------------------------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)
`------------------------------ADVERSE REACTIONS-------------------------------
`• The most common clinical adverse drug reactions to PREZISTA/ritonavir
`(incidence greater than or equal to 5%) of at least moderate intensity
`(greater than or equal to Grade 2) were diarrhea, nausea, rash, headache,
`abdominal pain and vomiting. (6)
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-
`1088 or www.fda.gov/medwatch.
`-------------------------------DRUG INTERACTIONS-------------------------------
`• 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)
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`• Pregnancy: Total darunavir exposures were generally lower during
`pregnancy compared to postpartum period. The reduction in darunavir
`exposures during pregnancy were greater for once daily dosing compared
`to the twice daily dosing regimen. (8.1, 12.3)
`• Lactation: Women infected with HIV should be instructed not to
`breastfeed due to the potential for HIV transmission. (8.2)
`• Pediatrics: Not recommended for patients less than 3 years of age. (8.4)
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`Revised: 08/2021
`
`5.5 Risk of Serious Adverse Reactions due to Drug
`Interactions
`5.6 Diabetes Mellitus/Hyperglycemia
`5.7 Fat Redistribution
`5.8
`Immune Reconstitution Syndrome
`5.9 Hemophilia
`5.10 Not Recommended in Pediatric Patients Below 3
`Years of Age
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Potential for PREZISTA/ritonavir to Affect Other
`Drugs
`7.2 Potential for Other Drugs to Affect Darunavir
`7.3 Established and Other Potentially Significant
`Drug Interactions
`7.4 Drugs without Clinically Significant Interactions
`with PREZISTA
`
`1
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`PREZISTA safely and effectively. See Full Prescribing Information for
`PREZISTA.
`PREZISTA® (darunavir) oral suspension
`PREZISTA® (darunavir) tablet, for oral use
`Initial U.S. Approval: 2006
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`Warnings and Precautions,
`Risk of Serious Adverse Reactions
`12/2020
`due to Drug Interactions (5.5)
`----------------------------INDICATIONS AND USAGE----------------------------
`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)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`• Testing:
`o 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)
`o 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)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`• Oral suspension: 100 mg per mL (3)
`• Tablets: 75 mg, 150 mg, 600 mg, and 800 mg (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`• Co-administration of PREZISTA/ritonavir is contraindicated with drugs
`that are highly dependent on CYP3A for clearance and for which elevated
`plasma concentrations are associated with serious and/or life-threatening
`events (narrow therapeutic index). (4)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
`
`INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Testing Prior to Initiation of PREZISTA/ritonavir
`2.2 Monitoring During Treatment with
`PREZISTA/ritonavir
`2.3 Recommended Dosage in Adult Patients
`2.4 Recommended Dosage During Pregnancy
`2.5 Recommended Dosage in Pediatric Patients (age
`3 to less than 18 years)
`2.6 Not Recommended in Patients with Severe
`Hepatic Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Importance of Co-administration with Ritonavir
`5.2 Hepatotoxicity
`5.3 Severe Skin Reactions
`5.4 Sulfa Allergy
`
`

`

`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2
`Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`
`
`12.4 Microbiology
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`14 CLINICAL STUDIES
`14.1 Description of Adult Clinical Trials
`14.2 Treatment-Naïve Adult Subjects
`14.3 Treatment-Experienced Adult Subjects
`14.4 Pediatric Patients
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`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)].
`
`2 DOSAGE AND ADMINISTRATION
`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.
`
`3
`
`

`

`Table 1:
`
`Baseline Resistance
`With no darunavir resistance
`associated substitutions*
`
`Recommended PREZISTA/ritonavir Dosage in Treatment-Experienced Adult Patients
`Formulation and Recommended Dosing
`PREZISTA oral suspension
`(100 mg/mL) with ritonavir oral
`solution (80 mg/mL)
`8 mL† PREZISTA oral suspension
`with 1.25 mL ritonavir oral solution,
`taken once daily with food
`6 mL PREZISTA oral suspension
`with 1.25 mL ritonavir oral
`solution, taken twice daily with
`food
`
`PREZISTA tablets with ritonavir
`tablets or capsule
`One 800 mg PREZISTA tablet with
`one 100 mg ritonavir tablet/capsule,
`taken once daily with food
`One 600 mg PREZISTA tablet with
`one 100 mg ritonavir tablet/capsule,
`taken twice daily with food
`
`With at least one darunavir
`resistance associated substitutions*,
`or
`with no baseline resistance
`information
`* V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V
`† An 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe
`
`
`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)].
`
`4
`
`

`

`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
`Substitutions*
`
`Formulation: PREZISTA oral suspension (100 mg/mL)
`and ritonavir oral solution (80 mg/mL)
`Dose: once daily with food
`Body weight (kg)
`PREZISTA 3.6 mL† (350 mg) with ritonavir 0.8 mL (64 mg)
`Greater than or equal to 10 kg to less than 11 kg
`PREZISTA 4 mL† (385 mg) with ritonavir 0.8 mL (64 mg)
`Greater than or equal to 11 kg to less than 12 kg
`PREZISTA 4.2 mL (420 mg) with ritonavir 1 mL (80 mg)
`Greater than or equal to 12 kg to less than 13 kg
`PREZISTA 4.6 mL† (455 mg) with ritonavir 1 mL (80 mg)
`Greater than or equal to 13 kg to less than 14 kg
`PREZISTA 5 mL† (490 mg) with ritonavir 1.2 mL (96 mg)
`Greater than or equal to 14 kg to less than 15 kg
`*
`darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
`† The 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.
`
`
`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 Substitutions*
`Formulation: PREZISTA oral
`suspension (100 mg/mL) and
`Formulation: PREZISTA tablet(s)
`ritonavir oral solution
`and ritonavir capsules or tablets
`(80 mg/mL)
`(100 mg)
`Dose: once daily with food
`Dose: once daily with food
`PREZISTA 6 mL (600 mg) with
`PREZISTA 600 mg with ritonavir
`ritonavir 1.25 mL (100 mg)
`100 mg
`PREZISTA 6.8 mL†‡ (675 mg) with
`PREZISTA 675 mg with ritonavir
`ritonavir 1.25 mL (100 mg)
`100 mg
`PREZISTA 8 mL‡ (800 mg) with
`PREZISTA 800 mg with ritonavir
`ritonavir 1.25 mL (100 mg)
`100 mg
`*
`darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
`† The 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
`
`Body weight (kg)
`Greater than or equal to 15 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
`
`
`
`5
`
`

`

`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 Substitution*
`Formulation: PREZISTA oral suspension (100 mg/mL)
`and ritonavir oral solution (80 mg/mL)
`Dose: twice daily with food
`Body weight (kg)
`PREZISTA 2 mL (200 mg) with ritonavir 0.4 mL (32 mg)
`Greater than or equal to 10 kg to less than 11 kg
`PREZISTA 2.2 mL (220 mg) with ritonavir 0.4 mL (32 mg)
`Greater than or equal to 11 kg to less than 12 kg
`PREZISTA 2.4 mL (240 mg) with ritonavir 0.5 mL (40 mg)
`Greater than or equal to 12 kg to less than 13 kg
`PREZISTA 2.6 mL (260 mg) with ritonavir 0.5 mL (40 mg)
`Greater than or equal to 13 kg to less than 14 kg
`PREZISTA 2.8 mL (280 mg) with ritonavir 0.6 mL (48 mg)
`Greater than or equal to 14 kg to less than 15 kg
`* darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
`
`
`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:
`
`Body weight (kg)
`Greater than or equal to 15 kg to
`less than 30 kg
`Greater than or equal to 30 kg to
`less than 40 kg
`
`for Pediatric Patients Weighing At Least 15 kg Who are
`Recommended Dose
`Treatment-Experienced with At Least One Darunavir Resistance Associated Substitution*
`Formulation: PREZISTA
`Formulation: PREZISTA oral
`tablet(s) and ritonavir tablets,
`suspension (100 mg/mL) and
`capsules (100 mg) or oral solution
`ritonavir oral solution
`(80 mg/mL)
`(80 mg/mL)
`Dose: twice daily with food
`Dose: twice daily with food
`PREZISTA 375 mg with ritonavir
`PREZISTA 3.8 mL (375 mg)† with
`0.6 mL (48 mg)
`ritonavir 0.6 mL (48 mg)
`PREZISTA 450 mg with ritonavir
`PREZISTA 4.6 mL (450 mg)† with
`0.75 mL (60 mg)
`ritonavir 0.75 mL (60 mg)
`PREZISTA 600 mg with ritonavir
`PREZISTA 6 mL (600 mg) with
`100 mg
`Greater than or equal to 40 kg
`ritonavir 1.25 mL (100 mg)
`*
`darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
`† 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.
`
`
`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)].
`
`6
`
`

`

`3 DOSAGE FORMS AND STRENGTHS
`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.
`4 CONTRAINDICATIONS
`Co-administration of PREZISTA/ritonavir is contraindicated with drugs that are highly dependent
`on CYP3A for clearance and for which elevated plasma concentrations are associated with serious
`and/or life-threatening events (narrow therapeutic index). These drugs and other contraindicated
`drugs (which may lead to reduced efficacy of darunavir) are listed 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
`• GI motility agent: cisapride
`• 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
`
`7
`
`

`

`5 WARNINGS AND PRECAUTIONS
`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.
`
`therapy with
`initiating
`to
`testing should be conducted prior
`laboratory
`Appropriate
`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,
`
`8
`
`

`

`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 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 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)].
`
`9
`
`

`

`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.
`
`Immune Reconstitution Syndrome
`5.8
`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, 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.
`
`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)].
`
`10
`
`

`

`6 ADVERSE REACTIONS
`The following adverse reactions are discussed in other sections of labeling:
`
`• Hepatotoxicity [see Warnings and Precautions (5.2)]
`• Severe Skin Reactions [see Warnings and Precautions (5.3)]
`• Diabetes Mellitus/Hyperglycemia [see Warnings and Precautions (5.6)]
`• Fat Redistribution [see Warnings and Precautions (5.7)]
`Immune Reconstitution Syndrome [see Warnings and Precautions (5.8)]
`•
`• Hemophilia [see Warnings and Precautions (5.9)]
`Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir
`prescribing information for ritonavir-associated adverse reactions.
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`another drug and may not reflect the rates observed in clinical practice.
`
`Treatment Naïve-Adults: TMC114-C211
`The safety assessment is based on all safety data from the Phase 3 trial TMC114-C211 comparing
`PREZISTA/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689
`antiretroviral treatment-naïve HIV-1-infected adult subjects. The total mean exposure for subjects
`in the PREZISTA/ritonavir 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg
`per day arm was 162.5 and 153.5 weeks, respectively.
`
`The majority of the adverse drug reactions (ADRs) reported during treatment with
`PREZISTA/ritonavir 800/100 mg once daily were mild in severity. The most common clinical
`ADRs to PREZISTA/ritonavir 800/100 mg once daily (greater than or equal to 5%) of at least
`moderate intensity (greater than or equal to Grade 2) were diarrhea, headache, abdominal pain and
`rash. 2.3% of subjects in the PREZISTA/ritonavir arm discontinued treatment due to ADRs.
`
`ADRs to PREZISTA/ritonavir 800/100 mg once daily of at least moderate intensity (greater than
`or equal to Grade 2) in antiretroviral treatment-naïve HIV-1-infected adult subjects are presented
`in Table 6 and subsequent text below the table.
`
`Table 6:
`
`Gastrointestinal Disorders
`Abdominal pain
`
`Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 800/100 mg Once Daily* of
`at Least Moderate Intensity (≥Grade 2) Occurring in ≥2% of Antiretroviral Treatment-Naïve
`HIV-1-Infected Adult Subjects (Trial TMC114-C211)
`System organ class,
`PREZISTA/ritonavir
`preferred term,
`800/100 mg once daily +
`%
`TDF/FTC
`N=343
`
`lopinavir/ritonavir
`800/200 mg per day +
`TDF/FTC
`N=346
`
`6%
`
`6%
`
`11
`
`

`

`Diarrhea
`Nausea
`Vomiting
`General Disorders and Administration Site Conditions
`Fatigue
`Metabolism and Nutrition Disorders
`Anorexia
`Nervous System Disorders
`Headache
`Skin and Subcutaneous Tissue Disorders
`6%
`Rash
`N=total number of subjects per treatment group; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate
`* Excluding laboratory abnormalities reported as ADRs.
`
`9%
`4%
`2%
`
`<1%
`
`2%
`
`7%
`
`16%
`4%
`4%
`
`3%
`
`<1%
`
`6%
`
`7%
`
`
`Less Common Adverse Reactions
`Treatment-emergent ADRs of at least moder