HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to
`use PREZIST A safely and effectively. See Full Prescribing
`Information for PREZIST A.
`
`PREZISTA (darunavir) Tablet, Film Coated for Oral use
`
`Initial U.S. Approval- 2006
`
`_____________________RECENT MAJOR CHANGES----------------­
`
`. Indications and Usage
`
`. Adult Patients (1.)
`
`
`. Pediatric Patients (1.2)
`
`. Dosage and Admiistrtion
`
`. Adult Patients (2.1)
`
`. Pediatric Patients (2.2)
`
`
`. Contraindications (4)
`
`
`. Warings and Precautions
`
`. Hemophilia (5.9)
`
`. Pediatrc Patients (5.11)
`
`
`1012008
`12/2008
`
`1012008
`1212008
`10/2008
`
`10/2008
`12/2008
`
`____________________ INDICATIONS AND USA GE--------------------­
`PREZISTA is a human immunodeficiency virs (HIV-I) protease
`inhibitor indicated tor the treatment of HIV infection in adult
`patients. PREZIST A is also indicated for the treatment of HIY
`infection in pediatric patients 6 years of age and older. PREZIST A
`must be co-administered with ritonavir (PREZIST Nrtv) and with
`other antiretroviral agents. (I)
`
`
`______________DOSAGE AND ADMINISTRA TlON--------------­
`
`. 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. I)
`. Pediatric patients (6 to oC i 8 years of age and weighing at least
`
`44 Ibs (20 kg)): dosage ofPREZISTA and ritonavir is based
`on body weight and should not exceed the treatment­
`expeienced adult dose. Do not use once daily dosing in
`pediatric patients. PREZIST A tablets should be taken with
`ritonavir twice daily and with food. (2.2)
`
`. PREZIST Nrtv 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)
`
`________---------------CONTRAIND I CA TI ONS--------------------­
`
`Co-administrtion with dihydroergotamine, ergonovine,
`
`ergotamie, methylergonovine, cisapride, pimozide, oral
`midazolam, triazolam, St. Johns Wort, lovastatin, simvastatin,
`
`rifampin. (4)
`
`
`. Due to the need for co-administration of PREZIST A with 100
`mg of ritonavir, please refer to ritonavir prescribing information
`for a description of ritonavir contraindications.
`
`_______________ WARNINGS AND PRECAUTIONS---------------­
`. Drg-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis)
`has been reported with PREZISTNrtv. Monitor liver
`function before and durig therapy, especially in patients
`with underlying chronic hepatitis, cirrhosis, or in patients
`who have pre-treatment elevations of transaminases. (5.2, 6)
`. Ski 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 melltus or
`
`hyperglycemia. Initiation or dose adjustments of insulin or
`oral hypoglycemic agents may be required. (5.6)
`. Patients may develop redistrbution/accumulation of
`
`(5.7) or immune reconstitution syndrome. (5.8)
`. Patients with hemophilia may develop increased bleeding
`
`events. (5.9)
`. PREZIST Nrtv should not be used in pediatrc patients below
`3 years of age. (5.11)
`
`
`body fat
`
`_______________________ ADVERSE REACTIONS-----------------------­
`. The most common adverse drg reactions to PREZIST Nrtv
`(incidence 2: 5%) of at least moderate intensity (2: 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-I088 or )¥)Y)Yifd!!.ggx(G.Gi,'Xl\tç!i
`
`______________________DRU G INTERACTI 0 NS----------------------­
`
`. Co-administration of PREZIST Nritonavir with other drugs can
`
`alter the concentrtion of other drugs and other drugs may
`alter the concentrations of daruavir. The potential drug-drg
`concentrations must be considered prior to and durig
`therapy. (4, 5.5, 7,12.3).
`
`------------------USE IN SPECIFIC POPULATIONS-------------­
`the potential benefit justifies the
`. Use durig pregnancy only if
`potential risk. (8.1)
`. An Antiviral Pregnancy Registry has been established.
`
`Register patients by callng 1-800-258-4263.
`. Mothers should be instrcted not to breastfeed due to the
`potential for HIV trnsmission and the potential for serious
`adverse reactions in nursing infants. (8.3)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA approved patient labeling.
`
`Revised: 06/2009
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`
`1. Adult Patients
`
`1.2 Pediatrc Patients
`
`2 DOSAGE AND ADMINISTRATION
`
`2. I Adult Patients
`
`2.2 Pediatric Patients (age 6 to
`
`oC 18 years)
`
`2.3 Patients with Hepatic
`
`Impairent
`3 DOSAGE FORMS AND STRENGTHS
`
`3.1 PREZISTA 75 mg Tablets
`
`3.2 PREZISTA 150 mg Tablets
`
`3.3 PREZISTA 300 mg Tablets
`
`3.4 PREZISTA 400 mg Tablets
`
`3.5 PREZIST A 600 mg Tablets
`
`4 CONTRAINDlCATlONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 General
`
`5.2 Hepatotoxicity
`
`5.3 Skin Rash
`
`5.4 Sulfa Allergy
`
`5.5 Drg Interactions
`
`5.6 Diabetes Mellitusl
`
`Hyperglycemia
`5.7 Fat Redistribution
`
`5.8 Immune Reconstitution
`
`Syndrome
`5.9 Hemophilia
`
`5. i 0 Resistance 1 Cross-Resistance
`
`5. i i Pediatrc Patients
`
`6 ADVERSE REACTIONS
`
`6. i Clincal Trials Experience:
`
`Treatment-Naïve Adults
`6.2 Clinical Trials Experience:
`
`Treatment-Experienced Adults
`6.3 Serious ADRs
`
`6.4 Additional ADRs to
`
`PREZIST Nrtv identified in
`adult subjects in other clinical
`trials
`6.5 Patients co-infected with
`
`hepatitis B and/or hepatitis C
`virus
`6.6 Clinical Trials Experence:
`
`Pediatric Patients
`
`6.7 Postmarketing Experience
`
`
`7
`
`8
`
`10
`11
`12
`
`13
`
`14
`
`16
`
`17
`
`DRUG INTERACTIONS
`7. i Potential for PREZIST Nrtv
`
`to Affect Other Drugs
`7.2 Potential for Other Drugs to
`
`Affect Darunavir
`7.3 Established and Other
`
`Potentially Significant Drg
`Interactions
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Hepatic Impairment
`
`8.7 Renal Impairment
`
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12. i Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Phannacokinetics
`
`12.4 Microbiology
`
`NON CLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`
`and Impairent of Fertilty
`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
`i 4.4 Pediatrc Patients
`
`HOW SUPPLIED/STORAGE AND
`
`HANDLING
`
`PATIENT COUNSELING
`
`INFORMATION
`
`17.1 General
`
`17.2 Instrctions for Use
`17.3 Drg Interactions
`i 7.4 Fat Redistribution
`
`i 7.5 FDA-Approved Patient
`
`Labeling
`
`(* Sections or subsections omitted from the Full Prescribing
`Information are not listed)
`
`

`

`FULL PRESCRIING INFORMATION
`
`
`1 INDICATIONS AND USAGE
`
`1.1 Adult Patients
`
`PREZISTAQî, co-administered with ritonavir (PREZISTAlrtv), and with other antiretroviral agents, is indicated for
`human immunodeficiency virus (HIV-l) infection.
`
`the treatment of
`
`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 of96 weeks duration in clinically advanced, treatment-experienced adult patients.
`
`1.2 Pediatric Patients
`
`PREZISTA, co-administered with ritonavir (PREZISTAlrt), and with other antiretroviral agents, is indicated for
`V infection in pediatric patients 6 years of age and older (see Use in Specifc Populations (8.4)).
`
`the treatment of
`
`HI
`
`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 PREZIST Alrt:
`
`. Treatment history and, when available, genotyic or phenotypic testing should guide the use of
`
`PREZISTAlrtv (see Clinical Pharmacology (12.4)).
`. The use of other active agents with PREZISTAlrt 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 wil result in plasma levels of darunavir that wil be insuffcient to achieve the desired
`antiviral effect and wil alter some drug interactions.
`
`Treatment-Naïve Adult Patients
`
`The recommended oral dose ofPREZISTA 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 ofPREZISTA 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 PREZIST A is not recommended in
`treatment-experienced adult patients.
`
`2.2 Pediatric Patients (age 6 to c: 18 years)
`
`Do not use once daily dosing in pediatric patients.
`
`Healthcare professionals should pay special attention to accurate dose selection of PREZIST A, transcription of the
`medication order, dispensing information and dosing instrction to minimize risk for medication errors, overdose,
`and underdose.
`
`Prescribers should select the appropriate dose ofPREZISTAIrt 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. Ifa child is unable to
`reliably swallow a tablet, the use ofPREZISTA tablets may not be appropriate.
`
`The recommended dose of PREZIST Alrt 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 (PREZISTAIrt 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
`
`
`ritonavir
`Bodv Weieht
`(Ii
`~ 20 kg - .: 30 kg
`
`(lbs)
`~ 44 lbs - .: 66 lbs
`
`age) for PREZISTA Tablets with
`
`Dose
`
`375 mg PREZISTAl50 mg ritonavir twice daily
`
`~ 30 kg - .: 40 kg
`
`~ 66lbs -.: 88 lbs
`
`450 mg PREZISTAl60 mg ritonavir twice daily
`
`~40kg
`
`~ 88 lbs
`
`600 mg PREZIST Ali 00 mg ritonavir twice daily
`
`The safety and effcacy ofPREZIST Alrt in pediatric patients 3 to .: 6 years of age have not been established.
`
`Do not use PREZIST Alrtv in pediatric patients below 3 years of age (see Warnings and Precautions (5.11) and
`Nonclinical Toxicology (13.2)).
`
`2.3 Patients with Hepatic Impairment
`
`No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are availa;ble
`regarding the use of PREZIST Alrt when co-administered to subjects with severe hepatic impairent; therefore,
`PREZISTAIrtv is not recommended for use in patients with severe hepatic impairment (see Use in Specifc
`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.
`
`3.2 PREZIST A 150 mg Tablets
`
`PREZISTA (daruavir) 150 mg tablets are supplied as white, oval-shaped, fim-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, fim-coated tablets containing darunavir
`ethanolate equivalent to 300 mg of darunavir per tablet. Each tablet is debossed with "300" on one side and
`"TMC 114" on the other side.
`
`3.4 PREZIST A 400 mg Tablets
`
`PREZISTA (darunavir) 400 mg tablets are supplied as light orange, oval-shaped, fim-coated tablets containig
`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, fim-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 PREZIST Alrt 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: Drul!s That Are Contraindicated With PREZISTAlrtv
`Drugs Within Class That Are
`Drug Class
`Contraindicated With PREZISTAlrtv
`Dihydroergotamine, Ergonovine,
`Ergotamine, Methylergonovine
`
`Ergot Derivatives
`
`Clinical Comment
`
`GI Motility Agent
`
`Neuroleptic
`
`Sedative/hypnotics
`
`Herbal Products
`
`Cisapride
`
`Pimozide
`
`St. John's Wort (Hypericumperforatum)
`
`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 arrhvtias.
`Orally administered Midazolam, Triazolam Triazolam and orally administered
`midazolam are extensively metabolized by
`CYP3A. Co-administration of triazolam or
`orally administered midazolam with
`PREZIST Alrtv 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 PREZISTAIrtv should not
`use products containing St. John's wort
`because co-adminstration 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.
`
`HMG CoÁReductase Lovastatin, Simvastatin
`Inhbitors
`
`F or 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. PREZIST Alrt should not be
`used in combination with rifampin, as this
`may cause significant decreases in
`darnavir plasma concentrations. This may
`result in loss of therapeutic effect to
`PREZISTA.
`
`Due to the need for co-administration ofPREZISTA with ritonavir, please refer to ritonavir prescribing information
`for a description of ritonavir contraindications.
`
`5 WARINGS AND PRECAUTIONS
`
`5.1 General
`
`PREZISTA must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to
`administer PREZIST A with ritonavir and food may result in a loss of effcacy 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 PREZISTAlrt. During the
`clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy
`with PREZIST Alrt. 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-l 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
`
`PREZIST Alrt therapy has not been established.
`
`Appropriate laboratory testing should be conducted prior to initiating therapy with PREZIST Alrt 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 ofPREZIST Alrtv 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
`PREZIST Alrtv should prompt consideration of interrption or discontinuation of treatment.
`
`5.3 Skin Rash
`
`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
`PREZISTAIrt was 0.5%.
`
`Severe skin rash, accompanied by fever and/or elevations oftransaminases 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.
`
`5.4 Sulfa Allergy
`
`
`Darunavir contains a sulfonamide moiety. PREZIST A should be used with caution in patients with a known
`
`sulfonamide allergy. In clinical studies with PREZIST Alrt, 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 PREZISTAIrtv due to potentially life-
`threatening adverse events, significant drg-drug interactions, or loss of therapeutic effect to PREZISTA (see
`indications (4)). Please refer to Table 7 for established and other potentially significant drug-drug interactions
`(see Drug Interactions (7.3)).
`
`Contra
`
`5.6 Diabetes Melltus / Hyperglycemia
`
`New onset diabetes melltus, exacerbation of pre-existing diabetes melltus, and hyperglycemia have been reported
`durig postmarketing surveilance in HIV -infected patients receiving protease inhibitor (PI) therapy. Some patients
`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.
`
`insulin or oral-hypoglycemic agents for treatment of
`
`required either initiation or dose adjustments of
`
`
`5.7 Fat Redistribution
`
`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
`these events are currently unkown.
`
`receiving antiretroviral therapy. The mechanism and long-term consequences of
`
`
`A causal relationship has not been established.
`
`5.8 Immune Reconstitution Syndrome
`
`During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory
`response to indolent or residual opportnistic infections (such as Mycobacterium avium complex, cytomegalovirus,
`Pneumocystisjeroveci pneumonia, and tuberculosis), which may necessitate furter evaluation and treatment.
`
`5.9 Hemophila
`
`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 VII was given. In more than half
`of the reported cases, treatment with PIs was continued or reintroduced if tréatment 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 PREZIST Alrt treated
`patients, the effect therapy with PREZIST A wil have on the activity of subsequently administered PIs is unkown
`(see Microbiology (12.4)).
`
`5.11 Pediatric Patients
`Do not administer PREZISTAIrt 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
`Specifc Populations (8.1 and 8.4), Clinical Pharmacology (12.3), and Nonclinical Toxicology (132)). The safety
`and effcacy ofPREZIST Alrtv 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 TMCI14-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 PREZISTAIrt in a total of3063 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 ofPREZISTA 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 TMC 114-C211 comparing PREZIST Alrt
`800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689 antiretroviral treatment-naïve HIV-l­
`infected adult subjects. The total mean exposure for subjects in the PREZISTAIrt 800/100 mg once daily ar 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 durig treatment with PREZISTAIrt 800/100 mg once
`daily were mild in severity. The most common ADRs to PREZISTAlrt 800/100 mg once daily (2: 5%) of at least
`moderate intensity (2: Grade 2) were diarrhea and headache. 2% of subjects in the PREZIST Alrt arm discontinued
`treatment due to ADRs.
`
`ADRs to PREZIST Alrt 800/1 00 mg once daily of at least moderate intensity (2: Grade 2) in antiretroviral treatment
`naïve HIV-l-infected adult subjects are presented in Table 3.
`
`Table 3: Selected Adverse Drug Reactions to PREZISTA/rtv 8001100 mg Once Daily* of At Least Moderate
`lnten.sitv (?'GniiIe2UiiAntiretrqviral Treatmen.HSalve liIT ~ l~ln(ected Ai;nltsJlbie~ts ...
`Randomized Study
`TMCU4~cni
`PREZIST Nit'l '.lopiiia'iirìritolùivir
`8001100 mg once daily 800/200 mg per day
`+ TDF/FTC + TDF/FTC
`
`N =343 N=34§
`
`System Orgaiiêiass,
`Preferred Term,
`%
`
`GastrQili.testilllll. J)jsnri:ers
`Abdominal i:ain .
`A:çu,te .paiicreatitis ..
`blaÎTliea
`Dvspensia '0
`r'laj;ençe
`Naus,ea
`Vomiting
`Gelleråi ÓIsQrllersili:4Ådmiiijstratjoi: Site çQlldItlQns
`
`
`A~Mma .
`
`Fatigue
`aeplliQbil.Iar'lDIsQiders
`Acute HepailHs (e.g., acuteliepatltls,cytoÌytic IÍepatiis,
`.hemitptpx.icitv) . .
`Meill"øljSJll. ani!'Niiidtl"oripisQrders
`'.Aôrex.ia
`.. Î)taQetesmemti~
`lVnsçQlQskeletaf llOd.êOi:lleÇtlye fissneî,jlsQrders
`Mvalgià ..
`
`NerYQlis Systemijisorders
`
`He.adache
`'Ps'lçbjåtr1çDisQrllers
`Abrioriàf dreànîs
`
`4%
`.: 1%
`6%
`.: 1%
`.:1%
`3%
`2%
`
`.:1%
`.: 1%
`
`.: 1.%
`
`... \%
`.: 1%
`
`.:1%
`
`5%
`
`. -:1%"
`
`S%
`.: 1%
`'13%
`0%
`.: 1%
`3%
`3%
`
`Q%
`i%
`
`.: 1%
`
`.¿l%
`.:1'%
`
`.:1%
`
`4%
`
`-:1%
`
`

`

`Skin iin4
`
`Subcutauenlls
`
`Jiss.ueJ)iS9rllers
`
`P~ritus .
`Rash
`Stevemi-:JQIisQu.s:v4Jome
`N~total number ofsûhJects per treatment. group
`TDF = tenofovir disoproxil fumarate
`FTC = emtricitabine
`* Excluding laboratorvabnormalities reoorted as ADRs
`
`.: 1%
`2%
`.:.1%
`
`.: 1%
`4%
`0%
`
`Laboratory abnormalities:
`
`The percentages of antiretroviral treatment-naïve HIV-l-infected adult subjects treated with PREZISTAlrt
`
`laboratory abnormalities, considered ADRs, are presented in Table 4.
`
`800/100 mg once daily with Grade 2 to 4
`
`
`Table 4:
`
`Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-l-
`Infected Adult Subiects*
`
`Laboratory Parameter
`Preferred Term,
`0/0
`
`Biochemistrv
`Alanine Aminotransferase
`Grade 2
`
`
`Grade 3
`
`Grade 4
`Aspartate Aminotransferase
`Grade 2
`
`
`Grade 3
`
`Grade 4
`Alkaline Phosohatase
`Grade 2
`
`
`Grade 3
`
`
`Grade
`
`4
`
`Hyperbilirubinemia
`Grade 2
`
`
`Grade 3
`
`Grade 4
`Triglycerides
`Grade 2
`
`
`Grade 3
`
`
`Grade 4
`
`Total Cholesterol
`
`
`Grade 2
`
`
`Örade 3
`
`
`Limit
`
`)- 2.5 to': 5.0 X ULN
`)- 5.0 to .: 10.0 X ULN
`)-10.0 XULN
`
`)- 2.5 to': 5.0 X ULN
`)- 5.0 to .: 10.0 X ULN
`)- lO.OX 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
`)- 5.0XULN
`
`5.65-8.48 mmollL
`500-750 mg/dL
`8.49-13.56 mmol/L
`751-1200 mgldL
`)- 13.56mmollL
`)- 1200 mg/dL
`
`6.20-7.77 mmollL
`
`240-300 mg/dL
`
`)- 7.77 mmollL
`
`)- 300 mg/dL
`
`
`Randomized Study
`TMC114-C211
`lopinavir/ritonavir
`PREZIST A/rtv
`800/200 mg per day
`8001100 mg once
`+TDF/FTC
`daily
`N=346
`+TDF/FTC
`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
`
`Pancreatic Lipase
`
`Grade
`
`2
`
`Grade 3
`
`
`Grade
`
`4
`
`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 mgJdL
`
`~ 1.5 to': 3.0X ULN
`~ 3.0 to .: 5.0 X ULN
`~5.0XULN
`
`Pancreatic Amvlase
`Grade 2
`
`
`~ 1.5 to .: 2.0 X ULN
`~ 2.0 to.. 5.0 X ULN
`Grade 3
`
`~5.0XULN
`Grade 4
`N=total number of subjects per treatment group
`TDF = tenofovir disoproxil fumarate
`FTC = emtricitabine
`* Grade 4 data not aoolicable in Division of AIDS grading scale.
`
`11%
`
`2%
`
`6%
`
`.: 1%
`
`0%
`
`2%
`.:1%
`0%
`
`4%
`3%
`0%
`
`6%
`
`4%
`
`7%
`
`0%
`
`0%
`
`.: 1%
`.: 1%
`.: 1%
`
`2%
`3%
`.: 1%
`
`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 PREZISTAIrt
`600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral treatment-
`experienced HIV-l-infected adult subjects. The total mean exposure for subjects in the PREZISTAlrt 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 PREZISTAIrt 600/100 mg twice daily were mild in
`severity. The most common ADRs to PREZISTAIrt 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 PREZISTAlrt arm
`discontinued treatment due to ADRs.
`
`ADRs to PREZIST Alrt 600/1 00 mg twice daily of at least moderate intensity (~Grade 2) in antiretroviral
`treatment-experienced HIV-l-infected adult subjects are presented in Table 5.
`. ... .. .-.
`
`Table 5: Selected Adverse Drug Reactions to PREZIST Alrtv 600/100 mg Twice Daily* of At Least Moderate
`Intensitv (~ Griic:e 2) in)\ntiretlQyjriil Ireatmellt- Exoerienr.ed RlY~1..Infeçte(lA4lJ.it Sqbiects
`RândomiiedStûdy
`.TMC1l4..C2H.
`lopinaVir/ritônavir
`400/100 mg twice
`daily
`+ OBR
`N.7'297
`
`PREZIST A/rtv
`600/100 mg twice daily
`+ OBR
`N7'.298
`
`System Organ Class,
`Preferred Term,
`0/0
`
`'Ga~trQi.itrsii.iiii'.pfs()rdei:š
`AbdòWíriiildistep.stoIl
`'Ab!:owúlcii tllllll
`Diarrhea
`
`i%
`5%
`12%
`
`.:1.%
`4%'
`fs%
`
`

`

`Dvspepsia
`flatulence
`Nansea
`Vqllting,
`Ge;oeriii Ì)lsn,(lersiùic:Ac:m.in.lstratlQJlsltecQ1iilltiQlls
`Asthenia
`Faiigue
`'MetabnHsll ami NiitridQl1pjš,Qrders
`AAQi:exia
`.' pia1:etes melÌtus
`Mnsçi.üQskelet~i arid cQl1necHye Tiš'Si.iJ~ Ì)isørcÎers
`'Mvalgia
`NervQtiš'svsh~lI)jsQrc:êrs "
`, Headache
`
`lsvcIil~tdc. DisQl'ders
`
`,,' AbllQr111aîdÚ~iiins .
`
`SkIJiand, Sp.iiçntanemis TissneJ)iSQÎ;d,ers
`
`,lwrlìUs
`Rasli . '
`N=totäfnuniber of sùbjêcts per treatrênIgroup
`OBR = optimized background regimen
`* Excluding laboratory abnormalities reported as ADRs
`
`2%
`.: 1%
`7%
`4%
`
`3%
`
`.1%
`
`Í%
`.: 1%
`
`1%
`
`2%
`
`':J
`
`~I%
`n%
`
`.:1%
`'1%
`6%
`3%
`
`1%
`i%
`
`
`2%
`Ö%
`
`.:1%
`
`..
`
`3%
`
`ö%
`
`1%
`3%
`
`Laboratory abnormalities:
`
`The percentages of antiretroviral treatment-experienced HIV-l-infected adult subjects treated with PREZISTAlrt
`
`laboratory abnormalities, considered ADRs, are presented in Table 6.
`
`600/100 mg twice daily with Grade 2 to 4
`
`
`Table 6:
`
`Grade 2 to 4 Laboratory Abnormaliies Observed in Antiretroviral Treatment-Experienced
`DIV-I-Infected Adult Subiects*
`
`
`Laboratory Parameter
`Preferred Term,
`
`%
`
`Biochemistrv
`Alanine Aminotransferase
`Grade 2
`
`Grade 3
`
`Grade
`
`4
`
`Aspartate Aminotransferase
`Grade 2
`
`Grade 3
`Grade 4
`Alkaline Phosphatase
`Grade 2
`
`Grade 3
`
`Grade
`
`4
`
`H voerbilirbinemia
`
`Grade 2
`
`Grade 3
`Grade 4
`
`Limit
`
`;: 2.5 to': 5.0 X ULN
`;: 5.0 to': 10.0 X ULN
`;:10.0XULN
`
`;: 2.5 to': 5.0 X ULN
`;: 5.0 to .: 10.0 X ULN
`;:10.0X ULN
`
`;: 2.5 to': 5.0 X lJN
`;: 5.0 to .: 10.0 X ULN
`;:10.0XULN
`
`;:1.5 to ':2.5XULN
`;: 2.5 to': 5.0 X ULN
`;:5.0XULN
`
`Randomized Study
`TMC114-C214
`lopinavir/ritonavir
`PREZISTAlrtv
`400/100 mg twice
`600/100 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%
`
`

`

`Triglvcerides
`Grade 2
`
`
`Grade 3
`
`
`Grade
`
`4
`
`Total Cholesterol
`Grade 2
`
`
`Grade 3
`
`
`Low-Density Lipoprotein
`Cholesterol
`Grade 2
`
`
`Grade 3
`
`
`Elevated Glucose Levels
`Grade 2
`
`
`Grade 3
`
`
`Grade
`
`4
`
`Pancreatic Lipase
`Grade 2
`
`
`Grade 3
`
`Grade 4
`Pancreatic Amvlase
`Grade 2
`
`Grade3
`
`Grade
`
`4
`
`N=total number of subjects per
`
`;: 1.5 to .: 2.0 X ULN
`;: 2.0 to': 5.0 X ULN
`;: 5.0
`treatment group
`OBR = optimized background regimen
`* Grade 4 data not applicable .in Division of AIDS grading sçale.
`
`5.65-8.48 mmollL
`
`500-750 m!!dL
`
`8.49-13.56 mmol/L
`
`751-1200 m!!dL
`
`;: 13.56 mmollL
`
`;: 1200 mg/dL
`
`
`6.20-7.77 mmollL
`
`240-300 mg/dL
`
`;: 7.77 mmollL
`
`;: 300mg/dL
`
`4.13-4.90 mmollL
`
`160-190 mg/dL
`
`~ 4.91 mmollL
`
`;: 191 mg/dL
`
`
`6.95-13.88 mmol/L
`
`126-250 mg/dL
`
`13.89-27.75 mmollL
`
`251-500 mg/dL
`
`;: 27.75 mmollL
`
`;: 500 mg/dL
`
`
`;: 1.5 to': 3.0 X ULN
`;: 3.0 to': 5.0 X ULN
`;: 5.0
`
`X ULN
`
`X ULN
`
`11%
`
`7%
`
`2%
`
`24%
`
`8%
`
`13%
`
`7%
`
`8%
`
`.:1%
`
`.: 1%
`
`2%
`2%
`.: 1%
`
`6%
`6%
`0%
`
`11%
`
`9%
`
`5%
`
`19%
`
`11%
`
`11%
`
`8%
`
`9%
`
`.: 1%
`
`0%
`
`4%
`.: 1%
`0%
`
`6%
`3%
`0%
`
`6.3 Serious ADRs
`
`The following serious ADRs of at least moderate intensity (~Grade 2) occured in the Phase 2b studies (Studies
`TMC114-C213, TMC114-C202, TMC114-C215, and TMC114-C208) and Phase 3 studies (TMC114-C211,
`TMCl14-C214, TMC114-C209, DUET-l (TMC125-C206), and DUET-2 (TMCI25-C216)) with PREZISTAlrt:
`abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache,
`hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemià, immune reconstitution
`syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson
`
`Syndrome, and vomiting.
`
`6.4 Additional ADRs to PREZISTAlrtv identified in adult subjects in other clinical trials
`In Studies TMCI14-C213, TMCI14-C202, TMCll4-C215, TMCl L4-C208, TMCl L4-C209, DUET-I, and DUET­
`2, the only additional ADR of interest identified was lipodystrophy.
`
`6.5 Patients co-infected with hepati