DRUG INTERACTIONS

7 No drug interaction trials have been performed with PREZCOBIX or with darunavir co-administered with cobicistat as single entities.

Drug interaction trials have been conducted with darunavir co-administered with ritonavir and with cobicistat alone.

Co-administration of PREZCOBIX with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of darunavir or cobicistat.

Consult the full prescribing information prior to and during treatment for potential drug interactions.

(4, 5.6, 7, 12.3).

7.1 Potential for PREZCOBIX to affect Other Drugs When evaluated separately, darunavir and cobicistat both inhibited CYP3A and CYP2D6.

Cobicistat inhibits the following transporters: p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3.

Therefore, co-administration of PREZCOBIX with drugs that are primarily metabolized by CYP3A and/or CYP2D6 or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events (see Table 2).

Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent.

The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data.

7.2 Potential for Other Drugs to affect PREZCOBIX Darunavir is metabolized by CYP3A.

Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6.

Drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations of darunavir and cobicistat which may lead to loss of therapeutic effect and development of resistance.

Co-administration of PREZCOBIX and other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 2).

7.3 Potentially significant Drug Interactions Table 2 provides dosing recommendations for expected clinically relevant interactions with PREZCOBIX.

These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.

Table 2: Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction Concomitant Drug Class: Drug Name Effect on Concentration of Darunavir, Cobicistat, or Concomitant Drug Clinical Comment HIV-1 Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) didanosine ↔ darunavir ↔ cobicistat ↔ didanosine Didanosine should be administered one hour before or two hours after PREZCOBIX (administered with food).

HIV-1 Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) efavirenz, ↓ cobicistat ↓ darunavir Co-administration with efavirenz is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.

etravirine, ↓ cobicistat darunavir: effect unknown Co-administration with etravirine is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.

neviraprine ↓ cobicistat darunavir: effect unknown Co-administration with nevirapine is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.

HIV-1 Antiviral Agents: CCR5 co-receptor antagonists maraviroc ↑ maraviroc Maraviroc is a substrate of CYP3A.

When co-administered with PREZCOBIX, patients should receive maraviroc 150 mg twice daily.

Other Agents Antiarrhythmics: e.g.

amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine, ↑ antiarrhythmics Clinical monitoring is recommended upon co-administration with antiarrhythmics.

digoxin ↑ digoxin When co-administering with digoxin, titrate the digoxin dose and monitor digoxin concentrations.

Antibacterial Agents clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of PREZCOBIX.

Anticancer Agents: dasatinib, nilotinib, ↑ anticancer agent A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary when co-administered with PREZCOBIX.

Consult the dasatinib and nilotinib prescribing information for dosing instructions.

vinblastine, vincristine For vincristine and vinblastine, consider temporarily withholding the cobicistat-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when PREZCOBIX is administered concurrently with vincristine or vinblastine.

If the antiretroviral regimen must be withheld for a prolonged period, consider initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.

Anticoagulants: apixaban, ↑ anticoagulant Concomitant use of apixaban is not recommended.

dabigatran etexilate, Concomitant use with dabigatran etexilate is not recommended in specific renal impairment groups (depending on the indication).

Please see the dabigatran US prescribing information for specific recommendations.

rivaroxaban, warfarin warfarin: effect unknown Co-administration with rivaroxaban is not recommended.

Monitor the international normalized ratio (INR) when co-administering with warfarin.

Anticonvulsants that induce CYP3A: e.g.

carbamazepine, oxcarbazepine, phenobarbital, phenytoin ↓ cobicistat darunavir effect unknown Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures.

If co-administration is necessary, monitor for lack or loss of virologic response.

phenobarbital, phenytoin phenobarbital: effect unknown phenytoin: effect unknown Monitor phenobarbital or phenytoin concentrations.

Anticonvulsants that are metabolized by CYP3A: e.g.

clonazepam, carbamazepine ↑ carbamazepine ↑ clonazepam Clinical monitoring is recommended.

Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs): e.g.

paroxetine, sertraline, SSRIs: effects unknown ↑ TCAs When co-administering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.

Tricyclic Antidepressants (TCAs): e.g.

amitriptyline, desipramine, imipramine, nortriptyline Other antidepressants: trazodone ↑ trazodone Antifungals: itraconazole, ketoconazole, posaconazole, ↑ darunavir ↑ cobicistat Monitor for increased darunavir or cobicistat adverse reactions.

↑ itraconazole ↑ ketoconazole ↔ posaconazole (not studied) Specific dosing recommendations are not available for co-administration with itraconazole or ketoconazole.

Monitor for increased itraconazole or ketoconazole adverse reactions.

voriconazole Voriconazole: effects unknown Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole.

Anti-gout: colchicine ↑ colchicine Treatment of gout flares – co-administration of colchicine: -0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later.

Treatment course to be repeated no earlier than 3 days.

Prophylaxis of gout flares – co-administration of colchicine: -If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever – co-administration of colchicine: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Co-administration with colchicine is contraindicated in patients with renal or hepatic impairment [see Contraindications (4)].

Antimalarial: artemether/lumefantrine artemether: effect unknown lumefantrine: effect unknown Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation.

Antimycobacterials: rifabutin ↑ rifabutin cobicistat: effects unknown darunavir: effects unknown When used in combination with PREZCOBIX, the recommended dose of rifabutin is 150 mg every other day.

Monitor for rifabutin-associated adverse reactions including neutropenia and uveitis.

rifapentine ↓ darunavir Co-administration with rifapentine is not recommended.

Antipsychotics: e.g.

perphenazine, risperidone, thioridazine ↑ antipsychotic A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with PREZCOBIX.

quetiapine ↑ quetiapine Initiation of PREZCOBIX in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure.

If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine- associated adverse reactions.

Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking PREZCOBIX: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

β-Blockers: e.g.

carvedilol, metoprolol, timolol ↑ beta-blockers Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized by CYP2D6.

Calcium Channel Blockers: e.g.

amlodipine, diltiazem, felodipine, nifedipine, verapamil ↑ calcium channel blockers Clinical monitoring is recommended for co-administration with calcium channel blockers metabolized by CYP3A.

Corticosteroids (inhaled/nasal) metabolized by CYP3A: e.g.

budesonide, fluticasone ↑ corticosteroid Co-administration with inhaled or nasal fluticasone or other corticosteroids that are metabolized by CYP3A may result in reduced serum cortisol concentrations.

Alternative corticosteroids should be considered, particularly for long-term use.

Corticosteroid systemic: e.g.

dexamethasone ↓ darunavir ↓ cobicistat ↑ corticosteroids Co-administration with dexamethasone or other corticosteroids that induce CYP3A may result in loss of therapeutic effect of and development of resistance to darunavir.

Consider alternative corticosteroids.

Corticosteroids (systemic) metabolized by CYP3A: e.g.

budesonide, prednisolone ↑ corticosteroid Co-administration with corticosteroids that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects.

Endothelin receptor antagonists: bosentan ↓ darunavir ↓ cobicistat ↑ bosentan Initiation of bosentan in patients taking PREZCOBIX: In patients who have been receiving PREZCOBIX for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Initiation of PREZCOBIX in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZCOBIX.

After at least 10 days following the initiation of PREZCOBIX, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

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

Hepatitis C Virus (HCV) NS3-4A protease inhibitors: boceprevir, telaprevir, simeprevir darunavir: effects unknown boceprevir: effects unknown telaprevir: effects unknown ↑ simeprevir No drug interaction data are available.

Co-administration with boceprevir, simeprevir, or telaprevir is not recommended.

HMG-CoA Reductase Inhibitors: e.g.

atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin ↑ atorvastatin ↑ fluvastatin ↑ pravastatin ↑ rosuvastatin pitavastatin: effect unknown For atorvastatin, fluvastatin, pitavastatin pravastatin, and rosuvastatin, start with the lowest recommended dose and titrate while monitoring for safety [see Contraindications (4)].

Hormonal Contraceptives: progestin/estrogen progestin: effects unknown estrogen: effects unknown No data are available to make recommendations on co-administration with oral or other hormonal contraceptives.

Additional or alternative (non-hormonal) forms of contraception should be considered.

Immunosuppressants: cyclosporine, sirolimus, tacrolimus ↑ immunosuppressants These immunosuppressant agents are metabolized by CYP3A.

Therapeutic drug monitoring is recommended with concomitant use.

Immunosuppressant/neoplastic: everolimus Co-administration of everolimus and PREZCOBIX is not recommended.

Inhaled beta agonist: salmeterol ↑ salmeterol Co-administration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

Narcotic Analgesics metabolized by CYP3A: e.g.

fentanyl, oxycodone ↑ fentanyl ↑ oxycodone Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration.

tramadol ↑ tramadol A dose decrease may be needed for tramadol with concomitant use.

Narcotic Analgesic for Treatment of Opioid Dependence: buprenorphine, buprenorphine/naloxone, methadone buprenorphine or buprenorphine/ naloxone: effects unknown methadone: effects unknown Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking PREZCOBIX: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose.

Initiation of PREZCOBIX in patients taking buprenorphine, buprenorphine/naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed.

Monitor clinical signs and symptoms.

Phosphodiesterase PDE-5 inhibitors: e.g.

avanafil, sildenafil, tadalafil, vardenafil ↑ PDE-5 inhibitors Co-administration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established.

Co-administration with PDE-5 inhibitors may result in an increase in PDE-5 inhibitor-associated adverse reactions including hypotension, syncope, visual disturbances and priapism.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration with sildenafil is contraindicated [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil with PREZCOBIX: Initiation of tadalafil in patients taking PREZCOBIX: In patients receiving PREZCOBIX for at least one week, start tadalafil at 20 mg once daily.

Increase to 40 mg once daily based upon individual tolerability.

Initiation of PREZCOBIX in patients taking tadalafil: Avoid use of tadalafil during the initiation of PREZCOBIX.

Stop tadalafil at least 24 hours prior to starting PREZCOBIX.

After at least one week following the initiation of PREZCOBIX, resume tadalafil at 20 mg once daily.

Increase to 40 mg once daily based upon individual tolerability.

Patients switching from darunavir co-administered with ritonavir to PREZCOBIX: Maintain tadalafil dose.

Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse reactions.

Sedatives/Hypnotics metabolized by CYP3A: e.g.

buspirone, diazepam, estazolam parenterally administered midazolam, zoldipem ↑ sedatives/hypnotics With concomitant use, titration is recommended with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for increased and prolonged effects or adverse reactions.

Co-administration of parenteral midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.

Dose reduction for parenteral midazolam should be considered, especially if more than a single dose of midazolam is administered.

Co-administration with oral midazolam or triazolam is CONTRAINDICATED [see Contraindications (4.0)].

Clinically relevant drug-drug interactions are not anticipated with concomitant use of darunavir and cobicistat with rilpivirine, dolutegravir, raltegravir, nucleoside reverse transcriptase inhibitors (NRTIs) other than didanosine, or acid modifying medications (antacids, H2-receptor antagonists, proton pump inhibitors).