`
`
`
` 1
`
`
`
`• 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 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)
`
`• 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 concentration of other drugs and other drugs may
`
`
`alter the concentrations of darunavir. The potential drug-drug
`
`
`
`concentrations 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: 11/2013
`
`
` 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, for oral use
`
`
` PREZISTA (darunavir) tablet, film coated for oral use
`
`
`
` Initial U.S. Approval – 2006
`
`
`
`
` ---------------------RECENT MAJOR CHANGES--------------------
`
` Indications and Usage
`
`•
`
` Pediatric Patients (1.2)
`
`•
` Dosage and Administration
`
` Pediatric Patients (2.2)
`
`
`•
`
`
`
`
`
`
`
`
`
` 04/2013
`
`
`
` 02/2013
`
`
`•
`
`
`---------------------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 or two 400 mg tablets) 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, 400 mg tablets, 600 mg
`
`
`
`
`
`
`
`
`
`•
`tablets, and 800 mg tablets (3)
`
`
`
`
`
`-----------------------CONTRAINDICATIONS----------------------
`
`Co-administration with alfuzosin, dihydroergotamine, ergonovine,
`
`
`ergotamine, methylergonovine, cisapride, pimozide, oral
`
`
`midazolam, triazolam, St. John’s Wort, lovastatin, simvastatin,
`
`rifampin and sildenafil (for treatment of pulmonary arterial
`
`
`
`hypertension). (4)
`
`
`0
`Reference ID: 3403336
`
`

`

`
`
`
`
` 2
`
`
`7.1
`
`
`7.2
`
`7.3
`
`Potential for
`
`PREZISTA/ritonavir to
`
`
`Affect Other Drugs
`
`Potential for Other Drugs to
`
`Affect Darunavir
`
`Established and Other
`
`Potentially Significant Drug
`
`Interactions
`
`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
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`Mechanism of Action
`12.1
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`
`12.4
`Microbiology
`
`NONCLINICAL TOXICOLOGY
`
`13.1
`Carcinogenesis, Mutagenesis,
`
`
`Impairment of Fertility
`
`13.2
`Animal Toxicology and/or
`
`
`Pharmacology
`
`CLINICAL STUDIES
`
`Description of Adult Clinical
`14.1
`
`Studies
`
`14.2
`Treatment-Naïve Adult
`
`
`Subjects
`
`14.3
`Treatment-Experienced Adult
`
`
`Subjects
`
`
`14.4
`Pediatric Patients
`HOW SUPPLIED/STORAGE AND
`
`
`
`HANDLING
`
`PATIENT COUNSELING
`
`
`
`INFORMATION
`
`Information About Therapy
`17.1
`
`
`with PREZISTA
`
`
`17.2
`Instructions for Use
`
`
`17.3
`Hepatotoxicity
`
`
`17.4
`Severe Skin Reactions
`
`
`17.5
`Drug Interactions
`
`
`17.6
`Fat Redistribution
`
`
`
`8
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`14
`
`
`16
`
`17
`
`
`
`
`[*Sections or subsections omitted from the full prescribing
`information are not listed]
`
`
`
`
`2
`
`
`3
`
`
`4
`
`5
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`Adult Patients
`1.1
`
`
`Pediatric Patients
`1.2
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1
`Adult Patients
`
`Pediatric Patients (age 3 to
`2.2
`
`
`
`less than 18 years)
`
`
`
`2.3
`Patients with Hepatic
`
`
`Impairment
`
`DOSAGE FORMS AND STRENGTHS
`
`PREZISTA 100 mg/mL Oral
`3.1
`
`
`
`Suspension
`
`
`3.2
`PREZISTA 75 mg Tablets
`
`
`
`PREZISTA 150 mg Tablets
`3.3
`
`
`
`3.4
`PREZISTA 400 mg Tablets
`
`
`
`3.5
`PREZISTA 600 mg Tablets
`
`
`
`3.6
`PREZISTA 800 mg Tablets
`
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1
`General
`
`
`5.2
`Hepatotoxicity
`
`
`5.3
`Severe Skin Reactions
`
`
`5.4
`Sulfa Allergy
`
`
`5.5
`Drug Interactions
`
`5.6
`Diabetes Mellitus /
`
`Hyperglycemia
`
`
`5.7
`Fat Redistribution
`
`Immune Reconstitution
`5.8
`
`
`Syndrome
`
`
`5.9
`Hemophilia
`
`
`Resistance/Cross-Resistance
`5.10
`
`
`5.11
`Pediatric Patients
`
`ADVERSE REACTIONS
`
`Clinical Trials Experience:
`6.1
`
`
`Treatment-Naïve Adults
`
`6.2
`Clinical Trials Experience:
`Treatment-Experienced
`
`
`Adults
`
`Serious ADRs
`Patients co-infected with
`
`hepatitis B and/or hepatitis C
`
`
`
`virus
`
`Clinical Trials Experience:
`6.5
`
`Pediatric Patients
`
`
`
`Postmarketing Experience
`6.6
`
`DRUG INTERACTIONS
`
`
`6
`
`
`7
`
`
`6.3
`
`6.4
`
`
`
`0
`Reference ID: 3403336
`
`

`

`
`
`
`
`
`
` 3
`
`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.
`
`
`Pediatric Patients
`1.2
`
`
`
`
`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 antiretroviral treatment-naïve subjects 12 to less than
`
`
`
`
`
`
`
`
`
`18 years of age and 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 Clinical Pharmacology (12.4)].
`
`• The use of other active agents with PREZISTA/ritonavir is associated with a greater likelihood of treatment
`
`
`
`
`
`response [see Clinical Pharmacology (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.
`
`
`
`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 two 400 mg tablets 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.
`
`
`
`
`
`
`
`Reference ID: 3403336
`
`

`

`
`
`
`
` 4
`
`
`
`
`
`
`
`Treatment-Experienced Adult Patients
`
`
`
`Treatment-Experienced Adult Patients
`Table 1:
`
`
`
`
`
`
` With no darunavir resistance associated
` With at least one 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 two
`
`
`
`
`
` 400 mg tablets) or 8 mL†(oral suspension) once
`
` daily with ritonavir 100 mg (one 100 mg
`
`
`
`
` tablet/capsule or 1.25 mL (oral 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
`
`
`
`
`
`
`
`
` PREZISTA 600 mg (e.g. one 600 mg tablet) or
`
` 6 mL (oral suspension) twice daily with ritonavir
`
`
`
` 100 mg (one 100 mg tablet/capsule or 1.25 mL
`
`
`
`
`
` (oral solution) twice daily and with food
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`Pediatric Patients (age 3 to less than 18 years)
`2.2
`
`
`
`
`
`
`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:
`
`
`
`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-naive pediatric subjects 12 to less than 18 years of age demonstrating
`
`
`
`
`
`similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-naive
`
`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
`
`
`
`
`
`Reference ID: 3403336
`
`

`

`
`
`
`
` 5
`
`
`
`• 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*
` Body weight
`
` (kg)
`
`
`
`
`
` Formulation: PREZISTA oral suspension (100 mg/mL)
` and Ritonavir oral solution (80 mg/mL)
`
`
`
`
`
` Dose: once daily with food
`
` 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 tablet(s)
` Formulation: PREZISTA oral
`
`
` Body Weight
`
`
` and ritonavir capsules or tablets
`
`
`
`
` suspension (100 mg/mL) and
`
` (kg)
`
`
` ritonavir oral solution (80 mg/mL)
` (100 mg)
`
`
`
`
` Dose: once daily with food
`
`
` Dose: once daily with food
`
`
`
`
` PREZISTA 600 mg with ritonavir
` PREZISTA 6 mL (600 mg) with
`
`
`
`
`
`
`
`
`
` Greater than or equal
`
`
` ritonavir 1.25 mL (100 mg)
`
`
`
`
` to 15 kg to less than 30 kg
`
`
`
`
`
` 100 mg
` PREZISTA 6.8 mL§∫ (675 mg) with
`
`
` PREZISTA 675 mg with ritonavir
` Greater than or equal
`
`
`
`
`
` to 30 kg to less than 40 kg
`
`
`
`
`
`
` ritonavir 1.25 mL (100 mg)
`
`
`
`
` 100 mg
` PREZISTA 8 mL∫ (800 mg) with
`
`
`
`
`
`
` Greater than or equal to 40 kg 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 mLor 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:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3403336
`
`

`

`
`
`
`
` 6
`
`
`
` 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)
`
`
` Body weight
` and Ritonavir oral solution (80 mg/mL)
`
`
`
`
`
`
` (kg)
`
` Dose: twice daily with food
`
`
`
`
` 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:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Recommended dose for pediatric patients weighing at least 15 kg who are
`
`
`treatment-experienced with at least one darunavir resistance associated substitution*
`
`
`
`
`
` Formulation: PREZISTA tablet(s)
` Formulation: PREZISTA oral suspension
`
`
` Body Weight
`
`
` and ritonavir tablets, capsules
`
`
`
`
` (kg)
` (100 mg/mL) and ritonavir oral solution
` (100 mg) or 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
`
`
`
` Greater than or equal
` ritonavir 0.6 mL (48 mg)
`
`
`
`
`
` 0.6 mL (48 mg)
`
`
`
` to 15 kg to less than 30 kg
`
`
`
`
`
` PREZISTA 4.6 mL (450 mg)§ with
`
`
`
`
` PREZISTA 450 mg with ritonavir
`
`
` Greater than or equal
`
` ritonavir 0.75 mL (60 mg)
`
`
`
`
` 0.75 mL (60 mg)
`
`
`
`
` to 30 kg to less than 40 kg
`
`
`
`
`
`
`
` PREZISTA 6 mL (600 mg) with
`
`
`
` PREZISTA 600 mg with ritonavir
`
` Greater than or equal
`
`
`
` ritonavir 1.25 mL (100 mg)
`
`
`
`
`
`
`
`
` 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.
`
`
`
`Do not use PREZISTA/ritonavir in pediatric patients below 3 years of age [see Warnings and Precautions (5.11)
`
`
`
`
`
`and Nonclinical Toxicology (13.2)].
`
`
`Patients with Hepatic Impairment
`2.3
`
`
`No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are available
`
`
`
`
`regarding the use of PREZISTA/ritonavir when co-administered to subjects with severe hepatic impairment;
`
`
`
`
`
`therefore, PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment [see Use in
`
`
`Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`
`
`3 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.
`
`
`
`
`
`
`
`
`
`Reference ID: 3403336
`
`

`

`
`
`
`
` 7
`
`
`
`PREZISTA 75 mg Tablets
`3.2
`
`
`
`
`PREZISTA (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing darunavir
`
`
`
`ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with “75” on one side and “TMC” on
`
`the other side.
`
`
`
`PREZISTA 150 mg Tablets
`3.3
`
`
`
`
`
`PREZISTA (darunavir) 150 mg tablets are supplied as white, oval-shaped, film-coated tablets containing darunavir
`
`
`
`
`ethanolate equivalent to 150 mg of darunavir per tablet. Each tablet is debossed with “150” on one side and “TMC”
`
`on the other side.
`
`
`
`
`PREZISTA 400 mg Tablets
`3.4
`
`
`PREZISTA (darunavir) 400 mg tablets are supplied as light orange, oval-shaped, film-coated tablets containing
`
`
`
`darunavir ethanolate equivalent to 400 mg of darunavir per tablet. Each tablet is debossed with “400MG” on one
`
`side and “TMC” on the other side.
`
`
`
`
`PREZISTA 600 mg Tablets
`3.5
`
`
`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.
`
`
`
`
`PREZISTA 800 mg Tablets
`3.6
`
`
`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:
` Drug Class
`
`
`
`
` Clinical Comment
`
`
`Drugs That Are Contraindicated With PREZISTA/ritonavir
`
` Drugs Within Class That Are
`Contraindicated With
`
` PREZISTA/ritonavir
`
`
`
` Alfuzosin
`
`Potential for serious and/or life-threatening
`
` reactions such as hypotension.
`
`
` Dihydroergotamine, Ergonovine,
`
`
` Ergotamine, Methylergonovine
`
`
`
` Cisapride
`
`
`
` Pimozide
`
`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.
`Potential for serious and/or life-threatening
`
` reactions such as cardiac arrhythmias.
`
`Alpha 1-
`
` adrenoreceptor
`
` antagonist
` Ergot Derivatives
`
`
`
`
` GI Motility Agent
`
`
`
`
`
` Neuroleptic
`
`
`
`Reference ID: 3403336
`
`

`

`
`
` 8
`
`
`
` St. John’s Wort (Hypericum perforatum)
`
`
`
` Lovastatin, Simvastatin
`
`
`
` Rifampin
`
`
`
`
`
` Sildenafil for treatment of pulmonary
`
` arterial hypertension
`
`
`
`
`
`
`
` Sedative/hypnotics
`
`
`
` Herbal Products
`
`
`
` HMG-CoA Reductase
`
` Inhibitors
`
`
`
` Antimycobacterial
`
`
`
` PDE-5 inhibitor
`
`
` Orally administered Midazolam, Triazolam 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
`
` 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 and pravastatin, 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).
`
`
`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.
`
`
`
`
`
`
`Reference ID: 3403336
`
`

`

`
`
`9
`
`
`
`Hepatotoxicity
`5.2
`
`
`
`
`
`
`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
`5.3
`
`
`
`
`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 and acute generalized exanthematous pustulosis have been reported. Discontinue PREZISTA/ritonavir
`
`
`
`immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe
`
`
`
`
`
`rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions,
`
`conjunctivitis, hepatitis and/or eosinophilia.
`
`
`Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with PREZISTA/ritonavir [also see
`
`
`Adverse Reactions (6)]. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment
`
`
`
`
`
`
`
`
`and resolving with continued dosing. The discontinuation rate due to rash in subjects using PREZISTA/ritonavir was
`
`0.5%.
`
`
`
`regimens
`receiving
`subjects
`treatment-experienced
`in
`Rash occurred more
`containing
`commonly
`
`
`
`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
`5.4
`
`
`
`
`
`
`
`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.
`
`
`Drug Interactions
`5.5
`
`
`
`
`
`
`See Table 6 for a listing of drugs that are contraindicated for use with PREZISTA/ritonavir due to potentially
`
`life-threatening adverse events, significant drug-drug interactions, or loss of therapeutic effect to PREZISTA [see
`
`
`Contraindications (4)]. Please refer to Table 11 for established and other potentially significant drug-drug
`
`
`
`
`
`
`
`
`
`
`interactions [see Drug