Prezista
FDA Label NDC 53808-0773

Full FDA labeling including Indications, Dosage, Usage, and Precautions

Structured Product Label

The following Structured Product Label (SPL) was submitted to the FDA by State Of Florida Doh Central Pharmacy for the product Prezista (NDC 53808-0773). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.

This specific version of the label includes detailed information regarding 1.1 adult patients, 1.2 pediatric patients, 2.1 adult patients, 2.2 pediatric patients (age 6 to < 18 years), 2.3 patients with hepatic impairment, 3.1 prezista 75 mg tablets, 3.2 prezista 150 mg tablets, 3.3 prezista 300 mg tablets, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.

Label Section Quick Index

1.1 Adult Patients

PREZISTA®, co-administered with ritonavir (PREZISTA/ritonavir), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection.

This indication is based on analyses of plasma HIV RNA levels and CD4+ cell counts from 2 controlled Phase 3 trials of 48 weeks duration in antiretroviral treatment-naïve and treatment-experienced patients and 2 controlled Phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients.

1.2 Pediatric Patients

PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), and with other antiretroviral agents, is indicated for the treatment of HIV infection in pediatric patients 6 years of age and older [see Use in Specific Populations (8.4)].

This indication is based on 24-week analyses of plasma HIV RNA levels and CD4+ cell counts from an open-label Phase 2 trial in antiretroviral treatment-experienced pediatric patients 6 to < 18 years of age.

In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with PREZISTA/ritonavir:

2.1 Adult Patients

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.

2.2 Pediatric Patients (Age 6 To < 18 Years)

Do not use once daily dosing in pediatric patients.

Healthcare professionals should pay special attention to accurate dose selection of PREZISTA, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose.

Prescribers should select the appropriate dose of PREZISTA/ritonavir for each individual child based on body weight (kg) and should not exceed the recommended dose for treatment-experienced adults.

Before prescribing PREZISTA, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a tablet, the use of PREZISTA tablets may not be appropriate.

The recommended dose of PREZISTA/ritonavir for pediatric patients (6 to < 18 years of age and weighing at least 44 lbs (20 kg)) is based on body weight (see Table 1) and should not exceed the recommended treatment-experienced adult dose (PREZISTA/ritonavir 600/100 mg b.i.d.). PREZISTA tablets should be taken with ritonavir twice daily and with food.

Table 1: Recommended Dose for Pediatric Patients (6 to < 18 years of age) for PREZISTA Tablets with ritonavir
Body WeightDose
(kg)(lbs) 
≥ 20 kg – < 30 kg ≥ 44 lbs – < 66 lbs375 mg PREZISTA/50 mg ritonavir twice daily
≥ 30 kg – < 40 kg ≥ 66 lbs – < 88 lbs450 mg PREZISTA/60 mg ritonavir twice daily
≥ 40 kg≥ 88 lbs600 mg PREZISTA/100 mg ritonavir twice daily

The safety and efficacy of PREZISTA/ritonavir in pediatric patients 3 to < 6 years of age have not been established.

Do not use PREZISTA/ritonavir in pediatric patients below 3 years of age [see Warnings and Precautions (5.11) and Nonclinical Toxicology (13.2)].

2.3 Patients With Hepatic Impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are available regarding the use of PREZISTA/ritonavir when co-administered to subjects with severe hepatic impairment; therefore, PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

3.1 Prezista 75 Mg Tablets

PREZISTA (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing darunavir ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with "75" on one side and "TMC" on the other side.

3.2 Prezista 150 Mg Tablets

PREZISTA (darunavir) 150 mg tablets are supplied as white, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 150 mg of darunavir per tablet. Each tablet is debossed with "150" on one side and "TMC" on the other side.

3.3 Prezista 300 Mg Tablets

PREZISTA (darunavir) 300 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 300 mg of darunavir per tablet. Each tablet is debossed with "300" on one side and "TMC114" on the other side.

3.4 Prezista 400 Mg Tablets

PREZISTA (darunavir) 400 mg tablets are supplied as light orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 400 mg of darunavir per tablet. Each tablet is debossed with "400" on one side and "TMC" on the other side.

3.5 Prezista 600 Mg Tablets

PREZISTA (darunavir) 600 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 600 mg of darunavir per tablet. Each tablet is debossed with "600" on one side and "TMC" on the other side.

4 Contraindications

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 (narrow therapeutic index). These drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed in Table 2 [also see Drug Interactions (7.3), Table 7].

Table 2: Drugs That Are Contraindicated With PREZISTA/ritonavir
Drug ClassDrugs Within Class That Are Contraindicated With PREZISTA/ritonavirClinical Comment
Alpha 1-adrenoreceptor antagonistAlfuzosinPotential for serious and/or life-threatening reactions such as hypotension.
Ergot DerivativesDihydroergotamine, Ergonovine, Ergotamine, MethylergonovinePotential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility AgentCisapridePotential for serious and/or life-threatening reactions such as cardiac arrhythmias.
NeurolepticPimozidePotential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnoticsOrally administered Midazolam, TriazolamTriazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with PREZISTA/ritonavir may cause large increases in the concentrations of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
Herbal ProductsSt. John's Wort (Hypericum perforatum)Patients taking PREZISTA/ritonavir should not use products containing St. John's wort because co-administration may result in reduced plasma concentrations of darunavir. This may result in loss of therapeutic effect and development of resistance.
HMG CoA Reductase InhibitorsLovastatin, SimvastatinPotential for serious reactions such as myopathy including rhabdomyolysis.
For dosing recommendation regarding atorvastatin and pravastatin, see Table 7: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction.
AntimycobacterialRifampinRifampin is a potent inducer of CYP450 metabolism. PREZISTA/ritonavir should not be used in combination with rifampin, as this may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
PDE-5 inhibitorSildenafil for treatment of pulmonary arterial hypertensionA safe and effective dose for the treatment of pulmonary arterial hypertension has not been established with PREZISTA/ritonavir. There is an increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).

Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications.

5.1 General

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.

Please refer to ritonavir prescribing information for additional information on precautionary measures.

5.2 Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/ritonavir. During the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with PREZISTA/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.

Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/ritonavir therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of PREZISTA/ritonavir treatment.

Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/ritonavir should prompt consideration of interruption or discontinuation of treatment.

5.3 Severe Skin Reactions

During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (<0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis has been reported. Discontinue PREZISTA/rtv immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with PREZISTA/rtv [also see Adverse Reactions (6)]. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using PREZISTA/rtv was 0.5%.

5.4 Sulfa Allergy

Darunavir contains a sulfonamide moiety. PREZISTA should be used with caution in patients with a known sulfonamide allergy. In clinical studies with PREZISTA/ritonavir, the incidence and severity of rash was similar in subjects with or without a history of sulfonamide allergy.

5.5 Drug Interactions

See Table 2 for a listing of drugs that are contraindicated for use with PREZISTA/ritonavir due to potentially life-threatening adverse events, significant drug-drug interactions, or loss of therapeutic effect to PREZISTA [see Contraindications (4)]. Please refer to Table 7 for established and other potentially significant drug-drug interactions [see Drug Interactions (7.3)].

5.6 Diabetes Mellitus / Hyperglycemia

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. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established.

5.7 Fat Redistribution

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. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.8 Immune Reconstitution Syndrome

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jirovecii pneumonia, and tuberculosis), which may necessitate further evaluation and treatment.

5.9 Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established.

5.10 Resistance/Cross-Resistance

Because the potential for HIV cross-resistance among PIs has not been fully explored in PREZISTA/ritonavir treated patients, the effect therapy with PREZISTA will have on the activity of subsequently administered PIs is unknown [see Microbiology (12.4)].

5.11 Pediatric Patients

Do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [see Use in Specific Populations (8.1 and 8.4), Clinical Pharmacology (12.3), and Nonclinical Toxicology (13.2)]. The safety and efficacy of PREZISTA/ritonavir in pediatric patients 3 to < 6 years of age have not been established.

6 Adverse Reactions

The safety assessment is based on all safety data from the Phase 2b studies (Studies TMC114-C213, TMC114-C202, TMC114-C215, and TMC114-C208) and Phase 3 studies (TMC114-C211, TMC114-C214, TMC114-C209, DUET-1 (TMC125-C206), and DUET-2 (TMC125-C216)) reported with PREZISTA/ritonavir in a total of 3063 subjects.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.

6.3 Serious Adrs

The following serious ADRs of at least moderate intensity (≥ Grade 2) occurred in the Phase 2b studies (Studies TMC114-C213, TMC114-C202, TMC114-C215, and TMC114-C208) and Phase 3 studies (TMC114-C211, TMC114-C214, TMC114-C209, DUET-1 (TMC125-C206), and DUET-2 (TMC125-C216)) with PREZISTA/ritonavir: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson Syndrome, and vomiting.

6.4 Additional Adrs To Prezista/Ritonavir Identified In Adult Subjects In Other Clinical Trials

The additional ADR of interest identified from other clinical trials was osteonecrosis.

6.5 Patients Co-Infected With Hepatitis B And/Or Hepatitis C Virus

In subjects co-infected with hepatitis B or C virus receiving PREZISTA/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/ritonavir who were not co-infected, except for increased hepatic enzymes [see Warnings and Precautions (5.2)]. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection.

6.6 Clinical Trials Experience: Pediatric Patients

PREZISTA/ritonavir has been studied in 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg) in combination with other antiretroviral agents [see Use in Specific Populations (8.4) and Clinical Studies (14.4)].

Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults. ADRs to PREZISTA/ritonavir (all grades, ≥ 3%), excluding laboratory abnormalities reported as ADRs, were vomiting (13%), diarrhea (11%), abdominal pain (10%), headache (9%), rash (5%), nausea (4%) and fatigue (3%).

Grade 3 or 4 laboratory abnormalities were ALT increased (Grade 3: 3%; Grade 4: 1%), AST increased (Grade 3: 1%), pancreatic amylase increased (Grade 3: 4%, Grade 4: 1%), pancreatic lipase increased (Grade 3: 1%), total cholesterol increased (Grade 3: 1%), and LDL increased (Grade 3: 3%).

6.7 Postmarketing Experience

The following events have been identified during postmarketing use of PREZISTA. Because these events are reported voluntarily from a population of unknown 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) and toxic epidermal necrolysis have been reported [see Warnings and Precautions (5.3)].

7.1 Potential For Prezista/Ritonavir To Affect Other Drugs

PREZISTA co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of PREZISTA and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see Table 7).

7.2 Potential For Other Drugs To Affect Darunavir

Darunavir and ritonavir are metabolized by CYP3A. 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 may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (see Table 7).

7.3 Established And Other Potentially Significant Drug Interactions

Table 7 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.

Table 7: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 10 and 11]
Concomitant Drug Class:
Drug Name		Effect on Concentration of Darunavir or Concomitant DrugClinical Comment
HIV-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-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir
 
(The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)		↑ darunavir
↑ indinavir		The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
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.
HIV-Antiviral Agents: CCR5 co-receptor antagonists
Maraviroc↑ maravirocMaraviroc concentrations are increased when co-administered with PREZISTA/rtv. When used in combination with PREZISTA/rtv, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics:
bepridil,
lidocaine (systemic),
quinidine,
amiodarone,
flecainide,
propafenone		↑ antiarrhythmicsConcentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin↑ digoxinThe 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.
Anticoagulant:
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.
Anticonvulsant:
carbamazepine		↔ darunavir
↑ carbamazepine		The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant:
phenobarbital,
phenytoin		↔ darunavir
↓ phenytoin
↓ phenobarbital		Co-administration of PREZISTA/ritonavir may cause decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant:
trazodone,
desipramine		↑ trazodone
↑ desipramine		Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered.
Anti-infective:
clarithromycin		↔ darunavir
↑ clarithromycin		No dose adjustment of the combination is required for patients with normal renal function. For 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%.
Antifungals:
ketoconazole,
itraconazole,
voriconazole		↑ ketoconazole
↑ darunavir
↑ itraconazole
(not studied)
↓ voriconazole
(not studied)		Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout:
colchicine		↑ colchicineTreatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
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 in patients on PREZISTA/ritonavir:
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 in patients on PREZISTA/ritonavir:
maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.

Antimycobacterial:
rifabutin		↑ 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.
The reference regimen for rifabutin was 300 mg once daily
β-Blockers:
 
metoprolol,
timolol		↑ beta-blockersCaution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines:
parenterally administered midazolam		↑ midazolamConcomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration 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. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel
Blockers:
felodipine,
nifedipine,
nicardipine		↑ calcium channel blockers Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Systemic:
dexamethasone		↓ darunavirSystemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid:
Inhaled/Nasal:
fluticasone		↑ fluticasoneConcomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long term use.
Endothelin receptor antagonists:
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.

HMG-CoA
Reductase Inhibitors:
pravastatin,
atorvastatin,
rosuvastatin		↑ pravastatin
↑ atorvastatin
↑ rosuvastatin		Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/ritonavir.
Immunosuppressants:
cyclosporine,
tacrolimus,
sirolimus		↑ immunosuppressantsPlasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist:
salmeterol		↑ salmeterolConcurrent 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.
Narcotic Analgesic/Treatment of Opioid Dependence:
methadone,
buprenorphine,
buprenorphine/naloxone		↓ methadone
↔ buprenorphine, naloxone
↑ norbuprenorphine (metabolite)		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.
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 coadministered.
Neuroleptics:
risperidone,
thioridazine		↑ neurolepticsA dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen:
ethinyl estradiol,
norethindrone		↓ ethinyl estradiol
↓ norethindrone		Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors:
sildenafil,
vardenafil,
tadalafil		↑ 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):

  • Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)].
  • The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir:
    Co-administration of tadalafil in patients on PREZISTA/ritonavir:
    In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
    Co-administration of PREZISTA/ritonavir in patients on tadalafil:
    Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

    • 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.

Selective Serotonin Reuptake Inhibitors (SSRIs):
sertraline,
paroxetine		↔ darunavir
↓ sertraline
↓ paroxetine		If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.

In addition to the drugs included in Table 7, the interaction between PREZISTA/ritonavir and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug [see Clinical Pharmacology (12.3)]: atazanavir, efavirenz, etravirine, nevirapine, omeprazole, ranitidine, and tenofovir disoproxil fumarate.

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV. Although it is not known whether darunavir is secreted in human milk, darunavir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving PREZISTA.

8.4 Pediatric Use

Do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [see Warnings and Precautions (5.11), Use in Specific Populations (8.1), Clinical Pharmacology (12.3) and Nonclinical Toxicology (13.2)].

The pharmacokinetics, safety, tolerability, and efficacy of PREZISTA/ritonavir in pediatric patients 3 to < 6 years of age have not been established.

Do not administer PREZISTA/ritonavir once daily in pediatric patients.

The safety, pharmacokinetic profile, and virologic and immunologic responses of PREZISTA/ritonavir were evaluated in treatment-experienced HIV-1-infected pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg) [see Adverse Reactions (6.6), Clinical Pharmacology (12.3) and Clinical Studies (14.4)]. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions (6.6)]. Please see Dosage and Administration (2.2) for dosing recommendations for pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg).

8.5 Geriatric Use

Clinical studies of PREZISTA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of PREZISTA in elderly patients reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

No dose adjustment of PREZISTA/ritonavir is necessary for patients with either mild or moderate hepatic impairment. No pharmacokinetic or safety data are available regarding the use of PREZISTA/ritonavir in subjects with severe hepatic impairment, therefore, PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30-60 mL/min, n=20). No pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end stage renal disease; however, because the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3)].

10 Overdosage

Human experience of acute overdose with PREZISTA/ritonavir is limited. Single doses up to 3200 mg of the oral solution of darunavir alone and up to 1600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.

No specific antidote is available for overdose with PREZISTA. Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since PREZISTA is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

11 Description

PREZISTA (darunavir) is an inhibitor of the human immunodeficiency virus (HIV) protease.

PREZISTA (darunavir), in the form of darunavir ethanolate, has the following chemical name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate. Its molecular formula is C27H37N3O7S • C2H5OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:

Chemical Structure (Prezista 01)

Chemical Structure (Prezista 01)

Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.15 mg/mL in water at 20°C.

PREZISTA 75 mg tablets are available as white, caplet-shaped, film-coated tablets for oral administration. PREZISTA 150 mg tablets are available as white, oval-shaped, film-coated tablets for oral administration. PREZISTA 300 mg and PREZISTA 600 mg tablets are available as orange, oval-shaped, film-coated tablets for oral administration. PREZISTA 400 mg is available as a light orange, oval-shaped, film-coated tablet for oral administration.

Each 75 mg tablet contains darunavir ethanolate equivalent to 75 mg of darunavir. Each 150 mg tablet contains darunavir ethanolate equivalent to 150 mg of darunavir. Each 300 mg tablet contains darunavir ethanolate equivalent to 300 mg of darunavir. Each 400 mg tablet contains darunavir ethanolate equivalent to 400 mg of darunavir. Each 600 mg tablet contains darunavir ethanolate equivalent to 600 mg of darunavir. During storage, partial conversion from ethanolate to hydrate may occur; however, this does not affect product quality or performance. Each tablet also contains the inactive ingredients colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The tablet film coating, OPADRY® White, contains polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide. The tablet film coating, OPADRY® Orange, contains FD&C Yellow No. 6, polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.

All dosages for PREZISTA are expressed in terms of the free form of darunavir.

12.2 Pharmacodynamics

In an open-label, randomized, placebo- and active-controlled, four-way crossover trial, 40 healthy subjects were administered supratheraputic doses of darunavir/ritonavir 1600/100 mg once daily and 800/100 mg twice daily for seven days.

At the mean maximum darunavir concentration of 6599 ng/mL observed in this study, the mean increase in QTcF was 2.2 ms with a 90% two-sided confidence interval (CI) of -2.0 to 6.3 ms. When evaluating the 2-sided 90% CI on the time-matched mean changes in QTcF versus placebo control, the upper bounds of both darunavir/ritonavir groups never exceeded the 10 ms boundary. In the setting of this trial, darunavir/ritonavir did not appear to prolong the QTc interval.

13.2 Animal Toxicology And/Or Pharmacology

In juvenile rats single doses of darunavir (20 mg/kg to 160 mg/kg at ages 5-11 days) or multiple doses of darunavir (40 mg/kg to 1000 mg/kg at age 12 days) caused mortality. The mortalities were associated with convulsions in some of the animals. Within this age range exposures in plasma, liver and brain were dose and age dependent and were considerably greater than those observed in adult rats. These findings were attributed to the ontogeny of the CYP450 liver enzymes involved in the metabolism of darunavir and the immaturity of the blood-brain barrier. No treatment-related mortalities were noted in juvenile rats after a single dose of darunavir at 1000 mg/kg on day 26 of age or after repeat dosing at 500 mg/kg from day 23 to 50 of age. The exposures and toxicity profile in the older animals (day 23 or day 26) were comparable to those observed in adult rats. Due to uncertainties regarding the rate of development of the human blood-brain barrier and liver enzymes, do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age.

14.1 Description Of Adult Clinical Studies

The evidence of efficacy of PREZISTA/ritonavir is based on the analyses of 96-week data from 2 randomized, controlled open-label Phase 3 trials in treatment-naïve (TMC114-C211) and antiretroviral treatment-experienced (TMC114-C214) HIV-1-infected adult subjects. In addition, 96-week data is included from 2 randomized, controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-infected adult subjects.

14.4 Pediatric Patients

The pharmacokinetic profile, safety and antiviral activity of PREZISTA/ritonavir were evaluated in a randomized, open-label, multicenter study. This study enrolled treatment-experienced pediatric subjects between the ages of 6 and < 18 years and weighing at least 44 lbs (20 kg). Patients were stratified according to their weight (≥ 20 - < 30 kg, ≥ 30 - < 40 kg, ≥ 40 kg) and received PREZISTA/ritonavir plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs. Eighty patients were randomized and received at least one dose of PREZISTA/ritonavir. Pediatric subjects who were at risk of discontinuing therapy due to intolerance of ritonavir oral solution (e.g., taste aversion) were allowed to switch to the capsule formulation. Of the 44 pediatric subjects taking ritonavir oral solution, 23 subjects switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.

The 80 randomized pediatric subjects had a median age of 14 (range 6 - < 18 years), and were 71% male, 54% Caucasian, 30% Black, 9% Hispanic and 8% other. The mean baseline plasma HIV-1 RNA was 4.64 log10 copies/mL, and the median baseline CD4+ cell count was 330 cells/mm3 (range: 6 to 1505 cells/mm3). Overall, 38% of pediatric subjects had baseline plasma HIV-1 RNA ≥ 100,000 copies/mL. Most pediatric subjects (79%) had previous use of at least one NNRTI and 96% of pediatric subjects had previously used at least one PI.

Seventy-seven pediatric subjects (96%) completed the 24 week period. Of the patients who discontinued, one patient discontinued treatment due to an adverse event. An additional 2 patients discontinued for other reasons, one patient due to compliance and another patient due to relocation.

The proportion of pediatric subjects with HIV-1 RNA < 400 copies/mL and < 50 copies/mL was 64% and 50%, respectively. The mean CD4+ cell count increase from baseline was 117 cells/mm3.

The dose selection was based on the following:

  • Similar darunavir plasma exposures in children compared to adults
  • Similar virologic response rates and safety profile in children compared to adults

16 How Supplied/Storage And Handling

PREZISTA (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing darunavir ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with "75" on one side and "TMC" on the other side.

PREZISTA (darunavir) 150 mg tablets are supplied as white, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 150 mg of darunavir per tablet. Each tablet is debossed with "150" on one side and "TMC" on the other side.

PREZISTA (darunavir) 300 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 300 mg of darunavir per tablet. Each tablet is debossed with "300" on one side and "TMC114" on the other side.

PREZISTA (darunavir) 400 mg tablets are supplied as light orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 400 mg of darunavir per tablet. Each tablet is debossed with "400" on one side and "TMC" on the other side.

PREZISTA (darunavir) 600 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 600 mg of darunavir per tablet. Each tablet is debossed with "600" on one side and "TMC" on the other side.

They are supplied by State of Florida DOH Central Pharmacy as follows:

NDCStrengthQuantity/FormColorSource Prod. Code
53808-0672-1400 mg30 Tablets in a Blister Packlight orange59676-561
53808-0773-1600 mg30 Tablets in a Blister PackORANGE59676-562

17 Patient Counseling Information

[See FDA-Approved Patient Labeling]

A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with PREZISTA. A Patient Package Insert for PREZISTA is available for patient information.

17.1 General

Patients should be informed that PREZISTA is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be told that there are currently no data demonstrating that therapy with PREZISTA can reduce the risk of transmitting HIV to others.

Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using PREZISTA.

17.3 Drug Interactions

PREZISTA/ritonavir may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.

Patients receiving estrogen-based contraceptives should be instructed to use alternate contraceptive measures during therapy with PREZISTA/ritonavir because hormonal levels may decrease.

17.4 Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including PREZISTA/ritonavir, and that the cause and long-term health effects of these conditions are not known at this time.

* Please review the disclaimer below.