NDA 21-976/S-005
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`PREZISTA™* (Tibotec, Inc.)
`(darunavir)
`
`Tablets
`Description
`PREZISTA™ (darunavir) is an inhibitor of the human immunodeficiency virus (HIV) protease.
`
`PREZISTA™ (darunavir), in the form of darunavir ethanolate, has the following chemical name:
`[(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-
`(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl
`ester
`(phenylmethyl)propyl]-carbamic
`acid
`monoethanolate. Its molecular formula is C27H37N3O7S • C2H5OH and its molecular weight is
`593.73. Darunavir ethanolate has the following structural formula:
`
`
`• C2H5OH
`
`NH2
`
`O
`
`S
`
`O
`
`N
`
`OH
`
`H3C
`
`O
`
`H
`
`H
`
`NH
`
`O
`
`O
`
`H
`
`H
`
`O
`
`H
`
`CH3
`
`
`
`
`Darunavir ethanolate is a white to off-white powder with a solubility of approximately
`0.15 mg/mL in water at 20°C.
`
`PREZISTA 300 mg and PREZISTA 600 mg tablets are available as orange, oval-shaped, film-
`coated tablets for oral administration. Each 300 mg tablet contains darunavir ethanolate
`equivalent to 300 mg of darunavir. Each 600 mg tablet contains darunavir ethanolate equivalent
`to 600 mg of darunavir. During storage, partial conversion from ethanolate to hydrate may occur;
`however, this does not affect product quality or performance. 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
`
`
`Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV
`encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus
`particles.
`
`
`MECHANISM OF ACTION
`
` *Trademark of Tibotec Pharmaceuticals Ltd
`
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`NDA 21-976/S-005
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`
`ANTIVIRAL ACTIVITY
`
`
`Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and
`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 O 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)RTIs abacavir, didanosine, emtricitabine, lamivudine,
`stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, efavirenz, or
`nevirapine, and the fusion inhibitor enfuvirtide.
`
`
`RESISTANCE
`
`
`Cell Culture: HIV-1 isolates with a decreased susceptibility to darunavir have been selected in
`cell culture and obtained from subjects treated with darunavir/ritonavir. 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, V77I, or I85V 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, V11I,
`I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S,
`L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V,
`L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least
`eight protease mutations and exhibited 50- to 641-fold decreases in 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 V32I
`developed on PREZISTA/rtv 600/100 mg b.i.d. in greater than 30% of virologic failure isolates
`and substitutions at amino acid position I54 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 I15, 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
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`of some darunavir virologic failure isolates. The resistance profile in treatment-naïve 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 ≥ 1 log10 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, ritonavir 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
`the nucleoside/nucleotide reverse
`Cross-resistance between darunavir and
`inhibitors, the non-nucleoside reverse transcriptase inhibitors or the fusion inhibitor is unlikely
`because the viral targets are different.
`
`
`BASELINE GENOTYPE/PHENOTYPE
`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 b.i.d. 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 V32I, I47V, or I54L 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 ≥ 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 TMC114-C215/C208 analysis, the presence at baseline of three or
`more of the mutations V11I, V32I, L33F, I47V, I50V, I54L or M, G73S, L76V, I84V or L89V
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`NDA 21-976/S-005
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`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 ≥4 of these mutations, respectively). Conclusions regarding
`the relevance of particular mutations or mutational patterns are subject to change pending
`additional data.
`
`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
`TMC114-C202
`
`Prezista/rtv 600/100 mg
`(n = 125)
`Proportion of
`subjects with
`< 50 copies/mL
`at Week 24
`
`
`
`Median
`DAVG24
`
`Comparative Arm
`(n = 120)
`Proportion of
`subjects with
`< 50 copies/mL
`at Week 24
`
`Median
`DAVG24
`
`n Proportion
`of subjects
`with
`≥ 1 log10
`decrease
`at
`Week 24
`23%
`
`
`
`PI
`Mutations^
`
`0 - 4
`
`5 - 6
`
`≥ 7
`
`n Proportion
`of subjects
`with
`≥ 1 log10
`decrease
`at
`Week 24
`81%
`
`57
`
`54
`
`14
`
`67%
`
`21%
`
`46%
`
`52%
`
`14%
`
`-2.16
`
`-2.13
`
`-0.87
`
`52
`
`51
`
`17
`
`24%
`
`6%
`
`13%
`
`16%
`
`0%
`
`-0.57
`
`-0.43
`
`-0.13
`
`
`^ Any change at protease amino acid positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 73, 82, 84, 88 and 90
`
`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 TMC114-C213 and TMC114-C202 and the TMC114-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.
`
`Table 2: Response to PREZISTA/rtv 600/100 mg b.i.d. by Baseline Darunavir Phenotype: As-
`Treated Analysis of Studies TMC114-C213, TMC114-C202, and TMC114-C215/C208
`
`Baseline Darunavir
`Phenotype
`N = 340
`(fold change ranges)
`
`
`Proportion of subjects with
`≥1 log10 decrease
`at Week 24
`
`All ranges
`
`0 - 2
`
`> 2 - 7
`
`70%
`238/340
`88%
`119/136
`73%
`62/85
`
`
`Proportion of subjects
`with
` < 50 copies/mL at
`Week 24
`43%
`147/340
`60%
`82/136
`47%
`40/85
`
`
`Clinical Response
`Range
`
`Overall Response
`
`Higher than Overall
`Response
`Similar to Overall
`Response
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`
`> 7 - 30
`
`> 30
`
`
`Clinical Pharmacology
`
`52%
`33/63
`43%
`24/56
`
`24%
`15/63
`18%
`10/56
`
`Lower than Overall
`Response
`Lower than Overall
`Response
`
`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 TMC114-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 of darunavir. Therefore,
`PREZISTA should only be used in combination with 100 mg of ritonavir to achieve sufficient
`exposures of darunavir.
`
`Table 3: Population Pharmacokinetic Estimates of Darunavir at the Darunavir/Ritonavir
`600/100 mg b.i.d. dose (Integrated data from TMC114-C213 and TMC114-
`C202, Primary 24-Week Analysis)
`Parameter
`
`Darunavir/Ritonavir 600/100 mg b.i.d.
`N = 119
`
`62349 ± 16143
`61668 (33857-106490)
`
`3578 ± 1151
`3539 (1255-7368)
`
`AUC12h (ng·h/mL)
`Geometric Mean ± Standard Deviation
`Median (Range)
`C0h (ng/mL)
`Geometric Mean ± Standard Deviation
`Median (Range)
`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.
`
`
`
`
`
`
`
`
`
`
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`NDA 21-976/S-005
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`
`
`Mean Steady-State Plasma Concentration-Time Profiles of Darunavir and Ritonavir at
`Figure 1:
`600/100 mg b.i.d. at Week 4 (Integrated data from TMC114-C213 and TMC114-C202, Primary 24-Week
`Analysis)
`
`
`
`10000
`
`Darunavir Mean
`
`90% Confidence Intervals
`
`Ritonavir Mean
`
`EC90 for wild type virus (adjusted for protein binding) = 200 ng/ml
`EC50 for resistant virus (adjusted for protein binding) = 550 ng/ml
`
`Darunavir
`
`Ritonavir
`
`2
`
`4
`
`6
`Time (hours)
`
`8
`
`10
`
`12
`
`9000
`
`8000
`
`7000
`
`6000
`
`5000
`
`4000
`
`3000
`
`2000
`
`1000
`
`0
`
`0
`
`Plasma Concentrations (ng/ml)
`
`
`Absorption and Bioavailability: Darunavir, co-administered with 100 mg ritonavir twice daily,
`was absorbed following oral administration with a Tmax of approximately 2.5-4 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.
`
`Effects of Food on Oral Absorption: When administered with food, the Cmax and AUC of
`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 1-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
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`enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after a
`single dose administration of 400 mg 14C-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 14C-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 hepatic metabolism. 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 TMC114-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 14C-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=12, age ≥ 65) (see PRECAUTIONS, Geriatric Use).
`
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`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
`CONTRAINDICATIONS, WARNINGS,
`AND PRECAUTIONS, DRUG
`INTERACTIONS.
`
`
`Darunavir and ritonavir are both inhibitors of CYP3A. Co-administration of darunavir and
`ritonavir with drugs primarily metabolized by CYP3A may result in increased plasma
`concentrations of such drugs, which could increase or prolong 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.
`
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`
`Table 4:
`
`Drug Interactions: Pharmacokinetic Parameters for Darunavir in the
`Presence of Co-administered Drugs
`
`LS Mean Ratio (90% CI) of
`Darunavir
`Pharmacokinetic Parameters
`With/Without Co-
`administered Drug
`No Effect =1.00
`
`Dose/Schedule
`Co-
`Co-
`Administered
`Darunavir/
`Administered
`N
`Drug
`rtv
`Drug
`Co-Administration With Other Protease Inhibitors
`13 ↔
`300 mg q.d. ^
`Atazanavir
`400/100 mg
`b.i.d. †
`400/100 mg
`b.i.d.
`300/100 mg
`b.i.d.
`400/100 mg
`b.i.d.
`
`Indinavir
`
`800 mg b.i.d.
`
`400/100 mg
`b.i.d.
`1000 mg b.i.d.
`
`PK
`
`↑
`
`↓
`
`↓
`
`Cmax
`
`AUC
`
`Cmin
`
`1.02
`1.03
`
`(0.96-1.09) (0.94-1.12)
`1.11
`1.24
`
`(0.98-1.26) (1.09-1.42)
`0.61
`0.47
`
`(0.51-0.74) (0.40-0.55)
`0.83
`0.74
`
`(0.75-0.92) (0.63-0.86)
`
`1.01
`(0.88-1.16)
`1.44
`(1.13-1.82)
`0.35
`(0.29-0.42)
`0.58
`(0.47-0.72)
`
`9
`
`9
`
`14
`
`12
`
`8
`
`12
`
`↓
`
`↑
`
`↑
`
`0.85
`0.87
`
`(0.72-1.00) (0.75-1.01)
`1.40 ‡
`1.24 ‡
`
`(1.14-1.73) (0.97-1.57)
`1.16
`1.21
`
`(0.94-1.42) (0.95-1.54)
`
`0.69
`(0.54-0.87)
`1.02 ‡
`(0.79-1.32)
`1.24
`(0.90-1.69)
`
`17 ↔
`
`14
`
`↑
`
`16 ↔
`
`16 ↔
`
`16 ↔
`
`13 ↔
`
`0.83
`0.87
`
`(0.72-0.96) (0.75-1.01)
`1.21
`1.42
`
`(1.04-1.40) (1.23-1.65)
`1.02
`1.04
`
`(0.95-1.09) (0.96-1.13)
`0.97
`1.02
`
`(0.92-1.02) (0.95-1.10)
`0.96
`0.95
`
`(0.89-1.05) (0.90-1.01)
`1.01
`0.98
`
`(0.89-1.14) (0.84-1.14)
`
`1.01
`(0.81-1.26)
`1.73
`(1.39-2.14)
`1.08
`(0.93-1.25)
`1.07
`(0.96-1.19)
`0.94
`(0.90-0.99)
`0.94
`(0.76-1.16)
`
`Lopinavir/
`Ritonavir
`Saquinavir
`hard gel
`capsule
`
`Co-Administration With Other Antiretrovirals
`Efavirenz
`600 mg q.d.
`300/100 mg
`b.i.d.
`400/100 mg
`b.i.d.
`300/100 mg
`b.i.d.
`
`Nevirapine
`
`200 mg b.i.d.
`
`300 mg q.d.
`
`Tenofovir
`Disoproxil
`Fumarate
`Co-Administration With Other Drugs
`Clarithromycin
`500 mg b.i.d.
`400/100 mg
`b.i.d.
`400/100 mg
`b.i.d.
`400/100 mg
`b.i.d.
`400/100 mg
`b.i.d.
`400/100 mg
`b.i.d.
`400/100 mg
`b.i.d.
`
`Ketoconazole
`
`200 mg b.i.d.
`
`Omeprazole
`
`20 mg q.d.
`
`Paroxetine
`
`20 mg q.d.
`
`Ranitidine
`
`150 mg b.i.d.
`
`Sertraline
`
`50 mg q.d.
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`
`
`N = number of subjects with data; - = no information available.
`^ q.d. = daily
`† b.i.d. = twice daily
`‡ Ratio based on between-study comparison.
`
`
`
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`
`Table 5:
`
`Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs
`in the Presence of Darunavir/Ritonavir
`
`PK
`
`LS Mean Ratio (90% CI) of
`Co-Administered Drug
`Pharmacokinetic Parameters
`With/Without Darunavir
`No effect =1.00
`
`Cmax
`
`0.89
`(0.78-
`1.01)
`
`AUC
`
`1.08
`(0.94-
`1.24)
`
`Cmin
`
`1.52
`(0.99-
`2.34)
`
`1.08
`(0.95-
`1.22)
`
`1.23
`(1.06-
`1.42)
`
`2.25
`(1.63-
`3.10)
`
`1.22
`(1.12-
`1.32)
`
`0.94
`(0.78-
`1.13)
`
`1.37
`(1.27-
`1.49)
`
`0.94
`(0.76-
`1.17)
`
`1.72
`(1.46-
`2.03)
`
`0.82
`(0.52-
`1.30)
`
`Dose/Schedule
`Co-
`Co-
`Administered
`Darunavir/
`Administered
`N
`Drug
`rtv
`Drug
`Co-Administration With Other Protease Inhibitors
`13 ↔
`300 mg q.d.^
`Atazanavir
`400/100 mg
`b.i.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
`b.i.d.
`
`Indinavir
`
`400/100 mg
`b.i.d.
`
`9
`
`↑
`
`Lopinavir/
`Ritonavir
`
`300/100 mg
`b.i.d.
`
`9
`
`↑
`
`400/100 mg
`b.i.d.
`
`12 ↔
`
`Saquinavir
`hard gel
`capsule
`
`1000 mg b.i.d.
`/100 mg RTV
`b.i.d. when
`administered
`alone
`
`1000 mg b.i.d.
`when
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`
`
`administered
`with darunavir/
`ritonavir
`
`Co-Administration With Other Antiretrovirals
`Efavirenz
`600 mg q.d.
`300/100 mg
`b.i.d.
`
`Nevirapine
`
`200 mg b.i.d.
`
`Tenofovir
`Disoproxil
`Fumarate
`
`300 mg q.d.
`
`400/100 mg
`b.i.d.
`
`300/100 mg
`b.i.d.
`
`12
`
`8
`
`12
`
`↑
`
`↑
`
`↑
`
`1.15
`(0.97-
`1.35)
`1.18
`(1.02-
`1.37)
`1.24
`(1.08-
`1.42)
`
`1.21
`(1.08-
`1.36)
`1.27
`(1.12-
`1.44)
`1.22
`(1.10-
`1.35)
`
`1.17
`(1.01-
`1.36)
`1.47
`(1.20-
`1.82)
`1.37
`(1.19-
`1.57)
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`
`
`Co-Administration With Other Drugs
`300/100 mg
`Atorvastatin
`40 mg q.d.
`b.i.d.
`when
`administered
`alone
`
`10 mg
`q.d. when
`administered
`with darunavir/
`ritonavir
`500 mg b.i.d.
`
`Clarithromycin
`
`400/100 mg
`b.i.d.
`
`Ketoconazole
`
`200 mg b.i.d.
`
`Paroxetine
`
`20 mg q.d.
`
`400/100 mg
`b.i.d.
`
`400/100 mg
`b.i.d.
`
`Pravastatin
`
`40 mg
`single dose
`
`600/100 mg
`b.i.d.
`
`Sertraline
`
`50 mg q.d.
`
`400/100 mg
`b.i.d.
`
`Sildenafil
`
`400/100 mg
`b.i.d.
`
`15
`
`↑
`
`0.56
`(0.48-
`0.67)
`
`0.85
`(0.76-
`0.97)
`
`1.81
`(1.37-
`2.40)
`
`17
`
`15
`
`16
`
`14
`
`13
`
`16
`
`↑
`
`↑
`
`↓
`
`↑
`
`↓
`
`↑
`
`1.26
`(1.03-
`1.54)
`2.11
`(1.81-
`2.44)
`0.64
`(0.59-
`0.71)
`1.63
`(0.95-
`2.82)
`0.56
`(0.49-
`0.63)
`0.62
`(0.55-
`0.70)
`
`1.57
`(1.35-
`1.84)
`3.12
`(2.65-
`3.68)
`0.61
`(0.56-
`0.66)
`1.81
`(1.23-
`2.66)
`0.51
`(0.46-
`0.58)
`0.97
`(0.86-
`1.09)
`
`2.74
`(2.30-
`3.26)
`9.68
`(6.44-
`14.55)
`0.63
`(0.55-
`0.73)
`
`-
`
`0.51
`(0.45-
`0.57)
`-
`
`100 mg (single
`dose)
`administered
`alone
`
`25 mg (single
`dose)
`when
`administered
`with darunavir/
`ritonavir
`N = number of subjects with data;- = no information available.
`^ q.d. = daily
`† b.i.d. = twice daily
`
`
`
`Indications and Usage
`PREZISTA, co-administered with 100 mg ritonavir (PREZISTA/rtv), and with other
`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.
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`
`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 PIs)
`adult patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
`
`The following points should be considered when initiating therapy with PREZISTA/rtv:
`
`
`• Treatment history and, when available, genotypic or phenotypic testing, should guide the
`use of PREZISTA/rtv (see MICROBIOLOGY).
`
`• 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).
`
`• The risks and benefits of PREZISTA/rtv have not been established in treatment-naïve
`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, TMC114-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 TMC114-C215 and TMC114-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.
`
`HIV-1 infected subjects who were eligible for these trials had plasma HIV-1 RNA
`> 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at least one
`primary PI mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at screening,
`and were on a stable PI-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 enfuvirtide.
`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 (OBR) versus a control group receiving an investigator-
`selected PI(s) regimen plus an OBR. Prior to randomization, PI(s) and OBR 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 PI(s) in the control arm included: lopinavir
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`
`in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 98% of control
`subjects received a ritonavir boosted PI regimen out of which 23% of control subjects used dual-
`boosted PIs. Approximately 47% of all subjects used enfuvirtide, and 35% of the use was in
`subjects who were ENF-naïve. Virologic response was defined as a decrease in plasma HIV-1
`RNA viral load of at least 1.0 log10 versus baseline.
`
`In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline
`characteristics were balanced between the PREZISTA/rtv arm and the comparator PI arm.
`Table 6 compares the demographic characteristics between subjects in the PREZISTA/rtv
`600/100 mg b.i.d. arm and subjects in the comparator PI arm.
`
`Table 6: Demographic Characteristics of Subjects in the Studies TMC114-C213 and
`TMC114-C202 (Pooled Analysis)
`Randomized Studies TMC114-C213 and TMC114-C202
`PREZISTA/rtv
`Comparator PI(s)
`600/100 mg b.i.d.
`+ OBR
`+ OBR
`N = 124
`N = 131
`
`43.0
`(27-73)
`
`89%
`11%
`
`81%
`10%
`7%
`4.52
`(3.0-6.4)
`
`
`44.0
`(25-65)
`
`88%
`12%
`
`73%
`15%
`8%
`4.56
`(2.2-6.1)
`
`
`
`
`153
`(3-776)
`
`24.4%
`
`67%
`
`4.3
`
`163
`(3-1274)
`
`29.0%
`
`58%
`
`3.3
`
`Demographic Characteristics
`Age (years)
`(range, years)
`Sex
` Male
` Female
`Race
` White
` Black
` Hispanic
`Median Baseline Plasma HIV-1 RNA
`(log10 copies/mL)
`(range, log10 copies/mL)
`Median Baseline CD4+ Cell Count
`(cells/mm3)
`(range, cells/mm3)
`Percentage of Patients with Baseline
`Viral Load > 100,000 copies/mL
`Percentage of Patients with Baseline
`CD4+ Cell Count < 200 cells/mm3
`Median Darunavir FC
`
`Table 7 compares the baseline characteristics between subjects in the PREZISTA/rtv 600/100 mg
`b.i.d. arm and subjects in the comparator PI arm.
`
`Table 7:
`
`Baseline Characteristics of Subjects in the Studies TMC114-C213 and
`TMC114-C202 (Pooled Analysis)
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` 8
`
`
`1
`6
`
`
`
`8%
`37%
`54%
`
`
`
`
`
`
`
`
` 6
`
` 1
`
` 5
`
`NDA 21-976/S-005
`Page 18
`
`
`
`
`Randomized Studies TMC114-C213 and TMC114-C202
`Comparator PI(s)
`PREZISTA/rtv
`+ OBR
`600/100 mg b.i.d.
`N = 124
`+ OBR
`N = 131
`
`
`
`
`
`
`
`64%
`
`
`61%
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`Baseline Characteristics
`Median Number of Resistance-
`Associated:
`PI mutations^
`NNRTI mutations
`NRTI mutations
`Percentage of Subjects with the
`following Baseline IAS Primary
`Protease Mutations†:
`≤ 1
`2
`≥ 3
`Median Number of ARVs
`Previously Used‡:
`NRTIs
`
`NNRTIs
`
`PIs (excluding low-dose
`ritonavir)
`
`Percentage of Subjects
`Resistant§ to All Available¶ PIs
`at Baseline, excluding
`Tipranavir
`
`
`Percentage of Subjects with
`16%
`19%
`Prior Use of Enfuvirtide
`
`
`
`^ L10F/I/R/V, K20I/L/M/R/T, L24I, D30N, V32I, L33F/I, M36I/L/V, M46I/L, I47A/V, G48V, I50L/V,
`F53L, I54A/L/M/S/T/V, A71V/T, G73A/C/S/T, V77I, V82A/F/L/S/T, I84A/C/V, N88D/S, L90M
`† Based on the IAS-USA list of mutations (March 2005): D30N, L33F/I, M46I/L, G48V, I50L/V,
`V82A/F/L/S/T, I84A/C/V, L90M
`‡ Only counting ARVs, excluding low-dose ritonavir, taken for at least 2 months, and for which start and
`stop dates were available
`§ Based on phenotype (Antivirogram™)
`¶ Commercially available PIs at the time of study enrollment
`
`Week 24 outcomes for subjects on the recommended dose PREZISTA/rtv 600/100 mg b.i.d.
`from the pooled Studies TMC114-C213 and TMC114-C202 are shown in Table 8.
`
`
` 8
`
`
`1
`5
`
`
`
`13%
`25%
`62%
`
`
`
`
`
`
`
`
` 6
`
` 1
`
` 5
`
`

`

`NDA 21-976/S-005
`Page 19
`
`Table 8:
`
`
`
`Outcomes of Randomized Treatment Through Week 24 of the Studies
`TMC114-C213 and TMC114-C202 (Pooled Analysis)
`Randomized Studies TMC114-C213 and TMC114-C202
`Comparator PI + OBR
`PREZISTA/rtv 600 mg b.i.d.
`N=124
`+ OBR
`N=131
`69.5%
`(45.0%)
`
`21.0%
`(12.1%)
`
`26.0%
`9.9%
`9.2%
`6.9%
`3.9%
`
`0.8%
`
`71.0%
`57.3%
`9.7%
`4.0%
`1.6%
`
`6.5%
`
`Virologic Responders
`confirmed at least 1 log10
`HIV-1 RNA below baseline
`through Week 24
`(< 50 copies/mL at
`Week 24)
`Virologic failures
`Lack of initial response^
`Rebound†
`Never Suppressed‡
`Death or discontinuation due
`to adverse events
`Discontinuation due to other
`reasons
`^ Subjects who did not achieve at least a confirmed 0.5 log10 HIV-1 RNA drop from baseline at
`Week 12
`† Subjects with an initial r