CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`»
`
`APPLICA TION NUMBER:
`
`2 1 -976
`
`APPROVED LABELING
`
`

`

`PREZISTATM* (Tibotec, Inc.)
`
`(darunavir)
`
`‘
`
`Tablets
`
`DESCRIPTION
`
`PREZISTATM (darunavir) is an inhibitor of the human immunodeficiency virus (HIV) protease.
`
`PREZISTATM (darunavir), in the form of darunavir ethanolate, has the following chemical name:
`[( 1 S,2R)—3 —[[(4—aminophenyl)sulfonyl](2—methylpropyl)amino]-2 -hydroxy- 1 -
`ester
`(phenylmethyl)propyl]—carbamic
`acid
`(3R,3aS,6aR)—hexahydrofuro[2,3—b]furan—37y]
`monoethanolate. Its molecular formula is C27H37N3O7S - CszOH and its molecular weight is
`593.73. Darunavir ethanolate has the following structural formula:
`
` \
`
`.
`
`H3O
`
`o
`o
`\ /
`/s
`
`N
`
`0H
`
`CH,
`
`- CZHSOH
`
`NHZ
`
`Darunavir ethanolate is a white to off—white powder with a solubility of approximately
`0.15 mg/mL in water at 20°C.
`
`PREZISTA is available as an orange, oval—shaped, film—coated tablet for oral administration.
`Each tablet contains darunavir ethanolate equivalent to 300 mg of darunavir. Each tablet also
`contains the inactive ingredients colloidal silicon dioxide, crospovidone, magnesium stearate,
`and microcrystalline cellulose. The tablet film coating, OPADRY® Orange, contains FD&C
`Yellow No. 6, polyethylene glycol 3350, polyvinyl alcohol—partially hydrolyzed,
`talc, and
`titanium dioxide.
`
`All dosages for PREZISTA are expressed in terms of the free form of darunavir.
`
`MICROBIOLOGY
`
`Mechanism ofA ction
`
`Darunavir is an inhibitor of the HIV—1 protease. It selectivelyinhibits the cleavage of HIV
`encoded Gag—Pol polyproteins in infected cells, thereby preventing the formation of mature virus
`particles.
`
`

`

`Antiviral Activity
`
`isolates of HIV—1 and
`laboratory strains and clinical
`Darunavir exhibits activity against
`laboratory strains of HIV-2 in acutely infected T—cell lines, human peripheral blOOd mononuclear
`cells and human monoCytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM
`(0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against a broad panel
`of HIV—1 group M (A, B, C, D, E, F, G), and group 0 primary isolates with EC50 values ranging
`from < 0.1 to 4.3 nM. The EC50 value of darunavir increases by a median factor of 5.4 in the
`presence of human serum. Darunavir did not show antagonism when studied in combination with
`the protease inhibitors amprenavir, atazanavir,
`indinavir,
`lopinavir, nelfinavir,
`ritonavir,
`saquinavir, or
`tipranavir,
`the N(t)RT1s abacavir, didanosine, emtricitabine,
`lamivudine,
`stavudine,
`tenofovir, zalcitabine, or zidovudine,
`the NNRTls delavirdine, efavirenz, or
`nevirapine, and the fusion inhibitor enfuvirtide.
`
`Resistance
`
`Cell Culture: HIV—l isolates with a decreased susceptibility to darunavir have been selected in
`cell culture and obtained from subjects treated with darunavir/Iitonavir. Darunavir-resistant virus
`derived in cell culture from wild—type HIV had 6— to 21—fold decreased susceptibility to darunavir
`and harbored 3 to 6 of the following amino acid substitutions S37N/D, R41E/S/T, K55Q, K70E,
`A71T, T74S, V771, or 185V in the protease. Selection in cell culture of darunavir resistant HIV-1
`from nine HIV-1 strains harboring multiple protease inhibitor resistance-associated mutations
`resulted in the overall emergence of 22 mutations in the protease gene, including L10F, V111,
`113V, 115V, G16E, L231, V321, L33F, S37N, M461, I47V, 150V, F53L, L63P, A71V, G73S,
`L76V, V821, 184V, T91A/S, and Q92R, of which L10F, V321, L33F, S37N, M461, I47V, 150V,
`L63P, A71V, and 184V were the most prevalent. These darunavir—resistant viruses had at least
`eight protease mutations and exhibited 50- to 641 -fold decreasesin darunavir susceptibility with
`final EC50 values ranging from 125 nM to 3461 nM.
`
`Clinical studies of darunavir/ritonavir in treatment—experienced subjects
`
`In the Phase 2b Studies TMC114—C213 and TMC114-C202 and the TMC114—C215/C208
`
`analysis, multiple protease inhibitor—resistant HIV-1 isolates from highly treatment—experienced
`subjects who received PREZISTA/rtv 600/100 mg b.i.d. and experienced virologic failure, either
`by rebound, or by never being suppressed, developed amino acid substitutions that were
`associated with a decrease in susceptibility to darunavir. The amino acid substitution V321
`developed on PREZISTA/rtv 600/ 100 mg b.i.d. in greater than 30% of virologic failure isolates
`and substitutions at amino acid position 154 developed in greater than 20% of virologic failure
`isolates. Other substitutions that developed in 10% to 20% of PREZISTA/rtv virologic failure
`isolates occurred at amino acid positions 115, L33, I47, G73 and L89. The median darunavir
`phenotype (fold change from reference) of the virologic failure isolates was 21—fold at baseline
`and 94—fold at failure. Amino acid substitutions were also observed in the protease cleavage sites
`of some darunavir virologic failure isolates. The resistance profile in treatment—naive subjects
`has not been characterized.
`
`

`

`Cross—resistance
`
`Cross—resistance among protease inhibitors has been observed. Darunavir has a <10—fold
`decreased susceptibility in cell culture against 90% of 3309 clinical
`isolates resistant
`to
`amprenavir, atazanavir,
`indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir
`showing that viruses resistant to these protease inhibitors remain susceptible to darunavir. In
`Studies TMC114—C213 and TMC114—C202 and the TMC114—C215/C208 analysis, 60% (88/147)
`of subjects on darunavir/rtv whose baseline isolates had decreased susceptibility to tipranavir
`(tipranavir fold change > 3) demonstrated a decrease of 2 1 logo in viral load at week 24, and
`36% (53/147) achieved < 50 copies/mL plasma HIV RNA levels.
`
`Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir,
`nelfinavir, iitonavir or saquinavir in cell culture. However, six of nine darunavir—resistant viruses
`selected in cell culture from protease inhibitor—resistant viruses showed a fold change in EC50
`values < 3 for tipranavir, indicative of limited cross—resistance between darunavir and tipranavir.
`Of the viruses isolated from subjects experiencing virologic failure on darunavir/ritonavir
`600/100 mg b.i.d., greater than 50% were still susceptible to tipranavir while less than 5% were
`susceptible to other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir,
`ritonavir, or saquinavir).
`
`transcriptase
`reverse
`and the nucleoside/nucleotide
`Cross—resistance between darunavir
`inhibitors, the non—nucleoside reverse transcriptase inhibitors or the fusion inhibitor is unlikely
`because the viral targets are different.
`
`Baseline Genotype/Phenolype and Virologic Outcome Analyses
`
`Genotypic and/or phenotypic analysis of baseline virus may aid in determining darunavir
`susceptibility before initiation of PREZISTA/rtv 600/100 mg bid.
`therapy. Analyses were
`conducted to evaluate the impact of specific baseline protease inhibitor resistance—associated
`mutations and the number of protease inhibitor resistance-associated mutations at baseline on
`virologic response. Both specific mutations and the number of baseline mutations, as well as
`susceptible drugs
`in the optimized background regimen and enfuvirtide use,
`affected.
`PREZISTA/rtv response rates in Phase 2b Studies TMC114—C213 and TMC114—C202.
`
`The presence at baseline of the mutations V321, I47V, or 154L or M, was associated with a
`decreased virologic response to darunavir and decreased susceptibility to darunavir. In addition,
`
`a diminished virologic response was observed in subjects with 2 7 protease inhibitor resistance—
`associated mutations (any change at amino acid positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 73,
`82, 84, 88, or 90) at baseline (see Table 1). In a supportive analysis of Studies TMC114-C213
`and TMC114-C202 and the TMCI l4-C215/C208 analysis, the presence at baseline of three or
`more of the mutations V111, V321, L33F, 147V, ‘150V, 154L or M, G738, L76V, I84V or L89V
`
`was associated with a decreased virologic response to PREZISTA/rtv (the proportion of subjects
`achieving viral load < 50 plasma HIV RNA copies/mL at week 24 was 50%, 22% and 10% when
`the baseline genotype had 0—2, 3 and 24 of these mutations, respectively). Conclusions regarding
`
`

`

`the relevance of particular mutations or mutational patterns are subject
`- additional data.
`
`
`to change pending
`
`
`
`
`
`
`
`
`
`
`Table 1: Response to PREZISTA/rtv 600/100 mg b.i.d. by Baseline Number of Protease Inhibitor
`Resistance—Associated Mutations: As-Treated Analysis of Studies TMC114-C213 and
`
`TMC l 14—C202
`
`
`
`Comparative Arm
`Prezista/rtv 600/100 mg
`
`(n = 125)
`.
`(n = 120)
`
`
`P]
`Proportion Median
`'
`Proportion
`Proportion
`Proportion
`
`
`
`
`
`
`Mutations“
`.
`of subjects
`of subjects
`of subjects
`of subjects
`DAVG24
`
`
`
`
`
`
`
`N
`with
`with
`with
`with
`2 1 log",
`2 1 log“,
`< 50 copies
`< 50 copies
`
`
`
`
`/
`decrease
`decrease
`/mL
`/mL
`
`
`
`
`
`at Week 24
`at Week 24
`at Week 24
`at Week 24
`
`
`
`
` 81%
`
`
`
`
`
`
`
`A An Chan e at
`nrotease amino acid nositions 30, 32, 36, 46, 47, 48, 50, 53, 54, 73, 82, 84, 88 and 90
`
`W
`
`Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be a
`predictive factor of virologic outcome. Response rates assessed by baseline darunavir phenotype
`are shown in Table 2. These baseline phenotype groups are based on the select subject
`populations in the Studies TMCll4—C213 and TMCll4-C202 and the TMCll4-C215/C208
`analysis, and are not meant
`to represent definitive clinical susceptibility breakpoints for
`PREZISTA/rtv. The data are provided to give clinicians information on the likelihood of
`virologic success based on pre—treatment susceptibility to darunavir in protease inhibitor—
`experienced patients.
`'
`'
`
`able 2: Response to PREZISTA/rtv 600/100 mg b.i.d. by Baseline Darunavir Phenotype:
`As-Treated Analysis of Studies TMC114-C213, TMCll4-C202, and TMCll4-
`C215/C208
`/
`Baseline Darunavir
`
`Phenotype
`N = 340
`(fold change ranges)
`
`Proportion of subjects with
`21 log“, decrease
`at Week 24
`
`Proportion of
`subjects with
`< 50 copies/mL at
`Week 24
`
`Clinical
`Response
`Range
`
`147/340
`
`All ranges
`
`'
`
`> 2 - 7
`
`70%
`238/340
`
`119/136
`
`'
`
`73%
`
`62/85
`52%
`33/63
`43%
`24/56
`
`43%
`
`Overall Response
`
`82/136
`
`47%
`
`40/85
`24%
`15/63
`18%
`10/56
`
`ReSnonse '
`
`Similar to Overall
`
`Res onse
`Lower than Overall
`Reswnse
`Lower than Overall
`'
`ReSn onse
`
`

`

`CLINICAL PHARMACOLOGY
`
`Pharmacokinetics in Adults
`
`The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg twice
`daily), have been evaluated in healthy adult volunteers and in HIV—1 infected subjects. Table 3
`displays the population pharmacokinetic estimates of darunavir from an analysis of integrated
`data from Studies TMC114—C213 and TMCl 14—C202 of 119 subjects administered the
`darunavir/ritonavir 600/100 mg b.i.d. dose. Darunavir is primarily metabolized by CYP3A.
`Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a
`single dose of 600 mg darunavir was given orally in combination with 100 mg ritonavir b.i.d.,
`there was an approximate 14—fold increase in the systemic exposure bf darunavir. Therefore,
`PREZISTA should only be used in combination with 100 mg of ritonavir to achieve sufficient
`exposures of darunavir.
`
`
`
`
`the
`Table 3: Population Pharmacokinetic Estimates of Darunavir ' at
`Darunavir/Ritonavir 600/100 mg b.i.d. dose (Integrated data from
`
`
`
`
`TMCll4—C213 and TMCl 14—C202, Primary 24-Week Analysis)
`
`
`Parameter
`Darunavir/Ritonavir 600/100 mg
`
`
`
`b.i.d.
`
`N = 119
`
`
`AUCizh (11-”
`
`
`Geometric Mean i Standard Deviation
`62349 d: 16143
`
`
`
`
`
`Median (Ran e)
`61668 (33857-106490)
`C011 (Hg/1111..)
`
`
`
`
`3578 i 1151
`Geometric Mean :t Standard Deviation
`
`
`
`Median (Range)
`3539 (1255—7368)
`
`
`N = number of subjects with data.
`
`
`
`
`Figure 1 displays the mean plasma concentrations of darunavir and ritonavir at steady—state for
`the darunavir/ritonavir 600/ 100 mg b.i.d. dose.
`7
`
`

`

`Figure 1: Mean Steady-State Plasma Concentration-Time Profiles of Darunavir and
`Ritonavir at 600/100 mg _b.i.d. at Week 4 (Integrated data from TMC114—C213
`and TMC114—C202, Primary 24-Week Analysis)
`
`10000 7.
`
`9000 a
`
`8000 ~
`
`+ Darunavir Mean
`
`- - - 90% Confidence Intervals
`
`. ~
`
`+ Ritonavir Mean
`
`
`
`
`
`PlasmaConcentrations(nglml)
`
`Ritonavir
`
`E030 for wild type virus (adjusted for protein bindirg) = 200 ng'rri
`ECa; for resistart virus (adjusted for prdein binding) = 550 ngrri
`
`Darunavir
`
`Absorptzbn and Bioavailability: Darunavir, co—administered with 100 mg ritonavir twice daily,
`was absorbed following oral administration with a Tmax of approximately 2.54 hours. The
`absolute oral bioavailability of a single 600 mg dose of darunavir alone and after
`co—
`administration with 100 mg ritonavir twice daily was 37% and 82%, respectively.
`
`the Cmax and AUC of
`Eflects of Food on Oral Absorption: When administered with food,
`darunavir, co—administered with ritonavir, is approximately 30% higher relative to the fasting
`state. Therefore, PREZISTA tablets, co—administered with ritonavir, should always be taken with
`food. Within the range of meals studied, darunavir exposure is similar. The total caloric content
`of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).
`
`Distribution: Darunavir is approximately 95% bound to plasma proteins. Darunavir binds
`primarily to plasma alpha l-acid glycoprotein (AAG).
`
`Metabolism: In vitro experiments with human liver microsomes (HLMs) indicate that darunavir
`primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP
`enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed, that after a
`single dose administration of 400 mg MC—darunavir, co-administered with 100 mg ritonavir, the
`
`

`

`majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites
`of darunavir have been identified in humans; all showed activity that was at least 90% less than
`the activity of darunavir against wild-type HIV.
`
`Elimination: A mass balance study in healthy volunteers showed that after single dose
`administration of 400 mg l4C-darunavir, co—administered with 100 mg ritonavir, approximately
`79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and
`
`urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the
`administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir
`was approximately 15 hours when combined with ritonavir. After intravenous administration, the
`clearance of darunavir, administered alone and co—administered with 100 mg twice daily
`ritonavir, was 32.8 L/h and 5.9 L/h, respectively.
`
`Special Populations
`
`Hepatic Impairment: Darunavir primarily undergoes hepaticmetabolism. PREZISTA has not
`been studied in patients with varying degrees of hepatic impairment (see PRECAUTIONS,
`Patients with
`co-existing
`conditions, Hepatic
`Impairment
`and DOSAGE AND
`ADMINISTRATION).
`
`Hepatitis B or Hepatitis C Virus Co-infection: The primary 24—week analysis of the data from
`Study TMCl l4—C213 in 31 HIV—1 infected subjects indicated that hepatitis B and/or hepatitis C
`virus co—infection status had no apparent effect on the exposure of darunavir.
`
`Renal Impairment: Results from a mass balance study with l4C-darunavir/ritonavir showed that
`approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged
`drug. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will
`be significantly removed by hemodialysis or peritoneal dialysis. Population pharmacokinetic
`analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV
`infected subjects with moderate renal impairment (CrCL between 30—60 mL/min, n=20). There
`are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or
`end stage renal disease: (see PRECAUTIONS, Patients with co-existing conditions, Renal
`Impairment, and DOSAGE AND ADMINISTRATION).
`
`Gender: Population pharmacokinetic analysis showed higher mean darunavir exposure (16.8%)
`in HIV infected females (n=68) compared to males. This difference is not clinically relevant.
`
`Race: Population pharmacokinetic analysis of darunavir in HIV infected subjects indicated that
`race had no apparent effect on the exposure to darunavir. _
`
`Geriatric Patients: Population pharmacokinetic analysis in HIV infected subjects showed that
`darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years)
`evaluated in HIV infected subjects (n=1 2, age 2 65) (see PRECAUTIONS, Geriatric Use).
`
`Pediatric Patients: The pharmacokinetics of darunavir in combination with ritonavir in pediatric
`patients has not been established. There' are insufficient data at this time to recommend a dose.
`
`

`

`Drug Interactions: See also CONTRAINDICA TIONS, WARNINGS, and PRECA UTIONS, Drug
`Interactions.
`
`Darunavir and ritonavir are both inhibitors of CYP3A. Co—administration of darunavir and
`
`in increased plasma
`ritonavir with drugs primarily metabolized by CYP3A may result
`concentrations of such drugs, which could increase orprolong their therapeutic effect and
`adverse events (see sections CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS,
`Drug Interactions).
`
`Darunavir and ritonavir are metabolized by CYP3A. Drugs that induce CYP3A activity would
`be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma
`concentrations of darunavir and ritonavir. Co—administration of darunavir and ritonavir and other
`
`drugs that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result
`in increased plasma concentrations of darunavir and ritonavir.
`
`_
`
`Drug interaction studies were performed with darunavir and other drugs likely to be co—
`administered and some drugs commonly used as probes for pharmacokinetic interactions. The
`effects of co—administration of darunavir on the AUC, Cmax, and Cmin values are summarized in
`Table 4 (effect of other drugs on darunavir) and Table 5 (effect of darunavir on other drugs). For
`information regarding clinical recommendations, see PRECAUTIONS, Drug Interactions.
`
`

`

`
`
`
`Table 4:
`Drug Interactions: Pharmacokinetic Parameters for Darunavir in the
`Presence of Co-administered Dru -_s
`
`
`
`
`LS Mean Ratio % (90% CI) of
`M
`Pharmacokinetic Parameters
`With/Without Co-
`
`
`
`administered Drug
`
`Dose/Schedule
`No Effect =1.00
`
`
`
`Co-
`Co-
`
`
`Administered
`
`
`Administered Darunvavir/
`
`Drug
`
`
`Dru_-
`Co Administration With Other Protease Inhibitors_
`
`Ib.i..d’ (0.96-..109)(0941.12)(0881.16)
`
`
`
`b.1.d.
`
`(0.98 1.26) (1.09—1.42)(1.13-1.82)
`
`
`
`(0.51 0.74) (0400.55) (0.290.42)
`
`
`
`0.69
`
`(1.14—1.73) (0.97—1.57) (0.79-1.32)
`
`Co-Administration With Other Dru - 5
`
`b.1.d.
`
`
`
`
`
`
`
`Ritonavir
`b.1.d.
`'
`Saquinavir
`1000 mg b.1.d.
`400/100 mg
`
`
`hard gel
`
`capsule
`
`
`
`
`
` Efavirenz
`
`.
`.
`b.1.d.
`(0.72-1.00) (0.75—1.01)-
`600 mg q.d.
`300/100 mg
`
`
`
`
`
`
` Nevirapine
`8
`T
`200 mg b.1.d.
`400/100 mg
`b.1.d.
`
`
`
`
`(0.94—1.42) (0.95—1.54) (0.90-1.69)
`Disoproxil
`
`
`'Fumarate
`
`
`
`
`--II---
`
`-—-II---
`bid.
`(1.04—1.40)(123—1.65 (1.39-.214
`
`
`Ib.1.d.
`
`
`
`
`bi. d.
`
`
`b.1.d.
`
`
`
`
`b.1.d.
`
`(072—096)(0.75-1.0.—1)(081126)
`
`(0 95- 1.09) (0.96— 1. 13 (0.93—1.25
`
`'
`
`b.1. d.
`
`

`

`
`
`N = number of subjects with data; — = no information available.
`‘ q.d. = daily
`l b.i.d. = twice daily
`
`l Ratio based on between-study comparison.
`
`

`

`Table 5:
`
`_ Drug Interactions: Pharmacokinetic Parameters for Co—administered Drugs
`in the Presence of Darunavir/Ritonavir
`
`LS Mean Ratio % (90% CI) of
`Co-Administered Drug
`Pharmacokinetic Parameters
`With/Without Darunavir
`
`Dose/Schedule
`
`N 0 effect =1.00
`
`Co-
`
`Administered Administered Darunavir/
`
`Drug
`
`Co-Administration With Other Protease Inhibitors
`
`
`
`Atazanavir
`
`Indinavir
`
`Lopinavir/
`Ritonavir
`
`Saquinavir
`hard gel
`capsule
`
`400/100 mg
`b.i.d. T
`
`400/100 mg
`b.i.d.
`
`300 mg q.d.“
`/100 mg RTV
`q.d. when
`administered
`alone
`
`300 mg q.d.
`when
`administered
`with darunavir/
`
`ritonavir
`
`800 mg b.i.d.
`/100 mg RTV
`b.i.d. when
`administered
`alone
`
`800 mg b.i.d.
`when
`
`administered
`with darunavir/
`ritonavir
`
`400/ 100 mg
`b1.d
`
`300/100 mg
`b1. d.
`
`1.22
`(1.12—
`1.32)
`
`1.37
`(1.27—
`1.49)
`
`1.72
`(1.46—
`2.03)
`
`400/ 100 mg
`b.1. d.
`
`1000 mg b.1. d.
`/100 mg RTV
`b.i.d. when
`administered
`alone
`
`1000 mg b.i.d.
`when
`
`

`

`Nevirapine
`
`200 mg b.i.d.
`
`300 mg q.d.
`
`12
`
`T
`
`T
`
`
`
`
`administered
`
`
`with darunavir/
`ritonavir
`
`
`Efavirenz
`
`
`
`600 mg q.d.
`
` Co-Administration With Other Antiretrovirals—
`
`300/100 mg
`b.i.d.
`'
`
`'
`
`12
`
`T
`
`1.15
`(0.97—
`1.35
`
`1.21
`(1.08-
`1.36
`
`1.17
`(1.01—
`1.36
`
`1.18
`1.27
`1.47
`(1 .02—
`(1.12-
`(1.20—
`
`1.37)
`1.44)
`1.82
`Tenofovir
`300/100 mg
`1.24
`1.22
`1.37
`Disoproxil
`b.i.d.
`(1 .08—
`(1.10-
`(1.19-
`
`Fumarate
`1.42)
`1.35)
`1.57)
`
`400/100 mg
`b.i.d.
`
`

`

`
`
`
`Co—Administration With Other Drugs
`Atorvastatin
`40 mg q.d.
`300/100 mg
`when
`b.i.d.
`administered
`alone
`
`15
`
`T
`
`0.56
`(0.48-
`0.67)
`
`10 mg
`q.d. when
`administered
`
`with darunavir/
`ritonavir
`
`500 mg b.i.d.
`
`20 mg q.d.
`
`
`,
`
`17
`
`15
`
`T
`
`T
`
`
`
`Clarithromycin
`
`Paroxetine
`
`
`
`Pravastatin
`
`Sertraline
`
`‘
`
`
`
`
`
`1.26
`400/100 mg
`(1.03—
`b.i.d.
`
`
`1.54)
`
`
`Ketoconazole
`200 mg b.i.d.
`2.1 1
`400/ 100 mg
`b.i.d.
`(1.8]—
`
`2.44
`
`
`
`0.64
`400/100 mg
`b.i.d.
`(0.59—
`
`
`
`0.71)
`
`
`
`40 mg
`600/100 mg
`1.63
`single dose
`b.i.d.
`(0.95— ‘
`
`2.82)
`
`
`
`50 mg q.d.
`400/100 mg
`0.56
`0.51
`b.i.d.
`(0.49—
`(0.46-
`
`
`
`0.63
`0.58
`
`
`
`
`100 mg (single
`Sildenafil
`400/ 10.0 mg
`b.i.d.
`
`
`dose)
`
`administered
`
`alone
`
`
`
` 25 mg (single
`dose)
`
`when
`
`N = number of subjects with data;— = no information available.
`
`A q.d. = daily
`
`* b.i.d. = twice dail
`
`)
`
`0.51
`(0.45—
`0.57
`
`administered
`with darunavir/
`
`
`ritonavir
`
`

`

`INDICATIONS AND USAGE
`
`and with other
`(PREZISTA/rtv),
`100 mg ritonavir
`co—administered with
`PREZISTA,
`antiretroviral agents,
`is indicated for the treatment of human immunodeficiency virus (HIV)
`infection in antiretroviral treatment-experienced adult patients, such as those with HIV—1 strains
`resistant to more than one protease inhibitor.
`
`This indication is based on Week 24 analyses of plasma HIV RNA levels and CD4+ cell counts
`from 2 controlled trials of PREZISTA/rtv in combination with other antiretroviral drugs. Both
`studies were conducted in clinically advanced, treatment—experienced (NRTIs, NNRTIs, and P15)
`adult patients with evidence of HIV—1 replication despite ongoing antiretroviral therapy.
`
`The following points should be considered when initiating therapy with PREZISTA/rtv:
`
`0 Treatment history and, when available, genotypic or phenotypic testing, should guide the
`use of PREZISTA/rtv (see MICROBIOLOGY).
`
`o The use of other active agents with PREZISTA/rtv is associated with a greater likelihood
`of treatment response (see MICROBIOLOGY and INDICATIONS AND USAGE,
`Description of Clinical Studies).
`
`0 The risks and benefits of PREZISTA/rtv have not been established in treatment-naive
`
`adult patients or pediatric patients.
`
`-
`
`Description of Clinical Studies
`
`The evidence of efficacy of PREZISTA/rtv is based on the analyses of 24—week data from
`2 ongoing, randomized, controlled trials, TMCll4—C213 and TMC114—C202,
`in antiretroviral
`treatment—experienced HIV—1 infected adult subjects. These efficacy results were supported by
`the 24-week pooled analysis of the open label trials TMCll4—C215 and TMCll4-C208 of
`subjects who initiated PREZISTA/rtv at the recommended dose.
`
`Treatment-Experienced Subjects:
`
`Studies TMC114—C213 and TMC114—C202: These are ongoing randomized, controlled, Phase 2b
`trials consisting of 2 parts: an initial partially—blinded, dose-finding part and a second long-term
`part in which all subjects randomized to PREZISTA/rtv received the recommended dose of
`600/100 mg b.i.d.
`
`these trials had plasma HIV—1 RNA
`infected subjects who were eligible for
`HIV—l
`> 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at
`least one
`primary PI mutation (D3ON, M46I/L, G48V, ISOL/V, V82A/F/S/T, 184V, L90M) at screening,
`and were on a stable Pl—containing regimen at screening for at least 8 weeks. Randomization was
`stratified by the-number of PI mutations, screening viral
`load, and the use of 'enfiivirtide.
`
`

`

`Analyses included 318 subjects in Study TMC114—C213 and 319 subjects in Study TMC114—
`C202 who had completed 24 weeks of treatment or discontinued earlier.
`
`At 24 weeks, the Virologic response rate was evaluated in subjects receiving PREZISTA/rtv plus
`an optimized background regimen (0BR) versus a control group receiving an investigator—
`selected Pl(s) regimen plus an 0BR. Prior to randomization, Pl(s) and 0BR were selected by the
`investigator based on genotypic resistance testing and prior ARV history. The OBR consisted of
`at
`least 2 NRTIs with or without enfuvirtide. Selected Pl(s) in the control arm included:
`lopinavir/ritonavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%;
`23% of the control subjects used dual-boosted PIs. Approximately 47% of all subjects used
`enfuvirtide, and 35% of the use was in subjects who were ENF—na’i've. Virologic response was
`defined as a decrease in plasma HIV—1 RNA viral load of at least 1.0 logic versus baseline.
`
`In the pooled analysis for TMC114-C213 andvTMC114-C202, demographics and baseline
`characteristics were balanced between the PREZISTA/rtv arm and the comparator PI arm.
`Table6 compares the demographic characteristics between subjects in the PREZISTA/Itv
`600/100 mg bid. arm and subjects in the comparator PI arm.
`
`Table 6: Demographic Characteristics of Subjects in the Studies TMC114—C213 and
`TMC114-C202 (Pooled Anal
`
`andomized Studies TMC114-C213 and TMC114—C202—
`
`
`
`
`
`PREZISTA/rtv
`Comparator PI(s)
`
`+ 0BR
`
`600/100 mg bid.
`
`N = 124
`+ 0BR .
`
`
`N = 131
`
`
`
`
`
`44 0
`(25 65
`
`
`
`
`
`
`
`Hispanic
`
`
`
`Median Baseline Plasma HIV-1 RNA
`
`
`
`
`(logm copies/mL)
`
`
`
`
`
`seline CD4+ Cell Count
`(cells/mm3)
`
`
`
`(ran e, cells/mm3
`
`
`
`
`
`
`
`
`
`
`Race
`
`'
`
`4.52
`
`(3.0-6.4)
`
`153
`(3-776)
`
`4.56
`
`(2.2—6.1)
`
`163
`@4274)
`
`-
`
`Viral Load > 100,000 c01es/mL
`
`Percentage of Patients With Basehne
`CD4+ Cell Count < 200 cells/mm}
`Median DarunavirFC
`
`
`
`67%
`
`58%
`
`'
`
`
`
`
`
`“—a
`
`43.0
`Age (years)
`(27—73
`(ran e, ears
`——
`
`

`

`Table 7 compares the baseline characteristics between subjects in the PREZISTA/rtv 600/100 mg
`b.i.d. arm and subjects in the comparator Pl arm.
`
`Table 7:
`
`
`
`
`
`
`
`Pl mutations“
`NNRTI mutations
`NRTI mutations
`
`Percentage of Subjects with the
`following Baseline IAS Primary
`Protease Mutationsl:
`S l
`
`
`
`8
`1
`6
`
`
`Baseline Characteristics of Subjects in the Studies TMC114—C213 and
`
`TMC114—C202 (Pooled Anal sis)
`
`Randomized Studies TMC114-C213 and TMC114-C202
`
`
`
`
`PREZISTA/rtv
`Comparator PI(s)
`
`
`600/100 mg b.i.d.
`+ 0BR
`
`+ OBR
`N = 124
`
`
`N = 13]
`Baseline Characteristics —
`Median Number of Resistance—
`Associated:
`'
`
`
`
`
`
`
`
`
`
`2 2
`
`3
`
`
`Median Number of ARVs
`
`Previously Usedi:
`
`
`NRTIs
`
`NNRTIs
`
` Pls (excluding low-dose
`
` ritonavir)
`
` Percentage of Subjects
`
`
`
`
`Resistant§ to All Available" Pls
`
`at Baseline, excluding
`Tiranavir
`
`
`
`
`
`Percentage of Subjects with
`Prior Use of Enfuvirtide
`
`
`
` A L10F/I/R/V, KZOI/L/M/R/T, L241, D30N, V321, L33F/l, M361/L/V, M461/L, I47A/V, G48V, ISOL/V,
`
`F53L, 154A/L/M/S/T/V, A71V/T, G73A/C/S/T, V771, V82A/F/L/S/T, 184A/C/V, N88D/S, L9OM
`
`
`T Based on the IAS-USA list ofmutations (March 2005): D30N, L33F/I, M461/L, G48V, lSOL/V,
`
`
`V82A/F/L/S/T, l84A/C/V, L90M
`iOnly counting ARVs, excluding low—dose ritonavir, taken for at least 2 months, and for which start and
`
`
`stop dates were available
`I
`§Based on phenotype (AntivirogramTM)
`
`
`l' Commerciall available PIs at the time of stud enrollment
`
`
`

`

`Week 24 outcomes for subjects on the recommended dose PREZISTA/rtv 600/ 100 mg b.i.d.
`from the pooled Studies TMCl l4—C213 and TMC] 14-C202 are shown in Table 8.
`
`Table 8:
`
`Outcomes of Randomized Treatment Through Week 24 of the Studies
`
`TMC114-C213 and TMC114-C202 (Pooled Anal sis)
`Randomized Studies TMC114—C2l3 and TMC114—C202
`
`PREZISTA/rtv 600 mg bid
`+ OBR
`N=l 31
`
`Comparator PI + 0BR
`N=124
`
`Virologic Responders
`confirmed at least 1 loglo
`HIV-1 RNA below baseline
`through Week 24
`(< 50 copies/mL at
`
`Week 24)
`.
`Virolo ic failures
`
`Lack of initial response“
`
`to adverse events
`
`Discontinuation due to other
`reasons
`
`69.5%
`(45.0%)
`
`26.0%
`
`3.
`
`‘
`
`.
`
`21.0%
`(12.1%)
`
`71.0%
`
`57.3%
`
`.
`
`3:Subjects who never reached a confirmed 1 logo drop in viral load before Week 24
`
`A Subjects who did not achieve at least a confirmed 0.5 loglo HIV—1 RNA drop from baseline at
`Week 12
`l Subjects with-an initial response (confirmed 1 loglo drop in viral load), but without a confirmed
`1 logo drop in viral load at Week 24
`
`Through 24 weeks of treatment, the proportion of subjects with HIV—1 RNA < 400 copies/mL in
`the arm receiving PREZISTA/rtv 600/100 mg b.i.d. compared to the comparator PI arm was 63%
`and 19%, respectively. In addition, the mean changes in plasma HIV-1 RNA from baseline were
`—1.89 loglo copies/mL in the arm receiving PREZISTA/rtv 600/ 100 mg b.i.d. and -0.48 logm
`copies/mL for the comparator PI arm. The mean increase from baseline in CD4+ cell counts was
`higher in the arm receiving PREZISTA/rtv 600/100 mg b.i.d.
`(92 cells/mm3)
`than in the ‘
`comparator Pl arm (17 cells/mm3).
`
`The TMC114-C215/C208 analysis: Additional data on the efficacy of PREZISTA/rtv
`600/ 100 mg b.i.d. have been obtained in treatment—experienced subjects participating in the non—
`randomized trials TMC] 14—C215 and TMCl l4—C208. The 246 subjects from these trials
`included in the TMC 1 14-C215/C208 24—week efficacy analysis
`initiated therapy with
`PREZISTA/rtv with the recommended dose of 600/ 100 mg b.i.d. The OBR consisted of at least
`two NRTIs with or without enfuvirtide. Entry criteria for the TMC114—C215/C208 analysis were
`the Same as those for Studies TMC114—C213 and TMC] 14-C202.
`
`

`

`Baseline characteristics of the subjects included in the TMCll4—C215/C208 analysis were
`comparable to those subjects in Studies TMCl l4—C2l3 and TMCl l4-C202.
`
`load reduction and
`The TMCl 14-C215/C208 24-week efficacy analysis supported the viral
`CD4+ cell count increases observed in the Studies TMCl l4—C2l3 and TMC] l4—C202. Of the
`
`246 subjects at Week 24, 65% had a virologic response defined as a decrease of at least 1.0 log“)
`in plasma viral load versus baseline and 40% of the subjects reached less than 50 HIV-1 RNA
`copies/mL. The mean increase in CD4+ cell count versus baseline was 80 cells/mm3 at Week 20.
`At Week 24, 57% of the subjects reached less than 400 HIV-1 RNA copies/mL, and the mean
`changes in plasma HIV—1 RNA from baseline were —1 .65 loglo copies/mL.
`
`CONTRAINDICATIONS
`
`PREZISTA is contraindicated in patients with known hypersensitivity to any of the ingredients
`of the product.
`
`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 are listed in Table 9 (also
`see PRECAUTIONS, Drug Interactions, Table 10).
`
`
`
`
`
`I Table 9:
`Drugs That Are Contraindicated With PREZISTA/rtv
`
`Drug Class '
`Drugs Within Class That Are Contraindicated
`
`With PREZISTA/rtv
`
`
`
`
`Antihistamines
`'
`Astemizole, Terfenadine
`
`
`
`Dihydroergotamine, Ergonovine, Ergotamine,
`Ergot Derivatives
`
`Methyler_onovine
`
`
`
`
`Cisapride
`GI Motility Agent
`
`Pimozide
`Neuroleptic
`
`
`
`Sedative/h notics
`
`Midazolam, Triazolam
`
`
`
`
`
`
`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
`
`ALERT: Find out about medicines that should not be taken with PREZISTA/rtv. This
`
`statement is included on the product’s bottle label.
`
`General
`
`-
`
`PREZISTA (darunavir) must be co-administered with ritonavir and food to exert its therapeutic
`effect (see DOSAGE and ADMINISTRATION). Failure to correctly administer PREZISTA with
`ritonavir and food will result
`in reduced plasma concentrations of darunavir that will be
`insufficient to achieve the desired antiviral effect.
`
`Please refer to ritonavir prescribing information for additional
`measures.
`
`information on precautionary
`
`

`

`Skin Rash
`
`During the clinical development program, severe skin rash, including erythema multiforrne and
`Stevens—Johnson Syndrome, has been reported.
`In some cases,
`fever and elevations of
`transaminases have also been reported. In clinical trials (n=924), rash (all grades, regardless of
`causality) occurred in 7% of subjects treated with PREZISTA; the discontinuation rate due to
`rash was 0.3%. Rashes were