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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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) ] .
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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) ] .
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
Antibacterials: clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of SYMTUZA.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
Anticonvulsants that are metabolized by CYP3A: e.g., clonazepam ↑ clonazepam Clinical monitoring of anticonvulsants is recommended.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
Antibacterials: clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of SYMTUZA.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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) ] .
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Co-administration of SYTMUZA with glecaprevir/pibrentasvir is not recommended.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
β-Blockers: e.g., carvedilol, metoprolol, timolol ↑ beta-blockers Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized by CYP2D6.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Co-administration of SYTMUZA with glecaprevir/pibrentasvir is not recommended.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
Antibacterials: clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of SYMTUZA.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
β-Blockers: e.g., carvedilol, metoprolol, timolol ↑ beta-blockers Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized by CYP2D6.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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) ] .
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
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) ] .
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
voriconazole voriconazole: effects unknown Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole.
Source: FDA drug label - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide