PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adult and pediatric patients 3 years of age and older.

In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus.

The recommended dose of PREZISTA/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at least 10 kg is based on body weight and should not exceed the recommended adult dose.

PREZISTA must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer PREZISTA with ritonavir and food may result in a loss of efficacy of darunavir.

PREZISTA should be used with caution in patients with a known sulfonamide allergy.

Patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases should be monitored for elevation in serum liver biochemistries, especially during the first several months of PREZISTA/ritonavir treatment.

PREZISTA must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer PREZISTA with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.

PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV infected patients receiving protease inhibitor (PI) therapy.

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs.

During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including PREZISTA. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Risk of significant adverse drug-drug interactions between the antipsychotic medication LATUDA (lurasidone hydrochloride).

Co-administration of PREZISTA/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Examples of these drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed below. Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications:

• Alpha 1-adrenoreceptor antagonist: alfuzosin
• Anti-gout: colchicine, in patients with renal and/or hepatic impairment
• Antimycobacterial: rifampin
• Antipsychotics: lurasidone, pimozide
• Cardiac Disorders: dronedarone, ivabradine, ranolazine
• Ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine
• Herbal product: St. John’s wort (Hypericum perforatum)
• Hepatitis C direct acting antiviral: elbasvir/grazoprevir
• Lipid modifying agents: lomitapide, lovastatin, simvastatin
• Opioid Antagonist: naloxegol
• PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension
• Sedatives/hypnotics: orally administered midazolam, triazolam

Use of PREZISTA may reduce the efficacy of combined hormonal contraceptives and the progestin only pill. Advise patients using combined hormonal contraceptives or the progestin only pill to use an effective alternative contraceptive method or add a barrier method of contraception.

Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).

The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.

It is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.

It is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.

When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.

For co-administration of clarithromycin and PREZISTA/ritonavir in patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30-60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of <30 mL/min, the dose of clarithromycin should be reduced by 75%.

Due to potentially increased bleeding risk, dosing recommendations for co-administration of apixaban with PREZISTA depends on the apixaban dose.

Co-administration of PREZISTA/ritonavir and rivaroxaban is not recommended because it may lead to an increased bleeding risk.

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.

Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.

Use a lower dose of the tricyclic antidepressants and trazodone due to potential increased adverse events such as nausea, dizziness, hypotension and syncope.

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 is not recommended for patients receiving PREZISTA/ritonavir unless an assessment comparing predicted benefit to risk ratio justifies the use of voriconazole.

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.

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.

Initiation of PREZISTA with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions.

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.

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.

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.

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.

Co-administration of PREZISTA/ritonavir with glecaprevir/pibrentasvir is not recommended.

Co-administration of everolimus and PREZISTA/ritonavir is not recommended.

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.

Co-administration of salmeterol and PREZISTA/ritonavir is not recommended.

Co-administration of PREZISTA/ritonavir with HMG-Co A reductase inhibitors may lead to adverse events such as myopathy.

Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.

Co-administration of PREZISTA/ritonavir and avanafil is not recommended.

Co-administration of PREZISTA/ritonavir and ticagrelor is not recommended.

Co-administration of PREZISTA/ritonavir and clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel.

When omeprazole is co-administered with PREZISTA/ritonavir, monitor patients for decreased efficacy of omeprazole.

When fesoterodine is co-administered with PREZISTA/ritonavir, do not exceed a fesoterodine
dose of 4 mg once daily.

When solifenacin is co-administered with PREZISTA/ritonavir, do not exceed a solifenacin dose of 5 mg once daily.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

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• Use in patients under the age of 3. GoToSource

• Monotherapy. GoToSource

Drug-induced hepatitis and liver damage. GoToSource

Increased risk for heart attack, stroke, invasive heart surgery and sudden cardiac death. GoToSource

Maculopapular rash, lipodystrophy syndrome (abnormal fat distribution), central adiposity (accumulation of fat in lower torso), insulin resistance, hyperglycemia (high blood sugar) and hyperlipidaemia (abnormal levels of fats (lipids) in blood). GoToSource

Myopathy including rhabdomyolysis (destruction of muscle tissue) when used with statins. GoToSource

Stevens-johnson syndrome and toxic epidermal necrolysis (life-threatening skin condition). GoToSource

Immune reconstitution inflammatory syndrome (paradoxical clinical worsening of a known condition or the appearance of a new condition), autoimmune disorders including graves’ disease, polymyositis and guillain-barré syndrome, hypersensitivity reactions and hepatitis B reactivation. GoToSource

Peripheral neuropathy (nerve damage). GoToSource

Gastrointestinal intolerance (diarrhea and nausea), insulin resistance and dyslipidemia (elevated lipids). GoToSource

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