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`CRIXIVAN®
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` (INDINAVIR SULFATE)
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` CAPSULES
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` DESCRIPTION
`CRIXIVAN® (indinavir sulfate) is an inhibitor of the human immunodeficiency virus (HIV) protease.
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`CRIXIVAN Capsules are formulated as a sulfate salt and are available for oral administration in strengths
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`of 200 and 400 mg of indinavir (corresponding to 250 and 500 mg indinavir sulfate, respectively). Each
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`capsule also contains the inactive ingredients anhydrous lactose and magnesium stearate. The capsule
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`shell has the following inactive ingredients and dyes: gelatin and titanium dioxide.
`The chemical name for indinavir sulfate is [1(1S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H­
`inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)­
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`D-erythro-pentonamide sulfate (1:1) salt. Indinavir sulfate has the following structural formula:
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`Indinavir sulfate is a white to off-white, hygroscopic, crystalline powder with the molecular formula
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`C36H47N5O4 • H2SO4 and a molecular weight of 711.88. It is very soluble in water and in methanol.
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`MICROBIOLOGY
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`Mechanism of Action: HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral
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`polyprotein precursors into the individual functional proteins found in infectious HIV-1. Indinavir binds to
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`the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the
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`viral polyproteins resulting in the formation of immature non-infectious viral particles.
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`Antiretroviral Activity In Vitro: The in vitro activity of indinavir was assessed in cell lines of
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`lymphoblastic and monocytic origin and in peripheral blood lymphocytes. HIV-1 variants used to infect the
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`different cell types include laboratory-adapted variants, primary clinical isolates and clinical isolates
`resistant to nucleoside analogue and nonnucleoside inhibitors of the HIV-1 reverse transcriptase. The
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`IC95 (95% inhibitory concentration) of indinavir in these test systems was in the range of 25 to 100 nM. In
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`drug combination studies with the nucleoside analogues zidovudine and didanosine, indinavir showed
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`synergistic activity in cell culture. The relationship between in vitro susceptibility of HIV-1 to indinavir and
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`inhibition of HIV-1 replication in humans has not been established.
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`Drug Resistance: Isolates of HIV-1 with reduced susceptibility to the drug have been recovered from
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`some patients treated with indinavir. Viral resistance was correlated with the accumulation of mutations
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`that resulted in the expression of amino acid substitutions in the viral protease. Eleven amino acid residue
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`positions, (L10l/V/R, K20l/M/R, L24l, M46l/L, l54A/V, L63P, l64V, A71T/V, V82A/F/T, l84V, and L90M), at
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`which substitutions are associated with resistance, have been identified. Resistance was mediated by the
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`co-expression of multiple and variable substitutions at these positions. No single substitution was either
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`necessary or sufficient for measurable resistance (≥4-fold increase in IC95). In general, higher levels of
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`resistance were associated with the co-expression of greater numbers of substitutions, although their
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`individual effects varied and were not additive. At least 3 amino acid substitutions must be present for
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`Reference ID: 3985816
`
`1
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`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2029, Page 1
`
`

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` phenotypic resistance to indinavir to reach measurable levels. In addition, mutations in the p7/ p1 and p1/
` p6 gag cleavage sites were observed in some indinavir resistant HIV-1 isolates.
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` In vitro phenotypic susceptibilities to indinavir were determined for 38 viral isolates from 13 patients
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` who experienced virologic rebounds during indinavir monotherapy. Pre-treatment isolates from five
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`patients exhibited indinavir IC95 values of 50-100 nM. At or following viral RNA rebound (after 12-76
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`weeks of therapy), IC95 values ranged from 25 to >3000 nM, and the viruses carried 2 to 10 mutations in
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`the protease gene relative to baseline.
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`Cross-Resistance to Other Antiviral Agents: Varying degrees of HIV-1 cross-resistance have been
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`observed between indinavir and other HIV-1 protease inhibitors. In studies with ritonavir, saquinavir, and
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`amprenavir, the extent and spectrum of cross-resistance varied with the specific mutational patterns
`observed. In general, the degree of cross-resistance increased with the accumulation of resistance-
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`associated amino acid substitutions. W ithin a panel of 29 viral isolates from indinavir-treated patients that
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`exhibited measurable (≥4-fold) phenotypic resistance to indinavir, all were resistant to ritonavir. Of the
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`indinavir resistant HIV-1 isolates, 63% showed resistance to saquinavir and 81% to amprenavir.
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`CLINICAL PHARMACOLOGY
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`Pharmacokinetics
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`Absorption: Indinavir was rapidly absorbed in the fasted state with a time to peak plasma
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`concentration (Tmax) of 0.8 ± 0.3 hours (mean ± S.D.) (n=11). A greater than dose-proportional increase in
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`indinavir plasma concentrations was observed over the 200-1000 mg dose range. At a dosing regimen of
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`800 mg every 8 hours, steady-state area under the plasma concentration time curve (AUC) was 30,691
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`± 11,407 nM•hour (n=16), peak plasma concentration (Cmax) was 12,617 ± 4037 nM (n=16), and plasma
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`concentration eight hours post dose (trough) was 251 ± 178 nM (n=16).
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`Effect of Food on Oral Absorption: Administration of indinavir with a meal high in calories, fat, and
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`protein (784 kcal, 48.6 g fat, 31.3 g protein) resulted in a 77% ± 8% reduction in AUC and an 84% ± 7%
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`reduction in Cmax (n=10). Administration with lighter meals (e.g., a meal of dry toast with jelly, apple juice,
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`and coffee with skim milk and sugar or a meal of corn flakes, skim milk and sugar) resulted in little or no
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`change in AUC, Cmax or trough concentration.
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`Distribution: Indinavir was approximately 60% bound to human plasma proteins over a concentration
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`range of 81 nM to 16,300 nM.
`Metabolism: Following a 400-mg dose of 14C-indinavir, 83 ± 1% (n=4) and 19 ± 3% (n=6) of the total
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`radioactivity was recovered in feces and urine, respectively; radioactivity due to parent drug in feces and
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`urine was 19.1% and 9.4%, respectively. Seven metabolites have been identified, one glucuronide
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`conjugate and six oxidative metabolites. In vitro studies indicate that cytochrome P-450 3A4 (CYP3A4) is
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`the major enzyme responsible for formation of the oxidative metabolites.
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`Elimination: Less than 20% of indinavir is excreted unchanged in the urine. Mean urinary excretion of
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`unchanged drug was 10.4 ± 4.9% (n=10) and 12.0 ± 4.9% (n=10) following a single 700-mg and 1000-mg
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`dose, respectively. Indinavir was rapidly eliminated with a half-life of 1.8 ± 0.4 hours (n=10). Significant
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`accumulation was not observed after multiple dosing at 800 mg every 8 hours.
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`Special Populations
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`Hepatic Insufficiency: Patients with mild to moderate hepatic insufficiency and clinical evidence of
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`cirrhosis had evidence of decreased metabolism of indinavir resulting in approximately 60% higher mean
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`AUC following a single 400-mg dose (n=12). The half-life of indinavir increased to 2.8 ± 0.5 hours.
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`Indinavir pharmacokinetics have not been studied in patients with severe hepatic insufficiency (see
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`DOSAGE AND ADMINISTRATION, Hepatic Insufficiency).
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`Renal Insufficiency: The pharmacokinetics of indinavir have not been studied in patients with renal
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`insufficiency.
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`Gender: The effect of gender on the pharmacokinetics of indinavir was evaluated in 10 HIV
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`seropositive women who received CRIXIVAN 800 mg every 8 hours with zidovudine 200 mg every 8
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`hours and lamivudine 150 mg twice a day for one week. Indinavir pharmacokinetic parameters in these
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`women were compared to those in HIV seropositive men (pooled historical control data). Differences in
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`indinavir exposure, peak concentrations, and trough concentrations between males and females are
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`shown in Table 1 below:
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`Reference ID: 3985816
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`
`
` 2
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2029, Page 2
`
`

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` PK Parameter
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` AUC 0-8h (nM•hr)
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` Cmax (nM)
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` Table 1
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` % change in PK parameter for females
` relative to males
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` ↓13%
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` ↓13%
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` 90% Confidence Interval
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` (↓32%, ↑12%)
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` (↓32%, ↑10%)
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` C 8h (nM)
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` ↓22%
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` ↓Indicates a decrease in the PK parameter; ↑indicates an increase in the PK parameter.
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` (↓47%, ↑15%)
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` The clinical significance of these gender differences in the pharmacokinetics of indinavir is not known.
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`Race: Pharmacokinetics of indinavir appear to be comparable in Caucasians and Blacks based on
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`pharmacokinetic studies including 42 Caucasians (26 HIV-positive) and 16 Blacks (4 HIV-positive).
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`Pediatric: The optimal dosing regimen for use of indinavir in pediatric patients has not been
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`established. In HIV-infected pediatric patients (age 4-15 years), a dosage regimen of indinavir capsules,
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`500 mg/m2 every 8 hours, produced AUC 0-8hr of 38,742 ± 24,098 nM•hour
`(n=34), Cmax of
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`17,181 ± 9809 nM (n=34), and trough concentrations of 134 ± 91 nM (n=28). The pharmacokinetic
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`profiles of indinavir in pediatric patients were not comparable to profiles previously observed in
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`HIV-infected adults receiving the recommended dose of 800 mg every 8 hours. The AUC and Cmax values
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`were slightly higher and the trough concentrations were considerably lower in pediatric patients.
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`Approximately 50% of the pediatric patients had trough values below 100 nM; whereas, approximately
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`10% of adult patients had trough levels below 100 nM. The relationship between specific trough values
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`and inhibition of HIV replication has not been established.
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`Pregnant Patients: The optimal dosing regimen for use of indinavir in pregnant patients has not been
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`established. A CRIXIVAN dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and
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`lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks
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`of gestation at enrollment (study PACTG 358). The mean indinavir plasma AUC 0-8hr at weeks 30-32 of
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`gestation (n=11) was 9231 nM•hr, which is 74% (95% CI: 50%, 86%) lower than that observed 6 weeks
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`postpartum. Six of these 11 (55%) patients had mean indinavir plasma concentrations 8 hours post-dose
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`(Cmin ) below assay threshold of reliable quantification. The pharmacokinetics of indinavir in these 11
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`patients at 6 weeks postpartum were generally similar to those observed in non-pregnant patients in
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`another study (see PRECAUTIONS, Pregnancy).
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`Drug Interactions: (also see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, Drug Interactions)
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`Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4. Coadministration of CRIXIVAN and
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`drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug,
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`which could increase or prolong its therapeutic and adverse effects (see CONTRAINDICATIONS and
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`WARNINGS). Based on in vitro data in human liver microsomes, indinavir does not inhibit CYP1A2,
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`CYP2C9, CYP2E1 and CYP2B6. However, indinavir may be a weak inhibitor of CYP2D6.
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`Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to
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`the clearance of
`indinavir, resulting
`in
`lowered plasma concentrations of
`indinavir.
`increase
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`Coadministration of CRIXIVAN and other drugs that inhibit CYP3A4 may decrease the clearance of
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`indinavir and may result in increased plasma concentrations of indinavir.
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`Drug interaction studies were performed with CRIXIVAN and other drugs likely to be coadministered
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`and some drugs commonly used as probes
`for pharmacokinetic
`interactions. The effects of
` coadministration of CRIXIVAN on the AUC, C max and C min are summarized in Table 2 (effect of other
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` drugs on indinavir) and Table 3 (effect of indinavir on other drugs). For information regarding clinical
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` recommendations, see Table 9 in PRECAUTIONS.
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` Coadministered drug
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` Cimetidine
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` 400 single dose
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` 12
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` Cmax
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` 1.07
` (0.77, 1.49)
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` Cmin
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` 0.82
` (0.69, 0.99)
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`Reference ID: 3985816
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` 3
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` Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS,
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` Table 9 for Recommended Alterations in Dose or Regimen)
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` Ratio (with/without coadministered drug) of Indinavir
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` Pharmacokinetic Parameters
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` Dose of Coadministered Dose of CRIXIVAN
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` n
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` drug (mg)
` (mg)
` (90% CI); No Effect = 1.00
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` AUC
` 600 twice daily, 6 days
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` 0.98
` (0.81, 1.19)
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`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2029, Page 3
`
`

`

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` Clarithromycin
`
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`
` Delavirdine
`
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` Delavirdine
`
`†
`
`Efavirenz
`
`†
`
`Fluconazole
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`
`
` Grapefruit Juice
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`
`
` Isoniazid
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` Itraconazole
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` Ketoconazole
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`Methadone
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` Quinidine
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` Rifabutin
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` Rifabutin
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` 500 q12h, 7 days
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` 400 three times daily
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` 400 three times daily
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`
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` 600 once daily, 10 days
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` 400 once daily, 8 days
`
` 8 oz.
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`
`
`300 once daily in the
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` morning, 8 days
` 200 twice daily, 7 days
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`
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`
` 400 once daily, 7 days
`
`
`
`400 once daily, 7 days
`
`20-60 once daily in the
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`
` morning, 8 days
` 200 single dose
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`
`
` 800 three times
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`
` daily, 7 days
`
` 400 three times
`
`
` daily, 7 days
`
` 600 three times
`
`
` daily, 7 days
`
` 1000 three times
`
` daily, 10 days
`
`After morning
`
`dose
`After afternoon
`
`dose
`After evening
`
` dose
`
` 1000 three times
`
`
` daily, 7 days
` 400 single dose
`
`
`
` 800 three times
`
`
` daily, 7 days
`
` 600 three times
`
`
` daily, 7 days
`
` 600 three times
`
`
` daily, 7 days
`
`
`400 three times
`
`
` daily, 7 days
`
` 800 three times
`
` daily, 8 days
` 400 single dose
`
`
`
`
` 10
`
`
` 28
`
` 28
`
`
`
`
` 20
`
`
`
`
` 11
`
`
`
` 10
`
`
`
` 11
`
`
`
` 12
`
`
` 12
`
`
`
`12
`
`
`
` 10
`
`
`
` 10
`
`
`
` 14
`
`
`
` 10
`
` 1.19
`
`
`
` (1.00, 1.42)
`
` No significant
`
` change*
`
` 1.53*
`
` (1.07, 2.20)
`
`
`
`
`0.67*
`
` (0.61, 0.74)
`
`
`
`0.63*
`
`
` (0.54, 0.74)
`
`
`0.54*
`
`
`
` (0.46, 0.63)
`
`
`0.76
`
` (0.59, 0.98)
`
` 0.73
` (0.60, 0.87)
`
`
`0.99
`
` (0.87, 1.13)
`
` 0.99*
`
` (0.91, 1.06)
`
` 0.80*
` (0.74, 0.87)
`
`
`
`
` 1.57
`
` 1.08
`
`
` (1.16, 2.12)
`
`
` (0.85, 1.38)
`
` 2.18*
`
` 0.64*
`
` (1.16, 4.12)
` (0.48, 0.86)
`
`
` 3.98*
` No significant
`
` (2.04, 7.78)
`
` change
`
`
`
`
`
`
`
`0.61*
`
`
`No significant
`
`change*
`
` (0.49, 0.76)
`
`
`0.48*
`
`
`
`No significant
`change*
`
`
` (0.43, 0.53)
`
`
`0.43*
`
`
`0.71*
`
` (0.37, 0.50)
`
`
` (0.57, 0.89)
`
`0.90
`
`0.87
`
` (0.72, 1.12)
`
` (0.72, 1.05)
`
` 0.90
`
` 0.65
`
` (0.71, 1.15)
`
`
` (0.53, 0.79)
`
`0.89
`
`0.95
` (0.75, 1.06)
`
` (0.88, 1.03)
`
`
`1.49*
`
`0.78*
`
`
` (1.28, 1.74)
`
`
` (0.69, 0.88)
`
` 1.29*
`
` 0.69*
`
` (1.11, 1.51)
`
` (0.61, 0.78)
`
`
`0.73*
`0.44*
`0.42*
`
`
`
`
` (0.62, 0.85)
` (0.41, 0.48)
` (0.37, 0.47)
`
`
`
`
` See text below for discussion of interaction.
`
`
`
`
`
`
` 800 Trimethoprim/
`
`
` 160 Sulfamethoxazole
` q12h, 7 days
`
`
` 1.06
`
`
` 1000 three times
`
` 200 three times daily, 7
`
` (0.91, 1.25)
`
`
`
` days
` daily, 7 days
`
` 1.05
`
` 800 three times
`
` 200/150 three times
`Zidovudine/Lamivudine
`†
`
` (0.83, 1.33)
`
`
`
`
` daily, 7 days
` daily, 7 days
`
`(3TC)
`
`
` All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
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`
`
` * Relative to indinavir 800 mg three times daily alone.
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` † Study conducted in HIV-positive subjects.
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` ‡ Comparison to historical data on 16 subjects receiving indinavir alone.
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`
`
`
` § 95% CI.
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`¶ Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.
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` See text below for discussion of interaction.
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`
` Not Available
`
` 0.95
`
`
` (0.80, 1.11)
`
` 1.12
` (0.87, 1.46)
`
`
`0.19
`
`§
`(0.06, 0.33)
`
`
`
`1.13
`
`
` (0.83, 1.53)
`
`0.83
` (0.72, 0.95)
`
`
` 1.02
`
`
` (0.77, 1.35)
`
` 0.98
` (0.56, 1.73)
`
`
`
` 0.46
`
`§
`
`
`(0.34, 0.58)
`
`0.95
`
`
` (0.80, 1.12)
`
`0.98
` (0.81, 1.18)
`
`
` 1.05
`
`
` (0.86, 1.28)
`
` 1.04
` (0.67, 1.61)
`
`
`
`
`
`
`
`
`1.07
`0.96
`
` (0.89, 1.28)
`
` (0.79, 1.18)
`
`0.68
`
` 0.80
`
` (0.60, 0.76)
` (0.72, 0.89)
`
`
`
` 0.66
`0.75
`
`
` (0.56, 0.77)
`
` (0.61, 0.91)
`
`0.08
`
` 0.13
` (0.06, 0.11)
` (0.08, 0.22)
`
`
`
` See text below for discussion of interaction.
`
`
` 0.93
`
`
`
` (0.73, 1.19)
`
`0.60
`
` (0.51, 0.72)
`
` 0.61
`
` (0.50, 0.75)
`
` Not Done
`
`
`
`
`
`
`
` See text below for discussion of interaction.
`
`
`
`
`
`
`
` Rifampin
`
`
`
` Ritonavir
`
`
`
` Ritonavir
`
`
`
` Sildenafil
`
` St. John’s wort
`
`
`(Hypericum perforatum,
`
` standardized to 0.3 %
`
` hypericin)
`†
`
`Stavudine (d4T)
`
`150 once daily in the
`
` morning, 10 days
`300 once daily in the
`
` morning, 10 days
`600 once daily in the
`
`
` morning, 8 days
` 100 twice daily, 14 days
`
`
`
`
`
` 200 twice daily, 14 days
`
`
`
`
`
` 25 single dose
`
`
`
` 300 three times daily
`
` with meals, 14 days
`
`
`
` 40 twice daily, 7 days
`
` Trimethoprim/
`
` Sulfamethoxazole
`
`
`Zidovudine
`
`†
`
`
`
` 800 three times
`
` daily, 10 days
`
` 800 three times
`
` daily, 10 days
`
` 800 three times
`
` daily, 7 days
`
` 800 twice daily,
`
` 14 days
`
` 800 twice daily,
`
` 14 days
`
` 800 three times
`
` daily
`
` 800 three times
`
` daily
`
`
` 800 three times
`
`
` daily, 7 days
`
` 400 four times
`
`
` daily, 7 days
`
`
`
`
`
`
`
` 12
`
`‡
`
`10, 16
`‡
`
`9, 16
`
`
`
` 6
`
`
`
` 8
`
`
`
` 11
`
`
`
` 12
`
`
`
` 12
`
`¶
`
`6, 9
`
`
`
`
`
`Reference ID: 3985816
`
`
`
` 4
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2029, Page 4
`
`

`

`
`
`
`
`
`
`
`
` Coadministered drug
`
`
`
`
` Clarithromycin
`
`
`
`
`
` Efavirenz
`
` Ethinyl Estradiol
`
`*
`(ORTHO-NOVUM 1/35)
`
`
` Isoniazid
`
`†
`
`Methadone
`
` Norethindrone
`
`*
`(ORTHO-NOVUM 1/35)
`
`
` Rifabutin
`
`
`
` 150 mg once daily in the
` morning, 11 days +
`
`
` indinavir compared to
`
` 300 mg once daily in the
`
`
` morning, 11 days alone
`
`
`
`
`Ritonavir
`
`
`
`
`
`
`
` Saquinavir
`
` Hard gel formulation
`
`
`
`
`
`
`Soft gel formulation
`
`
`
`Soft gel formulation
`
`
` 200 once daily, 14
`
` days
` 35 mcg, 8 days
`
`
`300 once daily in the
`
`
` morning, 8 days
` 20-60 once daily in
`
` the morning, 8 days
`
`
`
` 1 mcg, 8 days
`
`150 once daily in the
`
`morning, 10 days
`
`
`300 once daily in the
`
`morning, 10 days
`
`
` 100 twice daily, 14
`
` days
`
`
` 200 twice daily, 14
`
` days
`
`
`
`
`
`600 single dose
`
`
`800 single dose
`
`
`
`1200 single dose
`
`
`
`
` 800 three times
`
`
` daily, 14 days
`
` 800 three times
`
`
` daily, 8 days
`
` 800 three times
`
`
` daily, 8 days
` 800 three times
`
`
` daily, 8 days
`
`
`
` 800 three times
`
`
` daily, 8 days
`
` 800 three times
`
` daily, 10 days
`
`
`
`800 three times
`
`daily, 10 days
`
`
` 800 twice daily,
`
` 14 days
`
`
` 800 twice daily,
`
` 14 days
`
`
`
`800 three times
`
`daily, 2 days
`
`
`
`800 three times
`
`daily, 2 days
`
`
`
`800 three times
`
`daily, 2 days
`
`
`
` Sildenafil
`
` 25 single dose
`
`
`
` 20
`
`
`
` 18
`
`
`
` 11
`
`
`
` 12
`
`
`
` 18
`
`
` 14
`
`
`
`
`10
`
`‡
`
`10, 4
`
`
`
`‡
`
`9, 5
`
`
`
`
` 6
`
`
`
`6
`
`
`
`6
`
`
` 6
`
` Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9
`
`
`
`
`
` for Recommended Alterations in Dose or Regimen)
` Dose of
` Ratio (with/without CRIXIVAN) of Coadministered Drug
`
`
`
`
`
` Coadministered drug Dose of CRIXIVAN
`
`
` Pharmacokinetic Parameters
`
`
` n
`
`
`
` (mg)
` (mg)
` (90% CI); No Effect = 1.00
`
` AUC
`
` 1.47
` (1.30, 1.65)
`
`
`
`
`
`
`
` 500 twice daily, 7
`
` days
`
`
` 800 three times
`
`
` daily, 7 days
`
`
`
`
`
`
`
` 12
`
`
`
`
` Cmax
`
`1.19
`
` (1.02, 1.39)
`
` No significant
`
` change
`
` 1.02
`
` (0.96, 1.09)
`
`1.34
`
` (1.12, 1.60)
`
`0.93
`
` (0.84, 1.03)
`
`1.05
`
` (0.95, 1.16)
`
`1.29
`
` (1.05, 1.59)
`
`
`
`2.34
`
`(1.64, 3.35)
`
`1.61
`
`
` (1.13, 2.29)
`
` 1.19
`
`
` (0.85, 1.66)
`
`
`
`4.7
`
`
` (2.7, 8.1)
`
`
`6.5
`
`(4.7, 9.1)
`
`
`4.0
`
`(2.7, 5.9)
`
`
` No significant
`
` change
`
` 1.22
`
` (1.15, 1.30)
`
`1.12
`
` (1.03, 1.22)
`
`0.96
`
` (0.86, 1.06)
`
`1.26
`
` (1.20, 1.31)
`
`1.54
`
` (1.33, 1.79)
`
`
`
`2.73
`
`(1.99, 3.77)
`
`1.72
`
`
` (1.20, 2.48)
`
`1.96
`
` (1.39, 2.76)
`
`
`
`
`6.0
`
` (4.0, 9.1)
`
`
`
`7.2
`
`(4.3, 11.9)
`
`
`4.6
`
`(3.2, 6.7)
`
`
`
`
` Cmin
`
`1.97
`
` (1.58, 2.46)
`
` n=11
`
`--
`
`§
`
`
`§
`
`
`
`
`
`
` 1.37
`
`
` (1.24, 1.51)
`
`1.00
`
` (0.92, 1.08)
`
` 1.06
`
`
` (0.94, 1.19)
`
`1.44
`
` (1.32, 1.57)
`
`1.99
`
`(1.71, 2.31)
`n=13
`
`
`3.44
`
`(2.65, 4.46)
`
`
` n=9
`1.62
`
`
` (0.93, 2.85)
`
`4.71
`
`
` (2.66, 8.33)
`
` n=9, 4
`
`
`2.9
`
`(1.7, 4.7)
`
`5.5
`
`§
`(2.2, 14.1)
`
`
`5.5
`
`(3.7, 8.3)
`
` See text below for discussion of interaction.
`
`0.86
`
`
` (0.73, 1.03)
`
`0.88
`
` (0.76, 1.03)
`
`
`
`
`1.18
`
`
` (1.05, 1.32)
`
`
`
`
`1.01
`
`(0.95, 1.08)
`
`
`1.21
`
`
` (1.09, 1.33)
`
`1.14
`
` (1.04, 1.24)
`
`
`
`
`1.18
`
` (1.05, 1.33)
`
`
`
`
`
`1.05
`
`(1.01, 1.09)
`
`
`
`
` Not Done
`
`1.13
`
` (0.86, 1.49)
`
` n=7, 3
`
`
`
`1.18
`
`
` (1.00, 1.39)
`
`
`
`
`1.05
`
`(0.97, 1.14)
`
`
` See text below for discussion of interaction.
`
`
`
`
`
`
`
` 0.89
`
`
`
` (0.73, 1.09)
`
`
`
` 1.23
`
`
`
` (0.74, 2.03)
`
`
` 1.17
`
`
` (1.07, 1.29)
`
`
`
`
`
` 1.39
`
`
` (1.02, 1.89)
`
`
`
`
`1.51
`
`
` (0.71, 3.20)
`
` n=4
`
`
`1.08
`
`
` (0.77, 1.50)
`
` n=5, 5
`
`
`
`Stavudine
`
`¶
`
`
`
`
` Theophylline
`
` Trimethoprim/
`
` Sulfamethoxazole
`
`
`
`
`
` Trimethoprim
`
`
` Trimethoprim/
`
` Sulfamethoxazole
`
`
`
`Sulfamethoxazole
`
`
`
`
` Vardenafil
`
`¶
`
`Zidovudine
`
`¶
`
`Zidovudine/Lamivudine
`
`
`Zidovudine
`
`
`
`
`
`
`
`
`
`
`
`
` 40 twice daily, 7 days
`
` 250 single dose
`
` (on Days 1 and 7)
`
`
`
`
`
` 800 Trimethoprim/
`
`160 Sulfamethoxazole
`
`
` q12h, 7 days
`
`
`
`800 Trimethoprim/
`
`160 Sulfamethoxazole
`
`
` q12h, 7 days
` 10 single dose
`
`
`
`
`
`
`
`
`
`
` 200 three times daily,
`
` 7 days
`
`
`
`
` 200/150 three times
`
`
` daily, 7 days
`
`
` 800 three times
`
` daily
`
` 800 three times
`
`
` daily, 7 days
`
` 800 three times
`
`
` daily, 6 days
` (Days 2 to 7)
`
`
`
`
` 400 q6h, 7 days
`
`
`
`
`
`
`
`
`400 q6h, 7 days
`
`
`
`
` 800 three times
`
` daily
`
` 1000 three times
`
`
` daily, 7 days
`
`
`
`
` 800 three times
`
`
` daily, 7 days
`
`
`
`
`
` 13
`
`‡
`
`12, 4
`
`
`
`
` 12
`
`
`
`
`
`
`12
`
`
`
`
` 18
`
`
`
` 12
`
`
`
`‡
`6, 7
`
`
`
`
` 5
`
`Reference ID: 3985816
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2029, Page 5
`
`

`

`
`
` Lamivudine
`
`
`
`
`
`
`
`0.73
`
`
`
`800 three times
`200/150 three times
`
` (0.52, 1.02)
`
`
`
`
` daily, 7 days
` daily, 7 days
`
` All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
`
`
`
`
`
` * Registered trademark of Ortho Pharmaceutical Corporation.
`† Study conducted in subjects on methadone maintenance.
`
`
`
`
` ‡ Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.
`
`
`§ C 6hr
`
` ¶ Study conducted in HIV-positive subjects.
`
`
`Delavirdine: Delavirdine inhibits the metabolism of indinavir such that coadministration of 400-mg or
`
`
`
`
`600-mg indinavir three times daily with 400-mg delavirdine three times daily alters indinavir AUC, C max
`
`
`
`
`and Cmin (see Table 2). Indinavir had no effect on delavirdine pharmacokinetics (see DOSAGE AND
`
`
`
`ADMINISTRATION, Concomitant Therapy, Delavirdine), based on a comparison to historical delavirdine
`
`
`
`
`
`
`
`pharmacokinetic data.
`
`Methadone: Administration of indinavir (800 mg every 8 hours) with methadone (20 mg to 60 mg daily)
`
`
`
`
`for one week in subjects on methadone maintenance resulted in no change in methadone AUC. Based on
`
`
`
`
`
`a comparison to historical data, there was little or no change in indinavir AUC.
`
`
`Ritonavir: Compared to historical data in patients who received indinavir 800 mg every 8 hours alone,
`
`
`
`
`
`
`
`twice-daily coadministration to volunteers of indinavir 800 mg and ritonavir with food for two weeks
`
`
`
`resulted in a 2.7-fold increase of indinavir AUC 24h, a 1.6-fold increase in indinavir C max , and an 11-fold
`
`increase in indinavir C min for a 100-mg ritonavir dose and a 3.6-fold increase of indinavir AUC 24h, a 1.8­
`
`
`
`
`
`
`
`
`fold increase in indinavir C max , and a 24-fold increase in indinavir C min for a 200-mg ritonavir dose. In the
`
`
`
`
`
`
`
`
`
`same study, twice-daily coadministration of indinavir (800 mg) and ritonavir (100 or 200 mg) resulted in
`
`
`
`
`
`
`
`
`
`
`ritonavir AUC 24h increases versus the same doses of ritonavir alone (see Table 3).
`
`
`
`
`Sildenafil: The results of one published study in HIV-infected men (n=6) indicated that coadministration
`
`
`
`of indinavir (800 mg every 8 hours chronically) with a single 25-mg dose of sildenafil resulted in an 11%
`
`
`
`
`
`
`
`
`
`
`increase in average AUC 0-8hr of indinavir and a 48% increase in average indinavir peak concentration
`
`(Cmax) compared to 800 mg every 8 hours alone. Average sildenafil AUC was increased by 340%
`
`
`
`
`
`following coadministration of sildenafil and indinavir compared to historical data following administration of
`
`sildenafil alone (see CONTRAINDICATIONS, WARNINGS, Drug Interactions and PRECAUTIONS, Drug
`
`
`
`
`
`Interactions).
`
`Vardenafil: Indinavir (800 mg every 8 hours) coadministered with a single 10-mg dose of vardenafil
`
`
`
`
`resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C max , and a 2-fold increase
`
`in vardenafil half-life (see WARNINGS, Drug Interactions and PRECAUTIONS, Drug Interactions).
`
`
`
`
`
`¶
`Zidovudine/Lamivudine
`
`
`
`
`
`
`‡
`
`6, 7
`
`
`
`
`
` 0.91
`
`
` (0.66, 1.26)
`
`
`
`
`
`0.88
`
`
` (0.59, 1.33)
`
`
`
`INDICATIONS AND USAGE
`
`
`CRIXIVAN in combination with antiretroviral agents is indicated for the treatment of HIV infection.
`
`
`
`
`This indication is based on two clinical trials of approximately 1 year duration that demonstrated: 1) a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`reduction in the risk of AIDS-defining illnesses or death; 2) a prolonged suppression of HIV RNA.
`
`
`Description of Studies
`
`In all clinical studies, with the exception of ACTG 320, the AMPLICOR HIV MONITOR assay was used
`
`
`
`
`
`to determine the level of circulating HIV RNA in serum. This is an experimental use of the assay. HIV
`
`
`
`
`RNA results should not be directly compared to results from other trials using different HIV RNA assays or
`
`
`using other sample sources.
`
`Study ACTG 320 was a multicenter, randomized, double-blind clinical endpoint trial to compare the
`
`
`
`effect of CRIXIVAN in combination with zidovudine and lamivudine with that of zidovudine plus lamivudine
`
`
`
`
`
`
`on the progression to an AIDS-defining illness (ADI) or death. Patients were protease inhibitor and
`
`
`lamivudine naive and zidovudine experienced, with CD4 cell counts of ≤200 cells/mm3. The study enrolled
`
`
`
`
`1156 HIV-infected patients (17% female, 28% Black, 18% Hispanic, mean age 39 years). The mean
`
`baseline CD4 cell count was 87 cells/mm3. The mean baseline HIV RNA was 4.95 log10 copies/mL
`
`
`
`
`
`
`(89,035 copies/mL). The study was terminated after a planned interim analysis, resulting in a median
`
`
`
`
`follow-up of 38 weeks and a maximum follow-up of 52 weeks. Results are shown in Table 4 and Figures 1
`
`
`
`
`
`& 2.
`
`
`
`
`
`
`
`
`Reference ID: 3985816
`
`
`
` 6
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2029, Page 6
`
`

`

`
`
` Table 4: ACTG 320
` Number (%) of Patients with AIDS-defining Illness or Death
`
`
` IDV+ZDV+L
`
` ZDV+L
`
`(n=579)
`(n=577)
`
`
`
` 35 (6.1)
`
`
`
`
`HIV
`
`
` Death
`
` 19 (3.3)
` 10 (1.7)
`
`
`
` Death*
` * The number of deaths is inadequate to assess the impact of Indinavir on survival.
`
`
`
`
` IDV = Indinavir, ZDV = Zidovudine, L = Lamivudine
`
`
`
`
`
`
`
`
`
` Endpoint
`
`Progression
`
`
`
` or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3985816
`
`
`
`
`
`
`
`
`
` 63 (10.9)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 7
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2029, Page 7
`
`

`

` Study 028, a double-blind, multicenter, randomized, clinical endpoint trial conducted in Brazil,
`
`
`
`
`
`
` compared the effects of CRIXIVAN plus zidovudine with those of CRIXIVAN alone or zidovudine alone on
` the progression to an ADI or death, and on surrogate marker responses. All patients were antiretroviral
`
`
`
`
`
`
`
`
`
` naive with CD4 cell counts of 50 to 250 cells/mm3. The study enrolled 996 HIV-1 seropositive patients
`
`
`
`
`[28% female, 11% Black, 1% Asian/Other, median age 33 years, mean baseline CD4 cell count of
`
`
`
`
`
`
`
`
`
`
`
`
`152 cells/mm3, mean serum viral RNA of 4.44 log10 copies/mL (27,824 copies/mL)]. Treatment regimens
`
`
`containing zidovudine were modified in a blinded manner with the optional addition of lamivudine (median
`
`
`
`
`
`
`
`
`
`time: week 40). The median length of follow-up was 56 weeks with a maximum of 97 weeks. The study
`
`
`was terminated after a planned interim analysis, resulting in a median follow-up of 56 weeks and a
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`maximum follow-up of 97 weeks. Results are shown in Table 5 and Figures 3 and 4.
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` Table 5: Protocol 028
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` Number (%) of Patients with AIDS-defining Illness or Death
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` IDV+ZDV
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` IDV
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` ZDV
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` (n=332)
` (n=332)
` (n=332)
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` 27 (8.1)
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` 21 (6.3)
` HIV Progression or Death
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` 5 (1.5)
` 8 (2.4)
` Death*
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` * The number of deaths is inadequate to assess the impact of Indinavir on survival.
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` Endpoint
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`Reference ID: 3985816
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` 62 (18.7)
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` 11 (3.3)
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` 8
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2029, Page 8
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`

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` Study 035 was a multicenter, randomized trial in 97 HIV-1 seropositive patients who were zidovudine­
` experienced (median exposure 30 months), protease-inhibitor- and lamivudine-naive, with mean baseline
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`CD4 count 175 cells/mm3 and mean baseline serum viral RNA 4.62 log10 copies/mL (41,230 copies/mL).
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`Comparisons included CRIXIVAN plus zidovudine plus lamivudine vs. CRIXIVAN alone vs. zidovudine
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`plus lamivudine. After at least 24 weeks of randomized, double-blind therapy, patients were switched to
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`open-label CRIXIVAN plus lamivudine plus zidovudine. Mean changes in log10 viral RNA in serum, the
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`proportions of patients with viral RNA below 500 copies/mL in serum, and mean changes in CD4 cell
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`counts, during 24 weeks of randomized, double-blinded therapy are summarized in Figures 5, 6, and 7,
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`respectively. A limited number of patients remained on randomized, double-blind treatment for longer
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`periods; based on this extended treatment experience, it appears that a greater number of subjects
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`randomized to CRIXIVAN plus zidovudine plus lamivudine demonstrated HIV RNA levels below
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`500 copies/mL during one year of therapy as compared to those in other treatment groups.
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`Reference ID: 3985816
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` 9
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2029, Page 9
`
`

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`Genotypic Resistance in Clinical Studies
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`Study 006 (10/15/93-10/12/94) was a dose-ranging study in which patients were initially treated with
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`CRIXIVAN at a dose of <2.4 g/day followed by 2.4 g/day. Study 019 (6/23/94-4/10/95) was a randomized
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`comparison of CRIXIVAN 600 mg every 6 hours, CRIXIVAN plus zidovudine, and zidovudine alone.
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`Table 6 shows the incidence of genotypic resistance at 24 weeks in these studies.
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`Reference ID: 3985816
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` 10
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2029, Page 10
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`

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` Treatment Group
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