`
`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, 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
`
`Adult Patients (2.1)
`
`
`
`Pediatric Patients (2.2)
`
`
`
` Warnings and Precautions
`
`Severe Skin Reactions (5.3)
`
`
`Pediatric Patients (5.11)
`
`
`
`
`
`
`12/2011
`
`12/2011
`12/2011
`
`10/2011
`12/2011
`
`
`---------------------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 (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 treatment-
`experienced adult dose. Do not use once daily dosing in
`pediatric patients. PREZISTA should be taken with ritonavir
`
`
`twice daily 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, and 600 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)
`
`
`
` 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 and toxic epidermal necrolysis, 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
`
`Tibotec Therapeutics at 1-877-REACH-TT or 1-877-732-2488
`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)
`
`Pregnancy Registry available. (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: 12/2011
`
`
`
`0
`
`Reference ID: 3060124
`
`

`

`
`
`2
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`
`
`
`
`8
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`14
`
`
`16
`
`
`17
`
`
`
`
`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
`
` Pregnancy
`8.1
`
` Nursing Mothers
`8.3
`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
`Microbiology
`12.4
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis,
`13.1
`
`
`Impairment of Fertility
`Animal Toxicology and/or
`
`
`Pharmacology
`
`CLINICAL STUDIES
`
`Description of Adult Clinical
`14.1
`
`Studies
`
`Treatment-Naïve Adult
`Subjects
`Treatment-Experienced Adult
`Subjects
`
`Pediatric Patients
`14.4
`HOW SUPPLIED/STORAGE AND
`HANDLING
`
`PATIENT COUNSELING
`
`
`INFORMATION
`
`Information About Therapy
`17.1
`
`
`with PREZISTA
`
`
`Instructions for Use
`Hepatotoxicity
`
`Severe Skin Reactions
`Drug Interactions
`Fat Redistribution
`
`13.2
`
`14.2
`
`14.3
`
`17.2
`
`17.3
`17.4
`17.5
`17.6
`
`[*Sections or subsections omitted from the Full Prescribing
`
`Information are not listed]
`
`INDICATIONS AND USAGE
`1.1
` Adult Patients
`1.2
` Pediatric Patients
`DOSAGE AND ADMINISTRATION
`
`
` Adult Patients
`2.1
`2.2
`Pediatric Patients (age 3 to
`less than 18 years)
`
`Patients with Hepatic
`Impairment
`DOSAGE FORMS AND STRENGTHS
`PREZISTA 100 mg/mL Oral
`3.1
`Suspension
`
`3.2
`PREZISTA 75 mg Tablets
`3.3
`PREZISTA 150 mg Tablets
`3.4
`PREZISTA 400 mg Tablets
`3.5
`PREZISTA 600 mg Tablets
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`5.1
` General
`5.2
` Hepatotoxicity
`
`Severe Skin Reactions
`5.3
`5.4
` Sulfa Allergy
`5.5
` Drug Interactions
`5.6
` Diabetes Mellitus/
`Hyperglycemia
`
` Fat Redistribution
` Immune Reconstitution
`
`Syndrome
` Hemophilia
`5.9
`Resistance / Cross-Resistance
`
`5.10
`
`Pediatric Patients
`5.11
`ADVERSE REACTIONS
`Clinical Trials Experience:
`6.1
`Treatment-Naïve Adults
`Clinical Trials Experience:
`
`Treatment-Experienced Adults
`
` Serious ADRs
`Patients co-infected with
`hepatitis B and/or hepatitis C
`virus
`Clinical Trials Experience:
`Pediatric Patients
` Postmarketing Experience
`6.6
`DRUG INTERACTIONS
`
`2.3
`
`5.7
`5.8
`
`6.2
`
`6.3
`6.4
`
`6.5
`
`2
`
`
`3
`
`
`4
`
`5
`
`
`6
`
`
`7
`
`
`0
`
`
`
`
`Reference ID: 3060124
`
`
`
`
`
`
`
`
`
`

`

`
`
`3
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`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)].
`
`
`This indication is based on 24-week analyses of plasma HIV-1 RNA levels and CD4+ cell counts from 2 open-label
`
`
`Phase 2 trials in antiretroviral treatment-experienced pediatric patients (one trial in patients 6 to less than 18 years of
`
`
`
`age and one trial in patients 3 to less than 6 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 (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.
`
`Treatment-Experienced Adult Patients
`
`
`Treatment-Experienced Adult Patients
`
`
`
`
`With no darunavir resistance associated substitutions*
`With at least one darunavir
`resistance associated
`
`substitution*
`PREZISTA 600 mg (e.g. one
`
`600 mg tablet or 6 mL) twice
`
`
`daily with ritonavir 100 mg (one
`
`
`100 mg tablet/capsule or 1.25
`
`mL) twice daily and with food
`
`PREZISTA 800 mg (two 400 mg tablets or 8 mL†) once daily with
`
`
`
` ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL) once
`
`
`
` daily and with food
`
`
`
`
`
`Reference ID: 3060124
`
`

`

`
`
`4
`
`
`
`
`
`V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V
`
`
`An 8 mL 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.
`
`
`Pediatric Patients (age 3 to less than 18 years)
`2.2
`
`Do not use once daily dosing in pediatric patients.
`
`
`
`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 treatment-experienced 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 1, 2 and 3) and should not exceed the recommended treatment-
`
`experienced adult dose (PREZISTA/ritonavir 600/100 mg twice daily). PREZISTA should be taken with ritonavir
`
`
`twice daily and with food.
`
`
`Dosing recommendations for pediatric patients weighing at least 10 kg but less than 15 kg
`
`
`
`
`The weight-based dose in pediatric patients weighing less than 15 kg is PREZISTA 20 mg/kg with ritonavir 3 mg/kg
`
`
`
`
`which can be dosed using the following table:
`
`
`
`
`Table 1: Recommended Dose for Pediatric Patients with PREZISTA Oral Suspension (100 mg/mL) and
`
`
`Ritonavir Oral Solution* for Pediatric Patients Weighing 10 kg to Less Than 15 kg
`
`
`
`
`
`Dose
`Body weight
`
`(kg)
`(twice daily with food)
`
`
`
`
`Greater than or equal to 10 kg to less than 11 kg
`PREZISTA 200 mg (2 mL) with ritonavir 32 mg (0.4 mL)
`
`
`
`
`
`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
`
`
`
`*with ritonavir oral solution: 80 mg/mL
`
`
`
`Dosing recommendations for pediatric patients weighing at least 15 kg
`
`
`
`
`
`Pediatric patients who weigh at least 15 kg and are able to swallow tablets can be dosed using the following table:
`
`
`
`PREZISTA 220 mg (2.2 mL) with ritonavir 32 mg (0.4
`
`mL)
`
`
`
`PREZISTA 240 mg (2.4 mL) with ritonavir 40 mg (0.5
`
`mL)
`
`
`
`PREZISTA 260 mg (2.6 mL) with ritonavir 40 mg (0.5
`
`mL)
`
`
`
`PREZISTA 280 mg (2.8 mL) with ritonavir 48 mg (0.6
`
`mL)
`
`
`
`Table 2: Recommended Dose for Pediatric Patients with PREZISTA Tablets and Ritonavir Oral Solution
`
`
`or Tablets/Capsules for Pediatric Patients Weighing At Least 15 kg
`
`
`
`Reference ID: 3060124
`
`

`

`
`
`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
`
`
`
`
`
`Greater than or equal to 40 kg
`
`
`
`
`
`*with ritonavir oral solution: 80 mg/mL
`
`† with ritonavir capsules or tablets: 100 mg
`
`
`
`Dose
`(twice daily with food)
`
`
`PREZISTA 375 mg with ritonavir* 50 mg (0.6 mL)
`
`PREZISTA 450 mg with ritonavir* 60 mg (0.75 mL)
`
`
` PREZISTA 600 mg with ritonavir†100 mg
`
`
`
`
`
`
`
`
`Pediatric patients who weigh at least 15 kg but are unable to swallow tablets can be dosed using the following table:
`
`
`
`
`
`
`
`Table 3: Recommended Dose for Pediatric Patients with PREZISTA Oral Suspension (100 mg/mL) and
`
`
`Ritonavir Oral Solution* for Pediatric Patients Weighing At Least 15 kg
`
`
`
`
`Body Weight
`Dose
`
`(kg)
`(twice daily with food)
`PREZISTA 375 mg† (3.8 mL) with
`
`
`
`Greater than or equal to 15 kg to less than
`
`
` ritonavir 50 mg (0.6 mL)
` 30 kg
`
`
`
`PREZISTA 450 mg# (4.6 mL) with
`Greater than or equal to 30 kg to less than
`
`
`
`40 kg
`
`
` ritonavir 60 mg (0.75 mL)
`
`
`Greater than or equal to 40 kg
`PREZISTA 600 mg (6 mL) with
`
`
`
`ritonavir 100 mg (1.25 mL)
`
`
`
`*with ritonavir oral solution: 80 mg/mL
`
`
`† The 375 mg dose refers to the dose using darunavir tablets for this weight group, which is rounded off to 3.8 mL
`
`for suspension dosing.
`
`
`# The 450 mg dose refers to the dose using darunavir tablets for this weight group, which is rounded off to 4.6 mL
`
`for suspension dosing.
`
`
`
`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.
`
`
`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.
`
`
`
`
`Reference ID: 3060124
`
`

`

`
`
`6
`
`
`
`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.
`
`3.4
`PREZISTA 400 mg Tablets
`
`
`
`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.
`
`3.5
`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.
`
`
`
`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 4 [also see Drug Interactions (7.3), Table 9].
`
`
`Table 4: Drugs That Are Contraindicated With PREZISTA/ritonavir
`
`Drugs Within Class That Are
`Drug Class
`Contraindicated With
`PREZISTA/ritonavir
`
`Clinical Comment
`
`
`Alfuzosin
`
`
`Potential for serious and/or life-threatening
`
`
`reactions such as hypotension.
`
`Alpha 1­
`adrenoreceptor
`
`antagonist
`Ergot Derivatives
`
`GI Motility Agent
`
`Neuroleptic
`
`Sedative/hypnotics
`
`Herbal Products
`
`
`
`Reference ID: 3060124
`
`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.
`
`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.
`
`St. John’s Wort (Hypericum perforatum)
`
`
`

`

`
`
`7
`
`
`
`HMG-CoA Reductase
`Inhibitors
`
`
`Lovastatin, Simvastatin
`
`Antimycobacterial
`
`
`Rifampin
`
`PDE-5 inhibitor
`
`
`Sildenafil for treatment of pulmonary
`arterial hypertension
`
`
`Potential for serious reactions such as
`myopathy including rhabdomyolysis.
`
`For dosing recommendation regarding
`
`atorvastatin and pravastatin, see Table 9:
`
`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.
`
`
`
`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.
`
`
`
`Reference ID: 3060124
`
`

`

`
`
`8
`
`
`
`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 has 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%.
`
`containing
`regimens
`receiving
`subjects
`in
`commonly
`Rash occurred more
`treatment-experienced
`
`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 4 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 9 for established and other potentially significant drug-drug interactions
`
`
`[see Drug Interactions (7.3)].
`
`
`
`Diabetes Mellitus / Hyperglycemia
`5.6
`New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported
`during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy. Some patients
`
`
`
`required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In
`
`
`some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia
`persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of
`
`
`
`
`frequency cannot be made and causal relationships between PI therapy and these events have not been established.
`
`
`Fat Redistribution
`5.7
`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
`During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory
`
`response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus,
`
`Pneumocystis jirovecii pneumonia, and tuberculosis), which may necessitate further evaluation and 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
`
`
`
`
`
`
`
`Reference ID: 3060124
`
`

`

`
`
`9
`
`
`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
`Resistance/Cross-Resistance
`Because the potential for HIV cross-resistance among PIs has not been fully explored in PREZISTA/ritonavir
`
`treated patients, the effect therapy with PREZISTA will have on the activity of subsequently administered PIs is
`unknown [see Microbiology (12.4)].
`
`
`Pediatric Patients
`5.11
`Do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age 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), Clinical Pharmacology (12.3), and Nonclinical Toxicology (13.2)].
`
`
`
`
`
`6 ADVERSE REACTIONS
`The overall safety profile of PREZISTA/ritonavir 800/100 mg once daily and PREZISTA/ritonavir 600/100 mg
`
`
`
`
`twice daily is based on clinical trials and post-marketing data, and is consistent with the data presented below.
`
`
`
`
`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 practice.
`
`Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information
`for ritonavir-associated adverse reactions.
`
`
`Clinical Trials Experience: Treatment-Naïve Adults
`6.1
`
`Study 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 5 and subsequent
`text below the table.
`
`
`
`
`
`Table 5: 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
`
`
`System Organ Class,
`Preferred Term,
`%
`
`Gastrointestinal Disorders
`
`Abdominal pain
`Diarrhea
`
`
`
`Reference ID: 3060124
`
`Randomized Study
`
`TMC114-C211
`PREZISTA/ritonavir
`lopinavir/ritonavir
`
`
`
`800/100 mg once daily
`800/200 mg per day
`+ TDF/FTC
`+ TDF/FTC
`N = 343
`N = 346
`
`
`6%
`6%
`9%
`16%
`
`

`

`
`
`10
`
`
`4%
`2%
`
`< 1%
`
`2%
`
`7%
`
`6%
`
`4%
`4%
`
`3%
`
`< 1%
`
`6%
`
`7%
`
`Nausea
`Vomiting
`
`General Disorders and Administration Site Conditions
`Fatigue
`Metabolism and Nutrition Disorders
`Anorexia
`Nervous System Disorders
`Headache
`
`Skin and Subcutaneous Tissue Disorders
`Rash
`N=total number of subjects per treatment group
`TDF = tenofovir disoproxil fumarate
`FTC = emtricitabine
`* Excluding laboratory abnormalities reported as ADRs
`
`Less Common Adverse Reactions
`
`
`
`Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2%
`of antiretroviral treatment-naïve subjects receiving PREZISTA/ritonavir 800/100 mg once daily are listed below by
`
`body system:
`
`Gastrointestinal Disorders: acute pancreatitis, dyspepsia, flatulence
`General Disorders and Administration Site Conditions: asthenia
`Hepatobiliary Disorders: acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity)
`
`Immune System Disorders: (drug) hypersensitivity, immune reconstitution syndrome
`
`
`
`Metabolism and Nutrition Disorders: diabetes mellitus
`Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis
`
`Psychiatric Disorders: abnormal dreams
`
`Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson Syndrome, urticaria
`
`
`
`Laboratory abnormalities:
`
`
`Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral
`
`treatment-naïve adult subjects treated with PREZISTA/ritonavir 800/100 mg once daily are presented in Table 6.
`
`
`Table 6:
`
`
`Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1­
`Infected Adult Subjects*
`
`
`
`Laboratory Parameter
`Preferred Term,
`%
`
`
`Biochemistry
`Alanine Aminotransfer