PRODUCT INFORMATION
`
`AGENERASETM
`
`(amprenavir)
`
`Capsules
`
`AGENERASETM
`
`(amprenavir)
`
`Oral Solution
`
`AGENERASE (amprenavir) in combination with other antiretroviral agents is indicated for the treatment of
`
`HIV-1 infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in
`
`controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials
`
`evaluating long-term suppression of HIV RNA or disease progression with AGENERASE.
`
`DESCRIPTION: AGENERASE (amprenavir)is an inhibitor of the human immunodeficiency virus (HIV)
`
`protease. The chemical name of amprenavir is (3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-N-
`
`isobutylbenzenesulfonamido)-l-benzyl-2-hydroxypropyl]carbamate. Amprenavir is a single stereoisomer
`
`with the (3S)(1S,2R) configuration. It has a molecular formula of 025H35N306S and a molecular weight of
`
`505.64. It has the following structural formula:
`
`NH2
`
`0
`
`0
`
`-
`OH
`
`Amprenavir is a white to cream-colored solid with a solubility of approximately 0.04 mg/mL in water at
`
`25oc.
`
`AGENERASE Capsules are available for oral administration in strengths of 50 and 150 mg. Each
`
`capsule contains the inactive ingredients d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS),
`
`polyethylene glycol 400 (PEG 400), and propylene glycol. The capsule shell contains the inactive
`
`ingredients d-sorbitol and sorbitans solution, gelatin, glycerin, and titanium dioxide. The solt gelatin
`
`capsules are printed with edible red ink. Each 150-mg AGENERASE Capsule contains 109 IU vitamin E
`
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
`
`in the form of d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS). The total amount of vitamin
`
`E in the recommended daily adult dose of AGENERASE is 1744 IU.
`
`AGENERASE Oral Solution is for oral administration. One milliliter (1 mL) of AGENERASE Oral Solution
`
`contains 15 mg of amprenavir in solution and the inactive ingredients acesulfame potassium, artificial
`
`grape bubblegum flavor, citric acid (anhydrous), TPGS, menthol, natural peppermint flavor, polyethylene
`
`glycol 400 (PEG 400), propylene glycol, saccharin sodium, sodium chloride, and sodium citrate
`
`(dihydrate). Solutions of sodium hydroxide and/or diluted hydrochloric acid may have been added to
`
`adjust pH. Each mL of AGENERASE Oral Solution contains 46 IU vitamin E in the form of d-alpha
`
`tocopheryl polyethylene glycol 1000 succinate.
`
`MICROBIOLOGY:
`
`Mechanism of Action: Amprenavir is an inhibitor of HIV-1 protease. Amprenavir binds to the active site
`
`of HIV-1 protease and thereby prevents the processing of viral gag and gag-pol polyprotein precursors,
`
`resulting in the formation of immature non-infectious viral particles.
`
`Antiviral Activity in Vitro: The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in
`
`both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral
`
`blood lymphocytes. The 50% inhibitory concentration (IC5o) of amprenavir ranged from 0.012 to 0.08 I~M
`
`in acutely infected cells and was 0.41 I~M in chronically infected cells (1 I~M = 0.50 mcg/mL). Amprenavir
`
`exhibited synergistic anti-HIV-1 activity in combination with abacavir, zidovudine, didanosine, or
`
`saquinavir, and additive anti-HIV-1 activity in combination with indinavir, nelfinavir, and ritonavir in vitro.
`
`These drug combinations have not been adequately studied in humans. The relationship between in vitro
`
`anti-HIV-1 activity of amprenavir and the inhibition of HIV-1 replication in humans has not been defined.
`
`Resistance: HIV-1 isolates with a decreased susceptibility to amprenavir have been selected in vitro and
`
`were also obtained from patients treated with amprenavir. Genotypic analysis of isolates from
`
`amprenavir-treated patients showed mutations in the HIV-1 protease gene resulting in amino acid
`
`substitutions primarily at positions M46]/L, ]47V, ]50V, ]54L/V, and ]84V as well as mutations in the viral
`
`protease pl/p6 cleavage site. Phenotypic analysis of HIV-1 isolates from some patients on amprenavir
`
`monotherapy for 8 to 12 weeks showed a 5- to 10-fold decrease in susceptibility to amprenavir in vitro
`
`compared to baseline. Phenotypic analysis of HIV-1 isolates from 28 patients treated with amprenavir in
`
`combination with zidovudine and lamivudine for 16 to 36 weeks identified isolates from six patients that
`
`exhibited a 5- to 11-fold decrease in susceptibility to amprenavir in vitro compared to wild-type virus.
`
`Clinical isolates that exhibited a decrease in amprenavir susceptibility harbored amprenavir-associated
`
`mutations. The clinical relevance of the genotypic and phenotypic changes associated with amprenavir
`
`therapy has not been established.
`
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
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`Cross-Resistance: Varying degrees of HIV-1 cross-resistance among protease inhibitors have been
`
`observed. The potential for protease inhibitor cross-resistance in HIV-1 isolates from amprenavir-treated
`
`patients has not been fully evaluated.
`
`CLINICAL PHARMACOLOGY:
`
`Pharmacokinetics in Adults: The pharmacokinetic properties of amprenavir have been studied in
`
`asymptomatic, HIV-infected adult patients after administration of single oral doses of 150 to 1200 mg and
`
`multiple oral doses of 300 to 1200 mg twice daily.
`
`Absorption and Bioavailability: Amprenavir was rapidly absorbed after oral administration in
`
`HIV-l-infected patients with a time to peak concentration (tm~) typically between 1 and 2 hours after a
`
`single oral dose. The absolute oral bioavailability of amprenavir in humans has not been established.
`
`Increases in the area under the plasma concentration versus time curve (AUC) after single oral doses
`
`between 150 and 1200 mg were slightly greater than dose-proportional. Increases in AUC were
`
`dose-proportional after 3 weeks of dosing with doses from 300 to 1200 mg twice daily. The
`
`pharmacokinetic parameters after administration of amprenavir 1200 mg b.i.d, for 3 weeks to HIV-infected
`
`subjects are shown in Table 1.
`
`Table 1 : Average (%CV) Pharmacokinetic Parameters After 1200 mg b.i.d, of Amprenavir (n = 5)
`
`Cmax
`
`(mcg/mL)
`
`5.36
`
`(62%)
`
`trnax
`
`(hours)
`
`1.9
`
`(51%)
`
`AUCo-12
`
`Cavg
`
`Cmin
`
`CL/F
`
`(mcgoh/mL)
`
`(mcg/mL)
`
`(mcg/mL)
`
`(mL/min/kg)
`
`18.5
`
`(63%)
`
`1.54
`
`(63%)
`
`0.28
`
`(52%)
`
`31
`
`(132%)
`
`The relative bioavailability of AGENERASE Capsules and Oral Solution was assessed in healthy
`
`adults. AGENERASE Oral Solution was 14% less bioavailable compared to the capsules.
`
`Effects of Food on Oral Absorption: The relative bioavailability of AGENERASE Capsules was
`
`assessed in the fasting and fed states in healthy volunteers (standardized high-fat meal: 967 kcal,
`
`67 grams fat, 33 grams protein, 58 grams carbohydrate). Administration of a single 1200-mg dose of
`
`amprenavir in the fed state compared to the fasted state was associated with changes in C~a× (fed:
`
`6.18 + 2.92 mcg/mL, fasted: 9.72 + 2.75 mcg/mL), t~ (fed: 1.51 + 0.68, fasted: 1.05 + 0.63), and AUCo_oo
`
`(fed: 22.06 + 11.6 mcgoh/mL, fasted: 28.05 + 10.1 mcgoh/mL). AGENERASE may be taken with or
`
`without food, but should not be taken with a high fat meal (see DOSAGE AND ADMINISTRATION).
`
`Distribution: The apparent volume of distribution (Vz/F) is approximately 430 L in healthy adult
`
`subjects. In vitro binding is approximately 90% to plasma proteins. The high affinity binding protein for
`
`amprenavir is alphal-acid glycoprotein (AAG). The partitioning of amprenavir into erythrocytes is low, but
`
`3
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
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`increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher
`
`concentrations.
`
`Metabolism: Amprenavir is metabolized in the liver by the cytochrome P450 CYP3A4 enzyme system.
`
`The two major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide
`
`conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.
`
`Elimination: Excretion of unchanged amprenavir in urine and feces is minimal. Approximately 14%
`
`and 75% of an administered single dose of 14C-amprenavir can be accounted for as radiocarbon in urine
`
`and feces, respectively. Two metabolites accounted for >90% of the radiocarbon in fecal samples. The
`
`plasma elimination half-life of amprenavir ranged from 7.1 to 10.6 hours.
`
`Special Populations: Hepatic Insufficiency: AGENERASE has been studied in adult patients with
`
`impaired hepatic function using a single 600-mg oral dose. The AUCo_oo was significantly greater in
`
`patients with moderate cirrhosis (25.76 + 14.68 mcgoh/mL) compared with healthy volunteers
`
`(12.00 + 4.38 mcgoh/mL). The AUCo_oo and C~na× were significantly greater in patients with severe cirrhosis
`
`(AUCo_oo: 38.66 + 16.08 mcgoh/mL; C~n~: 9.43 + 2.61 mcg/mL) compared with healthy volunteers
`
`(AUCo_oo: 12.00 + 4.38 mcgoh/mL; C~n~: 4.90 + 1.39 mcg/mL). Patients with impaired hepatic function
`
`require dosage adjustment (see DOSAGE AND ADMINISTRATION).
`
`Renal insufficiency: The impact of renal impairment on amprenavir elimination in adult patients has
`
`not been studied. The renal elimination of unchanged amprenavir represents <3% of the administered
`
`dose.
`
`Pediatric Patients: The pharmacokinetics of amprenavir have been studied after either single or
`
`repeat doses of AGENERASE in 84 pediatric patients. Twenty HIV-l-infected children ranging in age
`
`from 4 to 12 years received single doses from 5 mg/kg to 20 mg/kg using 25-mg or 150-mg capsules. The
`
`C~na× of amprenavir increased less than proportionally with dose. The AUCo_oo increased proportionally at
`
`doses between 5 and 20 mg/kg. Amprenavir is 14% less bioavailable from the liquid formulation than from
`
`the capsules; therefore AGENERASE Capsules and AGENERASE Oral Solution are not
`
`interchangeable on a milligram per milligram basis.
`
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
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`Table 2: Average (%CV) Pharmacokinetic Parameters in Children Ages 4 to 12 Years Receiving
`
`20 mg/kg b.i.d, or 15 mg/kg t.i.d, of AGENERASE Oral Solution
`
`Cmax
`
`Dose
`
`n
`
`(mcg/mL)
`
`20 mg/kg
`
`b.i.d.
`
`20
`
`15 mg/kg
`
`t.i.d.
`
`17
`
`6.77
`
`(51%)
`
`3.99
`
`(37%)
`
`trnax
`
`(hours)
`
`1.1
`
`(21%)
`
`1.4
`
`(90%)
`
`AUCss*
`
`Cavg
`
`Cmin
`
`CL/F
`
`(mcgoh/mL)
`
`(mcg/mL)
`
`(mcg/mL)
`
`(mL/min/kg)
`
`15.46
`
`(59%)
`
`8.73
`
`(36%)
`
`1.29
`
`(59%)
`
`1.09
`
`(36%)
`
`0.24
`
`(98%)
`
`0.27
`
`(95%)
`
`29
`
`(58%)
`
`32
`
`(34%)
`
`*AUC is 0 to 12 hours for b.i.d, and 0 to 8 hours fort.i.d., therefore the Cavg is a better comparison of the
`
`exposures.
`
`Geriatric Patients: The pharmacokinetics of amprenavir have not been studied in patients over
`
`65 years of age.
`
`Gender: The pharmacokinetics of amprenavir do not differ between males and females.
`
`Race: The pharmacokinetics of amprenavir do not differ between Blacks and non-Blacks.
`
`Drug Interactions: See also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug
`
`Interactions.
`
`Amprenavir is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits
`
`CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or
`
`inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Amprenavir does
`
`not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1, or uridine glucuronosyltransferase
`
`(UDPGT).
`
`Drug interaction studies were performed with amprenavir and other drugs likely to be coadministered
`
`or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of
`
`amprenavir on the AUC, Cma×, and Cmin are summarized in Table 3 (effect of other drugs on amprenavir)
`
`and Table 4 (effect of amprenavir on other drugs). For information regarding clinical recommendations,
`
`see PRECAUTIONS.
`
`5
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
`
`Table 3: Drug Interactions: Pharmacokinetic Parameters for Amprenavir
`in the Presence of the Coadministered Drug
`
`% Change in Amprenavir Pharmacokinetic
`Parameters*
`(90% CI)
`AUC
`m29
`(¢18 to ~103)
`m18
`(~8 to ~29)
`
`Cmax
`~47
`(4~15 to ~154)
`~15
`(~1 to ~31)
`
`Groin
`m27
`(4~46 to ~197)
`m39
`(~31 to ~47)
`
`Co-
`administered
`Drug
`
`Abacavir
`
`Clarithromycin
`
`Indinavir
`
`Ketoconazole
`
`Lamivudine
`
`Nelfinavir
`
`Rifabutin
`
`Rifampin
`
`Saquinavir
`
`n
`
`4
`
`12
`
`9
`
`12
`
`11
`
`6
`
`5
`
`11
`
`7
`
`Dose of
`Dose of
`Coadministered
`AGENERASE
`Drug
`900 mg b.i.d.
`300 mg b.i.d.
`for 3 weeks
`for 3 weeks
`1200 mg b.i.d.
`500 mg b.i.d.
`for4 days
`for 4 days
`750 or 800 mg
`800 mg t.i.d.
`t.i.d, for 2 weeks
`for 2 weeks
`(fasted)
`(fasted)
`1200 mg
`400 mg
`single dose
`single dose
`600 mg
`150 mg
`single dose
`single dose
`750 or 800 mg
`750 mg t.i.d.
`t.i.d, for 2 weeks
`for 2 weeks
`(fed)
`(fed)
`1200 mg b.i.d.
`300 mg q.d.
`for 10 days
`for 10 days
`1200 mg b.i.d.
`300 mg
`for 4 days
`q.d. for 4 days
`750 or 800 mg
`800 mg t.i.d.
`t.i.d, for 2 weeks
`for 2 weeks
`(fed)
`(fed)
`600 mg
`300 mg
`single dose
`single dose
`Zidovudine
`*Based on total-drug concentrations.
`1" = Increase; 4, = Decrease; <=> = No change (1" or 4,<10%); NA = Cmin not calculated for single-dose
`study.
`
`~18
`(4~13 to ~58)
`4~16
`(4~25 to 4~6)
`
`(4~17 to ~9)
`
`4~14
`(¢38 to ~20)
`
`(4~21 to ~10)
`4~70
`(4~76 to 4~62)
`
`4~37
`(4~54 to 4~14)
`
`~I’25
`(4~27 to ~116)
`
`NA
`
`NA
`
`(¢19 to ~I’47)
`4~15
`(¢28 to 0)
`4~82
`(¢84 to ¢78)
`
`4~32
`(4~49 to 4~9)
`m13
`(4~2 to ~31)
`
`m189
`(~I’52 to ~I’448)
`4~15
`(¢38 to ~17)
`4~92
`(¢95 to ¢89)
`
`4~14
`(¢52 to ~54)
`
`NA
`
`12 (4~5 to ~24)
`
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
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`Table 4: Drug Interactions: Pharmacokinetic Parameters for
`Coadministered Drug in the Presence of Amprenavir
`
`Co-
`administered
`Drug
`
`Clarithromycin
`
`Ketoconazole
`
`Lamivudine
`
`Rifabutin
`
`Rifampin
`
`Zidovudine
`
`Dose of
`Coadministered
`Drug
`500 mg b.i.d.
`for 4 days
`400 mg
`single dose
`150 mg
`single dose
`300 mg q.d.
`for 10 days
`300 mg
`q.d. for 4 days
`300 mg
`single dose
`
`Dose of
`AGENERASE
`1200 mg b.i.d.
`for 4 days
`1200 mg
`single dose
`600 mg
`single dose
`1200 mg b.i.d.
`for 10 days
`1200 mg b.i.d.
`for4 days
`600 mg
`single dose
`
`n
`
`12
`
`12
`
`11
`
`5
`
`11
`
`12
`
`Cmax
`4~10
`(4~24 to ~7)
`~19
`(~8 to ~33)
`~>
`(4~17 to ~3)
`~119
`(~82 to ~164)
`~>
`(4~13 to ~12)
`~40
`(~14 to ~71)
`
`% Change in Pharmacokinetic Parameters of
`Coadministered Drug
`(90% CI)
`AUC
`
`Groin
`
`(4~17 to ~11)
`m44
`(~I’31 to ~I’59)
`
`(4~13 to ~I’20)
`
`NA
`
`(4~11 to 0)
`m193
`(~156 to ~235)
`
`NA
`~271
`(~171 to ~409)
`
`(4~10 to ~I’13)
`m31
`(,I,19 to ,I,45)
`
`ND
`
`NA
`
`~" = Increase; 4, = Decrease; ~> = No change (~" or 4,<10%); NA = Cmin not calculated for single-dose
`study, ND = Interaction cannot be determined as Cm~n was below the lower limit of quantitation.
`
`Nucleoside Reverse Transcriptase Inhibitors (NRTIs): There was no effect of amprenavir on
`
`abacavir in subjects receiving both agents based on historical data.
`
`HIVProtease Inhibitors: The effect of amprenavir on total drug concentrations of other HIV protease
`
`inhibitors in subjects receiving both agents was evaluated using comparisons to historical data. Indinavir
`
`steady-state Cma×, AUC, and C~in were decreased by 22%, 38%, and 27%, respectively, by concomitant
`
`amprenavir. Similar decreases in C~ and AUC were seen alter the first dose. Saquinavir steady-state
`
`C~a×, AUC, and C~in were increased 21%, decreased 19%, and decreased 48%, respectively, by
`
`concomitant amprenavir. Nelfinavir steady-state Cma×, AUC, and C~in were increased by 12%, 15%, and
`
`14%, respectively, by concomitant amprenavir.
`
`For information regarding clinical recommendations, see PRECAUTIONS: Drug Interactions.
`
`INDICATIONS AND USAGE: AGENERASE (amprenavir) in combination with other antiretroviral
`
`agents is indicated for the treatment of HIV-1 infection. This indication is based on analyses of
`
`plasma HIV RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. At
`
`present, there are no results from controlled trials evaluating long-term suppression of HIV RNA
`
`or disease progression with AGENERASE (see Description of Clinical Studies).
`
`Description of Clinical Studies: Therapy-Naive Adults: PROAB3001, an ongoing, randomized,
`
`double-blind, placebo-controlled, multicenter study, compared treatment with AGENERASE (1200 mg
`
`twice daily) plus lamivudine (150 mg twice daily) plus zidovudine (300 mg twice daily) versus lamivudine
`
`(150 mg twice daily) plus zidovudine (300 mg twice daily) in 232 patients, median age 37 years (range 18
`
`to 63 years), 75% Caucasian, 89% male, with a median CD4 cell count of 416 cells/mm3 (range 139 to
`
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
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`1800 cells/mm3) and a median plasma HIV-1 RNA of 4.67 Io91o copies/mL (range 3.06 to
`
`6.31 Io91o copies/mL) at baseline. Through 24 weeks of therapy, there was no significant difference in the
`
`median CD4 cell count between the treatment arms. Figure 1 shows the proportions of patients with
`
`plasma HIV-1 RNA levels <400 copies/mL through 24 weeks.
`
`Figure 1: Virologic Response Through Week 24, PROAB30011’2
`
`100
`
`Study Week
`
`© AGENERASE/Larnivudine/Zidovudine (n = 116)
`¯ Larnivudine/Zidovudine (n = 116)
`1RocheAMPLIOOR HIV-1 MONITOR assay.
`2Biscontinuations and missing data were considered as HIV-1 RNA _>400 copies/mL.
`
`HIV-1 RNA status and reasons for discontinuation of randomized treatment at 24 weeks are
`
`summarized (Table 5).
`
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
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`Table 5: Outcomes of Randomized Treatment Through Week 24 (PROAB3001)
`
`Outcome
`
`HIV RNA <400 copies/mL*
`
`HIV RNA _>400 copies/mLt’t
`
`CDC Class C event~;
`
`Discontinued due to adverse events~;
`
`Discontinued due to other reasons~;’§
`
`On treatment with missing HIV RNA value~;
`
`AGENERASE
`
`(n = 116)
`
`Placebo
`
`(n = 116)
`
`53%
`
`13%
`
`0
`
`15%
`
`19%
`
`0%
`
`11%
`
`62%
`
`0
`
`3%
`
`22%
`
`1%
`
`TOTAL
`
`100%
`
`100%
`
`*Corresponds to rates at Week 24 in Figure 1.
`tlncludes discontinuations due to virological failure at or before Week 24.
`~;Treatment failure in the analysis.
`§Consent withdrawn, lost to follow-up, and protocol violation.
`
`Therapy-ExperiencedAdults: PROAB3006, an ongoing, randomized, open-label multicenter study,
`
`compared treatment with AGENERASE (1200 mg twice daily) plus NRTIs versus indinavir (800 mg every
`
`8 hours) plus NRTIs in 504 NRTI- and non-nucleoside reverse transcriptase inhibitor- (NNRTI)
`
`experienced, protease inhibitor-naive patients, median age 37 years (range 20 to 71 years), 72%
`
`Caucasian, 80% male, with a median CD4 cell count of 399 cells/mm3 (range 9 to 1706 cells/mm3) and a
`
`median plasma HIV-1 RNA level of 3.93 Ioglo copies/mL (range 2.60 to 7.01 Ioglo copies/mL) at baseline.
`
`Through 24 weeks of therapy, there was a smaller increase in median CD4 cell count from baseline for
`
`the amprenavir group than for the indinavir group. Figure 2 shows the proportions of patients with plasma
`
`HIV-1 RNA levels <400 copies/mL through 24 weeks.
`
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
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`Figure 2: Virologic Response Through Week 24, PROAB3006~’4
`
`100
`
`~ 90
`
`"~.
`o° 80
`
`v 711
`
`= 511
`
`~ 411
`.~_
`
`~ 217
`
`Study Week
`
`0 AGENERASE plus NRTIs (n = 254)
`¯ Indinavir plus NRTIs (n = 250)
`3RocheAMPLICOR HIV-1 MONITOR assay.
`4Discontinuations and missing data were considered as HIV-1 RNA >400 copies/mL.
`
`HIV-1 RNA status and reasons for discontinuation of randomized treatment at 24 weeks are
`
`summarized (Table 6).
`
`Table 6: Outcomes of Randomized Treatment Through Week 24 (PROAB3006)
`
`Outcome
`
`HIV RNA <400 copies/mL*
`
`HIV RNA _>400 copies/mLt’t
`
`CDC Class C event~;
`
`Discontinued due to adverse events~;
`
`Discontinued due to other reasons~;’§
`
`On treatment with missing HIV RNA value~;
`
`AGENERASE
`
`(n = 254)
`
`43%
`
`22%
`
`<1%
`
`16%
`
`14%
`
`4%
`
`Indinavir
`(n = 250)
`53%
`
`18%
`
`2%
`
`8%
`
`12%
`
`7%
`
`TOTAL
`
`100%
`
`100%
`
`*Corresponds to rates at Week 24 in Figure 2.
`1Includes discontinuations due to virological failure at or before Week 24.
`~;Treatment failure in the analysis.
`§Consent withdrawn, lost to follow-up, and protocol violation.
`
`10
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`Lupin Ex. 1059 (Page 10 of 24)
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`

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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
`
`CONTRAINDICATIONS: AGENERASE should not be administered concurrently with astemizole,
`
`bepridil, cisapride, dihydroergotamine, ergotamine, midazolam, and triazolam. Although these
`
`drugs have not been specifically studied, coadministration may result in competitive inhibition of
`
`metabolism of these products and may cause serious or life-threatening adverse events. (See
`
`WARNINGS for agents whose coadministration may result in competitive inhibition of metabolism
`
`but for which concentration monitoring is recommended.)
`
`AGENERASE is contraindicated in patients with previously demonstrated clinically significant
`
`hypersensitivity to any of the components of this product.
`
`WARNINGS: Serious and/or life-threatening drug interactions could occur between amprenavir
`
`and amiodarone, lidocaine (systemic), tricyclic antidepressants, and quinidine. Concentration
`
`monitoring of these agents is recommended if these agents are used concomitantly with
`
`AGENERASE (see CONTRAINDICATIONS).
`
`Rifampin should not be used in combination with amprenavir because it reduces plasma
`
`concentrations and AUC of amprenavir by about 90%.
`
`Particular caution should be used when prescribing sildenafil in patients receiving amprenavir.
`
`Coadministration of AGENERASE with sildenafil is expected to substantially increase sildenafil
`
`concentrations and may result in an increase in sildenafil-associated adverse events, including
`
`hypotension, visual changes, and priapism. (see PRECAUTIONS: Drug Interactions and Information for
`
`Patients, and the complete prescribing information for sildenafil).
`
`Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, have
`
`occurred in patients treated with AGENERASE (see ADVERSE REACTIONS).
`
`Acute hemolytic anemia has been reported in a patient treated with AGENERASE.
`
`New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have
`
`been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor
`
`therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic
`
`agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients
`
`who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these
`
`events have been reported voluntarily during clinical practice, estimates of frequency cannot be made
`
`and causal relationships between protease inhibitor therapy and these events have not been established.
`
`PRECAUTIONS:
`
`General: AGENERASE Capsules and AGENERASE Oral Solution are not interchangeable on a
`
`milligram per milligram basis (see CLINICAL PHARMACOLOGY: Pediatric Patients).
`
`11
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
`
`Amprenavir is a sulfonamide. The potential for cross-sensitivity between drugs in the sulfonamide
`
`class and amprenavir is unknown. Patients with a known sulfonamide allergy should be treated with
`
`caution.
`
`AGENERASE is principally metabolized by the liver; therefore caution should be exercised when
`
`administering this drug to patients with hepatic impairment (see DOSAGE AND ADMINISTRATION).
`
`Formulations of AGENERASE provide high daily doses of vitamin E (see Information for Patients,
`
`DESCRIPTION, and DOSAGE AND ADMINISTRATION). The effects of long-term, high-dose vitamin E
`
`administration in humans is not well characterized and has not been specifically studied in HIV-infected
`
`individuals. High vitamin E doses may exacerbate the blood coagulation defect of vitamin K deficiency
`
`caused by anticoagulant therapy or malabsorption.
`
`Patients with Hemophilia: There have been reports of spontaneous bleeding in patients with hemophilia
`
`A and B treated with protease inhibitors. In some patients, additional factor VIII was required. In many of
`
`the reported cases, treatment with protease inhibitors was continued or restarted. A causal relationship
`
`between protease inhibitor therapy and these episodes has not been established.
`
`Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat
`
`enlargement (buffalo hump), peripheral wasting, breast enlargement, and "cushingoid appearance" have
`
`been observed in patients receiving protease inhibitors. The mechanism and long-term consequences of
`
`these events are currently unknown. A causal relationship has not been established.
`
`Resistance/Cross-Resistance: Because the potential for HIV cross-resistance among protease
`
`inhibitors has not been fully explored, it is unknown what effect amprenavir therapy will have on the
`
`activity of subsequently administered protease inhibitors (see MICROBIOLOGY).
`
`Information for Patients: A Patient Package Insert (PPI) for AGENERASE is available for patient
`
`information.
`
`Patients should be informed that AGENERASE is not a cure for HIV infection and that they may
`
`continue to develop opportunistic infections and other complications associated with HIV disease. The
`
`long-term effects of AGENERASE (amprenavir) are unknown at this time. Patients should be told that
`
`there are currently no data demonstrating that therapy with AGENERASE can reduce the risk of
`
`transmitting HIV to others through sexual contact.
`
`Patients should remain under the care of a physician while using AGENERASE. Patients should be
`
`advised to take AGENERASE every day as prescribed. AGENERASE must always be used in
`
`combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy
`
`without consulting their physician. If a dose is missed, patients should take the dose as soon as possible
`
`and then return to their normal schedule. However, if a dose is skipped, the patient should not double the
`
`next dose.
`
`Patients should inform their doctor if they have a sulfa allergy. The potential for cross-sensitivity
`
`between drugs in the sulfonamide class and amprenavir is unknown.
`
`12
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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
`
`Some drugs should not be used with AGENERASE. Therefore, patients should be advised that they
`
`must report to their doctor the use of any other prescription or nonprescription medication.
`
`Patients taking antacids (or didanosine) should take AGENERASE at least 1 hour before or after
`
`antacid (or didanosine) use.
`
`Patients receiving sildenafil should be advised that they may be at an increased risk of
`
`sildenafil-associated adverse events including hypotension, visual changes, and priapism, and should
`
`promptly report any symptoms to their doctor.
`
`Patients receiving hormonal contraceptives should be instructed that alternate contraceptive measures
`
`should be used during therapy with AGENERASE.
`
`High fat meals may decrease the absorption of AGENERASE and should be avoided. AGENERASE
`
`may be taken with meals of normal fat content.
`
`Patients should be informed that redistribution or accumulation of body fat may occur in patients
`
`receiving protease inhibitors and that the cause and long-term health effects of these conditions are not
`
`known at this time.
`
`Adult and pediatric patients should be advised not to take supplemental vitamin E since the vitamin E
`
`content of AGENERASE Capsules and Oral Solution exceeds the Reference Daily Intake (adults 30 IU,
`
`pediatrics approximately 10 IU).
`
`Drug Interactions: See also CONTRAINDICATIONS, WARNINGS, and CLINICAL
`
`PHARMACOLOGY: Drug Interactions.
`
`AGENERASE is an inhibitor of cytochrome P450 CYP3A4 metabolism and therefore should
`
`not be administered concurrently with medications with narrow therapeutic windows that are
`
`substrates of CYP3A4. There are other agents that may result in serious and/or life-threatening
`
`drug interactions (see CONTRAINDICATIONS and WARNINGS).
`
`13
`
`Lupin Ex. 1059 (Page 13 of 24)
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`

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`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
`
`Table 7: Drug Interactions with AGENERASE
`
`Drug Class
`
`Should Not Be Coadministered
`Drug Within Class Not To Be Coadministered
`Astemizole
`Antihistamines
`Rifampin*
`Antimycobacterials
`Benzodiazepines
`Midazolam, triazolam
`Bepridil
`Cardiovascular
`Dihydroergotamine, ergotamine
`Ergot derivatives
`Cisapride
`GI motility agents
`*Decreases plasma concentrations of amprenavir and should not be coadministered as it is likely to
`reduce antiviral activity.
`
`Coadministration Requires Concentration Monitoring
`Drug Class
`Drug Within Class to Monitor
`Amiodarone, lidocaine (systemic), quinidine
`Antiarrhythmics
`Warfarin*
`Anticoagulants
`Tricyclic antidepressants
`Antidepressants
`*Monitor INR (International Normalized Ratio).
`
`Dosage Adjustment Required
`Drug Within Class Requiring a Dosage Adjustment
`Drug Class
`Rifabutin (reduce dose to at least half that recommended)*
`Antimycobacterials
`¯ A complete blood count should be performed weekly and as clinically indicated in order to monitor for
`neutropenia in patients receiving amprenavir and rifabutin.
`
`Other Potentially Significant Drug Interactions
`Induce CYP3A4 and may decrease amprenavir
`Anticonvulsants: phenobarbital, phenytoin,
`concentrations.
`carbamazepine
`Cholesterol-lowering agents: atorvastatin,
`May have their serum concentrations increased by
`cerivastatin, Iovastatin, pravastatin, and
`AGENERASE, which could increase their activity or
`simvastatin
`toxicity.
`Expected to substantially increase sildenafil concentrations
`(consult sildenafil prescribing information for dose reduction
`of sildenafil in patients receiving ritonavir)
`
`Erectile dysfunction agents: sildenafil
`
`Antimycobacterials: Rifampin: Rifampin should not be used in combination with amprenavir since it
`
`reduces plasma concentrations and AUC of amprenavir by about 90%.
`
`Rifabutin: Coadministration of amprenavir with rifabutin results in a 15% decrease in amprenavir
`
`plasma AUC and a 193% increase in rifabutin plasma AUC. A dosage reduction of rifabutin to at least half
`
`the recommended dose is required when AGENERASE and rifabutin are coadministered (see CLINICAL
`
`PHARMACOLOGY: Drug Interactions). A complete blood count should be performed weekly and as
`
`clinically indicated in order to monitor for neutropenia in patients receiving amprenavir and rifabutin.
`
`Other Potentially Significant Drug Interactions: Other medications that interact at CYP3A4, either
`
`as substrates, inhibitors, or inducers of the enzyme, could have potential interactions when used
`
`14
`
`Lupin Ex. 1059 (Page 14 of 24)
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`

`

`AGENERASETM (amprenavir) Capsules
`AGENERASETM (amprenavir) Oral Solution
`
`concomitantly. The clinical significance of these potential interactions is unknown and has not been
`
`studied.
`
`Antibiotics: Dapsone and erythromycin may have their plasma concentrations increased by
`
`AGENERASE. Erythromycin may also increase amprenavir serum concentrations.
`
`Antifungals: Itraconazole may have its plasma concentrations increased by AGENERASE.
`
`Itraconazole may increase serum concentrations of amprenavir.
`
`Benzodiazepines: Alprazolam, clorazepate, diazepam, and flurazepam may have their serum
`
`concentrations increased by AGENERASE, which could increase their activity.
`
`Calcium Channel Blockers: Diltiazem, nicardipine, nifedipine, and nimodipine may have their
`
`serum concentrations increased by AGENERASE, which could increase their activity.
`
`Cholesterol-Lowering Agents: Atorvastatin, cerivastatin, Iovastatin, pravastatin, and simvastatin
`
`may have their serum concentrations increased by AGENERASE, which could increase their activity or
`
`toxicity.
`
`Erectile Dysfunction Agents: Particular caution should be used when prescribing sildenafil in
`
`patien