PREZISTA 600 MG Oral Tablet
Generic Name: DARUNAVIR
Brand Name: PREZISTA
- Substance Name(s):
- DARUNAVIR ETHANOLATE
DRUG INTERACTIONS
7 Co-administration of PREZISTA/ritonavir with other drugs can alter the concentrations of other drugs and other drugs may alter the concentrations of darunavir.
The potential drug-drug interactions must be considered prior to and during therapy.
(4, 5.5, 7, 12.3) 7.1 Potential for PREZISTA/ritonavir to Affect Other Drugs 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 (see Table 10).
7.2 Potential for Other Drugs to Affect Darunavir 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).
7.3 Established and Other Potentially Significant Drug Interactions 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 [see Contraindications (4) and Clinical Pharmacology (12.3)].
Table 10: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction (see Contraindications (4) for a complete list of contraindicated drugs) [see Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 15 and 16] Concomitant Drug Class Drug 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 coadministration with PREZISTA/ritonavir has not been studied, coadministration 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.
Other Agents Alpha 1-adrenoreceptor antagonist: alfuzosin ↑ alfuzosin Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.
Antianginal: ranolazine ↑ ranolazine Co-administration is contraindicated due to potential for serious and/or life-threatening reactions.
Antiarrhythmics: dronedarone ↑ dronedarone Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
e.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.
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: 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%.
Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban ↑ apixaban Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with PREZISTA depends on the apixaban dose.
Refer to apixaban dosing instructions for coadministration 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.
Other Anticoagulants 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, ketoconazole, posaconazole ↑ darunavir ↑ itraconazole ↑ ketoconazole ↔ posaconazole Monitor for increased PREZISTA/ritonavir adverse events with concomitant use of itraconazole, ketoconazole, or posaconazole.
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: Treatment 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).
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.
Antimycobacterials: rifampin ↓ darunavir ↓ cobicistat 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.
Antipsychotics: 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.
Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g.
betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone ↓ darunavir ↑ corticosteroids 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.Co-administration with corticosteroids 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 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.
Ergot derivatives: 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.
simeprevir ↑ simeprevir ↑ darunavir Co-administration of PREZISTA/ritonavir and simeprevir is not recommended Herbal product: St.
John’s wort (Hypericum perforatum) ↓ darunavir ↓ cobicistat 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.
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.
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 coadministered.
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.
Oral contraceptives/estrogen: Effective alternative (non-hormonal) contraceptive method or 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.
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: 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.
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.
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.
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.
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 CYP3A e.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.
7.4 Drugs without Clinically Significant Interactions with PREZISTA No dosage adjustments are recommended when PREZISTA/ritonavir is co-administered with the following medications: atazanavir, dolutegravir, efavirenz, etravirine, nevirapine, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, emtricitabine/tenofovir alafenamide, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), pitavastatin, raltegravir, ranitidine, or rilpivirine.
OVERDOSAGE
10 Human experience of acute overdose with PREZISTA/ritonavir is limited.
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.
Since PREZISTA is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
DESCRIPTION
11 PREZISTA (darunavir) is an inhibitor of the human immunodeficiency virus (HIV-1) 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: Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.15 mg per mL in water at 20°C.
PREZISTA 100 mg per mL oral suspension is available as a white to off-white opaque suspension for oral administration.
Each mL of the oral suspension contains darunavir ethanolate equivalent to 100 mg darunavir.
In addition, each mL contains the inactive ingredients citric acid monohydrate, hydrochloric acid (for pH adjustment), hydroxypropyl cellulose, masking flavor, methylparaben sodium, microcrystalline cellulose, purified water, sodium carboxymethylcellulose, strawberry cream flavor and sucralose.
PREZISTA 75 mg tablets are available as white, caplet-shaped, film-coated tablets for oral administration.
Each 75 mg tablet contains darunavir ethanolate equivalent to 75 mg of darunavir.
PREZISTA 150 mg tablets are available as white, oval-shaped, film-coated tablets for oral administration.
Each 150 mg tablet contains darunavir ethanolate equivalent to 150 mg of darunavir.
PREZISTA 600 mg tablets are available as orange, oval-shaped, film-coated tablets for oral administration.
Each 600 mg tablet contains darunavir ethanolate equivalent to 600 mg of darunavir.
PREZISTA 800 mg tablets are available as dark red, oval-shaped, film-coated tablets for oral administration.
Each 800 mg tablet contains darunavir ethanolate equivalent to 800 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 800 mg tablet also contains hypromellose.
The 75 and 150 mg tablet film coating, OPADRY® White, contains polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.
The 600 mg tablet film coating, OPADRY® Orange, contains FD&C Yellow No.
6, polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.
The 800 mg tablet film coating, OPADRY® Dark Red, contains iron oxide red, 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.
Chemical Structure
CLINICAL STUDIES
14 14.1 Description of Adult Clinical Trials The evidence of efficacy of PREZISTA/ritonavir is based on the analyses of 192-week data from a randomized, controlled open-label Phase 3 trial in treatment-naïve (TMC114-C211) HIV-1-infected adult subjects and 96-week data from a randomized, controlled, open-label Phase 3 trial in antiretroviral treatment-experienced (TMC114-C214) HIV-1-infected adult subjects.
In addition, 96-week data are included from 2 randomized, controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-infected adult subjects.
14.2 Treatment-Naïve Adult Subjects TMC114-C211 TMC114-C211 is a randomized, controlled, open-label Phase 3 trial comparing PREZISTA/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen) in antiretroviral treatment-naïve HIV-1-infected adult subjects.
Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily (TDF) and emtricitabine 200 mg once daily (FTC).
HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than or equal to 5000 copies/mL.
Randomization was stratified by screening plasma viral load (HIV-1 RNA less than 100,000 copies/mL or greater than or equal to 100,000 copies/mL) and screening CD4+ cell count (less than 200 cells/mm3 or greater than or equal to 200 cells/mm3).
Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL.
Analyses included 689 subjects in trial TMC114-C211 who had completed 192 weeks of treatment or discontinued earlier.
Demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the lopinavir/ritonavir arm (see Table 19).
Table 19 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and subjects in the lopinavir/ritonavir 800/200 mg per day arm in trial TMC114-C211.
Table 19: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C211 PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC N=343 lopinavir/ritonavir 800/200 mg per day + TDF/FTC N=346 FTC=emtricitabine; TDF=tenofovir disoproxil fumarate Demographic characteristics Median age (years) (range, years) 34 (18–70) 33 (19–68) Sex Male 70% 70% Female 30% 30% Race White 40% 45% Black 23% 21% Hispanic 23% 22% Asian 13% 11% Baseline characteristics Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.86 4.84 Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 228 (4–750) 218 (2–714) Percentage of patients with baseline viral load ≥100,000 copies/mL 34% 35% Percentage of patients with baseline CD4+ cell count <200 cells/mm3 41% 43% Week 192 outcomes for subjects on PREZISTA/ritonavir 800/100 mg once daily from trial TMC114-C211 are shown in Table 20.
Table 20: Virologic Outcome of Randomized Treatment of Trial TMC114-C211 at 192 Weeks PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC N=343 lopinavir/ritonavir 800/200 mg per day + TDF/FTC N=346 N = total number of subjects with data; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate Virologic success HIV-1 RNA <50 copies/mL 70%95% CI: 1.9; 16.1 61% Virologic failureIncludes patients who discontinued prior to Week 192 for lack or loss of efficacy and patients who are ≥50 copies in the 192-week window and patients who had a change in their background regimen that was not permitted by the protocol.
12% 15% No virologic data at Week 192 windowWindow 186–198 Weeks.
Reasons Discontinued trial due to adverse event or deathIncludes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
5% 13% Discontinued trial for other reasonsOther includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL 13% 12% Missing data during window but on trial <1% 0% In trial TMC114-C211 at 192 weeks of treatment, the median increase from baseline in CD4+ cell counts was 258 cells/mm3 in the PREZISTA/ritonavir 800/100 mg once daily arm and 263 cells/mm3 in the lopinavir/ritonavir 800/200 mg per day arm.
Of the PREZISTA/ritonavir subjects with a confirmed virologic response of <50 copies/mL at Week 48, 81% remained undetectable at Week 192 versus 68% with lopinavir/ritonavir.
In the 192 week analysis, statistical superiority of the PREZISTA/ritonavir regimen over the lopinavir/ritonavir regimen was demonstrated for both ITT and OP populations.
14.3 Treatment-Experienced Adult Subjects TMC114-C229 TMC114-C229 is a randomized, open-label trial comparing PREZISTA/ritonavir 800/100 mg once daily to PREZISTA/ritonavir 600/100 mg twice daily in treatment-experienced HIV-1-infected patients with screening genotype resistance test showing no darunavir resistance associated substitutions (i.e.
V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) and a screening viral load of greater than 1,000 HIV-1 RNA copies/mL.
Both arms used an optimized background regimen consisting of greater than or equal to 2 NRTIs selected by the investigator.
HIV-1-infected subjects who were eligible for this trial were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks.
Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL.
Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier.
Table 21 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm in trial TMC114-C229.
No imbalances between the 2 arms were noted.
Table 21: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C229 PREZISTA/ritonavir 800/100 mg once daily + OBR N=294 PREZISTA/ritonavir 600/100 mg twice daily + OBR N=296 OBR=optimized background regimen Demographic characteristics Median age (years) (range, years) 40 (18–70) 40 (18–77) Sex Male 61% 67% Female 39% 33% Race White 35% 37% Black 28% 24% Hispanic 16% 20% Asian 16% 14% Baseline characteristics Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.19 4.13 Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 219 (24–1306) 236 (44–864) Percentage of patients with baseline viral load ≥100,000 copies/mL 13% 11% Percentage of patients with baseline CD4+ cell count <200 cells/mm3 43% 39% Median darunavir fold change (range)Based on phenotype (Antivirogram®) 0.50 (0.1–1.8) 0.50 (0.1–1.9) Median number of resistance-associatedJohnson VA, Brun-Vézinet F, Clotet B, et al.
Update of the drug resistance mutations in HIV-1: December 2008.
Top HIV Med 2008; 16(5): 138–145: PI mutations 3 4 NNRTI mutations 2 1 NRTI mutations 1 1 Percentage of subjects susceptible to all available PIs at baseline 88% 86% Percentage of subjects with number of baseline primary protease inhibitor mutations: 0 84% 84% 1 8% 9% 2 5% 4% ≥3 3% 2% Median number of ARVs previously usedOnly counting ARVs, excluding low-dose ritonavir: NRTIs 3 3 NNRTIs 1 1 PIs (excluding low-dose ritonavir) 1 1 Week 48 outcomes for subjects on PREZISTA/ritonavir 800/100 mg once daily from trial TMC114-C229 are shown in Table 22.
Table 22: Virologic Outcome of Randomized Treatment of Trial TMC114-C229 at 48 Weeks PREZISTA/ritonavir 800/100 mg once daily + OBR N=294 PREZISTA/ritonavir 600/100 mg twice daily + OBR N=296 N = total number of subjects with data; OBR=optimized background regimen Virologic success HIV-1 RNA <50 copies/mL 69% 69% Virologic failureIncludes patients who discontinued prior to Week 48 for lack or loss of efficacy, patients who are ≥50 copies in the 48-week window, patients who had a change in their background regimen that was not permitted in the protocol (provided the switch occurred before the earliest onset of an AE leading to permanent stop of trial medication) and patients who discontinued for reasons other than AEs/death and lack or loss of efficacy (provided their last available viral load was detectable (HIV RNA ≥50 copies/mL).
26% 23% No virologic data at Week 48 windowWindow 42–54 Weeks Reasons Discontinued trial due to adverse event or deathPatients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
3% 4% Discontinued trial for other reasonsOther includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL.
2% 3% Missing data during window but on trial 0% <1% The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm3 and 112 cells/mm3 in the PREZISTA/ritonavir 800/100 mg once daily arm and the PREZISTA/ritonavir 600/100 mg twice daily arm, respectively).
TMC114-C214 TMC114-C214 is a randomized, controlled, open-label Phase 3 trial comparing PREZISTA/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced, lopinavir/ritonavir-naïve HIV-1-infected adult subjects.
Both arms used an optimized background regimen consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).
HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than 1000 copies/mL and were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks.
Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 400 copies/mL.
Analyses included 595 subjects in trial TMC114-C214 who had completed 96 weeks of treatment or discontinued earlier.
Demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the lopinavir/ritonavir arm (see Table 23).
Table 23 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and subjects in the lopinavir/ritonavir 400/100 mg twice daily arm in trial TMC114-C214.
Table 23: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C214 PREZISTA/ritonavir 600/100 mg twice daily + OBR N=298 lopinavir/ritonavir 400/100 mg twice daily + OBR N=297 OBR=optimized background regimen Demographic characteristics Median age (years) (range, years) 40 (18–68) 41 (22–76) Sex Male 77% 81% Female 23% 19% Race White 54% 57% Black 18% 17% Hispanic 15% 15% Asian 9% 9% Baseline characteristics Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.33 4.28 Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 235 (3–831) 230 (2–1096) Percentage of patients with baseline viral load ≥100,000 copies/mL 19% 17% Percentage of patients with baseline CD4+ cell count <200 cells/mm3 40% 40% Median darunavir fold change (range) 0.60 (0.10–37.40) 0.60 (0.1–43.8) Median lopinavir fold change (range) 0.70 (0.40–74.40) 0.80 (0.30–74.50) Median number of resistance-associatedJohnson VA, Brun-Vezinet F, Clotet B, et al.
Update of the drug resistance mutations in HIV-1: Fall 2006.
Top HIV Med 2006; 14(3): 125–130: PI mutations 4 4 NNRTI mutations 1 1 NRTI mutations 2 2 Percentage of subjects with number of baseline primary protease inhibitor mutations: ≤1 78% 80% 2 8% 9% ≥3 13% 11% Median number of ARVs previously usedOnly counting ARVs, excluding low-dose ritonavir: NRTIs 4 4 NNRTIs 1 1 PIs (excluding low-dose ritonavir) 1 1 Percentage of subjects resistantBased on phenotype (Antivirogram®) to all availableCommercially available PIs at the time of trial enrollment PIs at baseline, excluding darunavir 2% 3% Week 96 outcomes for subjects on PREZISTA/ritonavir 600/100 mg twice daily from trial TMC114-C214 are shown in Table 24.
Table 24: Virologic Outcome of Randomized Treatment of Trial TMC114-C214 at 96 Weeks PREZISTA /ritonavir 600/100 mg twice daily + OBR N=298 lopinavir/ritonavir 400/100 mg twice daily + OBR N=297 N = total number of subjects with data; OBR=optimized background regimen Virologic success HIV-1 RNA <50 copies/mL 58% 52% Virologic failureIncludes patients who discontinued prior to Week 96 for lack or loss of efficacy and patients who are ≥50 copies in the 96-week window and patients who had a change in their OBR that was not permitted by the protocol.
26% 33% No virologic data at Week 96 windowWindow 90–102 Weeks Reasons Discontinued trial due to adverse event or deathIncludes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
7% 8% Discontinued trial for other reasonsOther includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL.
8% 7% Missing data during window but on trial 1% <1% In trial TMC114-C214 at 96 weeks of treatment, the median increase from baseline in CD4+ cell counts was 81 cells/mm3 in the PREZISTA/ritonavir 600/100 mg twice daily arm and 93 cells/mm3 in the lopinavir/ritonavir 400/100 mg twice daily arm.
TMC114-C213 and TMC114-C202 TMC114-C213 and TMC114-C202 are randomized, controlled, Phase 2b trials in adult subjects with a high level of PI resistance consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all subjects randomized to PREZISTA/ritonavir received the recommended dose of 600/100 mg twice daily.
HIV-1-infected subjects who were eligible for these trials had plasma HIV-1 RNA greater than 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at least one primary PI mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at screening, and were on a stable PI-containing regimen at screening for at least 8 weeks.
Randomization was stratified by the number of PI mutations, screening viral load, and the use of enfuvirtide.
The virologic response rate was evaluated in subjects receiving PREZISTA/ritonavir plus an OBR versus a control group receiving an investigator-selected PI(s) regimen plus an OBR.
Prior to randomization, PI(s) and OBR were selected by the investigator based on genotypic resistance testing and prior ARV history.
The OBR consisted of at least 2 NRTIs with or without enfuvirtide.
Selected PI(s) in the control arm included: lopinavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 98% of control subjects received a ritonavir boosted PI regimen out of which 23% of control subjects used dual-boosted PIs.
Approximately 47% of all subjects used enfuvirtide, and 35% of the use was in subjects who were ENF-naïve.
Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1 log10 versus baseline.
In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the comparator PI arm (see Table 25).
Table 25 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and subjects in the comparator PI arm in the pooled analysis of trials TMC114-C213 and TMC114-C202.
Table 25: Demographic and Baseline Characteristics of Subjects in the Trials TMC114-C213 and TMC114-C202 (Pooled Analysis) PREZISTA/ritonavir 600/100 mg twice daily + OBR Comparator PI(s) + OBR N=131 N=124 OBR=optimized background regimen Demographic characteristics Median age (years) (range, years) 43 (27–73) 44 (25–65) Sex Male 89% 88% Female 11% 12% Race White 81% 73% Black 10% 15% Hispanic 7% 8% Baseline characteristics Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.61 4.49 Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 153 (3–776) 163 (3–1274) Percentage of patients with baseline viral load >100,000 copies/mL 24% 29% Percentage of patients with baseline CD4+ cell count <200 cells/mm3 67% 58% Median darunavir fold change 4.3 3.3 Median number of resistance-associatedJohnson VA, Brun-Vezinet F, Clotet B, et al.
Update of the drug resistance mutations in HIV-1: Fall 2006.
Top HIV Med 2006; 14(3): 125–130: PI mutations 12 12 NNRTI mutations 1 1 NRTI mutations 5 5 Percentage of subjects with number of baseline primary protease inhibitor mutations: ≤1 8% 9% 2 22% 21% ≥3 70% 70% Median number of ARVs previously usedBased on phenotype (Antivirogram®): NRTIs 6 6 NNRTIs 1 1 PIs (excluding low-dose ritonavir) 5 5 Percentage of subjects resistant to all availableCommercially available PIs at the time of trial enrollment PIs at baseline, excluding tipranavir and darunavir 63% 61% Percentage of subjects with prior use of enfuvirtide 20% 17% Week 96 outcomes for subjects on the recommended dose PREZISTA/ritonavir 600/100 mg twice daily from the pooled trials TMC114-C213 and TMC114-C202 are shown in Table 26.
Table 26: Outcomes of Randomized Treatment Through Week 96 of the Trials TMC114-C213 and TMC114-C202 (Pooled Analysis) Randomized trials TMC114-C213 and TMC114-C202 PREZISTA/ritonavir 600/100 mg twice daily + OBR Comparator PI(s) + OBR N=131 N=124 OBR=optimized background regimen Virologic responders confirmed at least 1 log10 HIV-1 RNA below baseline through Week 96 (<50 copies/mL at Week 96) 57% (39%) 10% (9%) Virologic failures 29% 80% Lack of initial responseSubjects who did not achieve at least a confirmed 0.5 log10 HIV-1 RNA drop from baseline at Week 12 8% 53% RebounderSubjects with an initial response (confirmed 1 log10 drop in viral load), but without a confirmed 1 log10 drop in viral load at Week 96 17% 19% Never suppressedSubjects who never reached a confirmed 1 log10 drop in viral load before Week 96 4% 8% Death or discontinuation due to adverse events 9% 3% Discontinuation due to other reasons 5% 7% In the pooled trials TMC114-C213 and TMC114-C202 through 48 weeks of treatment, the proportion of subjects with HIV-1 RNA less than 400 copies/mL in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily compared to the comparator PI arm was 55.0% and 14.5%, respectively.
In addition, the mean changes in plasma HIV-1 RNA from baseline were –1.69 log10 copies/mL in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily and –0.37 log10 copies/mL for the comparator PI arm.
The mean increase from baseline in CD4+ cell counts was higher in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily (103 cells/mm3) than in the comparator PI arm (17 cells/mm3).
14.4 Pediatric Patients The pharmacokinetic profile, safety and antiviral activity of PREZISTA/ritonavir were evaluated in 3 randomized, open-label, multicenter studies.
TMC114-C212 Treatment-experienced pediatric subjects between the ages of 6 and less than 18 years and weighing at least 20 kg were stratified according to their weight (greater than or equal to 20 kg to less than 30 kg, greater than or equal to 30 kg to less than 40 kg, greater than or equal to 40 kg) and received PREZISTA tablets with either ritonavir capsules or oral solution 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 to less than 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 less than 400 copies/mL and less than 50 copies/mL was 64% and 50%, respectively.
The mean increase in CD4+ cell count from baseline was 117 cells/mm3.
TMC114-C228 Treatment-experienced pediatric subjects between the ages of 3 and less than 6 years and weighing greater than or equal to 10 kg to less than 20 kg received PREZISTA oral suspension with ritonavir oral solution plus background therapy consisting of at least two active non-protease inhibitor antiretroviral drugs.
Twenty-one subjects received at least one dose of PREZISTA/ritonavir.
The 21 subjects had a median age of 4.4 years (range 3 to less than 6 years), and were 48% male, 57% Black, 29%, Caucasian and 14% other.
The mean baseline plasma HIV-1 was 4.34 log10 copies/mL, the median baseline CD4+ cell count was 927 × 106 cells/L (range: 209 to 2,429 × 106 cells/L) and the median baseline CD4+ percentage was 27.7% (range: 15.6% to 51.1%).
Overall, 24% of subjects had a baseline plasma HIV-1 RNA greater than or equal to 100,000 copies/mL.
All subjects had used greater than or equal to 2 NRTIs, 62% of subjects had used greater than or equal to 1 NNRTI and 76% had previously used at least one HIV PI.
Twenty subjects (95%) completed the 48 week period.
One subject prematurely discontinued treatment due to vomiting assessed as related to ritonavir.
The proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 48 was 71%.
The mean increase in CD4+ percentage from baseline was 4%.
The mean change in CD4+ cell count from baseline was 187 × 106 cells/L.
TMC114-C230 Treatment-naïve pediatric subjects between the ages of 12 and less than 18 years and weighing at least 40 kg received the adult recommended dose of PREZISTA/ritonavir 800/100 mg once daily plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs.
The 12 randomized pediatric subjects had a median age of 14.4 years (range 12.6 to 17.3 years), and were 33.3% male, 58.3% Caucasian and 41.7% Black.
The mean baseline plasma HIV-1 RNA was 4.72 log10 copies/mL, and the median baseline CD4+ cell count was 282 cells/mm3 (range: 204 to 515 cells/mm3).
Overall, 41.7% of pediatric subjects had baseline plasma HIV-1 RNA ≥100,000 copies/mL.
All subjects completed the 48 week treatment period.
The proportion of subjects with HIV-1 RNA less than 50 copies/mL and less than 400 copies/mL was 83.3% and 91.7%, respectively.
The mean increase in CD4+ cell count from baseline was 221 × 106 cells/L.
HOW SUPPLIED
16 /STORAGE AND HANDLING Product: 50090-1327 Product: 50090-1491 NDC: 50090-1491-0 60 TABLET, FILM COATED in a BOTTLE, PLASTIC
RECENT MAJOR CHANGES
Contraindications (4) 09/2018
GERIATRIC USE
8.5 Geriatric Use Clinical studies of PREZISTA did not include sufficient numbers of patients aged 65 years 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)].
DOSAGE FORMS AND STRENGTHS
3 Oral suspension: 100 mg per mL (3) Tablets: 75 mg, 150 mg, 600 mg, and 800 mg (3) PREZISTA Oral Suspension PREZISTA 100 mg per mL is supplied as a white to off-white opaque suspension for oral use, containing darunavir ethanolate equivalent to 100 mg of darunavir per mL of suspension.
PREZISTA Tablets 75 mg: white, caplet-shaped, film-coated tablets containing darunavir ethanolate equivalent to 75 mg of darunavir.
Each tablet is debossed with “75” on one side and “TMC” on the other side.
150 mg: white, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 150 mg of darunavir.
Each tablet is debossed with “150” on one side and “TMC” on the other side.
600 mg: orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 600 mg of darunavir.
Each tablet is debossed with “600MG” on one side and “TMC” on the other side.
800 mg: dark red, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 800 mg of darunavir.
Each tablet is debossed with “800” on one side and “T” on the other side.
MECHANISM OF ACTION
12.1 Mechanism of Action Darunavir is an HIV-1 antiviral drug [see Microbiology (12.4)].
INDICATIONS AND USAGE
1 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 [see Use in Specific Populations (8.4) and Clinical Studies (14)].
PREZISTA is a human immunodeficiency virus (HIV-1) protease inhibitor indicated for the treatment of HIV-1 infection in adult and pediatric patients 3 years of age and older.
PREZISTA must be co-administered with ritonavir (PREZISTA/ritonavir) and with other antiretroviral agents.
(1)
PEDIATRIC USE
8.4 Pediatric Use PREZISTA/ritonavir is not recommended 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 (5.10) , Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].
The safety, pharmacokinetic profile, and virologic and immunologic responses of PREZISTA/ritonavir administered twice daily were evaluated in treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighting at least 10 kg.
These subjects were evaluated in clinical trials TMC114-C212 (80 subjects, 6 to less than 18 years of age) and TMC114-228 (21 subjects, 3 to less than 6 years of age) [see Adverse Reactions (6.1) , 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 (6.1)].
Refer to Dosage and Administration (2.5) for twice-daily dosing recommendations for pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg.
In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of PREZISTA/ritonavir administered once daily were evaluated in treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age (12 subjects) [see Adverse Reactions (6.1) , 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 (6.1)].
Once daily dosing recommendations for pediatric patients 3 to less than 12 years of age were derived using population pharmacokinetic modeling and simulation.
Although a PREZISTA/ritonavir once daily dosing pediatric trial was not conducted in children less than 12 years of age, there is sufficient clinical safety data to support the predicted PREZISTA exposures for the dosing recommendations in this age group [see Clinical Pharmacology (12.3)].
Please see Dosage and Administration (2.5) for once-daily dosing recommendations for pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg.
Juvenile Animal Data In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels.
In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.
PREGNANCY
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PREZISTA during pregnancy.
Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263.
Risk Summary Available limited data from the APR show no difference in rate of overall birth defects for darunavir (2.7%) compared with the background rate for major birth defects of 2.7% in a U.S.
reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data].
The APR uses the MACDP as the U.S.
reference population for birth defects in the general population.
The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation.
The rate of miscarriage is not reported in the APR.
The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S.
general population is 15-20%.
The background risk of major birth defects and miscarriage for the indicated population is unknown.
Studies in animals did not show evidence of developmental toxicity.
Exposures (based on AUC) in rats were 3-fold higher, whereas in mice and rabbits, exposures were lower (less than 1-fold) than human exposures at the recommended daily dose [see Data].
Clinical Considerations The recommended dosage in pregnant patients is PREZISTA 600 mg taken with ritonavir 100 mg twice daily with food.
PREZISTA 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable PREZISTA 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily PREZISTA 600 mg with ritonavir 100 mg may compromise tolerability or compliance [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
Data Human Data PREZISTA/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 34 pregnant women during the second and third trimesters, and postpartum.
Seventeen subjects were enrolled in each BID and QD treatment arms.
Twenty-seven subjects completed the trial through the postpartum period (6–12 weeks after delivery) and 7 subjects discontinued before trial completion, 5 subjects in the BID arm and 2 subjects in the QD arm.
The pharmacokinetic data demonstrate that exposure to darunavir and ritonavir as part of an antiretroviral regimen was lower during pregnancy compared with postpartum (6–12 weeks).
Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen [see Clinical Pharmacology (12.3)].
Virologic response was preserved.
In the BID arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 35% (6/17) at baseline, 59% (10/17) through the third trimester visit, and 59% (10/17) through the 6–12 week postpartum visit.
Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for 12% (2/17) of subjects and were missing for 5 subjects (1 subject discontinued prematurely due to virologic failure).
In the QD arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 59% (10/17) at baseline, 82% (14/17) through the third trimester visit, and 82% (14/17) through the 6–12 week postpartum visit.
Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for none of the subjects and were missing for 3 subjects (1 subject discontinued prematurely due to virologic failure).
PREZISTA/ritonavir was well tolerated during pregnancy and postpartum.
There were no new clinically relevant safety findings compared with the known safety profile of PREZISTA/ritonavir in HIV-1-infected adults.
Among the 29 infants with HIV test results available data, born to the 29 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 29 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum.
All 29 infants received antiretroviral prophylactic treatment containing zidovudine.
Based on prospective reports to the APR of 615 live births following exposure to darunavir-containing regimens during pregnancy (including 385 exposed in the first trimester and 230 exposed in the second/third trimester), there was no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects in a U.S.
reference population of the MACDP.
The prevalence of birth defects in live births was 2.6% (95% CI: 1.2% to 4.7%) with first trimester exposure to darunavir containing regimens and 1.7% (95% CI: 0.5% to 4.4%) with second/third trimester exposure to darunavir containing regimens.
Animal Data Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 with darunavir alone).
In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/ritonavir.
Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases.
Post-marketing cases of liver injury, including some fatalities, have been reported.
(5.2) Skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms and acute generalized exanthematous pustulosis, have been reported.
Discontinue treatment if severe reaction develops.
(5.3) Use with caution in patients with a known sulfonamide allergy.
(5.4) Patients may develop new onset diabetes mellitus or hyperglycemia.
Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required.
(5.6) Patients may develop redistribution/accumulation of body fat or immune reconstitution syndrome.
(5.7, 5.8) Patients with hemophilia may develop increased bleeding events.
(5.9) PREZISTA/ritonavir is not recommended in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir up to days 23 to 26 of age.
(5.10) 5.1 Importance of Co-administration with Ritonavir 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 (less than 0.1%) reported during the clinical development program.
During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported.
Discontinue PREZISTA/ritonavir 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/ritonavir [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/ritonavir was 0.5%.
Rash occurred more commonly in treatment-experienced subjects receiving regimens containing PREZISTA/ritonavir + raltegravir compared to subjects receiving PREZISTA/ritonavir without raltegravir or raltegravir without PREZISTA/ritonavir.
However, rash that was considered drug related occurred at similar rates for all three groups.
These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.
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 were similar in subjects with or without a history of sulfonamide allergy.
5.5 Risk of Serious Adverse Reactions due to Drug Interactions Initiation of PREZISTA/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PREZISTA/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A.
Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PREZISTA/ritonavir, respectively.
These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.
Clinically significant adverse reactions from greater exposures of PREZISTA/ritonavir.
Loss of therapeutic effect of PREZISTA/ritonavir and possible development of resistance.
See Table 10 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)].
Consider the potential for drug interactions prior to and during PREZISTA/ritonavir therapy; review concomitant medications during PREZISTA/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant drugs [see Contraindications (4) and Drug Interactions (7)].
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 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.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral 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 Not Recommended in Pediatric Patients Below 3 Years of Age PREZISTA/ritonavir in pediatric patients below 3 years of age is not recommended 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) and Clinical Pharmacology (12.3)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instruction for Use).
Instructions for Use Advise patients to take PREZISTA and ritonavir with food every day on a regular dosing schedule, as missed doses can result in development of resistance.
PREZISTA must always be used with ritonavir in combination with other antiretroviral drugs.
Advise patients not to alter the dose of either PREZISTA or ritonavir, discontinue ritonavir, or discontinue therapy with PREZISTA without consulting their physician [see Dosage and Administration (2)].
Hepatotoxicity Inform patients that drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA co-administered with 100 mg of ritonavir.
Advise patients about the signs and symptoms of liver problems [see Warnings and Precautions (5.2)].
Severe Skin Reactions Inform patients that skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, have been reported with PREZISTA co-administered with 100 mg of ritonavir.
Advise patients to discontinue PREZISTA/ritonavir 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 [see Warnings and Precautions (5.3)].
Drug Interactions PREZISTA/ritonavir may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St.
John’s wort [see Contraindications (4), Warnings and Precautions (5.4, 5.5) and Drug Interactions (7)].
Contraception Instruct patients receiving combined hormonal contraception or the progestin only pill to use an effective alternative (non-hormonal) contraceptive method or add a barrier method during therapy with PREZISTA/ritonavir because hormonal levels may decrease [see Drug Interactions (7.3) and Use in Specific Populations (8.3)].
Fat Redistribution Inform patients 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 [see Warnings and Precautions (5.7)].
Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.8)].
Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to PREZISTA [see Use in Specific Populations (8.1)].
Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].
DOSAGE AND ADMINISTRATION
2 Testing: In treatment-experienced patients, treatment history genotypic and/or phenotypic testing is recommended prior to initiation of therapy with PREZISTA/ritonavir to assess drug susceptibility of the HIV-1 virus (2.1, 12.4) Monitor serum liver chemistry tests before and during therapy with PREZISTA/ritonavir.
(2.1, 2.2, 5.2) Treatment-naïve adult patients and treatment-experienced adult patients with no darunavir resistance associated substitutions: 800 mg (one 800 mg tablet) taken with ritonavir 100 mg once daily and with food.
(2.3) Treatment-experienced adult patients with at least one darunavir resistance associated substitution: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food.
(2.3) Pregnant patients: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food.
(2.4) Pediatric patients (3 to less than 18 years of age and weighing at least 10 kg): dosage of PREZISTA and ritonavir is based on body weight and should not exceed the adult dose.
PREZISTA should be taken with ritonavir and with food.
(2.5) PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment.
(2.6) 2.1 Testing Prior to Initiation of PREZISTA/ritonavir In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus [see Microbiology (12.4)].
Refer to Dosage and Administration (2.3), (2.4) and (2.5) for dosing recommendations.
Appropriate laboratory testing such as serum liver biochemistries should be conducted prior to initiating therapy with PREZISTA/ritonavir [see Warnings and Precautions (5.2)].
2.2 Monitoring During Treatment with PREZISTA/ritonavir 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 [see Warnings and Precautions (5.2)].
2.3 Recommended Dosage in 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.
Patients who have difficulty swallowing PREZISTA tablets can use the 100 mg per mL PREZISTA oral suspension.
Treatment-Naïve Adult Patients The recommended oral dose of PREZISTA is 800 mg (one 800 mg tablet or 8 mL of the oral suspension) taken with ritonavir 100 mg (one 100 mg tablet or capsule or 1.25 mL of a 80 mg per mL ritonavir oral solution) once daily and with food.
An 8 mL PREZISTA dose should be taken as two 4 mL administrations with the included oral dosing syringe.
Treatment-Experienced Adult Patients The recommended oral dosage for treatment-experienced adult patients is summarized in Table 1.
Baseline genotypic testing is recommended for dose selection.
However, when genotypic testing is not feasible, PREZISTA 600 mg taken with ritonavir 100 mg twice daily is recommended.
Table 1: Recommended PREZISTA/ritonavir Dosage in Treatment-Experienced Adult Patients Formulation and Recommended Dosing Baseline Resistance PREZISTA tablets with ritonavir tablets or capsule PREZISTA oral suspension (100 mg/mL) with ritonavir oral solution (80 mg/mL) With no darunavir resistance associated substitutionsV11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V One 800 mg PREZISTA tablet with one 100 mg ritonavir tablet/capsule, taken once daily with food 8 mLAn 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe PREZISTA oral suspension with 1.25 mL ritonavir oral solution, taken once daily with food With at least one darunavir resistance associated substitutions, or with no baseline resistance information One 600 mg PREZISTA tablet with one 100 mg ritonavir tablet/capsule, taken twice daily with food 6 mL PREZISTA oral suspension with 1.25 mL ritonavir oral solution, taken twice daily with food 2.4 Recommended Dosage During Pregnancy The recommended dosage in pregnant patients is PREZISTA 600 mg taken with ritonavir 100 mg twice daily with food.
PREZISTA 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable PREZISTA 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily PREZISTA 600 mg with ritonavir 100 mg may compromise tolerability or compliance.
2.5 Recommended Dosage in Pediatric Patients (age 3 to less than 18 years) 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 adults.
Before prescribing PREZISTA, children weighing greater than or equal to 15 kg should be assessed for the ability to swallow tablets.
If a child is unable to reliably swallow a tablet, the use of PREZISTA oral suspension should be considered.
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 (see Tables 2, 3, 4, and 5) and should not exceed the recommended adult dose.
PREZISTA should be taken with ritonavir and with food.
The recommendations for the PREZISTA/ritonavir dosage regimens were based on pediatric clinical trial data and population pharmacokinetic modeling and simulation [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].
Dosing Recommendations for Treatment-Naïve Pediatric Patients or Antiretroviral Treatment-Experienced Pediatric Patients with No Darunavir Resistance Associated Substitutions Pediatric patients weighing at least 10 kg but less than 15 kg The weight-based dose in antiretroviral treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions is PREZISTA 35 mg/kg once daily with ritonavir 7 mg/kg once daily using the following table: Table 2: Recommended Dose for Pediatric Patients Weighing 10 kg to Less Than 15 kg Who are Treatment-Naïve or Treatment-Experienced with No Darunavir Resistance Associated Substitutionsdarunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V Body weight (kg) Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) Dose: once daily with food Greater than or equal to 10 kg to less than 11 kg PREZISTA 3.6 mLThe 350 mg, 385 mg, 455 mg and 490 mg darunavir dose for the specified weight groups were rounded up for suspension dosing convenience to 3.6 mL, 4 mL, 4.6 mL and 5 mL, respectively.
(350 mg) with ritonavir 0.8 mL (64 mg) Greater than or equal to 11 kg to less than 12 kg PREZISTA 4 mL (385 mg) with ritonavir 0.8 mL (64 mg) Greater than or equal to 12 kg to less than 13 kg PREZISTA 4.2 mL (420 mg) with ritonavir 1 mL (80 mg) Greater than or equal to 13 kg to less than 14 kg PREZISTA 4.6 mL (455 mg) with ritonavir 1 mL (80 mg) Greater than or equal to 14 kg to less than 15 kg PREZISTA 5 mL (490 mg) with ritonavir 1.2 mL (96 mg) Pediatric patients weighing at least 15 kg Pediatric patients weighing at least 15 kg can be dosed with PREZISTA oral tablet(s) or suspension using the following table: Table 3: Recommended Dose for Pediatric Patients Weighing At Least 15 kg Who are Treatment-Naïve or Treatment-Experienced with No Darunavir Resistance Associated Substitutionsdarunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V Body weight (kg) Formulation: PREZISTA tablet(s) and ritonavir capsules or tablets (100 mg) Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) Dose: once daily with food Dose: once daily with food Greater than or equal to 15 kg to less than 30 kg PREZISTA 600 mg with ritonavir 100 mg PREZISTA 6 mL (600 mg) with ritonavir 1.25 mL (100 mg) Greater than or equal to 30 kg to less than 40 kg PREZISTA 675 mg with ritonavir 100 mg PREZISTA 6.8 mLThe 675 mg dose using darunavir tablets for this weight group is rounded up to 6.8 mL for suspension dosing convenience.
The 6.8 mL and 8 mL darunavir dose should be taken as two (3.4 mL or 4 mL respectively) administrations with the included oral dosing syringe (675 mg) with ritonavir 1.25 mL (100 mg) Greater than or equal to 40 kg PREZISTA 800 mg with ritonavir 100 mg PREZISTA 8 mL (800 mg) with ritonavir 1.25 mL (100 mg) Dosing Recommendations for Treatment-Experienced Pediatric Patients with At Least One Darunavir Resistance Associated Substitutions Pediatric patients weighing at least 10 kg but less than 15 kg The weight-based dose in antiretroviral treatment-experienced pediatric patients with at least one darunavir resistance associated substitution is PREZISTA 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily using the following table: Table 4: Recommended Dose for Pediatric Patients Weighing 10 kg to Less Than 15 kg Who are Treatment-Experienced with At Least One Darunavir Resistance Associated Substitutiondarunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V Body weight (kg) Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) Dose: twice daily with food Greater than or equal to 10 kg to less than 11 kg PREZISTA 2 mL (200 mg) with ritonavir 0.4 mL (32 mg) Greater than or equal to 11 kg to less than 12 kg PREZISTA 2.2 mL (220 mg) with ritonavir 0.4 mL (32 mg) Greater than or equal to 12 kg to less than 13 kg PREZISTA 2.4 mL (240 mg) with ritonavir 0.5 mL (40 mg) Greater than or equal to 13 kg to less than 14 kg PREZISTA 2.6 mL (260 mg) with ritonavir 0.5 mL (40 mg) Greater than or equal to 14 kg to less than 15 kg PREZISTA 2.8 mL (280 mg) with ritonavir 0.6 mL (48 mg) Pediatric patients weighing at least 15 kg Pediatric patients weighing at least 15 kg can be dosed with PREZISTA oral tablet(s) or suspension using the following table: Table 5: Recommended Dose for Pediatric Patients Weighing At Least 15 kg Who are Treatment-Experienced with At Least One Darunavir Resistance Associated Substitutiondarunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V Body weight (kg) Formulation: PREZISTA tablet(s) and ritonavir tablets, capsules (100 mg) or oral solution (80 mg/mL) Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) Dose: twice daily with food Dose: twice daily with food Greater than or equal to 15 kg to less than 30 kg PREZISTA 375 mg with ritonavir 0.6 mL (48 mg) PREZISTA 3.8 mL (375 mg)The 375 mg and 450 mg dose using darunavir tablets for this weight group is rounded up to 3.8 mL and 4.6 mL for suspension dosing convenience.
with ritonavir 0.6 mL (48 mg) Greater than or equal to 30 kg to less than 40 kg PREZISTA 450 mg with ritonavir 0.75 mL (60 mg) PREZISTA 4.6 mL (450 mg) with ritonavir 0.75 mL (60 mg) Greater than or equal to 40 kg PREZISTA 600 mg with ritonavir 100 mg PREZISTA 6 mL (600 mg) with ritonavir 1.25 mL (100 mg) The use of PREZISTA/ritonavir in pediatric patients below 3 years of age is not recommended [see Warnings and Precautions (5.10) and Use in Specific Populations (8.4)].
2.6 Not Recommended in Patients with Severe Hepatic Impairment No dosage 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)].