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) Tablet, Film Coated for Oral use
`Initial U.S. Approval – 2006
`
`---------------------RECENT MAJOR CHANGES--------------------
`
`Dosage and Administration
`•
`
`
`Adult Patients (2.1)
`•
`
`
`Contraindications (4)
`•
`
`• Warnings and Precautions
`
`Severe Skin Reactions (5.3)
`•
`
`12/2010
`04/2010
`
`10/2011
`
`
`---------------------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 6 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 (6 to less than 18 years of age and weighing at
`least 44 lbs (20 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 tablets 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---------------
`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. Johns Wort, lovastatin, simvastatin,
`rifampin and sildenafil (for treatment of pulmonary arterial
`
`hypertension). (4)
`
`• Due to the need for co-administration of PREZISTA with 100
`mg of ritonavir, please refer to ritonavir prescribing information
`
`for a description of ritonavir contraindications.
`
`
`-----------------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 The safety and efficacy of PREZISTA/ritonavir
`in pediatric patients 3 to < 6 years of age have not been
`
`established. (5.11)
`
`
`-----------------------ADVERSE REACTIONS-------------------------
`
`• The most common clinical adverse drug reactions to
`PREZISTA/ritonavir (incidence ≥ 5%) of at least moderate
`
`intensity (≥ 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)
`
`An Antiviral Pregnancy Registry has been established.
`
`•
`Register patients by calling 1-800-258-4263.
`
`
`• 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:10/2011
`
`
`
`
`
`Reference ID: 3031443
`
`
`
`0
`
`

`

`
`2
`
`
`3
`
`
`4
`
`5
`
`
`6
`
`
`7
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`FULL PRESCRIBING INFORMATION
`
`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`1
`
`
`1.1
`Adult Patients
`
`
`Pediatric Patients
`1.2
`
`DOSAGE AND ADMINISTRATION
`
`
`
`2.1
`Adult Patients
`
`Pediatric Patients (age 6 to
`2.2
`
`less than 18 years)
`
`2.3
`Patients with Hepatic
`
`Impairment
`
`DOSAGE FORMS AND STRENGTHS
`
`
`PREZISTA 75 mg Tablets
`3.1
`
`
`PREZISTA 150 mg Tablets
`3.2
`
`
`3.3
`PREZISTA 400 mg Tablets
`
`
`3.4
`PREZISTA 600 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-
`5.10
`
`Resistance
`
`
`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
`
`7.1
`Potential for
`
`PREZISTA/ritonavir to
`
`Affect Other Drugs
`Potential for Other Drugs to
`
`Affect Darunavir
`
`
`6.3
`
`6.4
`
`
`7.2
`
`
`
`
`
`
`7.3
`
`Established and Other
`Potentially Significant Drug
`Interactions
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`8.7
`Renal Impairment
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1
`Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`12.4
`Microbiology
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis,
`Mutagenesis, and
`Impairment of Fertility
`13.2
`Animal Toxicology and/or
`Pharmacology
`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
`HOW SUPPLIED/STORAGE AND
`HANDLING
`PATIENT COUNSELING
`INFORMATION
`17.1
`General
`17.2
`Instructions for Use
`17.3
`Hepatotoxicity
`17.4
`Severe Skin Reactions
`17.5
`Drug Interactions
`17.6
`Fat Redistribution
`WHAT IS PREZISTA?
`
`WHO SHOULD NOT TAKE PREZISTA?
`
`WHAT SHOULD I TELL MY DOCTOR
`
`BEFORE I TAKE PREZISTA?
`HOW SHOULD I TAKE PREZISTA?
`WHAT ARE THE POSSIBLE SIDE
`EFFECTS OF PREZISTA?
`HOW SHOULD I STORE PREZISTA
`TABLETS?
`
`8
`
`10
`11
`12
`
`13
`
`14
`
`16
`17
`
`
`
`[*Sections or subsections omitted from the Full Prescribing
`Information are not listed]
`
`
`
`Reference ID: 3031443
`
`
`
`0
`
`

`

`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 6 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 an open-
`
`label Phase 2 trial in antiretroviral treatment-experienced pediatric patients 6 to < 18 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.
`
`Treatment-Naïve Adult Patients
`The recommended oral dose of PREZISTA tablets is 800 mg (two 400 mg tablets) taken with ritonavir 100 mg 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*
`
`600 mg PREZISTA twice daily
`
`taken with ritonavir 100 mg
`
`twice daily and with food
`
`
`V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V
`
`
`
`
`800 mg PREZISTA once daily with ritonavir 100 mg once 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.
`
`
`
`
`
`Reference ID: 3031443
`
`
`
`

`

`
`
`
`
`
` Pediatric Patients (age 6 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 should be assessed for the ability to swallow tablets. If a child is unable to
`
`
`
`
` reliably swallow a tablet, the use of PREZISTA tablets may not be appropriate.
`
`The recommended dose of PREZISTA/ritonavir for pediatric patients (6 to less than 18 years of age and weighing at
`
`
`
`
`least 44 lbs (20 kg)) is based on body weight (see Table 1) and should not exceed the recommended treatment-
`experienced adult dose (PREZISTA/ritonavir 600/100 mg b.i.d.). PREZISTA tablets should be taken with ritonavir
`
`
`twice daily and with food.
`
`
`Table 1: Recommended Dose for Pediatric Patients (6 to less than 18 years of age) for PREZISTA Tablets
`
`
`
`
`with ritonavir
`
`Body Weight
`
`
`(kg)
`
`
`
`Greater than or equal to
`
`
`20 kg – less than 30 kg
`
`
`Greater than or equal
`
`
`
`to 30 kg – less than 40 kg
`
`(lbs)
`
`Greater than or equal
`to 44 lbs – less
`
`than 66 lbs
`
`Greater than or equal
`to 66 lbs – less
`
`than 88 lbs
`
`Greater than or equal
`to 88 lbs
`
`Dose
`
`
`375 mg PREZISTA/50 mg ritonavir twice daily
`
`
`
`450 mg PREZISTA/60 mg ritonavir twice daily
`
`
`
`600 mg PREZISTA/100 mg ritonavir twice daily
`
`
`
`Greater than or equal
`
`
`to 40 kg
`
`
`
`The safety and efficacy of PREZISTA/ritonavir in pediatric patients 3 to less than 6 years of age have not been
`established.
`
`
`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 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.
`
`
`
`PREZISTA 150 mg Tablets
`3.2
`
`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: 3031443
`
`
`
`

`

`3.3
`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 “400” on one side
`and “TMC” on the other side.
`
`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 “600” 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 2 [also see Drug Interactions (7.3), Table 7].
`
`
`Table 2: 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
`
`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)
`
`
`
`
`Reference ID: 3031443
`
`
`
`

`

`
`
` 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 7:
`
`
` 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.
`
`
`
`
`5.2 Hepatotoxicity
`Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/ritonavir. During
`the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination
`therapy with PREZISTA/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B
`
`or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.
`
`
`Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in
`
`
`patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including
`
`
`hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with
`
`PREZISTA/ritonavir therapy has not been established.
`
`
`
`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: 3031443
`
`
`
`

`

`
`
`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
`
`
`(<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 2 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 7 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: 3031443
`
`
`
`

`

`
`
`
`
` 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.
`
` Resistance/Cross-Resistance
`
`5.10
`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)]. The safety
`
` and efficacy of PREZISTA/ritonavir in pediatric patients 3 to < 6 years of age have not been established.
`
`
`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.
`
`
`
`6.1 Clinical Trials Experience: Treatment-Naïve Adults
`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
`
`
`(≥ 5%) of at least moderate intensity (≥ 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 (≥ Grade 2) in antiretroviral
`
`
`
`treatment-naïve HIV-1-infected adult subjects are presented in Table 3 and subsequent text below the table.
`
`Table 3: 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
`Nausea
`
`
`
`Reference ID: 3031443
`
`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%
`4%
`4%
`
`
`
`

`

`2%
`
`< 1%
`
`2%
`
`7%
`
`6%
`
`4%
`
`3%
`
`< 1%
`
`6%
`
`7%
`
`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 (≥ 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 4.
`
`
`Table 4:
`
`
`Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1­
`Infected Adult Subjects*
`
`
`
`Laboratory Parameter
`Preferred Term,
`%
`
`
`Biochemistry
`Alanine Aminotransferase
`Grade 2
`Grade 3
`Grade 4
`Aspartate Aminotransferase
`Grade 2
`Grade 3
`Grade 4
`Alkaline Phosphatase
`Grade 2
`Grade 3
`Grade 4
`Hyperbilirubinemia
`Grade 2
`
`Limit
`
`
`
`
`
`> 2.5 to ≤ 5.0 X ULN
`
`> 5.0 to ≤ 10.0 X ULN
`
`> 10.0 X ULN
`
`
`> 2.5 to ≤ 5.0 X ULN
`
`> 5.0 to ≤ 10.0 X ULN
`
`> 10.0 X ULN
`
`
`> 2.5 to ≤ 5.0 X ULN
`
`> 5.0 to ≤ 10.0 X ULN
`
`> 10.0 X ULN
`
`
`> 1.5 to ≤ 2.5 X ULN
`
`
`
`Reference ID: 3031443
`
`Randomized Study
`
`TMC114-C211
`PREZISTA/ritonavir
`lopinavir/ritonavir
`
`
`800/100 mg once
`800/200 mg per day
`
`daily
`+ TDF/FTC
`
`+ TDF/FTC
`
`
`
`9%
`3%
`< 1%
`
`7%
`4%
`1%
`
`1%
`0%
`0%
`
`< 1%
`
`
`9%
`3%
`3%
`
`10%
`2%
`3%
`
`1%
`< 1%
`0%
`
`5%
`
`
`
`

`

`Grade 3
`Grade 4
`Triglycerides
`Grade 2
`
`Grade 3
`
`
`Grade 4
`
`Total Cholesterol
`Grade 2
`
`Grade 3
`
`Low-Density Lipoprotein
`Cholesterol
`Grade 2
`
` > 2.5 to ≤ 5.0 X ULN
`
`> 5.0 X ULN
`
`
`
`5.65-8.48 mmol/L
`500-750 mg/dL
`
`
`8.49-13.56 mmol/L
`751-1200 mg/dL
`
`> 13.56 mmol/L
`> 1200 mg/dL
`
`
`
`6.20-7.77 mmol/L
`240-300 mg/dL
`
`> 7.77 mmol/L
`> 300 mg/dL
`
`
`Grade 3
`
`Elevated Glucose Levels
`Grade 2
`
`Grade 3
`
`Grade 4
`
`
`< 1%
`0%
`
`3%
`
`2%
`
`1%
`
`
`23%
`
`1%
`
`
`
`14%
`
`9%
`
`
`11%
`
`1%
`
`0%
`
`
`3%
`< 1%
`0%
`
`5%
`5%
`0%
`
`< 1%
`0%
`
`10%
`
`5%
`
`1%
`
`
`27%
`
`5%
`
`
`
`12%
`
`6%
`
`
`10%
`
`<1%
`
`0%
`
`
`2%
`1%
`< 1%
`
`2%
`4%
`< 1%
`
`4.13-4.90 mmol/L
`
`
`160-190 mg/dL
`≥ 4.91 mmol/L
`
`
`≥ 191 mg/dL
`
`6.95-13.88 mmol/L
`
`
`126-250 mg/dL
`13.89-27.75 mmol/L
`
`251-500 mg/dL
`> 27.75 mmol/L
`
`> 500 mg/dL
`Pancreatic Lipase
`
`> 1.5 to ≤ 3.0 X ULN
`Grade 2
`
`> 3.0 to ≤ 5.0 X ULN
`Grade 3
`
`> 5.0 X ULN
`Grade 4
`
`Pancreatic Amylase
`
`> 1.5 to ≤ 2.0 X ULN
`Grade 2
`
`> 2.0 to ≤ 5.0 X ULN
`Grade 3
`> 5.0 X ULN
`Grade 4
`N=total number of subjects per treatment group
`TDF = tenofovir disoproxil fumarate
`FTC = emtricitabine
`
`
`* Grade 4 data not applicable in Division of AIDS grading scale.
`
`
`
`6.2 Clinical Trials Experience: Treatment-Experienced Adults
`
`Study TMC114-C214
`
`The safety assessment is based on all safety data from the Phase 3 trial TMC114-C214 comparing
`
`
`
`
`PREZISTA/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral
`
`treatment-experienced HIV-1-infected adult subjects. The
`total mean exposure
`for subjects
`the
`in
`
`
`PREZISTA/ritonavir 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was
`80.7 and 76.4 weeks, respectively.
`
`
`
`
`The majority of the ADRs reported during treatment with PREZISTA/ritonavir 600/100 mg twice daily were mild in
`
`
`
`severity. The most common clinical ADRs to PREZISTA/ritonavir 600/100 mg twice daily (≥ 5%) of at least
`
`
`
`moderate intensity (≥ Grade 2) were diarrhea, nausea, rash, abdominal pain and vomiting. 4.7% of subjects in the
`PREZISTA/ritonavir arm discontinued treatment due to ADRs.
`
`
`
`
`Reference ID: 3031443
`
`
`
`

`

` ADRs to PREZISTA/ritonavir 600/100 mg twice daily of at least moderate intensity (≥ Grade 2) in antiretroviral
`
`
`
`
` treatment-experienced HIV-1-infected adult sub