Darunavir, Cobicistat, Emtricitabine, And Tenofovir Alafenamide

Tenofovir alafenamide (TAF) is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Anticonvulsants: carbamazepine, phenobarbital, phenytoin ↓ cobicistat ↓ darunavir ↓ tenofovir alafenamide Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g., eslicarbazepine, oxcarbazepine ↓ cobicistat ↓ tenofovir alafenamide darunavir: effect unknown Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures.

Table 4: Significant Drug Interactions Concomitant Drug Class: Drug Name Examples Effect on Concentration Clinical Comment This table is not all inclusive ↑ = increase, ↓ = decrease, ↔ = no effect Alpha 1-adrenoreceptor antagonist: alfuzosin ↑ alfuzosin Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.

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. Dosage recommendations with atorvastatin or rosuvastatin are as follows: atorvastatin dosage should not exceed 20 mg/day rosuvastatin dosage should not exceed 20 mg/day Other lipid modifying agents : lomitapide ↑ lomitapide Co-administration is contraindicated due to potential for markedly increased transaminases associated with increased plasma concentrations of lomitapide.

dronedarone ↑ dronedarone Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias Other antiarrhythmics e.g., amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine ↑ antiarrhythmics Clinical monitoring is recommended upon co-administration with antiarrhythmics.

Hepatitis C virus (HCV): Direct-Acting Antivirals: elbasvir/grazoprevir ↑ elbasvir/grazoprevir Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations.

Hepatitis C virus (HCV): Direct-Acting Antivirals: elbasvir/grazoprevir ↑ elbasvir/grazoprevir Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations.

Lipid modifying agents: HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

Sedatives/hypnotics: orally administered midazolam, triazolam ↑ midazolam ↑ triazolam Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. parenterally administered midazolam 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.

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. Dosage recommendations with atorvastatin or rosuvastatin are as follows: atorvastatin dosage should not exceed 20 mg/day rosuvastatin dosage should not exceed 20 mg/day Other lipid modifying agents : lomitapide ↑ lomitapide Co-administration is contraindicated due to potential for markedly increased transaminases associated with increased plasma concentrations of lomitapide.

Lipid modifying agents: HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

Sedatives/hypnotics: orally administered midazolam, triazolam ↑ midazolam ↑ triazolam Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

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.

Co-administration may result in increased plasma concentrations of darunavir and cobicistat.

Co-administration may increase clearance of darunavir and cobicistat, resulting in lowered plasma concentrations and potential loss of therapeutic effect and development of resistance.

Co-administration may increase concentrations of emtricitabine and tenofovir, increasing risk of adverse reactions.

Co-administration may result in increased plasma concentrations of CYP3A substrates, which could increase or prolong their therapeutic effect and adverse events.

Tricyclic Antidepressants (TCAs): e.g., amitriptyline, desipramine, imipramine, nortriptyline ↑ TCAs Other antidepressants: trazodone ↑ trazodone Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole ↑ darunavir ↑ cobicistat Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions. ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole (not studied) Specific dosing recommendations are not available for co-administration with these antifungals.

Tricyclic Antidepressants (TCAs): e.g., amitriptyline, desipramine, imipramine, nortriptyline ↑ TCAs Other antidepressants: trazodone ↑ trazodone Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole ↑ darunavir ↑ cobicistat Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions. ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole (not studied) Specific dosing recommendations are not available for co-administration with these antifungals. Monitor for increased itraconazole or ketoconazole adverse reactions.

Tricyclic Antidepressants (TCAs): e.g., amitriptyline, desipramine, imipramine, nortriptyline ↑ TCAs Other antidepressants: trazodone ↑ trazodone Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole ↑ darunavir ↑ cobicistat Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions. ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole (not studied) Specific dosing recommendations are not available for co-administration with these antifungals. Monitor for increased itraconazole or ketoconazole adverse reactions.

Co-administration may result in increased plasma concentrations of P-gp substrates due to transporter inhibition.

Tricyclic Antidepressants (TCAs): e.g., amitriptyline, desipramine, imipramine, nortriptyline ↑ TCAs Other antidepressants: trazodone ↑ trazodone Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole ↑ darunavir ↑ cobicistat Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions. ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole (not studied) Specific dosing recommendations are not available for co-administration with these antifungals.

Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.6) ] .

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.

Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.6) ] .

Antibacterials: clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of SYMTUZA.

Anticonvulsants that are metabolized by CYP3A: e.g., clonazepam ↑ clonazepam Clinical monitoring of anticonvulsants is recommended.

7.2 Potential for SYMTUZA to Affect Other Drugs Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. 7.3 Potential for Other Drugs to Affect SYMTUZA Darunavir is metabolized by CYP3A. Co-administration of drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations which may lead to loss of therapeutic effect and development of resistance.

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 SYMTUZA. Consult the dasatinib and nilotinib prescribing information for dosing instructions.

metabolized by CYP3A: e.g., buspirone, diazepam, estazolam, zolpidem ↑ 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.

Antibacterials: clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of SYMTUZA.

metabolized by CYP3A: e.g., buspirone, diazepam, estazolam, zolpidem ↑ 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.

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.

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.

Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.6) ] .

glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Co-administration of SYTMUZA with glecaprevir/pibrentasvir is not recommended.

Corticosteroids primarily metabolized by CYP3A: e.g., betamethasone budesonide ciclesonide fluticasone methylprednisolone mometasone triamcinolone ↑ corticosteroids Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression.

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.

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 SYMTUZA. Consult the dasatinib and nilotinib prescribing information for dosing instructions.

glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Co-administration of SYTMUZA with glecaprevir/pibrentasvir is not recommended.

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.

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.

Corticosteroids primarily metabolized by CYP3A: e.g., betamethasone budesonide ciclesonide fluticasone methylprednisolone mometasone triamcinolone ↑ corticosteroids Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use.

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

Antibacterials: clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of SYMTUZA.

Tenofovir alafenamide (TAF) is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. 7.4 Drugs Affecting Renal Function Because emtricitabine and tenofovir are primarily excreted by the kidneys through glomerular filtration and active tubular secretion, co-administration of SYMTUZA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs.

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

Corticosteroids primarily metabolized by CYP3A: e.g., betamethasone budesonide ciclesonide fluticasone methylprednisolone mometasone triamcinolone ↑ corticosteroids Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression.

Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.6) ] .

Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.6) ] .

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