`
`
`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---------------------------
`
`
`Contraindications (4)
`05/2015
`
`
`Warnings and Precautions
`
`
`
`
`• Risk of Serious Adverse Reactions due to Drug Interactions (5.5) 03/2015
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------­
`
`PREZISTA is a human immunodeficiency virus (HIV-1) protease inhibitor
`
`
`
`indicated for the treatment of HIV-1 infection in adult patients. PREZISTA is
`
`
`also indicated for the treatment of HIV-1 infection in 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----------------------­
`
`• 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. (2.1)
`
`
`
`
`• 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. (2.1)
`
`
`
`
`
`• 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. (2.2)
`
`
`
`
`• PREZISTA/ritonavir is not recommended for use in patients with severe
`
`
`hepatic impairment. (2.3)
`
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`• 100 mg/mL oral suspension (3)
`
`
`
`
`
`• 75 mg tablets, 150 mg tablets, 600 mg tablets, and 800 mg tablets (3)
`
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------­
`
`
`
`• Co-administration with alfuzosin, cisapride, colchicine (in patients with
`
`
`
`
`renal and/or hepatic impairment), dronedarone, dihydroergotamine,
`
`
`ergotamine, lovastatin, methylergonovine, oral midazolam, pimozide,
`
`ranolazine, rifampin, sildenafil (for treatment of pulmonary arterial
`
`
`
`hypertension), simvastatin, St. John’s Wort, and triazolam. (4)
`
`
`
`
`• Due to the need for co-administration of PREZISTA with ritonavir, please
`
`
`
`
`refer to ritonavir prescribing information for a description of ritonavir
`
`contraindications. (4)
`
`
`
`
`
`------------------------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, 6)
`
`
`• 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, 6)
`
`
`
`
`• Use with caution in patients with a known sulfonamide allergy. (5.4)
`
`
`
`
`
`• The concomitant use of PREZISTA/ritonavir and certain other drugs may
`
`
`
`result in known or potentially significant drug interactions. Consult the full
`
`
`
`
`
`prescribing information prior to and during treatment for potential drug
`
`interactions. (5.5, 7.3)
`
`• 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 (5.7) or
`
`
`immune reconstitution syndrome. (5.8)
`
`
`
`
`• Patients with hemophilia may develop increased bleeding events. (5.9)
`
`
`
`
`
`
`• PREZISTA/ritonavir should not be used 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. (5.11)
`
`------------------------------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-----------------------­
`
`
`
`
`
`
`• Use during pregnancy only if the potential benefit justifies the potential
`
`
`risk. (8.1)
`
`
`
`
`• Mothers should be instructed not to breastfeed due to the potential for HIV
`
`
`
`
`
`transmission and the potential for serious adverse reactions in nursing
`
`infants. (8.3)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`approved patient labeling.
`
`
`
`
`
`
`
`
`Revised: 05/2015
`
`
`
`
`
` 1
`
`Reference ID: 3766215
`
`

`

`
`
`
`6.4 Patients co-infected with hepatitis B and/or
`
`
`
`
`hepatitis C virus
`
`
`
`
`6.5 Clinical Trials Experience: Pediatric Patients
`
`
`
`
`
`6.6 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
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.3 Nursing Mothers
`
`
`
`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
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Description of Adult Clinical Studies
`
`
`
`
`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: CONTENTS*
`
`
`
`1
`
`INDICATIONS AND USAGE
`
`
`
`1.1 Adult Patients
`
`
`
`1.2 Pediatric Patients
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`2.1 Adult Patients
`
`
`
`
`2.2 Pediatric Patients (age 3 to less than 18 years)
`
`
`
`
`2.3 Patients with Hepatic Impairment
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`3.1 PREZISTA 100 mg/mL Oral Suspension
`
`
`
`
`
`3.2 PREZISTA 75 mg Tablets
`
`
`
`
`3.3 PREZISTA 150 mg Tablets
`
`
`
`
`3.4 PREZISTA 600 mg Tablets
`
`
`
`
`3.5 PREZISTA 800 mg Tablets
`
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 General
`
`
`
`5.2 Hepatotoxicity
`
`
`
`5.3 Severe Skin Reactions
`
`
`
`5.4 Sulfa Allergy
`
`
`5.5 Risk of Serious Adverse Reactions due to Drug
`
`
`
`Interactions
`
`
`
`5.6 Diabetes Mellitus / Hyperglycemia
`
`
`
`
`Fat Redistribution
`
`5.7
`
`
`5.8
`Immune Reconstitution Syndrome
`
`
`
`5.9 Hemophilia
`
`
`
`5.10 Resistance/Cross-Resistance
`
`
`
`5.11 Pediatric Patients
`
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience: Treatment-Naïve
`
`
`
`Adults
`
`
`6.2 Clinical Trials Experience: Treatment-
`
`
`
`Experienced Adults
`
`
`
`6.3 Serious ADRs
`
`
`
`
`
`
`
`
`Reference ID: 3766215
`
`

`

`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Adult Patients
`PREZISTA® , co-administered with ritonavir (PREZISTA/ritonavir), and with other
`
`
`
`
`
`antiretroviral agents, is indicated for the treatment of human immunodeficiency virus
`
`(HIV-1) infection.
`
`
`
`This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts
`
`
`from 2 controlled Phase 3 trials of 48 weeks duration in antiretroviral treatment-naïve and
`treatment-experienced patients and 2 controlled Phase 2 trials of 96 weeks duration in
`
`
`clinically advanced, treatment-experienced adult patients.
`
`
`
`1.2 Pediatric Patients
`
`
`PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), and with other
`
`antiretroviral agents, is indicated for the treatment of HIV-1 infection in pediatric patients
`3 years of age and older [see Use in Specific Populations (8.4)].
`
`
`
`
`
`The indication for treatment-experienced pediatric patients 3 to less than 18 years of age
`is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from two open-
`
`
`label Phase 2 trials in antiretroviral treatment-experienced pediatric subjects (24-week
`
`
`
`analysis for one trial in patients 6 to less than 18 years of age; 48-week analysis for one
`
`
`trial in patients 3 to less than 6 years of age). The indication for treatment-naïve pediatric
`
`patients or antiretroviral treatment-experienced patients with no darunavir resistance
`
`associated substitutions is based on one open-label Phase 2 trial of 48 weeks duration in
`
`
`than 18 years of age and
`treatment-naïve subjects 12 to
`antiretroviral
`less
`
`pharmacokinetic modeling and simulation for patients 3 to less than 12 years of age.
`
`
`In treatment-experienced adult and pediatric patients, the following points should be
`
`considered when initiating therapy with PREZISTA/ritonavir:
`
`
`
`• Treatment history and, when available, genotypic or phenotypic testing should guide
`
`
`the use of PREZISTA/ritonavir [see Microbiology (12.4)].
`
`
`
`
`• The use of other active agents with PREZISTA/ritonavir is associated with a greater
`
`
`
`likelihood of treatment response [see Microbiology (12.4) and Clinical Studies
`
`
`(14.3)].
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Adult Patients
`
`
`PREZISTA must be co-administered with ritonavir to exert its therapeutic effect. Failure
`
`
`to correctly co-administer PREZISTA with ritonavir will result in plasma levels of
`
`darunavir that will be insufficient to achieve the desired antiviral effect and will alter
`
`some drug interactions.
`
`
`
`Reference ID: 3766215
`
`
`
` 3
`
`

`

`
`
`
`
` Patients who have difficulty swallowing PREZISTA tablets can use the 100 mg/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/capsule or 1.25 mL of a
`
` 80 mg/mL ritonavir oral solution) once daily and with food. An 8 mL darunavir dose
`
`
`
` should be taken as two 4 mL administrations with the included oral dosing syringe.
`
`
`
`
`
` Treatment-Experienced Adult Patients
`
`
`
`
` Table 1:
` Treatment-Experienced Adult Patients
` With at least one darunavir resistance associated
` With no darunavir resistance associated
`
`
`
` substitutions*
` substitution*
` Formulations: PREZISTA tablets or oral suspension (100 mg/mL) and ritonavir tablets/capsules (100
` mg) or solution (80 mg/mL)
`
`
`
` PREZISTA 800 mg (one 800 mg tablet) or 8 mL†
`
` PREZISTA 600 mg (e.g. one 600 mg tablet) or 6
`
`
`
`
` mL (oral suspension) twice daily with ritonavir 100
`
`
` (oral suspension) once daily with ritonavir 100 mg
`
`
`
`
` mg (one 100 mg tablet/capsule or 1.25 mL (oral
`
`
` (one 100 mg tablet/capsule or 1.25 mL (oral
`
`
` solution) twice daily and with food
`
`
`
` solution) once daily and with food
`
`
` * 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
`
`
`
`
`
`
`
`
` For antiretroviral treatment-experienced patients genotypic testing is recommended.
`
` However, when genotypic testing is not feasible, PREZISTA/ritonavir 600/100 mg twice
`
` daily dosing is recommended.
`
`
`
` 2.2 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 the
`
` following:
`
`
`
`Reference ID: 3766215
`
`
`
` 4
`
`

`

`
`
` Twice daily dosing
`
` • Results from two trials in treatment-experienced pediatric subjects 3 to less 18 years
`
`
`
`
`
` of age demonstrating similar darunavir plasma exposures, virologic response rate and
` safety profile compared to treatment-experienced adults.
`
` Once daily dosing
`
`
`
`
`
`
` • Results from one trial in treatment-naïve pediatric subjects 12 to less than 18 years of
`
`
` age demonstrating similar darunavir plasma exposures, virologic response rate and
`
`
` safety profile compared to treatment-naïve adults.
`• Results from population pharmacokinetic modeling and simulation in children 3 to
`
`
`
` less than 12 years of age predicting similar darunavir plasma exposures compared to
`treatment-naïve adults. Although no clinical trial was conducted to collect exposure-
`safety data, the predicted exposures from the once daily dosing is supported by
`
`
`exposures observed in a pediatric clinical trial where twice-daily dosing was
`
`
`administered.
`
`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.
`
`
`
`
`
`
` Recommended dose for pediatric patients weighing 10 kg to less than 15 kg who are
`
`
` Table 2:
`
` treatment-naïve or treatment-experienced with no darunavir resistance associated
`
`
`
` substitutions*
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Formulation: PREZISTA oral suspension (100
`
` Body weight
`
` mg/mL) and Ritonavir oral solution (80 mg/mL)
` (kg)
`
`
`
` Dose: once daily with food
` PREZISTA 3.6 mL‡ (350 mg) with ritonavir 0.8 mL
`
`Greater than or equal to 10 kg to less than
`
`
`
`
`
` 11 kg
` (64 mg)
`
`
` PREZISTA 4 mL‡ (385 mg) with ritonavir 0.8 mL
` Greater than or equal to 11 kg to less than
`
`
`
`
` 12 kg
` (64 mg)
` PREZISTA 4.2 mL (420 mg) with ritonavir 1 mL
`Greater than or equal to 12 kg to less than
`
`
`
`
` 13 kg
` (80 mg)
`
` PREZISTA 4.6 mL‡ (455 mg) with ritonavir 1 mL
` Greater than or equal to 13 kg to less than
`
`
`
`
` 14 kg
` (80 mg)
`
`
` PREZISTA 5 mL‡ (490 mg) with ritonavir 1.2 mL
` Greater than or equal to 14 kg to less than
`
`
`
`
` 15 kg
` (96 mg)
` 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:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3766215
`
`
`
` 5
`
`

`

`
`
`
`
` 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*
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Formulation: PREZISTA oral
` Formulation: PREZISTA
`
`
` suspension (100 mg/mL) and
` tablet(s) and ritonavir capsules
`
`
`
` ritonavir oral solution
`
` 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)
`
`
` PREZISTA 675 mg with ritonavir
` with 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)
`
` Greater than or equal to 40 kg
`
`
` 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
`
` 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:
`
`
`
`
`
`
` Body weight
`
` (kg)
`
` 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
`
`
` PREZISTA 2 mL (200 mg) with ritonavir 0.4 mL (32
`
` mg)
` PREZISTA 2.2 mL (220 mg) with ritonavir 0.4 mL (32
`
` mg)
` PREZISTA 2.4 mL (240 mg) with ritonavir 0.5 mL (40
`
` mg)
`
` PREZISTA 2.6 mL (260 mg) with ritonavir 0.5 mL (40
`
` mg)
` PREZISTA 2.8 mL (280 mg) with ritonavir 0.6 mL (48
`
` mg)
`
` darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
`
`
`
`Greater than or equal to 10 kg to less than 11
`
` kg
`Greater than or equal to 11 kg to less than 12
`
` kg
`Greater than or equal to 12 kg to less than 13
`
` kg
`Greater than or equal to 13 kg to less than 14
`
` kg
`Greater than or equal to 14 kg to less than 15
`
` kg
`*
`
`
`
` • 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:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3766215
`
`
`
` 6
`
`

`

`
`
`
`
` Table 5:
`
`
`
`
` least 15 kg who are
`Recommended dose for pediatric patients weighing at
`
` 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 3.8 mL (375 mg) with
`
` PREZISTA 375 mg with ritonavir
`
`
`
`
`
` 0.6 mL (48 mg)
` ritonavir 0.6 mL (48 mg)
`
` PREZISTA 4.6 mL (450 mg)§
`
` PREZISTA 450 mg with ritonavir
`
` with ritonavir 0.75 mL (60 mg)
`
` 0.75 mL (60 mg)
` PREZISTA 6 mL (600 mg) with
`
`
` PREZISTA 600 mg with ritonavir
`
`
` ritonavir 1.25 mL (100 mg)
`
`
` Greater than or equal to 40 kg
` 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.
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`Do not use PREZISTA/ritonavir in pediatric patients below 3 years of age [see Warnings
`
`
`
`and Precautions (5.11) and Nonclinical Toxicology (13.2)].
`
`
`
`
`
`2.3 Patients with Hepatic Impairment
`
`
`No dose adjustment is required in patients with mild or moderate hepatic impairment. No
`
`
`data are available regarding the use of PREZISTA/ritonavir when co-administered to
`
`is not
`subjects with severe hepatic
`impairment;
`therefore, PREZISTA/ritonavir
`
`
`recommended for use in patients with severe hepatic impairment [see Use in Specific
`Populations (8.6) and Clinical Pharmacology (12.3)].
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`3.1 PREZISTA 100 mg/mL Oral Suspension
`
`
`
`PREZISTA (darunavir) 100 mg/mL oral suspension 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.
`
`
`3.2 PREZISTA 75 mg Tablets
`
`
`PREZISTA (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated
`
`
`tablets containing darunavir ethanolate equivalent to 75 mg of darunavir per tablet. Each
`
`tablet is debossed with “75” on one side and “TMC” on the other side.
`
`
`3.3 PREZISTA 150 mg Tablets
`
`
`PREZISTA (darunavir) 150 mg tablets are supplied as white, oval-shaped, film-coated
`
`
`
`tablets containing darunavir ethanolate equivalent to 150 mg of darunavir per tablet. Each
`
`
`tablet is debossed with “150” on one side and “TMC” on the other side.
`
`
`
`
`Reference ID: 3766215
`
`
`
` 7
`
`

`

`
`
` 3.4 PREZISTA 600 mg Tablets
`
`
`
`
`
` PREZISTA (darunavir) 600 mg tablets are supplied as orange, oval-shaped, film-coated
`
` tablets containing darunavir ethanolate equivalent to 600 mg of darunavir per tablet. Each
`
` tablet is debossed with “600MG” on one side and “TMC” on the other side.
`
`
` 3.5 PREZISTA 800 mg Tablets
`
`
`
` PREZISTA (darunavir) 800 mg tablets are supplied as dark red, oval-shaped, film-coated
`
` tablets containing darunavir ethanolate equivalent to 800 mg of darunavir per tablet. Each
`
` tablet is 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 in Table 6 [also see Drug Interactions (7.3), Table 11].
`
`
`
`
`
` Table 6:
`
`
`
`
`
` Drugs That Are Contraindicated With PREZISTA/ritonavir
`
` Drugs Within Class That Are
`Contraindicated With
`
` PREZISTA/ritonavir
`
` Alfuzosin
`
`
`
` Drug Class
`
` Alpha 1-adrenoreceptor
`
` antagonist
` Antiarrhythmic
`
`
`
`
`
` Anti-gout
`
`
`
` Anti-anginal
`
`
`
` Dronedarone
`
`
`
` Colchicine
`
`
`
` Ranolazine
`
`
` Antipsychotic/Neuroleptic Pimozide
`
`
` Ergot Derivative
` Dihydroergotamine,
`
` Ergotamine, Methylergonovine
`
`
`
`
`
` GI Motility Agent
`
`
`
`
`
` Sedative/hypnotic
`
`
`
` Cisapride
`
` Orally administered
`
` Midazolam, Triazolam
`
`
`
`
` Herbal Product
`
`
`
` St. John’s Wort (Hypericum
`
` Clinical Comment
`
`Potential for serious and/or life-threatening
`
` reactions such as hypotension.
`Potential for serious and/or life-threatening
`
` reactions such as cardiac arrhythmias.
`Potential for serious and/or life-threatening
`
`
` reactions in patients with renal and/or
`
` hepatic impairment.
`Potential for serious and/or life-threatening
`
` reactions.
`Potential for serious and/or life-threatening
`
` reactions such as cardiac arrhythmias.
`Potential for serious and/or life-threatening
`
` events such as acute ergot toxicity
` characterized by peripheral vasospasm and
`
` ischemia of the extremities and other
`
` tissues.
`Potential for serious and/or life-threatening
`
` reactions such as cardiac arrhythmias.
`Triazolam and orally administered
`
`
` midazolam are extensively metabolized by
`
` CYP3A. Co-administration of triazolam or
`
` orally administered midazolam with
`
`
`
` PREZISTA/ritonavir may cause large
`
`increases in the concentrations of these
`
` benzodiazepines. Potential for serious
`
` and/or life-threatening events such as
`
` prolonged or increased sedation or
`
`
` respiratory depression.
` Patients taking PREZISTA/ritonavir should
`
`
`
`
`
`
`
`Reference ID: 3766215
`
`
`
` 8
`
`

`

` not use products containing St. John’s wort
`
` because co-administration may result in
`
`
` reduced plasma concentrations of
`
`
` darunavir. This may result in loss of
`
` therapeutic effect and development of
`
`
` resistance.
`
`
` Potential for serious reactions such as
`
` myopathy including rhabdomyolysis.
`For dosing recommendation regarding
`
`atorvastatin, pravastatin and rosuvastatin,
`
`see Table 11: Established and Other
`Potentially Significant Drug Interactions:
`Alterations in Dose or Regimen May Be
`
`Recommended Based on Drug Interaction
`
` Studies or Predicted Interaction.
`Rifampin is a potent inducer of CYP450
` metabolism. PREZISTA/ritonavir should
`
`
` not be used in combination with rifampin,
` as this may cause significant decreases in
`
`
`
` darunavir plasma concentrations. This may
`
`
` result in loss of therapeutic effect to
`
` PREZISTA.
`
` A safe and effective dose for the treatment
`
` of pulmonary arterial hypertension has not
`
` been established with PREZISTA/ritonavir.
`
` There is an increased potential for
`
`
` sildenafil-associated adverse events (which
`
` include visual disturbances, hypotension,
`
` prolonged erection, and syncope).
`
`
`
`
`
`
`
`
`
` perforatum)
`
`
`
` HMG-CoA Reductase
`
` Inhibitor
`
`
`
` Lovastatin, Simvastatin
`
`
`
` Antimycobacterial
`
`
`
` Rifampin
`
`
`
` PDE-5 inhibitor
`
`
`
` Sildenafil for treatment of
`
` pulmonary arterial
`
` hypertension
`
`
` Due to the need for co-administration of PREZISTA with ritonavir, please refer to
`
`
` ritonavir prescribing information for a description of ritonavir contraindications.
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
` 5.1 General
`PREZISTA must be co-administered with ritonavir and food to achieve the desired
`
`
` antiviral effect. Failure to administer PREZISTA with ritonavir and food may result in a
`
` loss of efficacy of darunavir.
`
`
`
`
`
` Please refer to ritonavir prescribing information for additional information on
`
` precautionary measures.
`
`
`
` 5.2 Hepatotoxicity
`
`
`
` Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with
`
` PREZISTA/ritonavir. During the clinical development program (N=3063), hepatitis was
`
` reported in 0.5% of patients receiving combination therapy with PREZISTA/ritonavir.
`
`Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C,
`
`
` have an increased risk for liver function abnormalities including severe hepatic adverse
`
` events.
`
`
`
`Reference ID: 3766215
`
`
`
` 9
`
`

`

`
`
`
` 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
`
`
` in subjects using
`rate due
`continued dosing. The discontinuation
`to
`rash
`
` 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.
`
`
`
`Reference ID: 3766215
`
`
`
` 10
`
`

`

`
`
` 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:
`
`
`
`
`
`exposures
`
`
`
` of
`
`
`
` • Clinically significant adverse reactions, potentially leading to severe, life threatening,
`
` or fatal events from greater exposures of concomitant medications.
`
`
`significant
`greater
`• Clinically
`adverse
`reactions
`from
`
`
` PREZISTA/ritonavir.
` • Loss of therapeutic effect of PREZISTA/ritonavir and possible development of
`
`
` resistance.
` See Table 11 for steps to prevent or manage