appearance of adverse effects with venlafaxine 4 and adjust the dose if necessary. 12. Suspected in the AUC of venlafaxine due to possible CYP3A4 and CYP2D6 inhibition. The venlafaxine monograph suggests avoiding a combination with agents that inhibit both CYP3A4 and CYP2D6. However, a pharmacokinetic modeling study demonstrated a decrease of 8% in the venlafaxine AUC, which is not considered to be clinically significant. In a study with ketoconazole (a potent inhibitor of CYP3A4), a 21% increase in venlafaxine was observed in individuals who were rapid metabolizers of CYP2D6, and a 70% increase was observed in slow metabolizers. An increase of 23% and 33% of the active metabolite was also respectively observed in fast and slow metabolizers. Recommendation: Avoid this combination as per the product monograph. Opt for an alternative solution. If used: Monitor for the appearance of adverse effects with venlafaxine 5 and adjust the dose if necessary. The authors of the pharmacokinetic modeling study (Siccardi M et al. Clin Pharmacokinet 2013) consider venlafaxine and desvenlafaxine, in combination with protease inhibitors, to be a viable alternative solution. 1. Adverse effects of bupropion: headache, dizziness, agitation, anxiety, sleep disorder, seizures (very rare). 2. Adverse effects of duloxetine: nausea, dizziness, orthostatic hypotension, sweating, headache, anxiety, insomnia. 3. Adverse effects of mirtazapine: drowsiness, increased appetite, weight gain. 4. Adverse effects of trazodone: dizziness, orthostatic hypotension, priapism. 5. Adverse effects of venlafaxine and desvenlafaxine: nausea, insomnia, dizziness, sexual dysfunction, headache, sweating, anxiety. Psychotropics and HIV 25

26 Other antidepressants and CCR5 or II Bupropion (Wellbutrin) Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Mirtazapine (Remeron) Trazodone (Desyrel) Venlafaxine (Effexor) Dolutegravir (Tivicay) Elvitegravir/ cobicistat (Stribild) Maraviroc (Celsentri) Raltegravir (Isentress) No interaction Adjustement and/or follow-up Avoid Contraindicated Legend 1. No interaction is anticipated. 2. Possible in antidepressants according to the Stribild monograph, since ritonavir and cobicistat have the potential to inhibit CYP450. Additional studies will be required to determine the actual effect of Stribild on antidepressants. 26 Psychotropics and HIV

27 Metabolism of antipsychotics Substrates s/inducers Elimination Aripiprazole (Abilify) 2D6 and 3A4 (major) as an active metabolite dehydro-aripiprazole has properties similar to that of the parent drug, and this metabolite represents 40% of the total concentration Slow metabolizers: observed of about 80% of aripiprazole and observed of about 30% of the active metabolite, which represents a 60% increase in exposure to the total active drug of a given aripiprazole dose compared to rapid metabolizers Urine: 25% (less than 1% as unchanged drug) Feces: 55% (about 18% as unchanged drug) T½: 75 h (146 hours slow metabolizers) T½ of dehydro-aripiprazole: 94 hours Asenapine (Saphris) UGT 1A4 (major) 1A2 (major) 2D6 (weak) Urine: 50% Feces: 40% 2D6 and 3A4 (minor) T½: 24 h Clozapine (Clozaril) 1A2 (major) and 3A4 (minor) and other CYPs Active Metabolite: norclozapine Urine: 50% Feces: 30% T½: 30 h (average12 h) Chlorpromazine (Largactil) 2D6 (major) 1A2 and 3A4 (minor) UGT1A4 2D6 (strong) 1A2, 3A4, 2C9, 2C19 and 2E1 (weak) P-gp Urine: (< 1% as unchanged drug) T½ biphasic Initial: 2 h End: 30 h Haloperidol (Haldol) 3A4 (major) 2D6 (moderate) and 1A2 (negligible) 2D6 and 3A4 (moderate) P-gp (weak) Urine: 30%, with 1% as unchanged drug Feces: 15% Complex formation of the metabolite called reduced haloperidol, which will be transformed back into haloperidol T½: h Lurasidone (Latuda) 3A4 (major) Urine: 9% Feces: 80% T½: 18 h Olanzapine (Zyprexa) 1A2 (major) and 2D6 (minor). Formation of metabolites N-desmethyl and 2-hydroxymethyl. Both exhibit less activity than olanzapine UGT1A4 (major) Also metabolized by FMOs (flavin-monooxygenases) Urine: 57% (7% as unchanged drug) Feces: 30% T½: h Psychotropics and HIV 27

28 Metabolism of antipsychotics Substrates s/inducers Elimination Paliperidone (Invega, Invega Sustenna) Active metabolite of risperidone Quetiapine (Seroquel) Risperidone (Risperdal, Risperdal Consta) Mainly renal elimination. Cytochrome P450 very little involvement in the metabolism 3A4 > 2D6 (minor) P-gp 3A4 (major): active metabolite: Norquetiapine (concentration at 35% of that for quetiapine) 2D6 (major): active metabolite 9-hydroxyrisperidone, also known as paliperidone, (activity similar to risperidone) 3A4 (minor) P-gp Urine: 80% Feces: 11% T ½ (po): h T ½ (IM): days Less than 5% of the parent drug found in the urine. T½: 6-7 h T ½ metabolite actif: 12 h Urine: 70% Risperidone and 9-hydroxy-risperidone combined represent 35-45% of the dose administered. The rest is composed of inactive metabolites. Feces: 14% T ½ (po) T½: 3 h for risperidone and 21 h for 9-hydroxyrisperidone Slow metabolizers of CYP2D6 : T½: h for risperidone and 30 h for 9-hydroxyrisperidone Rapid metabolizers of CYP2D6: T½ injectable: 3-6 days Ziprasidone (Zeldox) 3 metabolic routes produce 4 inactive metabolites Aldehyde oxydase: 66% CYP3A4: 33% Urine: 20% (less than 1% as unchanged drug) Feces: 66% (less than 4% as unchanged drug) T ½ po: 6-10 h 28 Psychotropics and HIV

29 Antipsychotics and NNRTIs Table1 de 2 Aripiprazole (Abilify) Asenapine (Saphris) Clozapine (Clozaril) Chlorpromazine (Largactil) Haloperidol (Haldol) Lurasidone (Latuda) Efavirenz (Sustiva, Atripla) Etravirine (Intelence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) 2,3 2,3 2,3 2,3 2,3 2,3 Table 2 de 2 Olanzapine (Zyprexa) Paliperidone (Invega) Quetiapine (Seroquel) Risperidone (Risperdal, Risperdal Consta) Ziprasidone (Zeldox) Efavirenz (Sustiva, Atripla) Etravirine (Intelence) Nevirapine (Viramune) Rilpivirine (Edurant, Complera) 2-3 2,3 2,3 2,3 2,3 No interaction Adjustement and/or follow-up Avoid Contraindicated Psychotropics and HIV 29

30 Antipsychotics and NNRTIs Legend 1. Possible in aripiprazole due to CYP3A4 induction. The concomitant administration of carbamazepine (200 mg BID), a potent inducer of CYP3A4, and aripiprazole (30 mg QD) decreased the Cmax and AUC of aripiprazole and its active metabolite, dehydroaripiprazole, by approximately 70%. Recommendation: Monitor the clinical efficacy of aripiprazole and increase the dose as necessary. If NNRTI (CYP3A4 inducer) is subsequently stopped, the dose of aripiprazole should be reduced. 2. No clinically significant pharmacokinetic interaction is expected. 3. No clinically significant pharmacokinetic interaction is anticipated. However, since most antipsychotics are associated with a potential risk of QTc prolongation, caution must be exercised in patients with risk factors for QTc prolongation (e.g., electrolyte imbalances, bradycardia, combination with other medications that prolong the QTc, presence of pharmacokinetic drug interactions, etc.). Recommendation: Ensure close monitoring with rilpivirine administered in combination with other drugs that could increase the QTc interval, specifically if the individual presents with other QTc prolongation risk factors. 4. Possible in clozapine due to the potential induction of CYP3A4 by efavirenz, etravirine and nevirapine. Recommendation: Monitor the clinical efficacy of clozapine and increase the dose as necessary. If NNRTI (CYP3A4 inducer) is subsequently stopped, the dose of clozapine can be reduced. 5. Possible in haloperidol, lurasidone and quetiapine due to the potential induction of CYP3A4 by efavirenz, etravirine and nevirapine. In a pharmacokinetic study with rifampicine (potent inducer of CYP3A4) and lurasidone, a marked decrease was observed in the AUC of lurasidone. Only one-fifth of the dose (of the latter) remained. According to the product monograph, lurasidone is contraindicated for use with rifampicine. The inducing effects of NNRTIs should not be as marked as rifampicine but they can be significant enough to compromise clinical efficacy. Recommendation: Monitor the efficacy of haloperidol, lurasidone and quetiapine, and adjust the dose if necessary. 6. Possible in olanzapine when combined with efavirenz since the latter appears to induce UGT1A4. Recommendation: Monitor the clinical efficacy and adjust the dose if necessary. 7. Possible in paliperidone due to the potential induction of CYP3A4 by efavirenz, etravirine and nevirapine. However, paliperidone is eliminated mainly by renal route. In a study with carbamazepine (inducer of CYP3A4 and P-gp), the carbamazepine decreased the mean AUC of paliperidone by approximately 37%. Recommendation: The clinical significance is unknown. Monitor the clinical efficacy of paliperidone and adjust the dose if necessary. 8. Possible in ziprasidone due to the potential induction of CYP3A4 by efavirenz, etravirine and nevirapine. A reduction of approximately 36% was observed in ziprasidone when administered with carbamazepine 200 mg BID for 25 days. Recommendation: Monitor the clinical efficacy of ziprasidone and adjust the dose if necessary. 30 Psychotropics and HIV