`
`
`
`
`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--------------------
`
`• Indications and Usage
`
`
`Adult Patients (1.1)
`•
`
`
`Pediatric Patients (1.2)
`•
`
`• Dosage and Administration
`
`
`Adult Patients (2.1)
`•
`
`
`Pediatric Patients (2.2)
`•
`
`
`• Contraindications (4)
`
`• Warnings and Precautions
`
`Hemophilia (5.9)
`•
`
`
`Pediatric Patients (5.11)
`•
`
`10/2008
`12/2008
`
`10/2008
`12/2008
`10/2008
`
`10/2008
`12/2008
`
`
`---------------------INDICATIONS AND USAGE---------------------
`PREZISTA is a human immunodeficiency virus (HIV-1) protease
`inhibitor indicated for the treatment of HIV infection in adult
`patients. PREZISTA is also indicated for the treatment of HIV
`infection in pediatric patients 6 years of age and older. PREZISTA
`must be co-administered with ritonavir (PREZISTA/rtv) and with
`other antiretroviral agents. (1)
`
`----------------DOSAGE AND ADMINISTRATION-----------------
`
`
`• Treatment-naïve adult patients: 800 mg (two 400 mg tablets)
`
`taken with ritonavir 100 mg once daily and with food. (2.1)
`
`
`• Treatment-experienced adult patients: 600 mg (one 600 mg
`
`
`tablet or two 300 mg tablets) taken with ritonavir 100 mg
`twice daily and with food. (2.1)
`
`• Pediatric patients (6 to < 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/rtv is not recommended for use in patients with
`
`severe hepatic impairment. (2.3)
`
`
`--------------DOSAGE FORMS AND STRENGTHS---------------
`75 mg tablets, 150 mg tablets, 300 mg tablets, 400 mg tablets, and
`
`600 mg tablets (3)
`
`-----------------------CONTRAINDICATIONS----------------------
`
`Co-administration with dihydroergotamine, ergonovine,
`
`ergotamine, methylergonovine, cisapride, pimozide, oral
`
`midazolam, triazolam, St. Johns Wort, lovastatin, simvastatin,
`rifampin. (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/rtv. 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. (5.2, 6)
`
`
`• Skin rashes ranging from mild to severe, including Stevens-
`Johnson Syndrome, have been reported. Discontinue
`
`treatment if severe rash 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/rtv should not be used in pediatric patients below
`3 years of age. (5.11)
`
`
`-----------------------ADVERSE REACTIONS-------------------------
`
`• The most common adverse drug reactions to PREZISTA/rtv
`(incidence ≥ 5%) of at least moderate intensity (≥ Grade 2)
`
`
`were diarrhea, nausea, headache and abdominal pain. (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: 02/2009
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`2.3
`
`5.7
`
`5.8
`
`6.2
`
`6.3
`6.4
`
`6.5
`
`6.6
`
`6.7
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`FULL PRESCRIBING INFORMATION
`
` 1
`INDICATIONS AND USAGE
`1.1
` Adult Patients
`1.2
`Pediatric Patients
`
`DOSAGE AND ADMINISTRATION
`
` Adult Patients
`2.1
`2.2
`Pediatric Patients (age 6 to
`< 18 years)
`
`Patients with Hepatic
`Impairment
`
`DOSAGE FORMS AND STRENGTHS
`PREZISTA 75 mg Tablets
`3.1
`3.2
`PREZISTA 150 mg Tablets
`3.3
`PREZISTA 300 mg Tablets
`3.4
`PREZISTA 400 mg Tablets
`3.5
`PREZISTA 600 mg Tablets
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`5.1
` General
`5.2
` Hepatotoxicity
`
`5.3
` Skin Rash
`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
`Additional ADRs to
`PREZISTA/rtv identified in
`adult subjects in other clinical
`trials
`Patients co-infected with
`hepatitis B and/or hepatitis C
`virus
`Clinical Trials Experience:
`Pediatric Patients
` Postmarketing Experience
`
`
`
`2
`
`
`3
`
`
`4
`
`5
`
`
`6
`
`
`
`
`
`
`
`
`
`
`
`
`7
`
`
`8
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`14
`
`
`16
`
`
`17
`
`
`
`
`
`
`DRUG INTERACTIONS
`7.1
`Potential for PREZISTA/rtv
`
`to Affect Other Drugs
`
`Potential for Other Drugs to
`
`Affect Darunavir
`
`
`Established and Other
`
`
`Potentially Significant Drug
`
`Interactions
`
`
`7.2
`
`
`7.3
`
`
`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
`
`
`and 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
`
`
`General
`17.1
`17.2
`Instructions for Use
`
`
`17.3
`Drug Interactions
`17.4
`Fat Redistribution
`17.5
`FDA-Approved Patient
`Labeling
`
`
`13.2
`
`14.2
`
`14.3
`
`[*Sections or subsections omitted from the Full Prescribing
`
`
`Information are not listed]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`1.1 Adult Patients
`
`PREZISTA®, co-administered with ritonavir (PREZISTA/rtv), 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 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/rtv), and with other antiretroviral agents, is indicated for
`the treatment of HIV 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 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/rtv:
`
`
`
`
`
`
`• Treatment history and, when available, genotypic or phenotypic testing should guide the use of
`PREZISTA/rtv [see Clinical Pharmacology (12.4)].
`
`
`
`• The use of other active agents with PREZISTA/rtv 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
`
`
`
`
`The recommended oral dose of PREZISTA tablets is 600 mg (one 600 mg tablet or two 300 mg tablets) taken with
`
`ritonavir 100 mg twice daily and with food. Once daily administration of PREZISTA is not recommended in
`treatment-experienced adult patients.
`
`
`Pediatric Patients (age 6 to < 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/rtv 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/rtv for pediatric patients (6 to < 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/rtv 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 < 18 years of age) for PREZISTA Tablets with
`
`
`
`ritonavir
`
`Body Weight
`
`(kg)
`
`
`≥ 20 kg – < 30 kg
`
`(lbs)
`
`≥ 44 lbs – < 66 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
`
`
`
`≥ 30 kg – < 40 kg
`
`
`≥ 66 lbs – < 88 lbs
`
`
`≥ 40 kg
`
`
`≥ 88 lbs
`
`
`
`The safety and efficacy of PREZISTA/rtv in pediatric patients 3 to < 6 years of age have not been established.
`
`Do not use PREZISTA/rtv 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/rtv when co-administered to subjects with severe hepatic impairment; therefore,
`PREZISTA/rtv 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.
`
`3.3
`PREZISTA 300 mg Tablets
`PREZISTA (darunavir) 300 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing darunavir
`
`ethanolate equivalent to 300 mg of darunavir per tablet. Each tablet is debossed with “300” on one side and
`
`
`“TMC114” 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 “400” 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 “600” on one side and “TMC”
`
`
`
`
`on the other side.
`
`
`4 CONTRAINDICATIONS
`
`Co-administration of PREZISTA/rtv 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/rtv
`Drugs Within Class That Are
`Drug Class
`
`Contraindicated With PREZISTA/rtv
`Dihydroergotamine, Ergonovine,
`Ergotamine, Methylergonovine
`
`Clinical Comment
`
`
`
`
`Ergot Derivatives
`
`GI Motility Agent
`
`Neuroleptic
`
`Sedative/hypnotics
`
`Herbal Products
`
`HMG CoA Reductase
`
`Inhibitors
`
`
`
`
`Cisapride
`
`Pimozide
`
`
`St. John’s Wort (Hypericum perforatum)
`
`
`Lovastatin, Simvastatin
`
`
`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/rtv 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/rtv 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 7:
`
`Established and Other Potentially
`
`Significant Drug Interactions: Alterations
`in Dose or Regimen May Be
`Recommended Based on Drug Interaction
`Studies or Predicted Interaction.
`
`
`

`

`
`
`
`Antimycobacterial
`
`
`
` Rifampin
`
` Rifampin is a potent inducer of CYP450
`
` metabolism. PREZISTA/rtv 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.
`
`
`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/rtv. During the
`clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy
`
`
`with PREZISTA/rtv. 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/rtv therapy has not been established.
`
`
`Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv 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/rtv 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/rtv should prompt consideration of interruption or discontinuation of treatment.
`
`
`Skin Rash
`5.3
`
`
`
`In clinical trials (n=3063), rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with
`PREZISTA [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/rtv was 0.5%.
`
`
`
`Severe skin rash, accompanied by fever and/or elevations of transaminases in some cases, has been reported in 0.4%
`
`of subjects. Stevens-Johnson Syndrome has been rarely (<0.1%) reported. Treatment with PREZISTA should be
`discontinued if severe rash develops.
`
`
`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/rtv, the incidence and severity of rash was similar in
`
`
`subjects with or without a history of sulfonamide allergy.
`
`
`
`
`
`

`

`
`
`
`
`5.5 Drug Interactions
`See Table 2 for a listing of drugs that are contraindicated for use with PREZISTA/rtv 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)].
`
`
`
`5.6 Diabetes Mellitus / Hyperglycemia
`New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported
`during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy. Some patients
`
`
`
`required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In
`
`some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia
`persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of
`
`
`
`
`frequency cannot be made and causal relationships between PI therapy and these events have not been established.
`
`
`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 jeroveci 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
`
`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/rtv 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/rtv 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/rtv in pediatric patients 3 to < 6 years of age have not been established.
`
`
`6 ADVERSE REACTIONS
`
`The safety assessment is based on all safety data from the Phase 2b studies (Studies TMC114-C213, TMC114-C202,
`
`TMC114-C215, and TMC114-C208) and Phase 3 studies (TMC114-C211, TMC114-C214, TMC114-C209, DUET­
`
`
`
`
`1 (TMC125-C206), and DUET-2 (TMC125-C216)) reported with PREZISTA/rtv in a total of 3063 subjects.
`
`
`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.
`
`
`
`
`
`

`

`
`
`
`System Organ Class,
`Preferred Term,
`%
`
`
`
`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/rtv
`
`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/rtv 800/100 mg once daily arm and
`
`
`
`in the lopinavir/ritonavir 800/200 mg per day arm was 54.8 and 53.3 weeks, respectively.
`
`
`The majority of the adverse drug reactions (ADRs) reported during treatment with PREZISTA/rtv 800/100 mg once
`
`daily were mild in severity. The most common ADRs to PREZISTA/rtv 800/100 mg once daily (≥ 5%) of at least
`
`
`
`moderate intensity (≥ Grade 2) were diarrhea and headache. 2% of subjects in the PREZISTA/rtv arm discontinued
`
`treatment due to ADRs.
`
`
`
`ADRs to PREZISTA/rtv 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.
`
`Table 3: Selected Adverse Drug Reactions to PREZISTA/rtv 800/100 mg Once Daily* of At Least Moderate
`
`
`
`Intensity (≥ Grade 2) in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects
`
`Randomized Study
`TMC114-C211
`
`PREZISTA/rtv
`
`lopinavir/ritonavir
`800/100 mg once daily
`
`
`800/200 mg per day
`
`+ TDF/FTC
`+ TDF/FTC
`N = 343
`N = 346
`
`
`4%
`5%
`< 1%
`< 1%
`6%
`13%
`< 1%
`0%
`< 1%
`< 1%
`3%
`3%
`2%
`3%
`
`
`
`
`< 1%
`0%
`< 1%
`2%
`
`
`
`
`< 1%
`< 1%
`
`
`1%
`< 1%
`< 1%
`< 1%
`
`
`< 1%
`< 1%
`
`
`5%
`4%
`
`
`< 1%
`< 1%
`
`Gastrointestinal Disorders
`
`Abdominal pain
`Acute pancreatitis
`Diarrhea
`Dyspepsia
`Flatulence
`Nausea
`Vomiting
`
`General Disorders and Administration Site Conditions
`Asthenia
`Fatigue
`Hepatobiliary Disorders
`Acute Hepatitis (e.g., acute hepatitis, cytolytic hepatitis,
`hepatotoxicity)
`Metabolism and Nutrition Disorders
`Anorexia
`Diabetes mellitus
`Musculoskeletal and Connective Tissue Disorders
`Myalgia
`Nervous System Disorders
`Headache
`Psychiatric Disorders
`
`Abnormal dreams
`
`
`
`
`

`

`
`
`
`
`
`
`< 1%
`2%
`< 1%
`
`
`< 1%
`4%
`0%
`
` Skin and Subcutaneous Tissue Disorders
`Pruritus
`Rash
`
`Stevens-Johnson Syndrome
`N=total number of subjects per treatment group
`TDF = tenofovir disoproxil fumarate
`FTC = emtricitabine
`* Excluding laboratory abnormalities reported as ADRs
`
`Laboratory abnormalities:
`
`The percentages of antiretroviral treatment-naïve HIV-1-infected adult subjects treated with PREZISTA/rtv
`
`
`800/100 mg once daily with Grade 2 to 4 laboratory abnormalities, considered ADRs, are presented in Table 4.
`
`
`Table 4:
`
`
`Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1­
`Infected Adult Subjects*
`
`
`
`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
`
`> 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
`
`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
`Grade 3
`Grade 4
`Triglycerides
`Grade 2
`
`Grade 3
`
`
`Grade 4
`
`Total Cholesterol
`Grade 2
`
`Grade 3
`
`
`
`
`Randomized Study
`
`TMC114-C211
`
`PREZISTA/rtv
`lopinavir/ritonavir
`
`
`800/100 mg once
`800/200 mg per day
`
`daily
`+ TDF/FTC
`+ TDF/FTC
`N = 346
`
`N = 343
`
`
`
`5%
`3%
`< 1%
`
`6%
`3%
`< 1%
`
`1%
`0%
`0%
`
`< 1%
`0%
`0%
`
`2%
`
`1%
`
`< 1%
`
`
`12%
`
`1%
`
`
`5%
`2%
`3%
`
`6%
`2%
`2%
`
`< 1%
`< 1%
`0%
`
`3%
`< 1%
`0%
`
`6%
`
`4%
`
`< 1%
`
`
`19%
`
`4%
`
`

`

`
`
`
`Low-Density Lipoprotein
`Cholesterol
`Grade 2
`
`Grade 3
`
`Elevated Glucose Levels
`Grade 2
`
`Grade 3
`
`Grade 4
`
`
`
`
`
`
`
`
`11%
`
`2%
`
`
`6%
`
`< 1%
`
`0%
`
`
`2%
`< 1%
`0%
`
`4%
`3%
`0%
`
`6%
`
`4%
`
`
`7%
`
`0%
`
`0%
`
`
`< 1%
`< 1%
`< 1%
`
`2%
`3%
`< 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/rtv
`
`
`
`
`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 in the PREZISTA/rtv 600/100 mg
`
`twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was 53.5 and 51.5 weeks, respectively.
`
`
`
`The majority of the ADRs reported during treatment with PREZISTA/rtv 600/100 mg twice daily were mild in
`
`
`
`
`
`severity. The most common ADRs to PREZISTA/rtv 600/100 mg twice daily (≥ 5%) of at least moderate intensity
`
`
`
`(≥ Grade 2) were diarrhea, nausea, rash, and abdominal pain. 3.7% of subjects in the PREZISTA/rtv arm
`
`discontinued treatment due to ADRs.
`
`
`ADRs to PREZISTA/rtv 600/100 mg twice daily of at least moderate intensity (≥ Grade 2) in antiretroviral
`treatment-experienced HIV-1-infected adult subjects are presented in Table 5.
`
`
`
`
`Table 5: Selected Adverse Drug Reactions to PREZISTA/rtv 600/100 mg Twice Daily* of At Least Moderate
`Intensity (≥ Grade 2) in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects
`
`Randomized Study
`
`TMC114-C214
`lopinavir/ritonavir
`
` 400/100 mg twice
`
` daily
`+ OBR
`N = 297
`
`< 1%
`2%
`18%
`
`System Organ Class,
`Preferred Term,
`%
`
`
`Gastrointestinal Disorders
`
`Abdominal distension
`
`Abdominal pain
`Diarrhea
`
`
`
`
` PREZISTA/rtv
`
` 600/100 mg twice daily
`
`
`+ OBR
`N = 298
`
`2%
`5%
`12%
`
`

`

`
`
`
`
`
`2%
`< 1%
`7%
`4%
`
`
`3%
`1%
`
`1%
`< 1%
`
`1%
`
`2%
`
`< 1
`
`< 1%
`6%
`
`< 1%
`1%
`6%
`3%
`
`
`1%
`1%
`
`2%
`0%
`
`< 1%
`
`3%
`
`0%
`
`1%
`3%
`
`Dyspepsia
`Flatulence
`Nausea
`Vomiting
`
`General Disorders and Administration Site Conditions
`Asthenia
`Fatigue
`Metabolism and Nutrition Disorders
`Anorexia
`Diabetes mellitus
`Musculoskeletal and Connective Tissue Disorders
`Myalgia
`Nervous System Disorders
`Headache
`Psychiatric Disorders
`
`Abnormal dreams
`
`Skin and Subcutaneous Tissue Disorders
`Pruritus
`Rash
`N=total number of subjects per treatment group
`
`OBR = optimized background regimen
`* Excluding laboratory abnormalities reported as ADRs
`
`Laboratory abnormalities:
`
`The percentages of antiretroviral treatment-experienced HIV-1-infected adult subjects treated with PREZISTA/rtv
`
`
`
`
`600/100 mg twice daily with Grade 2 to 4 laboratory abnormalities, considered ADRs, are presented in Table 6.
`
`
`Table 6:
`
`
`Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced
`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
`Grade 3
`Grade 4
`
`
`
`
`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
`
`> 2.5 to ≤ 5.0 X ULN
`> 5.0 X ULN
`
`Randomized Study
`
`TMC114-C214
`
`PREZISTA/rtv
`lopinavir/ritonavir
`
`
`600/100 mg twice
`400/100 mg twice
`
`
`daily
`daily
`+ OBR
`+ OBR
`N = 298
`N = 297
`
`
`
`
`6%
`2%
`1%
`
`4%
`2%
`< 1%
`
`< 1%
`< 1%
`0%
`
`0%
`< 1%
`< 1%
`
`
`5%
`2%
`2%
`
`6%
`2%
`2%
`
`0%
`< 1%
`0%
`
`1%
`0%
`0%
`
`

`

`
`
`
`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
`
`
`
`11%
`
`7%
`
`2%
`
`
`24%
`
`8%
`
`
`
`
`11%
`
`9%
`
`5%
`
`
`19%
`
`11%
`
`
`
`13%
`
`7%
`
`
`8%
`
`< 1%
`
`< 1%
`
`
`2%
`2%
`< 1%
`
`6%
`6%
`0%
`
`11%
`
`8%
`
`
`9%
`
`< 1%
`
`0%
`
`
`4%
`< 1%
`0%
`
`6%
`3%
`0%
`
`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
`Gr