Prezista
(darunavir)Dosage & Administration
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Prezista Prescribing Information
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)] .
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)] .
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)] .
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.
| 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 substitutions * | One 800 mg PREZISTA tablet with one 100 mg ritonavir tablet/capsule, taken once daily with food | 8 mL †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 |
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.
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:
| 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 mL †(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:
| 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 mL † ‡(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:
| 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:
| 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) †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)] .
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)] .
PREZISTA Oral Suspension
PREZISTA 100 mg per mL is supplied as a white to off-white opaque suspension for oral use, containing 100 mg of darunavir per mL of suspension.
PREZISTA Tablets
- 75 mg: white, caplet-shaped, film-coated tablets debossed with "75" on one side and "TMC" on the other side.
- 150 mg: white, oval-shaped, film-coated tablets debossed with "150" on one side and "TMC" on the other side.
- 600 mg: orange, oval-shaped, film-coated tablets debossed with "600MG" on one side and "TMC" on the other side.
- 800 mg: dark red, oval-shaped, film-coated tablets debossed with "800" on one side and "T" on the other side.
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
Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. Available limited data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir 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 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 36 pregnant women during the second and third trimesters, and postpartum. Eighteen subjects were enrolled in each BID and QD treatment arms. Twenty-nine 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 39% (7/18) at baseline, 61% (11/18) through the third trimester visit, and 61% (11/18) through the 6–12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for 11% (2/18) 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 61% (11/18) at baseline, 83% (15/18) through the third trimester visit, and 78% (14/18) 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 31 infants with HIV test results available data, born to the 31 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 31 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum. All 31 infants received antiretroviral prophylactic treatment containing zidovudine.
Based on prospective reports to the APR of over 980 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 660 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6.% (95% CI: 2.3% to 5.3.%) with first trimester exposure to darunavir-containing regimens and 2.5% (95% CI: 1.1% to 4.8%) 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.
Lactation
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
There are no data on the presence of darunavir in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir is present in the milk of lactating rats [see Data] . Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving PREZISTA [see Use in Specific Populations (8.4)] .
Data
Animal Data
Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose with ritonavir.
Females and Males of Reproductive Potential
Contraception
Use of PREZISTA may reduce the efficacy of combined hormonal contraceptives and the progestin only pill. Advise patients to use an effective alternative (non-hormonal) contraceptive method or add a barrier method of contraception. For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia [see Drug Interactions (7.3)] .
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.
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)] .
Hepatic Impairment
No dosage 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 (2.6)and Clinical Pharmacology (12.3)] .
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)] .
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). Examples of these drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed below [see Drug Interactions (7.3)] . Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications.
- Alpha 1-adrenoreceptor antagonist: alfuzosin
- Anti-gout: colchicine, in patients with renal and/or hepatic impairment
- Antimycobacterial: rifampin
- Antipsychotics: lurasidone, pimozide
- Cardiac Disorders: dronedarone, ivabradine, ranolazine
- Ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine
- Herbal product: St. John's wort ( Hypericum perforatum)
- Hepatitis C direct acting antiviral: elbasvir/grazoprevir
- Lipid modifying agents: lomitapide, lovastatin, simvastatin
- Opioid Antagonist: naloxegol
- PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension
- Sedatives/hypnotics: orally administered midazolam, triazolam
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.
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.
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 [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.
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.
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 and reduce plasma concentrations of active metabolite(s) formed 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 the concomitant medications from lower exposures of active metabolite(s).
- Loss of therapeutic effect of PREZISTA/ritonavir and possible development of resistance from lower exposures of PREZISTA/ritonavir.
See Table 10for 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)] .
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.
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.
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 aviuminfection, cytomegalovirus, Pneumocystis jiroveciipneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) 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.
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.
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 (8.1and 8.4)and Clinical Pharmacology (12.3)] .