The following events have been identified during post approval use of PREZISTA. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Redistribution of body fat has been reported.
Rarely, rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and PREZISTA/ritonavir) has been reported.
In addition, toxic epidermal necrolysis, acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms have been reported rarely [see Warnings and Precautions (5.3)].
PREZISTA co-administered with ritonavir is an inhibitor of CYP3A, CYP2D6, and P-gp. Co-administration of PREZISTA and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 or are transported by P-gp may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events. PREZISTA co-administered with ritonavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 10).
Darunavir and ritonavir are metabolized by CYP3A. In vitro data indicate that darunavir may be a P-gp substrate. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A, or P-gp may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (see Table 10).
Table 10 provides dosing recommendations as a result of drug interactions with PREZISTA/ritonavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. The table includes potentially significant interactions but is not all inclusive [see Contraindications (4) and Clinical Pharmacology (12.3)].
|Concomitant Drug ClassDrug Name||Effect on Concentration of Darunavir Or Concomitant Drug||Clinical Comment|
|HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)|
|didanosine||↔ darunavir↔ didanosine||Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).|
|HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)|
|indinavir||↑ darunavir↑ indinavir||The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.|
|(The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)|
|lopinavir/ritonavir||↓ darunavir↔ lopinavir||Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.|
|saquinavir||↓ darunavir↔ saquinavir||Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.|
|Other HIV protease inhibitors, except atazanavir [see Drug Interactions (7.4)]||As co-administration with PREZISTA/ritonavir has not been studied, co-administration is not recommended.|
|HIV-1-Antiviral Agents: CCR5 co-receptor antagonists|
|maraviroc||↑ maraviroc||When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.|
|Alpha 1-adrenoreceptor antagonist:|
|alfuzosin||↑ alfuzosin||Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.|
|Antibacterial:clarithromycin||↔ darunavir↑ clarithromycin||No dose adjustment of the combination is required for patients with normal renal function. For co-administration of clarithromycin and PREZISTA/ritonavir in patients with renal impairment, the following dose adjustments should be considered: |
|Anticoagulants:Direct Oral Anticoagulants (DOACs)|
|apixaban||↑ apixaban||Due to potentially increased bleeding risk, dosing recommendations for co-administration of apixaban with PREZISTA depends on the apixaban dose. Refer to apixaban dosing instructions for co-administration with strong CYP3A and P-gp inhibitors in apixaban prescribing information.|
|rivaroxaban||↑ rivaroxaban||Co-administration of PREZISTA/ritonavir and rivaroxaban is not recommended because it may lead to an increased bleeding risk.|
|betrixaban dabigatran edoxaban||↔ betrixaban ↔ dabigatran ↔ edoxaban||No dose adjustment is needed when betrixaban, dabigatran, or edoxaban is co-administered with PREZISTA.|
|warfarin||↓ warfarin↔ darunavir||Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.|
|Anticonvulsants:carbamazepine||↔ darunavir↑ carbamazepine||The dose of either PREZISTA/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with PREZISTA/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.|
|clonazepam||↑ clonazepam||Clinical monitoring of anticonvulsants that are metabolized by CYP3A is recommended.|
|phenobarbital, phenytoin||↔ darunavir↓ phenytoin↓ phenobarbital||Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.|
|Antidepressants:Selective Serotonin Reuptake Inhibitors (SSRIs):paroxetine, sertraline||↓ paroxetine↓ sertraline||If either sertraline or paroxetine is initiated in patients receiving PREZISTA/ritonavir, dose titrating the SSRI based on a clinical assessment of antidepressant response is recommended. Monitor for antidepressant response in patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir.|
|Tricyclic Antidepressants (TCAs):|
|amitriptyline, desipramine, imipramine, nortriptyline||↑ amitriptyline↑ desipramine↑ imipramine↑ nortriptyline||Use a lower dose of the tricyclic antidepressants and trazodone due to potential increased adverse events such as nausea, dizziness, hypotension and syncope.|
|Other: trazodone||↑ trazodone|
|Antifungals:itraconazole, isavuconazole, ketoconazole, posaconazole||↑ darunavir↑ itraconazole↑ isavuconazole↑ ketoconazole↔ posaconazole||Monitor for increased PREZISTA/ritonavir and/or antifungal adverse events with concomitant use of these antifungals. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg with monitoring for increased antifungal adverse events.|
|voriconazole||↓ voriconazole||Voriconazole is not recommended for patients receiving PREZISTA/ritonavir unless an assessment comparing predicted benefit to risk ratio justifies the use of voriconazole.|
|Anti-gout:colchicine||↑ colchicine||Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions. |
For patients without renal or hepatic impairment:
|Antimalarial:artemether/lumefantrine||↓ artemether↓ dihydroartemisinin↑ lumefantrine↔ darunavir||The combination of PREZISTA/ritonavir and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation.|
|rifampin||↓ darunavir||Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance.|
|rifabutin(The reference regimen for rifabutin was 300 mg once daily.)||↑ darunavir↑ rifabutin↑ 25-O -desacetylrifabutin||Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.|
|rifapentine||↓ darunavir||Co-administration of PREZISTA/ritonavir with rifapentine is not recommended.|
|Antineoplastics: dasatinib, nilotinib||↑ antineoplastics||A decrease in the dosage or an adjustment of the dosing interval of dasatinib and nilotinib may be necessary for patients. Please refer to the dasatinib and nilotinib prescribing information for dosing instructions.|
|vinblastine, vincristine||For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when PREZISTA/ritonavir is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.|
|lurasidone||↑ lurasidone||Co-administration is contraindicated due to potential for serious and/or life-threatening reactions.|
|pimozide||↑ pimozide||Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.|
|quetiapine||↑ quetiapine||Initiation of PREZISTA with ritonavir in patients taking quetiapine:Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. 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 PREZISTA with ritonavir:Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.|
|e.g. perphenazine, risperidone, thioridazine||↑ antipsychotics||A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with PREZISTA/ritonavir.|
|β-Blockers:e.g. carvedilol, metoprolol, timolol||↑ beta-blockers||Clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir and a lower dose of the beta blocker should be considered.|
|Calcium Channel Blockers:amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil||↑ calcium channel blockers||Clinical monitoring of patients is recommended.|
|ranolazine, ivabradine||↑ ranolazine ↑ ivabradine||Co-administration is contraindicated due to potential for serious and/or life-threatening reactions.|
|dronedarone||↑ dronedarone||Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.|
|Other antiarrhythmicse.g. amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine||↑ antiarrhythmics||Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.|
|digoxin||↑ digoxin||The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.|
|dexamethasone (systemic)||↓ darunavir||Co-administration of PREZISTA/ritonavir with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to darunavir. Consider alternative corticosteroids.|
|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.|
|Endothelin receptor antagonist:|
|bosentan||↑ bosentan|| |
Co-administration of bosentan in patients on PREZISTA/ritonavir:In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of PREZISTA/ritonavir in patients on bosentan:Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
|e.g. dihydroergotamine, ergotamine, methylergonovine||↑ ergot derivatives||Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.|
|GI motility agent:|
|cisapride||↑ cisapride||Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.|
|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.|
|glecaprevir/pibrentasvir||↑ glecaprevir↑ pibrentasvir||Co-administration of PREZISTA/ritonavir with glecaprevir/pibrentasvir is not recommended.|
|St. John’s wort (Hypericum perforatum)||↓ darunavir||Co-administration is contraindicated due to potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance.|
|Hormonal contraceptives:||Effective alternative (non-hormonal) contraceptive method or a barrier method of contraception is recommended [see Use in Specific Populations (8.3)].|
|ethinyl estradiol, norethindrone, drospirenone||↓ ethinyl estradiol ↓ norethindrone drospirenone: effects unknown||For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia.No data are available to make recommendations on co-administration with other hormonal contraceptives.|
|Immunosuppressants:e.g. cyclosporine, tacrolimus, sirolimus||↑ immunosuppressants||Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.|
|Immunosuppressant/neoplastic: everolimus||Co-administration of everolimus and PREZISTA/ritonavir is not recommended.|
|irinotecan||Discontinue PREZISTA/ritonavir at least 1 week prior to starting irinotecan therapy. Do not administer PREZISTA/ritonavir with irinotecan unless there are no therapeutic alternatives.|
|Inhaled beta agonist:|
|salmeterol||↑ salmeterol||Co-administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.|
|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.|
|atorvastatin, pravastatin, rosuvastatin||↑ HMG-CoA reductase inhibitors||Co-administration of PREZISTA/ritonavir with HMG-Co A reductase inhibitors may lead to adverse events such as myopathy. Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for adverse events. Do not exceed atorvastatin 20 mg/day.|
|Other lipid modifying agents:|
|lomitapide||↑ lomitapide||Co-administration is contraindicated due to potential for markedly increased transaminases.|
|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 analgesics/treatment of opioid dependence:buprenorphine, buprenorphine/naloxone||↔ buprenorphine, naloxone↑ norbuprenorphine (metabolite)||No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are co-administered.|
|methadone||↓ methadone||No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.|
|naloxegol||↑ naloxegol||Co-administration of PREZISTA/ritonavir and naloxegol is contraindicated due to potential for precipitating opioid withdrawal symptoms.|
|PDE-5 inhibitors:e.g. avanafil, sildenafil, tadalafil, vardenafil||↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir)|| |
Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
Co-administration with sildenafil used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope). The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir:
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 events.
Co-administration of PREZISTA/ritonavir and avanafil is not recommended.
|Platelet aggregation inhibitor: ticagrelor||↑ ticagrelor||Co-administration of PREZISTA/ritonavir and ticagrelor is not recommended.|
|clopidogrel||↓ clopidogrel active metabolite||Co-administration of PREZISTA/ritonavir and clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel.|
|prasugrel||↔ prasugrel active metabolite||No dose adjustment is needed when prasugrel is co-administered with PREZISTA/ritonavir.|
|Proton pump inhibitor: omeprazole||↓ omeprazole↔ darunavir||When omeprazole is co-administered with PREZISTA/ritonavir, monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.|
|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. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with PREZISTA may cause large increases in the concentrations of these benzodiazepines.|
|metabolized by CYP3Ae.g. buspirone, diazepam, estazolam, zolpidem||↑ sedatives/hypnotics||Titration is recommended when co-administering PREZISTA/ritonavir with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for adverse events.|
|parenterally administered midazolam||Co-administration of parenteral midazolam should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.|
|fesoterodine||↑ fesoterodine||When fesoterodine is co-administered with PREZISTA/ritonavir, do not exceed a fesoterodine dose of 4 mg once daily.|
|solifenacin||↑ solifenacin||When solifenacin is co-administered with PREZISTA/ritonavir, do not exceed a solifenacin dose of 5 mg once daily.|
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