HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to
`use PREZISTA safely and effectively. See Full Prescribing
`Information for PREZISTA.
`
`PREZISTA (darunavir) oral suspension, for oral use
`PREZISTA (darunavir) tablet, film coated for oral use
`Initial U.S. Approval - 2006
`
`-RECENT MAJOR CHANGES
`Warnings and Precautions
`¯
`Severe Skin Reactions (5.3)
`¯ Risk of Serious Adverse Reactions due to
`Drug Interactions (5.5)
`
`04/2014
`
`03/2015
`
`-INDICATIONS AND USAGE-
`PREZISTA is a human immunodeficiency virus (HIV-1) protease
`inhibitor indicated for the treatment of HIV-1 infection in adult
`patients. PREZISTA is also indicated for the treatment of HIV-1
`infection in pediatric patients 3 years of age and older. PREZISTA
`must be co-administered with ritonavir (PREZISTAJritonavir) and
`with other antiretroviral agents. (1)
`
`-DOSAGE AND ADMINISTRATION-
`¯ Treatment-naive adult patients and treatment-experienced adult
`patients with no damnavir resistance associated substitutions:
`800 mg (one 800 mg tablet) 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)
`taJ~en with ritonavir 100 mg twice daily and with food. (2.1)
`¯ Pediatric patients (3 to less than 18 years of age and weighing at
`least 10 kg): dosage of PREZISTA and ritonavir is based on
`body weight and should not exceed the adult dose. PREZISTA
`should be taken with ritonavir aaad with food. (2.2)
`¯ PREZISTAJritonavir is not recommended for use in patients
`with severe hepatic impairment. (2.3)
`
`DOSAGE FORMS AND STRENGTHS-
`100 mg/mL oral suspension (3)
`75 mg tablets, 150 mg tablets, 600 mg tablets, and 800 mg
`tablets (3)
`
`CONTRAINDICATIONS
`Co-administration with alfuzosin, dihydroergotamine, ergotamine,
`methylergonovine, cisapride, pimozide, oral midazolam, triazolam,
`St. John’s Wort, lovastatin, simvastatin, rifampin and sildenafil
`(for treatment of pulmonary arterial hypertension). (4)
`¯ Due to the need for co-administration of PREZISTA with
`ritonavir, please refer to ritonavir prescribing information for a
`description of ritonavir contraindications. (4)
`
`WARNINGS AND PRECAUTIONS
`¯ Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis)
`has been reported with PREZISTAJritonavir. Monitor liver
`function before and during therapy, especially in patients with
`underlying chronic hepatitis, cirrhosis, or in patients who have
`
`pre-treatment elevations oftransaminases. Post-marketing cases
`of liver injury, including some fatalities, have been reported.
`(5.2, 6)
`¯ Skin reactions raaaging from mild to severe, including Stevens-
`Johnson Syndrome, toxic epidermal necrolysis, drug rash with
`eosinophilia and systemic symptoms and acute generalized
`exanthematous pustulosis, have been reported. Discontinue
`treatment if severe reaction develops. (5.3, 6)
`¯ Use with caution in patients with a known sulfonamide allergy.
`(5.4)
`¯ The concomitaaat use of PREZISTAJritonavir and certain other
`drugs may result in known or potentially significant drug
`interactions. Consult the full prescribing information prior to
`and during treatment for potential drug interactions. (5.5, 7.3)
`¯ 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)
`¯ PREZISTAJritonavir should not be used in pediatric patients
`below- 3 years of age in view- of toxicity and mortality observed
`in juvenile rats dosed with darunavir up to days 23 to 26 of age.
`(5.11)
`
`-ADVERSE REACTIONS-
`¯ The most common clinical adverse drug reactions to
`PREZISTAJritonavir (incidence greater than or equal to 5%) of
`at least moderate intensity (greater than or equal to Grade 2)
`were diarrhea, nausea, rash, headache, abdominal pain and
`vomiting. (6)
`To report SUSPECTED ADVERSE REACTIONS, contact
`Janssen Products, LP at 1-800-JANSSEN(1-800-526-7736) or
`FDA at 1-800-FDA-1088 or www.fda.gov/medwateh.
`
`DRUG INTERACTIONS.
`
`Co-administration of PREZISTA/ritonavir with other drugs cam
`alter the concentration of other drugs and other drags may alter
`the concentrations of damnavir. The potential drag-drug
`concentrations must be considered prior to and during therapy.
`(4, 5.5, 7, 12.3).
`
`-USE IN SPECIFIC POPULATIONS
`Use during pregnancy only if the potential benefit justifies the
`potential risk. (8.1)
`Mothers should be instructed not to breastfeed due to the
`potential for HIV transmission aaad the potential for serious
`adverse reactions in nursing in~ants. (8.3)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA approved patient labeling.
`
`Revised:03/2015
`
`Reference ID: 3722330
`
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`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`2
`
`3
`
`4
`5
`
`6
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`1.1
`Adult Patients
`1.2
`Pediatric Patients
`DOSAGE AND ADMINISTRATION
`2.1
`Adult Patients
`2.2
`Pediatric Patients (age 3 to
`less than 18 years)
`Patients with Hepatic
`Impairment
`DOSAGE FORMS AND STRENGTHS
`3.1 PREZISTA 100 mg/mL Oral
`Suspension
`PREZISTA 75 mg Tablets
`3.2
`PREZISTA 150 mg Tablets
`3.3
`PREZISTA 600 mg Tablets
`3.4
`PREZISTA 800 mg Tablets
`3.5
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`General
`5.2
`Hepatotoxicity
`5.3
`Severe Skin Reactions
`5.4
`Sulfa Allergy
`5.5
`Risk of Serious Adverse
`Reactions due to Drug
`Interactions
`Diabetes Mellitus /
`Hyperglycemia
`Fat Redistribution
`Immune Reconstitution
`Syndrome
`Hemophilia
`5.9
`Resistance/Cross -Resistance
`5.10
`Pediatric Patients
`5.11
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience:
`Treatment-Naive Adults
`Clinical Trials Experience:
`Treatment-Experienced
`Adults
`Serious ADRs
`Patients co-infected with
`hepatitis B and/or hepatitis C
`
`2.3
`
`5.6
`
`5.7
`5.8
`
`6.2
`
`6.3
`6.4
`
`7.2
`
`7.3
`
`6.6 Postmarketing Experience
`DRUG INTERACTIONS
`7.1
`Potential for
`PREZISTAJritonavir to
`Affect Other Drugs
`Potential for Other Drugs to
`Affect Darunavir
`Established and Other
`Potentially Significant Drug
`Interactions
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`8.7
`Renal Impairment
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1
`Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`12.4
`Microbiology
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`Animal Toxicology and/or
`Pharmacology
`CLINICAL STUDIES
`14.1 Description of Adult Clinical
`Studies
`Treatment-Naive Adult
`Subjects
`Treatment-Experienced Adult
`Subjects
`Pediatric Patients
`14.4
`HOW SUPPLIED/STORAGE AND
`HANDLING
`PATIENT COUNSELING
`INFORMATION
`
`13.2
`
`14.2
`
`14.3
`
`10
`11
`12
`
`13
`
`14
`
`16
`
`17
`
`* Sections or subsections omitted from the full prescribing
`information are not listed.
`
`6.5
`
`Clinical Trials Experience:
`Pediatric Patients
`
`Reference ID: 3722330
`
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`
`

`

`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`1.1 Adult Patients
`PREZISTA®, co-administered with ritonavir (PREZISTA/ritonavir), and with other antiretroviral agents, is indicated
`for the treatment of human immunodeficiency virus (HIV-1) infection.
`
`This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from 2 controlled Phase 3
`trials of 48 weeks duration in antiretroviral treatment-naive and treatment-experienced patients and 2 controlled
`Phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients.
`
`Pediatric Patients
`1.2
`PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), and with other antiretroviral agents, is indicated
`for the treatment of HIV-1 infection in pediatric patients 3 years of age and older [see Use in Specific Populations
`(s. 4) ] .
`
`The indication for treatment-experienced pediatric patients 3 to less than 18 years of age is based on analyses of
`plasma HIV-1 RNA levels and CD4+ cell counts from two open-label Phase2 trials in antiretroviral
`treatment-experienced pediatric subjects(24-week analysis for one trial in patients 6 to less than 18 years of age;
`48-week analysis for one trial in patients 3 to less than 6 years of age). The indication for treatment-naive pediatric
`patients or antiretroviral treatment-experienced patients with no darunavir resistance associated substitutions is
`based on one open-label Phase 2 trial of 48 weeks duration in antiretroviral treatment-naive subjects 12 to less than
`18 years of age and pharmacokinetic modeling and simulation for patients 3 to less than 12 years of age.
`
`In treatment-experienced adult and pediatric patients, the following points should be considered when initiating
`therapy with PREZISTA/ritonavir:
`
`¯
`
`¯
`
`Treatment history and, when available, genotypic or phenotypic testing should guide the use of
`PREZISTA/ritonavir [see Clinical Pharmacology (12.4)].
`The use of other active agents with PREZISTA/ritonavir is associated with a greater likelihood of treatment
`response [see Clinical Pharmacology (12.4) and Clinical Studies (14.3)].
`
`DOSAGE AND ADMINISTRATION
`2
`Adult Patients
`2.1
`PREZISTA must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer
`PREZISTA with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired
`antiviral effect and will alter some drug interactions.
`
`Patients who have difficulty swallowing PREZISTA tablets can use the 100 mg/mL PREZISTA oral suspension.
`
`Treatment-Na~e Adult Patients
`The recommended oral dose of PREZISTA is 800 mg (one 800 mg tablet or 8 mL of the oral suspension) taken with
`ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL of a 80 mg/mL ritonavir oral solution) once daily and with
`food. An 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe.
`
`Reference ID: 3722330
`
`Lupin Ex. 1064 (Page 3 of 60)
`
`

`

`Treatment-Experienced Adult Patients
`
`Table 1:
`
`Treatment-Experienced Adult Patients
`
`With at least one darunavir resistance associated
`With no darunavir resistance associated
`substitution*
`substitutions*
`Formulations: PREZISTA tablets or oral suspension (100 mg/mL) and ritonavir
`tablets/capsules (100 rag) or solution (80 mg/mL)
`PREZISTA 600 mg (e.g. one 600 mg tablet) or
`PREZISTA 800 mg (one 800 mg tablet) or
`8 mLt(oral suspension) once daily with ritonavir
`6 mL(oral suspension) twice daily with ritonavir
`100 mg (one 100 mg tablet/capsule or 1.25
`100 mg (one 100 mg tablet/capsule or
`1.25 mL(oral solution) once daily and with food mL(oral solution) twice daily and with food
`*
`V1 lI, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V
`An 8 mL damnavir dose should be taken as two 4 mL administrations with the included oral
`?
`dosing syringe
`
`For antiretroviral treatment-experienced patients genotypic testing is recommended. However, when genotypic
`testing is not feasible, PREZI STA/ritonavir 600/100 mg twice daily dosing is recommended.
`
`Pediatric Patients (age 3 to less than 18 years)
`2.2
`Healthcare professionals should pay special attention to accurate dose selection of PREZISTA, transcription of the
`medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose,
`and underdose.
`
`Prescribers should select the appropriate dose of PREZISTA/ritonavir for each individual child based on body
`weight (kg) and should not exceed the recommended dose for adults.
`
`Before prescribing PREZISTA, children weighing greater than or equal to 15 kg should be assessed for the ability to
`swallow tablets. If a child is unable to reliably swallow a tablet, the use of PREZISTA oral suspension should be
`considered.
`
`The recommended dose of PREZISTA/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at
`least 10 kg is based on body weight (see Tables 2, 3, 4, and 5) and should not exceed the recommended adult dose.
`PREZISTA should be taken with ritonavir and with food.
`
`The recommendations for the PREZISTA/ritonavir dosage regimens were based on the following:
`
`Twice daily dosing
`¯ Results from two trials in treatment-experienced pediatric subjects 3 to less 18 years of age demonstrating
`similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-
`experienced adults.
`
`Once daily dosing
`¯ Results from one trial in treatment-naive pediatric subjects 12 to less than 18 years of age demonstrating
`similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-naive
`adults.
`¯ Results from population pharmacokinetic modeling and simulation in children 3 to less than 12 years of age
`predicting similar darunavir plasma exposures compared to treatment-naive adults. Although no clinical
`trial was conducted to collect exposure-safety data, the predicted exposures from the once daily dosing is
`supported by exposures observed in a pediatric clinical trial where twice-daily dosing was administered.
`
`Dosing recommendations for treatment-na~e pediatric patients or antiretroviral treatment-experienced pediatric
`patients with no darunavir resistance associated substitutions
`
`¯ Pediatricpatients weighing at least 10 kg but less than 15 kg
`
`Reference ID: 3722330
`
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`
`

`

`The ~veight-based dose in antiretroviral treatment-naive pediatric patients or antiretroviral treatment-experienced
`pediatric patients ~vith no darunavir resistance associated substitutions is PREZISTA 35 mg/kg once daily ~vith
`ritonavir 7 mg/kg once daily using the follo~ving table.
`
`Table 2:
`
`Recommended dose for pediatric patients weighing 10 kg to less than 15 kg who are
`treatment-naive or treatment-experienced with no darunavir resistance associated
`substitutions*
`Body weight
`(kg)
`
`Formulation: PREZISTA oral suspension (100 mg/mL)
`and Ritonavir oral solution (80 mg/mL)
`Dose: once daily with food
`PREZISTA 3.6 mL; (350 mg) with ritonavir 0.8 mL (64 mg)
`Greater than or equal to 10 kg to less than 11 kg
`PREZISTA 4 mL; (385 mg) ~vith ritonavir 0.8 mL (64 mg)
`Greater than or equal to 11 kg to less than 12 kg
`PREZISTA 4.2 mL (420 mg) ~vith ritonavir 1 mL (80 mg)
`Greater than or equal to 12 kg to less than 13 kg
`PREZISTA 4.6 mL; (455 mg) ~vith ritonavir 1 mL (80 mg)
`Greater than or equal to 13 kg to less than 14 kg
`PREZISTA 5 mL; (490 mg) ~vith ritonavir 1.2 mL (96 mg)
`Greater than or equal to 14 kg to less than 15 kg
`*darunavir resistance associated substitutions: V1 lI, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and
`L89V
`; The 350 mg, 385 mg, 455 mg and 490 mg darunavir dose for the specified ~veight groups ~vere rounded up for
`suspension dosing convenience to 3.6 mL, 4 mL, 4.6 mL and 5 mL, respectively.
`
`Pediatric patients weighing at least 15 kg
`Pediatric patients weighing at least 15 kg can be dosed with PREZISTA oral tablet(s) or suspension using the
`follo~ving table:
`
`Table 3:
`
`Greater than or equal
`to 15 kg to less than 30 kg
`Greater than or equal
`to 30 kg to less than 40 kg
`Greater than or equal to 40 kg
`
`Recommended dose for pediatric patients weighing at least 15 kg who are treatment-naive or
`treatment-experienced with no darunavir resistance associated substitutions*
`Body Weight
`Formulation: PREZISTA oral
`Formulation: PREZISTA tablet(s)
`(kg)
`and ritonavir capsules or tablets
`suspension(100 mg/mL) and ritonavir
`oral solution(80 mg/mL)
`(100 mg)
`Dose: once daily with food
`Dose: once daily with food
`PREZISTA 600 mg with ritonavir
`PREZISTA 6 mL (600 mg) with
`100 mg
`ritonavir 1.25 mL (100 mg)
`PREZISTA 6.8 mL~J(675 mg) with
`PREZISTA 675 mg with ritonavir
`100 mg
`ritonavir 1.25 mL(100 mg)
`PREZISTA 8 mLJ(800 mg)with
`PREZISTA 800 mg with ritonavir
`100 mg
`ritonavir 1.25 mL (100 mg)
`*darunavir resistance associated substitutions: V1 lI, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and
`L89V
`~The 675 mg dose using darunavir tablets for this weight group is rounded up to 6.8 mL for suspension dosing
`convenience.
`fThe 6.8 mL and 8 mL darunavir dose should be taken as two (3.4 mL or 4 mL respectively) administrations with the
`included oral dosing syringe
`
`Dosing recommendations for treatment-experienced pediatric patients with at least one darunavir resistance
`associated substitutions
`¯ Pediatric patients weighing at least 10 kg but less than 15 kg
`The weight-based dose in antiretroviral treatment-experienced pediatric patients with at least one darunavir
`resistance associated substitution is PREZISTA 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily using the
`following table:
`
`Reference ID: 3722330
`
`Lupin Ex. 1064 (Page 5 of 60)
`
`

`

`Table 4:
`
`Recommended dose for pediatric patients weighing 10 kg to less than 15 kg who are
`treatment-experienced with at least one darunavir resistance associated substitution*
`Body weight
`Formulation: PREZISTA oral suspension (100 mg/mL)
`(kg)
`and Ritonavir oral solution(80 mg/mL)
`Dose: twice daily with food
`Greater than or equal to 10 kg to less than 11 kg
`PREZISTA 2 mL (200 mg) with ritonavir 0.4 mL (32 mg)
`Greater than or equal to 11 kg to less than 12 kg
`PREZISTA 2.2 mL (220 mg) with ritonavir 0.4 mL (32 mg)
`Greater than or equal to 12 kg to less than 13 kg
`PREZISTA 2.4 mL (240 mg) with ritonavir 0.5 mL (40 mg)
`Greater than or equal to 13 kg to less than 14 kg
`PREZISTA 2.6 mL (260 mg) with ritonavir 0.5 mL (40 mg)
`Greater than or equal to 14 kg to less than 15 kg
`PREZISTA 2.8 mL (280 mg) with ritonavir 0.6 mL (48 mg)
`* darunavir resistance associated substitutions: V1 lI, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and
`L89V
`
`¯ Pediatric patients weighing at least 15 kg
`Pediatric patients weighing at least 15 kg can be dosed with PREZISTA oral tablet(s) or suspension using the
`following table:
`
`Table 5:
`
`Recommended dose for pediatric patients weighing at least 15 kg who are
`treatment-experienced with at least one darunavir resistance associated substitution*
`Body Weight
`Formulation: PREZISTA oral suspension
`Formulation: PREZISTA tablet(s)
`(kg)
`(100 mg/mL) and ritonavir oral solution
`and ritonavir tablets,
`(80 mg/mL)
`capsules(100 mg) or oral solution
`(80 mg/mL)
`Dose: twice daily with food
`Dose: twice daily with food
`PREZISTA 3.8 mL (375 mg) with
`PREZISTA 375 mg with ritonavir
`Greater than or equal
`ritonavir 0.6 mL (48 mg)
`0.6 mL (48 mg)
`to 15 kg to less than 30 kg
`PREZISTA 4.6 mL (450 mg)~with
`PREZISTA 450 mg with ritonavir
`Greater than or equal
`ritonavir 0.75 mL (60 mg)
`0.75 mL (60 mg)
`to 30 kg to less than 40 kg
`PREZISTA 6 mL (600 mg) with
`PREZISTA 600 mg with ritonavir
`Greater than or equal
`100 mg
`ritonavir 1.25 mL(100 mg)
`to 40 kg
`*darunavir resistance associated substitutions: V1 lI, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and
`L89V
`~The 375 mg and 450 mg dose using darunavir tablets for this weight group is rounded up to 3.8 mL and 4.6 mL for
`suspension dosing convenience.
`
`Do not use PREZISTA/ritonavir in pediatric patients below 3 years of age [see Warnings and Precautions (5.11)
`and Nonclinical Toxicology (13.2)].
`
`2.3
`
`Patients with Hepatic Impairment
`
`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)].
`
`DOSAGE FORMS AND STRENGTHS
`3
`PREZISTA 100 mg/mL Oral Suspension
`3.1
`PREZISTA (darunavir) 100 mg/mL oral suspension is supplied as a white to off-white opaque suspension for oral
`use, containing darunavir ethanolate equivalent to 100 mg of darunavir per mL of suspension.
`
`Reference ID: 3722330
`
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`
`

`

`PREZISTA 75 mg Tablets
`3.2
`PREZISTA (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing darunavir
`ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with ~75" on one side and ~TMC" on
`the other side.
`
`PREZISTA 150 mg Tablets
`3.3
`PREZISTA (darunavir) 150 mg tablets are supplied as white, oval-shaped, film-coated tablets containing darunavir
`ethanolate equivalent to 150 mg of darunavir per tablet. Each tablet is debossed with ~150" on one side and ~TMC"
`on the other side.
`
`PREZISTA 600 mg Tablets
`3.4
`PREZISTA (darunavir) 600 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing darunavir
`ethanolate equivalent to 600 mg of darunavir per tablet. Each tablet is debossed with ~600MG" on one side and
`~TMC" on the other side.
`
`PREZISTA 800 mg Tablets
`3.5
`PREZISTA (darunavir) 800 mg tablets are supplied as dark red, oval-shaped, film-coated tablets containing
`darunavir ethanolate equivalent to 800 mg of darunavir per tablet. Each tablet is debossed with ~800" on one side
`and ~T" on the other side.
`
`CONTRAINDICATIONS
`4
`Co-administration of PREZISTA/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for
`clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events
`(narrow therapeutic index). These drugs and other contraindicated drugs (which may lead to reduced efficacy of
`darunavir) are listed in Table 6 [also see Drug Interactions (7.3), Table 11].
`
`Table 6:
`Drug Class
`
`Drugs That Are Contraindicated With PREZISTA/ritonavir
`Drugs Within Class That Are
`Contraindicated With
`PREZISTA/ritonavir
`
`Clinical Comment
`
`Alpha 1-
`adrenoreceptor
`antagonist
`Ergot Derivative
`
`Alfuzosin
`
`Dihydroergotamine, Ergotamine,
`Methylergonovine
`
`GI Motility Agent
`
`Cisapride
`
`Neuroleptic
`
`Pimozide
`
`Sedative/hypnotic
`
`Orally administered Midazolam, Triazolam
`
`Potential for serious and/or life-threatening
`reactions such as hypotension.
`
`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.
`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.
`
`Reference ID: 3722330
`
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`
`

`

`Herbal Product
`
`St. John’s Wort (Hypericum pe~foratum)
`
`HMG-CoA Reductase
`Inhibitor
`
`Lovastatin, Simvastatin
`
`Antimycobacterial
`
`Rifampin
`
`PDE-5 inhibitor
`
`Sildenafil for treatment of pulmonary
`arterial hypertension
`
`Patients taking PREZISTA/ritonavir should
`not use products containing St. John’s wort
`because co-administration may result in
`reduced plasma concentrations of
`darunavir. This may result in loss of
`therapeutic effect and development of
`resistance.
`Potential for serious reactions such as
`myopathy including rhabdomyolysis.
`
`For dosing recommendation regarding
`atorvastatin and pravastatin, see Table 11:
`Established and Other Potentially
`Significant Drug Interactions: Alterations
`in Dose or Regimen May Be
`Recommended Based on Drug Interaction
`Studies or Predicted Interaction.
`Rifampin is a potent inducer of CYP450
`metabolism. PREZISTA/ritonavir should
`not be used in combination with rifampin,
`as this may cause significant decreases in
`darunavir plasma concentrations. This may
`result in loss of therapeutic effect to
`PREZISTA.
`A safe and effective dose for the treatment
`of pulmonary arterial hypertension has not
`been established with PREZISTA/ritonavir.
`There is an increased potential for
`sildenafil-associated adverse events (which
`include visual disturbances, hypotension,
`prolonged erection, and syncope).
`
`Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information
`for a description of ritonavir contraindications.
`
`5 WARNINGS ANI) 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.
`
`Hepatotoxieity
`5.2
`Drug-induced hepatitis (e. g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/ritonavir. During
`the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination
`therapy with PREZISTA/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B
`or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.
`
`Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in
`patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including
`hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with
`PREZISTA/ritonavir therapy has not been established.
`
`Reference ID: 3722330
`
`Lupin Ex. 1064 (Page 8 of 60)
`
`

`

`Appropriate laboratory testing should be conducted prior to initiating therapy ~vith PREZISTA/ritonavir and patients
`should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients ~vith
`underlying chronic hepatitis, cirrhosis, or in patients ~vho have pre-treatment elevations of transaminases, especially
`during the first several months of PREZISTA/ritonavir treatment.
`
`Evidence of ne~v or ~vorsening liver dysfunction (including clinically significant elevation of liver enzymes and/or
`symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on
`PREZISTA/ritonavir should prompt consideration of interruption or discontinuation of treatment.
`
`Severe Skin Reactions
`5.3
`During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations
`of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (less
`than 0.1%) reported during the clinical development program.During post-marketing experience toxic epidermal
`necrolysis, drug rash with eosinophilia and systemic symptoms,and acute generalized exanthematous pustulosis
`have been reported. Discontinue PREZISTA/ritonavir immediately if signs or symptoms of severe skin reactions
`develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise,
`fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
`
`Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with PREZISTA/ritonavir [also see
`Adverse Reactions(6)]. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment
`and resolving with continued dosing. The discontinuation rate due to rash in subjects using PREZISTA/ritonavir was
`0.5%.
`
`Rash occurred more commonly in treatment-experienced subjects receiving regimens containing
`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.
`
`Risk of Serious Adverse Reactions due to Drug Interactions
`5.5
`Initiation of PREZISTA2ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or
`initiation of medications metabolized by CYP3A in patients already receiving PREZISTA2ritonavir, may increase
`plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce
`CYP3A may increase or decrease concentrations of PREZISTA2ritonavir, respectively. These interactions may lead
`to:
`
`¯ Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from
`greater exposures of concomitant medications.
`¯ Clinically significant adverse reactions from greater exposures of PREZISTA/ritonavir.
`¯ Loss of therapeutic effect of PREZISTA/ritonavir and possible development of resistance.
`
`See Table 11 for steps to prevent or manage these possible and known significant druginteractions, including dosing
`recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during
`PREZISTA/ritonavir therapy; review concomitant medications during PREZISTA/ritonavir therapy; and monitor for
`the adverse reactions associated with the concomitant drugs [see Contraindications (4) and Drug Interactions (7)].
`
`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
`
`Reference ID: 3722330
`
`Lupin Ex. 1064 (Page 9 of 60)
`
`

`

`10
`
`persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of
`frequency cannot be made and causal relationships bet~veen 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 ~vasting, facial ~vasting, breast enlargement, and "cushingoid appearance" have been observed in patients
`receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unkno~vn.
`A causal relationship has not been established.
`
`Immune Reconstitution Syndrome
`5.8
`Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy,
`including PREZISTA. During the initial phase of combination antiretroviral treatment, patients whose immune
`systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as
`Mycobacterium avium infection, cytomegalovirus, Pneumocystisfirovecii pneumonia [PCP], or tuberculosis), which
`may necessitate further evaluation and treatment.
`
`Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barrd syndrome) have also been
`reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur
`many months after initiation of antiretroviral treatment.
`
`Hemophilia
`5.9
`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/ritonavir
`treated patients, the effect therapy with PREZISTA will have on the activity of subsequently administered