BULKY DOCUMENTS
`(exceeds 300 pages)
`
`Proceeding] Serial No:
`
`i
`
`/ 2 C95 Y 0 3
`
`Filed:
`
`//~/3-09,
`
`Title:
`
`fl
`
`{C of
`
`e /fan <2 2:
`
`Part L of _‘L
`
`

`
`Latest Status Info
`
`Page 3 of 3
`
`1998-05-15 - Assigned To Examiner
`
`
`
`CORRESPONDENCE INFORMATION
`
`Correspondent
`SHELDON R PONTAOE
`GLAXOSMITHKLINE
`MALB443
`FIVE MOORE DR.
`
`RESEARCH TRIANGLE PARK NC 27709
`
`Domestic Representative
`BACON & THOMAS
`
`http://tarr.usptcngov/servlet/tarr?regser=seria1&entry=75366369
`
`6/2 7/2006
`
`

`
`Page 1
`
`5 of 201 DOCUMENTS
`
`Copyright 2006 Micromedex, Inc. All Rights Reserved
`Physician's Desk Reference for Prescription Drugs
`
`Agenerase Capsules(GlaxoSmithKline)
`
`BODY:
`
`Because of the potential risk of toxicity from the large amount of the excipient, propylene glycol, contained in
`AGENERASE Oral Solution , that fonnulation is contraindicated in infants and children below the age of 4 years
`and certain other patient populations and should be used with caution in others. Consult the complete prescribing
`information for AGENERASE Oral Solution for full infonnation.
`
`DESCRIPTION
`
`AGENERASE (amprenavir) is an inhibitor of the human immunodeficiency virus (HIV) protease. The chemical name
`of amprenavir is (3 S )—tetrahydro—3-furyl N — (l S ,2 R )—3—(4—amino—N—isobutylbenzenesulfonamido)—1—benzyl—
`2—hydroxypropyl carbamate. Amprenavir is a single stereoisomer with the (3 S )(1 S ,2 R ) configuration. It has a
`molecular formula of C[25] I-I[35] N[3] O[6] S and a molecular weight of 505.64.
`
`Amprenavir is a white to cream—colored solid with a solubility of approximately 0.04 mg/mL in water at 25 deg. C.
`
`AGENERASE Capsules are available for oral administration. Each 50—mg capsule contains the inactive ingredients
`d—alpha tocopheryl polyethylene glycol 1000 succiriate (TPGS), polyethylene glycol 400 (PEG 400) 246.7 mg, and
`propylene glycol 19 mg. The capsule shell contains the inactive ingredients d—sorbitol and sorbitans solution, gelatin,
`glycerin, and titanium dioxide. The soft gelatin capsules are printed with edible red ink. Each 50—mg AGENERASE
`Capsule contains 36.3 IU vitamin E in the form of TPGS. The total amount of vitamin E in the recommended daily
`adult dose of AGENERASE is 1,744 IU.
`
`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 IllB in
`both acutely and chronically infected lymphoblastic cell lines (MT—4, CEM—-CCRF, H9) and in peripheral blood
`lymphocytes. The 50% inhibitory concentration (lC[50] ) of amprenavir ranged from 0.012 to 0.08 micro M in acutely
`infected cells and was 0.41 micro M in chronically infected cells (1 micro M = 0.50 meg/mL). Amprenavir exhibited
`synergistic anti—HIV—l 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 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 V321, M461/L, 147V, 150V,
`l54L/M, and 184V as well as mutations in the p7/pl and 131196 gag cleavage sites. Phenofypic analysis of HIV-
`l isolates from 21 nucleoside reverse transcriptase inhibitor—(NRTl—) experienced, protease inhibitor-naive patients
`treated with amprenavir in combination with NRTls for 16 to 48 weeks identified isolates from 15 patients who
`exhibited a 4—to 17-fold decrease in susceptibility to amprenavir in vitro compared to wild—type virus. Clinical isolates
`that exhibited a decrease in amprenavir susceptibility harbored one or more amprenavir—associated mutations. The
`
`é'"LexisNexis"
`
`é"’LexisNexis"'
`
`é"'LexisNexis'"
`
`

`
`Physician's Desk Reference for Prescription Drugs
`
`Page 2
`
`clinical relevance of the genotypic and phenotypic changes associated with amprenavir therapy is under evaluation.
`
`Cross—Resistance: Varying degrees of HIV-1 cross-resistance among protease inhibitors have been observed. Five of
`15 amprenavir—resistant isolates exhibited 4—to 8-fold decrease in susceptibility to ritonavir. However, amprenavir-
`resistant isolates were susceptible to either indinavir or saquinavir.
`
`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 1,200 mg and multiple oral doses of 300 to
`1,200 mg twice daily.
`
`Absorption and Bi0avaiIabiliIy.' Amprenavir was rapidly absorbed after oral administration in HIV-l—infected patients
`with a time to peak concentration (T[max] ) 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
`1,200 mg were slightly greater than dose proportional.
`
`Increases in AUC were close proportional after 3 weeks of dosing with doses from 300 to 1,200 mg twice daily. The
`pharmacokinetic parameters after administration of amprenavir 1,200 mg twice daily for 3 weeks to HIV—infected
`subjects are shown in Table 1.
`
`Table 1. Average (%CV) Pharmacokinelic Parameters After 1,200 mg Twice
`Daily of Amprenavir Capsules (11 = 54)
`
`C[max]
`(meg/mL)
`
`7.66
`
`(54 %)
`
`T[max]
`(hours)
`
`1.0
`
`(42%)
`
`AUC[0— 12]
`
`(mcg*hrImL
`)
`17.7
`
`(47 %)
`
`C[avg]
`(mcg.t'mL)
`
`C[min]
`(mcg/mL)
`
`1.48
`
`(47 %)
`
`0.32
`
`(77 %)
`
`CL/F
`(mL/min/k
`g)
`
`19.5
`
`(46 %)
`
`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.
`
`Eflects 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 1,200—mg dose of amprenavir in the fed state compared to the fasted state
`was associated with changes in C[max] (fed: 6.18 +f—2.92 mcg/mL, fasted: 9.72 +f—2.75 mcglmL), T[max] (fed:
`1.51 +l—0.68, fasted: 1.05 +/-0.63), and AUC[0—(infinity)] (fed: 22.06 +l—l1.6 mcg*hrfmL, fasted: 28.05 +2’-
`l0.l mcg"‘hr/mL). AGENERASE may be taken with or without food, but should not be taken with a high-fat meal
`(see DOSAGE AND ADMINISTRATION ).
`
`Distriburion.- The apparent volume of distribution (V{z] /F) is approximately 430 L in healthy adult subjects. In
`vitro binding is approximately 90% to plasma proteins. The highaffinity binding protein for amprenavir is aIpha[l]—
`acid glycoprotein (AAG). The partitioning of amprenavir into erythrocytes is low, but 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 3A4 (CYP3A4) enzyme system. The
`2 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.
`
`6"" LexisNexis"
`
`LexisNexis"
`
`LexisNexis'"
`
`

`
`Physician's Desk Reference for Prescription Drugs
`
`Page 3
`
`Eliminan'on: Excretion of unchanged amprenavir in urine and feces is minimal. Approximately 14% a.nd 75% of an
`administered single dose of[l4] C—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 Insufi‘ict'ency: AGENERASE has been studied in adult patients with impaired hepatic
`function using a single 600—mg oral dose. The AUC[0—(infinity)] was significantly greater in patients with moderate
`cirrhosis (25.76 +/-14.68 mcg*hr/mL) compared with healthy volunteers (12.00 +l-4.38 mcg"‘hrlmL). The AUC[O—
`(infinity)] and C[max] were significantly greater in patients with severe cirrhosis (AUC[0—(infinity)] : 38.66 +l—l6.08
`mcg*hr/mL; C[max] : 9.43 +f—2.6l rncg/ml.) compared with healthy volunteers (AUC[0—(infinity)] : 12.00 +/-4.38
`mcg*hrlmL; C[max] : 4.90 +/-1.39 mcg/mL). Patients with impaired hepatic function require dosage adjustment (see
`DOSAGE AND ADMINISTRATION ).
`
`Renal Insujjficiencys 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 Capsules or Oral Solution in 84 pediatric patients. Twenty I-llV—1—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[max]
`of amprenavir increased less than proportionally with dose. The AUC[0-(infinity)] increased proportionally at doses
`between 5 and 20 mgfkg. 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.
`
`AGENERASE Oral Solution is contraindicated in infants and children below the age of 4 years due to the potential risk
`of toxicity from the large amount of the excipient, propylene glycol. Please see the complete prescribing infomiation
`for AGENERASE Oral Solution for full infomiation.
`
`Table 2. Average (%CV) Pharmacokinetic Parameters in Children Ages 4 to 12
`Years Receiving 20 mg/kg Twice Daily or 15 mg/kg Three Times Daily of
`AGENERASE Oral Solution
`
`Dose
`
`20 rnglkg
`
`b.i.d.
`
`l5 mg/kg
`
`t.i.d.
`
`n
`
`20
`
`17
`
`C[max]
`
`T[max]
`
`(meg/mL
`)
`
`6.77
`(51%)
`
`3.99
`(37%)
`
`(hours)
`
`1.1
`(21%)
`
`1.4
`(90%)
`
`AUC[ss]
`*
`(mcg*hr
`fmL)
`
`15.46
`(59%)
`
`C[avg]
`
`C[min]
`
`(mcglm
`L)
`
`1.29
`(59%)
`
`(mcglm
`L)
`
`0.24
`(98%)
`
`8.73
`(36%)
`
`1.09
`(36%)
`
`0.27
`(95%)
`
`CUF
`(mL/mi
`n/kg)
`
`29
`(58%)
`
`32
`(34%)
`
`*AUC is 0 to 12 hours for b.i.d. and 0 to 8 hours for t.i.d., therefore the
`
`C[avg] 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 .
`
`é"LexisNexis"
`
`é"LexisNexis*" LexisNexis*"
`
`

`
`Physician's Desk Reference for Prescription Drugs
`
`Page 4
`
`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, CYP2Cl9, CYP2E1, or uridine glucuronosyltransferase (UDPGT).
`
`Drug interaction studies were performed with amprenavir capsules 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, C[max] , and C[min] 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 .
`
`Table 3. Drug Interactions: Pharmacokinetic Parameters for Amprenavir in
`the Presence of the Coadministered Drug
`
`Coadminist
`ered
`
`Dose of
`Coadmini
`
`Dose of
`AGENERAS
`
`C[min]
`
`% Change in Amprenavir
`Pharmacokinetic
`
`Drug
`
`Abacavir
`
`Clarithrom
`ycin
`
`Delavirdin
`e
`
`Ethinyl
`estradio
`1/
`Norethin
`drone
`
`Indinavir
`
`Ketoconazo
`Ie
`
`Larnivudine
`
`Nelfinavir
`
`stered
`Drug
`
`300 mg
`b.i.d.
`for 3
`weeks
`
`500 mg
`b.i.d.
`for 4
`days
`600 mg
`b.i.d.
`for 10
`
`days
`0.035 mg/1
`mg
`for 1
`cycle
`
`800 mg
`t.i.d.
`for 2
`weeks
`
`(fasted)
`
`400 mg
`single
`dose
`
`150 mg
`single
`dose
`750 mg
`t.i.d.
`for 2
`weeks
`
`E
`
`900 mg
`b.i.d.
`for 3
`weeks
`
`1,200 mg
`b.i.d.
`for 4
`days
`600 mg
`b.i.d.
`for 10
`
`days
`1,200 mg
`b.i.d.
`for 28
`days
`
`750 or 800
`mg
`t.i.d.
`for 2
`
`weeks
`(fasted)
`1,200 mg
`single
`dose
`
`600 mg
`single
`dose
`750 or 800
`mg
`t.i.d.
`for 2
`
`4
`
`12
`
`9
`
`10
`
`9
`
`12
`
`11
`
`6
`
`Parameters *
`(90% CI)
`C[max]
`up 29
`(down 18
`to up103)
`
`up18
`(up 8 to
`up 29)
`
`n
`up 47
`(down 15
`to up154)
`
`upl5
`(upl to
`up3l)
`
`AUC
`up 27
`(down 46
`to up197)
`
`up39
`(up3l to
`up 47)
`
`up 40[#]
`
`upl30[#]
`
`upl25[#]
`
`<— >
`(down 20
`to up 3)
`
`up18
`(down 13
`to up 58)
`
`down 16
`(down 25
`to down
`6)
`< - >
`(down 17
`to up 9)
`down 14
`(down 38
`to up20)
`
`down 22
`(down 35
`to down
`8)
`
`up33
`(up2 to
`up73)
`
`up3l
`(up20 to
`up42)
`
`< - >
`(down 15
`to up14)
`<— >
`(down 19
`to up 47)
`
`down 20
`(down 41
`to up 8)
`
`up 25
`(down 27
`to up116)
`
`NA
`
`NA
`
`up189
`(up52 to
`up 448)
`
`é'"LexisNexis" LexisNexis*" LexisNexis'"
`
`

`
`Physician's Desk Reference for Prescription Drugs
`
`Page 5
`
`Table 3. Drug Interactions: Pharmacokinetic Parameters for Amprenavir in
`the Presence of the Coadministered Drug
`weeks
`(fed)
`
`(fed)
`
`Rifabutin
`
`Rifampin
`
`Ritonavir
`
`Ritonavir
`
`Saquinavir
`
`300 mg
`q.d.
`for 10
`days
`300 mg
`q.d.
`for 4
`
`days
`100 mg
`b.i.d.
`for 2 to
`4 weeks
`
`200 mg
`q.d.
`for 2 to
`4 weeks
`
`800 mg
`t.i.d.
`for 2
`weeks
`(fed)
`
`Zidovudine
`
`1,200 mg
`b.i.d.
`for 10
`days
`1,200 mg
`b.i.d.
`for 4
`
`days
`600 mg
`b.i.d.
`
`1,200 mg
`q.d.
`
`750 or 800
`mg
`t.i.d.
`for 2
`weeks
`(fed)
`600 mg
`single
`dose
`
`300 mg
`single
`dose
`*Based on total—drug concentrations.
`[**."*] Compared to amprenavir 1,200 mg b.i.d. in the same patients.
`[if] Median percent change; confidence interval not reported.
`up = Increase; down =Decrease; <—> = No change (up or down < 10%); NA =
`C[min] not calculated for single—dose study.
`
`5
`
`11
`
`18
`
`12
`
`7
`
`<—>
`(down 21
`to up10)
`
`down 70
`(down 76
`to down
`
`62)
`down
`30[**/*
`]
`(down 44
`to down
`14)
`< - > [**I*
`]
`(down 17
`to up30)
`
`down 37
`(down 54
`to down
`l4)
`
`down 15
`(down 28
`to 0)
`
`down 82
`(down 84
`to down
`
`78)
`up
`64[**/*
`]
`(up37 to
`up 97)
`
`up
`62{**/*
`]
`(up35 to
`up 94)
`down 32
`(down 49
`to down
`9)
`
`12
`
`<— >
`(down 5
`to up 24)
`
`up13
`(down 2
`to up 31)
`
`down 15
`(down 38
`to up17)
`
`down 92
`(down 95
`to down
`
`89)
`up
`508[**/*
`]
`(up394
`to up
`649)
`up
`319[**/*
`]
`(up190
`to up508)
`down 14
`(down 52
`to up54)
`
`NA
`
`Table 4. Drug Interactions: Pharmacokinetic Parameters for Coadministered
`Drug in the Presence of Amprenavir
`
`Coadministe
`red
`
`Dose of
`Coadminis
`
`Dose of
`AGENERASE
`
`n
`
`% Change in Pharmacokinetic
`Parameters of
`
`Drug
`
`Clarithromy
`cin
`
`Delavirdine
`
`tered
`Drug
`
`500 mg
`b.i.d.
`for 4
`days
`600 mg
`b.i.d.
`for 10
`
`1,200 mg
`b.i.d.
`for 4
`days
`600 mg
`b.i.d.
`for 10
`
`12
`
`C[max]
`down 10
`(down 24
`to up 7)
`
`Coadministered Drug
`(90% Cl)
`AUC
`< — >
`(down 17
`to up 11)
`
`9
`
`down 47 *
`
`down 61 *
`
`C[min]
`< — >
`(down
`13 to up
`20)
`down 88
`*
`
`6'" LexisNexis"'
`
`LexisNexis'"
`
`LexisNexis'"
`
`

`
`Physician's Desk Reference for Prescription Drugs
`
`Page 6
`
`Table 4. Drug Interactions: Pharmacokinetic Parameters for Coadministered
`Drug in the Presence of Amprenavir
`days
`1,200 mg
`b.i.d.
`for 28
`
`10
`
`< — >
`
`( down
`25 to up
`15)
`< - >
`
`( down
`20 to up
`18)
`up 19
`( up 8
`to up
`33)
`< - >
`
`( down
`17 to up
`3)
`
`up 32
`( down
`3 to up
`79)
`up 45
`( up 13
`to up
`88)
`NA
`
`NA
`
`<—>
`
`( down 14
`to up
`38)
`up 18
`(up 1 to
`up 38)
`
`up 44
`(up 31
`to up
`59)
`<— >
`
`( down
`11 to O)
`
`R—Methadone (active)
`
`Ethinyl
`estradiol
`
`Norethindro
`ne
`
`Ketoconazol
`e
`
`Lamivudine
`
`days
`0.035 mg
`for 1
`
`cycle
`
`1.0 mg
`for 1
`
`cycle
`
`400 mg
`single
`dose
`
`150 mg
`single
`dose
`
`Methadone
`
`44 to 100
`
`mg q.d.
`for >30
`
`days
`
`Rifabutin
`
`300 mg q.d.
`
`Rifampin
`
`Zidovudine
`
`for 10
`
`days
`300 mg
`q.d. for
`4 days
`
`300 mg
`single
`dose
`
`days
`1,200 mg
`b.i.d.
`for 28
`
`days
`1,200 mg
`single
`dose
`
`600 mg
`single
`dose
`
`1,200 mg
`b.i.d.
`for 10
`
`days
`
`1,200 mg
`b.i.d.
`for 10
`
`days
`1,200 mg
`b.i.d.
`for 4
`
`days
`600 mg
`single
`dose
`
`10
`
`12
`
`11
`
`I6
`
`11
`
`12
`
`down 25
`
`down 13
`
`down 21
`
`( down
`32 to
`
`down 18)
`
`down 48
`
`( down
`55 to
`
`down 40)
`up 119
`(up 82
`to up 164)
`
`<—>
`
`(down
`13 to up
`12)
`up 40
`(up 14
`to up
`71)
`
`( down
`21 to
`
`down 5)
`
`S—Methadone (inactive)
`down 40
`
`( down
`46 to
`
`down 32)
`up 193
`(up 156
`to
`
`up 235)
`< - >
`
`( down
`10 to up
`13)
`up 31
`( up 19
`to up
`45)
`
`( down
`32 to
`
`down 9)
`
`down 53
`
`( down
`60 to
`
`down 43)
`up 271
`( up 171
`to up
`409)
`ND
`
`NA
`
`*Median percent change; confidence interval not reported.
`up = Increase; down = Decrease; <—> = No change (up or down < 10%); NA =
`C[min] not calculated for single—dose study; ND = Interaction cannot be
`determined as C[min] was below the lower limit of quantitation.
`
`Nucleoside Reverse Transcriptase Inhibitors (NRT1s): There was no effect of amprenavir on abacavir in subjects
`receiving both agents based on historical data.
`
`HIV Protease Inht‘bitors.- The effect of amprenavir on total drug concentrations of other HIV protease inhibitors in
`
`6'" LexisNexis"
`
`LexisNexis*"
`
`LexisNexis"
`
`

`
`Physician's Desk Reference for Prescription Drugs
`
`Page 7
`
`subjects receiving both agents was evaluated using comparisons to historical data. lndinavir steady—state C[max] ,
`AUC, and C[min] were decreased by 22%, 38%, and 27%, respectively, by concomitant amprenavir. Similar decreases
`in C[max] and AUC were seen after the first dose. Saquinavir steady—state C[max] , AUC, and C[min] were increased
`21%, decreased 19%, and decreased 48%, respectively, by concomitant arnprenavir. Nelfinavir steady—state C[max] ,
`AUC, and C[min] were increased by 12%, 15%, and 14%, respectively, by concomitant arnprenavir.
`
`Methadone: Coadrninistration of amprenavir and methadone can decrease plasma levels of methadone.
`
`Coadministration of amprenavir and methadone as compared to a non—matched historical control group resulted in a
`30%, 27%, and 25% decrease in serum amprenavir AUC, C[max] , and C[min] , respectively.
`
`For information regarding clinical recommendations, see PRECAUTIONS : Drug Interactions .
`
`INDICATIONS AND USAGE
`
`AGENERASE (amprenavir) is indicated in combination with other antiretroviral agents for the treatment of HIV-1
`infection.
`
`The following points should be considered when initiating therapy with AGENERASE:
`
`In a study of NRTI—experienced, protease inhibitor—naive patients, AGENERASE was found to be significantly less
`effective than indinavir (see Description of Clinical Studies ).
`
`Mild to moderate gastrointestinal adverse events led to discontinuation of AGENERASE primarily during the first 12
`weeks of therapy (see ADVERSE REACTIONS ).
`
`There are no data on response to therapy with AGENERASE in protease inhibitor—experienced patients.
`
`Description of Clinical Studies: Therapy—Nat've Adults.‘ PROAB3001, a randomized, double-blind, placebo—controlled,
`multicenter study, compared treatment with AGENERASE Capsules (1,200 mg twice daily) plus lamivudine (150 mg
`twice daily) plus zidovudine (300 mg twice daily) versus larnivudine (150 mg twice daily) plus zidovudine (300 mg twice
`daily) in 232 patients. Through 24 weeks of therapy, 53 % of patients assigned to AGENERASElzidovudinellamivudine
`achieved HIV-1 RNA <400 copies/mL. Through week 48, the antiviral response was 41%. Through 24 weeks of
`therapy, 11% of patients assigned to zidovudine/lamivudine achieved HIV-1 RNA < 400 copiesfmL. Antiviral response
`beyond week 24 is not interpretable because the majority of patients discontinued or changed their antiretroviral
`therapy.
`
`NRTI—Expen'em:ed Adults: PROAB3006, a randomized, open—label multicenter study, compared treatment with
`AGENERASE Capsules (1,200 mg twice daily) plus NRTIS versus indinavir (800 mg every 8 hours) plus NRTIs in
`504 NRTI—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 404 cellsfmm[3} (range 9 to 1,706 cells/mm[3] ) and a median plasma
`HIV-1 RNA level of 3.93 log[ 10] copiesfml. (range 2.60 to 7.01 log[l0] copieslml.) at baseline. Through 48 weeks of
`therapy, the median CD4 cell count increase from baseline in the amprenavir group was significantly lower than in the
`indinavir group, 97 cells/mm[3] versus 144 cells/mm[3] , respectively. There was also a significant difference in the
`proportions of patients with plasma HIV-1 RNA levels <400 copies/mL through 48 weeks (see Figure 1 and Table 5).
`
`See Image
`
`HIV-1 RNA status and reasons for discontinuation of randomized treatment at 48 weeks are summarized (Table 5).
`
`Table 5. Outcomes of Randomized Treatment Through Week 48 (PROAB3006)
`
`Outcome
`
`AGENERASE
`
`Indinavir
`
`6” LexisNexis"
`
`LexisNexis‘“
`
`LexisNexis'“
`
`

`
`Physician's Desk Reference for Prescription Drugs
`
`Page 8
`
`Table 5. Outcomes of Randomized Treatment Through Week 48 (PROAB3006)
`(n = 254)
`(n = 250)
`30%
`49%
`38%
`26%
`
`HIV-1 RNA <400 copies/mL *
`HIV-1 RNA >/=400
`
`copies/mL[**/*,]{#]
`Discontinued due to adverse
`
`events *[,#]
`Discontinued due to other
`
`16%
`
`16%
`
`12%
`
`13%
`
`reasons[#,][§]
`*Corresponds to rates at Week 48 in Figure 1.
`[**I*] Virological failures at or before Week 48.
`[#1 Considered to be treatment failure in the analysis.
`[§] Includes discontinuations due to consent withdrawn, loss to
`follow—up, protocol violations, non—compliance, pregnancy, never
`treated, and other reasons.
`
`CONTRAINDICATIONS
`
`Coadministration of AGENERASE is contraindicated with drugs that are highly dependent on CYP3A4 for clearance
`and for which elevated plasma concentrations are associated with serious andlor life-threatening events. These drugs
`are listed in Table 6.
`
`Table 6. Drugs That Are Contraindicated With AGENERASE
`
`Drug Class
`
`Ergot derivatives
`
`GI motility agent
`Neuroleptic
`Sedatives/hypnotics
`
`Drugs Within Class That Are
`CONTRAINDICATED with AGENERASE
`
`Dihydroergotamine, ergonovine, ergotarnine,
`rnethylergonovine
`Cisapride
`Pimozide
`Midazolarn, triazolam
`
`If AGENERASE is coadministered with ritonavir,
`contraindicated .
`
`the antiarrhythmic agents flecainide and propafenone are also
`
`Because of the potential toxicity from the large amount of the excipient, propylene glycol, contained in AGENERASE
`Oral Solution , that formulation is contraindicated in certain patient populations and should be used with caution in
`others. Consult the complete prescribing information for AGENERASE Oral Solution for full information.
`
`AGENERASE is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any
`of the components of this product.
`
`WARNINGS
`
`ALERT: Find out about medicines that should not be taken with AGENERASE.
`
`Serious and/or life—threatening drug interactions could occur between amprenavir and arniodarone, lidocaine (systemic),
`tricyclic antidepressants, and quinidine. Concentration monitoring of these agents is recommended if these agents are
`used concomitantly with AGENERASE (see CONTRAINDICATIONS ).
`
`Rifarnpin should not be used in combination with aniprenavir because it reduces plasma concentrations and AUC of
`
`6'" LexisNexis‘"
`
`LexisNexis““
`
`LexisNexis"
`
`

`
`Physician's Desk Reference for Prescription Drugs
`
`Page 9
`
`arnprenavir by about 90%.
`
`A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate
`exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of AGENERASE with
`ritonavir and fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including
`Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients receiving
`ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone
`propionate and AGENERASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the
`risk of systemic corticosteroid side effects (see PRECAUTIONS : Drug Interactions ).
`
`Concomitant use of AGENERASE and St. John's wort (hypericum perforatum) or products containing St. John's
`wort is not recommended. Coadmjnistration of protease inhibitors, including AGENERASE, with St. John's wort is
`expected to substantially decrease protease inhibitor concentrations and may result in suboptimal levels of amprenavir
`and lead to loss of virologic response and possible resistance to AGENERASE or to the class of protease inhibitors.
`
`Concomitant use of AGENERASE with lovastatin or simvastatin is not recommended. Caution should be exercised if
`
`HIV protease inhibitors, including AGENERASE, are used concurrently with other HMG—CoA reductase inhibitors
`that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin). The risk of myopathy, including rhabdomyolysis,
`may be increased when HIV protease inhibitors, including amprenavir, are used in combination with these drugs.
`
`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).
`
`Because of the potential toxicity from the large amount of the excipient, propylene glycol, contained in AGENERASE
`Oral Solution , that formulation is contraindicated in certain patient populations and should be used with caution in
`others. Consult the complete prescribing information for AGENERASE Oral Solution for full information.
`
`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 close 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 ).
`
`Amprenavir is a sulfonamide. The potential for cross—sensitivity between drugs in the sulfonarnide class and amprenavir
`is unknown. AGENERASE should be used with caution in patients with a known sulfonamide allergy.
`
`AGENERASE is principally metabolized by the liver. AGENERASE, when used alone and in combination with
`low—dose ritonavir, has been associated with elevations of SGOT (AST) and SGPT (ALT) in some patients.
`Caution should be exercised when administering AGENERASE to patients with hepatic impairment (see DOSAGE
`AND ADMINISTRATION ). Appropriate laboratory testing should be conducted prior to initiating therapy with
`AGENERASE and at periodic intervals during treatment.
`
`é"'LexisNexis"
`
`é'"LexisNexis” é"‘LexisNexis“
`
`

`
`Physician's Desk Reference for Prescription Drugs
`
`Page 10
`
`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.
`
`Immune reconstitution syndrome has been reported in patients treated with
`Immune Reconstitution Syndrome:
`combination antiretroviral therapy, including AGENERASE. During the initial phase of combination antiretroviral
`treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual
`opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystisjirovecii pneumonia
`PCP , or tuberculosis), which may necessitate further evaluation and treatment.
`
`Fat Redistribution: Redistributionlaccumulation of body fat, including central obesity, dorsocervical fat enlargement
`(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," have been
`observed in patients receiving antiretroviral therapy. The mechanism and long—term consequences of these events are
`currently unknown. A causal relationship has not been established.
`
`Lipid Elevations: Treatment with AGENERASE alone or in combination with ritonavir has resulted in increases
`in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed
`prior to initiation of therapy with AGENERASE and at periodic intervals during treatment. Lipid disorders should be
`managed as clinically appropriate. See PRECAUTIONS Table 8: Established and Other Potentially Significant Drug
`Interactions for additional information on potential drug interactions with AGENERASE and HMG—CoA reductase
`inhibitors.
`
`ResistancefCross—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. It is also unknown what effect previous treatment with other protease inhibitors will have on the
`activity of arnprenavir (see MICROBIOLOGY ).
`
`lnforrnation for Patients: A statement to patients and healthcare providers is included on the product's bottle label:
`ALERT: Find out about medicines that should NOT be taken with AGENERASE. A Patient Package Insert (PPI) for
`AGENERASE Capsules is available for patient infonnation.
`
`Patients treated with AGENERASE Capsules should be cautioned against switching to AGENERASE Oral Solution
`because of the increased risk of adverse events from the large amount of propylene glycol in AGENERASE Oral
`Solution . Please see the complete prescribing information for AGENERASE Oral Solution for full 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 close 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
`
`é"‘LexisNexis“
`
`é'"LexisNexis"' LexisNexis“
`
`

`
`Physician's Desk Reference for Prescription Drugs
`
`Page 11
`
`sulfonamide class and amprenavir is unknown.
`
`AGENERASE may interact with many drugs; therefore, patients should be advised to report to their doctor the use of
`any other prescription or nonprescription medication or herbal products, particularly St. John's wort.
`
`Patients taking antacids (or the buffered formulation of didanosine) should t