CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-110
`
`APPROVED DRAFT LABELING
`
`West-Ward Exhibit 1058
`Rapamune Prescribing Information
`Page 001
`
`

`

`•••••••••••••••••••••••••••••••••••••••••••••••••••••••
`* WARNING:
`*
`*
`•
`Increased susceptibility to infection and the possible
`* development of lymphoma may result from immunosuppression.
`• Only physicians experienced in imrnunosuppressive therapy and
`• management ofrenal transplant patients should use Rapamune®. *
`• Patients receiving the drug should be managed in facilities
`•
`* equipped and staffed with adequate laboratory and supportive *
`* medical resources. The physician responsible for maintenance •
`* therapy should have complete information requisite for the
`*
`* follow-up of the patient.
`*
`*******************************************************
`
`1 Rapamune®
`2
`(sirolimus)
`3 Oral Solution and Tablets
`4
`5
`6
`7
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`10
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`17
`18
`DESCRIPTION
`19
`Rapamune® (sirolimus) is an imrnunosuppressive agent. Sirolimus is a macrocyclic lactone
`20
`produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as
`21
`rapamycin) is (3S,6R, 7E,9R,1OR,12R, l 4S,15£, 17£,19£,21 S,23S,26R,27 R,34aS)-
`22
`9, l 0, 12, 13, 14,21,22,23,24,25,26,27 ,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[ ( 1 R)-2-
`23
`[ ( 1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-
`24
`6,8, 12, l 4,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2, 1-c ][ 1,4] oxaazacyclohentriacontine-
`25
`1,5, 11,28,29 ( 4H,6H,31H)-pentone. Its molecular formula is C51H 79N013 and its molecular
`26
`27 weight is 914.2. The structural formula of sirolimus is shown below.
`28
`
`*
`•
`
`Title: I SIS/Draw: 11943
`Creator: Windows PS
`Creation Date:
`
`29
`30
`31
`32
`33
`34
`
`Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in
`bi::nzyl alcohol, chloroform, acetone, and acetonitrile.
`
`West-Ward Exhibit 1058
`Rapamune Prescribing Information
`Page 002
`
`

`

`Rapamune® is available for administration as an oral solution containing I mg/mL sirolimus
`and as a white, triangular-shaped tablet containing 1 mg sirolimus.
`
`The inactive ingredients in Rapamune~ Oral Solution are PhosaJ 50 PG~
`(phosphatidylcholine, propylene glycol, monodiglycerides, ethanol, soy fatty acids, and
`ascorbyl palmitate) and polys--hate 80. Rapamune Oral Solution contains 1.5% - 2.5%
`ethanol.
`
`The inactive ingredients in Rapamune~ Tablets include sucrose, lactose, polyethylene glycol
`8000, caJcium sulfate, microcrystalline cellulose, pharmaceutical glaze, taJc, titanium
`dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000,
`glyceryl monooleate, camauba wax, and other ingredients.
`
`35
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`48
`49 CLINICAL PHARMACOLOGY
`50 Mechanism of Action
`51
`Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to
`antigenic and cytokine (Interleukin [IL ]-2, IL-4, and IL-15) stimulation by a mechanism that
`52
`is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody
`53
`54
`production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-
`55
`12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no
`56
`effect on cakineurin activity. This complex binds to and inhibits the activation of the
`57 mammalian Target OfRapamycin (mTOR), a key regulatory kinase. This inhibition
`58
`suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G 1 to the
`S phase of the cell cycle.
`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`71
`72
`73
`74
`75
`76
`77
`78 Absorption
`
`Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin,
`islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs,
`and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and
`prolonged the graft survival in presensitized rats. In some studies, the immunosuppressive
`effect of sirolimus lasted up to 6 months after discontinuation of therapy. This tolerization
`effect is alloantigen specific.
`
`ln rodent models of autoimmune disease, sirolimus suppresses immune-mediated events
`associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I
`diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host
`disease, and autoimmune uveoretinitis.
`
`Pbarmacokinetics
`Sirolimus pharmacokinetic activity has been determined following oral administration in
`healthy subjects, pediatric dialysis patients, hepatically-impaired patients, and renal
`transplant patients.
`
`West-Ward Exhibit 1058
`Rapamune Prescribing Information
`Page 003
`
`

`

`(
`
`FoJlowing administration of Rapamune® Oral Solution, sirolimus is rapidly absorbed, with a
`mean time-to-peak concentration (lma,) of approximately 1 hour after a single dose in healthy
`subjects and approximately 2 hours after multiple oral doses in renal transplant recipients.
`The systemic availability of sirolimus was estimated to be approximately 14 % after the
`administration of Rapamune Oral Solution. The mean bioavailability of sirolimus after
`administration of the tablet is about 27% higher relative to the oral solution. Sirolimus oral
`tablets are not bioequivalent to the oral solution; however, clinical equivalence has been
`demonstrated at the 2-mg dose level. (See Clinical Studies and Dosage and Administration).
`Sirolimus concentrations, following the administration of Rapamune Oral Solution to stable
`renal transplant patients, are dose proportional between 3 and 12 mg/m2
`•
`
`Food effects: In 22 healthy volunteers receiving Rapamune Oral Solution, a high-fat meal
`( 1.88 kcal, 54. 7% fat) altered the bioavailability characteristics of sirolimus. Compared to
`fasting, a 34% decrease in the peak blood sirolimus concentration (CmaJ, a 3.5-fold increase
`in the time-to-peak concentration (\nax}, and a 35% increase in total exposure (AUC) was
`observed. After administration ofRapamune Tablets and a high-fat meal in 24 healthy
`volunteers, Cm.ax• lmax• and AUC showed increases of 65%, 32%, and 23%, respectively. To
`minimize variability, both Rapamune Oral Solution and Tablets should be taken consistently
`with or without food (See DOSAGE AND ADMINJSTRA TION).
`
`Distribution
`The mean (± SD) blood-to-plasma ratio of sirolimus was 36 (± 17 .9) in stable renal allograft
`recipients, indicating that sirolimus is extensively partitioned into formed blood elements.
`The mean volume of distribution {V5/F) of sirolimus is 12 ± 7.52 L/kg. Sirolimus is
`extensively bound (approximately 92%) to human plasma proteins. In man, the binding of
`sjrolimus was shown mainly to be associated with serum albumin (97%), a 1-acid
`glycoprotein, and lipoproteins.
`
`Metabolism
`Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein.
`Sirolimus is extensively metabolized by 0-demethylation and/or hydroxylation. Seven (7)
`major metabolites, including hydroxy, demethyl, and hydroxydemethyl, are identifiable in
`whole blood. Some of these metabolites are also detectable in plasma, fecal, and urine
`samples. Glucuronide and sulfate conjugates are not present in any of the biologic matrices.
`Sirolimus is the major component in human whole blood and contributes to more than 90%
`of the immunosuppressive activity.
`
`Excretion
`After a single dose of [1"C]sirolimus in healthy volunteers, the majority (91 %) of
`radioactivity was recovered from the feces, and only a minor amount (2.2%) was excreted in
`unne.
`
`79
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`110
`111
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`113
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`119
`120
`
`West-Ward Exhibit 1058
`Rapamune Prescribing Information
`Page 004
`
`

`

`Pharmacokinetics in renal transplant patients
`121
`122 Rapamune Oral Solution: Pharmacokinetic parameters for sirolimus oral solution given
`123
`daily in combination with cyclosporine and corticosteroids in renal transplant patients are
`124
`summarized below based on data collected at months 1, 3, and 6 after transplantation. There
`125 were no significant differences in any of these parameters with respect to treatment group or
`126 month.
`127
`
`SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN± SD) IN RENAL
`TRANSPLANT PATIENTS (MULTIPLE DOSE ORAL SOLUTION) Lb
`t..-...
`C.,_ .. '
`AUC, ... '
`CL/FfVITd
`(ng/mL)
`(ng•h/mL)
`(mL/h/kg)
`n
`(h)
`Dose
`12.2 ± 6.2
`158 ± 70
`3.01±2.40
`182 ± 72
`19
`2mg
`23
`37.4 ± 21
`1.84 ± 1.30
`396 ± 193
`221±143
`5mg
`a: Sirolimus administered four hours after cyclosporine oral solution (MODIFIED) (e.g.,
`Neoralir; Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g., Neora1• Soft
`Gelatiu Capsules).
`b: As measured by the Liquid Chromatographicffandem Mass Spectrometric Method
`(LC/MS/MS).
`c: These parameters were dose normalized prior to the statistical comparison.
`d: CL/F/WT = oral dose clearance.
`
`128
`129 Whole blood sirolimus trough concentrations, as measured by immunoassay, (mean± SD)
`for the 2 mg/day and 5 mg/day dose groups were 8.59 ± 4.01 ng/mL (n = 226) and 17.3 ±
`130
`7.4 ng/mL (n = 219), respectively. Whole blood trough sirolimus concentrations, as
`131
`132 measured by LC/MS/MS, were significantly correlated (r = 0.96) with AUC,,ss- Upon
`133
`repeated twice daily administration without an initial loading dose in a multiple-dose study,
`the average trough concentration of sirolimus increases approximately 2 to 3-fold over the
`134
`135
`initial 6 days of therapy at which time steady state is reached. A loading dose of 3 times the
`136 maintenance dose will provide near steady-state concentrations within 1 day in most
`13 7
`patients. The mean ± SD terminal elimination half life (t•h) of sirolimus after multiple
`138
`dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours.
`139
`140 Rapamune Tablets: Pharmacokinetic parameters for sirolimus tablets administered daily in
`141
`combination with cyclosporine and corticosteroids in renal transplant patients are
`summarized below based on data co11ected at months I and 3 after transplantation.
`142
`143
`
`West-Ward Exhibit 1058
`Rapamune Prescribing Information
`Page 005
`
`

`

`SIROLIMUS PHARMACOK.INETIC PARAMETERS (MEAN± SD) IN RENAL
`TRANSPLANT PATIENTS (MULTIPLE DOSE TABLETS) a.b
`emu ... c
`AUC, .... c
`t.n.. ....
`CLIF!Wr
`Dose
`(2 mg/day)
`n
`(ml/h/kg)
`(ng•h/ml)
`(ng/mL)
`(h)
`Oral solution
`17
`2.12 ± 0.84
`194 ± 78
`14.4 ± 5.3
`173 ± 50
`Tablets
`3.46 ± 2.40
`15.0 ± 4.9
`230± 67
`13
`139 ± 63
`a: Sirolimus administered four hours after cyclosporine oral solution (MODIFIED, \t.g.,
`Neoral:1 Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g., Neoral* Soft
`Gelatin Capsules).
`b: As measured by the Liquid Chrornatographicffandem Mass Spectrometric Method
`(LC/MS/MS).
`c: These parameters were dose normalized prior to the statistical comparison.
`d: CL/F/WT = weight-nonnalized oral dose clearance.
`
`144
`145 Who]e bJood siro]imus trough concentrations (mean± SD), as measured by immunoassay,
`146
`for the 2 mg ora] so]ution and 2 mg tab]ets over 6 months, were 8.94 ± 4.36 ng/mL (n = 172)
`147
`and 9.48 ± 3.85 ng/mL (n = 179), respectiveJy. Whole bJood trough sirolimus
`concentrations, as measured by LC/MS/MS, were significant1y correlated (r= 0.85) with
`148
`149 AUC,.ss· Mean whole b]ood sirolimus trough concentrations in patients receiving either
`150 Rapamune Ora] SoJution or Rapamune Tablets with a loading dose of three times the
`151 maintenance dose achieved steady-state concentrations within 24 hours after the start of dose
`152
`administration.
`153
`Special Populations
`154
`155 Hepatic impairment: Siro1imus (15 mg) was administered as a single oral dose to 18
`156
`subjects with norma] hepatic function and to 18 patients with Chi1d-Pugh classification A or
`15 i
`B hepatic impairment, in which hepatic impairm~nt was primary and not related to an
`underlying systemic disease. Shown be]ow are the mean ± SD pharmacokinetic parameters
`158
`foJlowing the administration of sirolimus ora] so]ution.
`159
`160
`
`SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN± SD) IN 18
`HEAL TIIY SUBJECTS AND 18 PATIENTS WITII HEPA TIC IMPAIRMENT
`( 15 MG SINGLE DOSE - ORAL SOLUTION)
`t,,,.,.
`C,,_3'$•
`AUCo..,
`(ng/ml)
`(h)
`(ng•hlml)
`Population
`78.2 ± 18.3
`0.82 ± 0.17
`970 ± 272
`Healthy subjects
`77.9±23.l
`0.84±0.17
`1567±616
`Hepatic impairment
`a: As measured by LC/MS/MS.
`
`CL/FtWT
`(mL!h/kg)
`215 ± 76
`144 ± 62
`
`161
`162 Compared with the va]ues in the nonna] hepatic group, the hepatic impairment group had
`163
`higher mean values for sirolimus AUC (61%) and t 112 (43%) and had lower mean values for
`siro1imus CL/FIWT (33%). The mean t112 increased from 79 ± 12 hours in subjects with
`164
`normal hepatic function to 113 ± 41 hours in patients with impaired hepatic function. The
`165
`rate of absorption of simlimus was not altered by hepatic disease, as evidenced by cmax and
`166
`167 ~ va]ues. However, hepatic diseases with varying etiologies may show different effects
`and the pharmacokinetics of sirolimus in patients with severe hepatic dysfunction is
`168
`
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`Rapamune Prescribing Information
`Page 006
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`

`

`(
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`169
`170
`171
`172
`173
`174
`175
`176
`177
`178
`
`unknown. Dosage adjustment is recommended for patients with mild to moderate hepatic
`impairment (see DOSAGE AND ADMINISTRATION).
`
`Renal impairment: The effect of renal impairment on the pharmacokinetics of sirolimus is
`not known. However, there is minimal (2.2%) renal excretion of the drug or its metabolites.
`
`Pediatric: Limited pharmacokinetic data are available in pediatric patients. The table below
`summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically
`impaired renal function.
`
`SIROLIMUS PHARMA CO KINETIC PARAMETERS (MEAN ±SD) IN PEDIATRIC PATIENTS
`WIIB ST ABLE CHRONIC RENAL FAIL URE MAINTAINED ON HEMODIAL YSIS OR
`PERITONEAL DIALYSIS (1, 3, 9, 15 MG/M2 SINGLE DOSE)
`CL/F/WT (mL/h/kg)
`t,,... (h)
`t112 (h)
`D
`9
`1.1 ± 0.5
`71 ± 40
`580 ± 450
`11
`0.79±0.17
`55±18
`450±232
`
`Age Group (y)
`5-11
`12-18
`
`179
`180 Geriatric: Clinical studies of Rapamune did not include a sufficient numbe; of patients > 65
`181
`years of age to determine whether they will respond differently than younger patients. After
`182
`the administration of Rapamune Oral Solution, sirolimus trough concentration data in 35
`renal transplant patients > 65 years of age were similar to those in the adult population
`183
`(n=822) 18 to 65 years of age. Similar results were obtained after the administration of
`184
`Rapamune Tablets to 12 renal transplant patients > 65 years of age compared with adults
`185
`186
`(n=167) 18 to 65 years of age.
`187
`188 Gender: After the administration of Rapamune Oral Solution, sirolimus oral dose clearance
`189
`in males was 12% lower than that in females; male subjects had a significantly longer 1112
`190
`than did female subjects (72.3 hours versus 61.3 hours). A similar trend in the effect of
`gender on sirolimus oral dose clearance and ty, was observed after the administration of
`191
`192
`Rapamune Tablets. Dose adjustments based on gender are not recommended.
`193
`194
`195
`196
`197
`198
`199
`200
`201
`202
`203 CLINICAL STUDIES
`Rapamune~ Oral Solution: The saf~ty and efficacy of Rapamune~ Oral Solution for the
`204
`205
`prevention of organ rejection following renal transplantation were assessed in two
`206
`randomized, double-blind, multicenter, controlled trials. These studies compared two dose
`levels ofRapamune Oral Solution (2 mg and 5 mg, once daily) with azathioprine (Study 1)
`207
`
`Race: In large phase III trials using Rapamune Oral Solution and cycJosporine oral solution
`(MODIFIED) (eg, Neoral~Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g.,
`Neoral~ Soft Gelatin Capsules), there were no significant differences in mean trough
`siroliMus concentrations over time between black (n = 139) and non-black (n = 724) patients
`during the first 6 months after transplantation at sirolimus doses of 2 mg/day and 5 mg/day.
`Similarly, after administration of Rapamune Tablets (2 mg/day) in a phase Ill trial, mean
`sirolimus trough concentrations over 6 months were not significantly different among black
`(n = 51) and non-black (n = 128) patients.
`
`West-Ward Exhibit 1058
`Rapamune Prescribing Information
`Page 007
`
`

`

`or placebo (Study 2) when administered in combination with cycJosporine and
`corticosteroids. Study 1 was conducted in the United States at 38 sites. Seven hundred
`nineteen (719) patients were enroJled in this trial and randomized foJlowing transplantation;
`284 were randomized to receive Rapamune Oral Solution 2 mg/day, 274 were randomized to
`receive Rapamune Oral Solution 5 mg/day, and 161 to receive azathioprine 2-3 mg/kg/day.
`Study 2 was conducted in Au~.n1lia, Canada, Europe, and the United States, at a total of 34
`sites. Five hundred seventy-six (576) patients were enrolled in this trial and randomized
`before transplantation; 227 were randomized to receive Rapamune Oral Solution 2 mg/day,
`219 were randomized to receive Rapamune Oral Solution 5 mg/day, and 130 to receive
`placebo. In both studies, the use of antilymphocyte antibody induction therapy was
`prohibited. In both studies, the primary efficacy endpoint was the rate of efficacy failure in
`the first 6 months after transplantation. Efficacy failure was defined as the first occurrence
`of an acute rejection episode ( confinned by biopsy), graft loss, or death.
`
`The tables below summarize the results of the primary efficacy analyses from these trials.
`Rapamune Oral Solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the
`incidence of efficacy failure (statistical1y significant at the <0.025 level; nominal
`significance level adjusted for multiple [2] dose comparisons) at 6 months following
`transplantation compared to both azathioprine and placebo.
`
`Parameter
`
`INCIDENCE(%) OF THE PRIMARY ENDPOTh'T AT 6 MONTHS: STIJDY 11
`Rapamune®
`Rapamune®
`Azathioprine
`2-3 mg/kg/day
`Oral Solution
`Oral Solution
`2 mg/day
`(n= 161)
`5 mg/day
`(n = 284)
`(n = 274)
`16.8
`
`l 8.7
`
`Efficacy failure at 6 months
`Components of efficacy failure
`16.5
`Biopsy-proven acute rejection
`1.1
`Graft Joss
`0.7
`Death
`0.4
`Lost to follow-up
`Patients received cyclosporine and corticosteroids.
`
`32.3
`
`11.3
`2.9
`1.8
`0.7
`
`29.2
`2.5
`0
`0.6
`
`a:
`
`INCIDENCE (%)OF THE PRIMARY ENDPOINT AT 6 MONTHS: STIIDY 2 1
`Rapamune1
`Rapamune1
`Oral Solution
`Oral Solution
`5 mg/day
`2 mg/day
`(n = 227)
`(n = 219)
`30.0
`25.6
`
`Placebo
`(n = 130)
`
`47.7
`
`Parameter
`Efficacy failure at 6 months
`Components of efficacy failure
`24.7
`Biopsy-proven acute rejection
`Graft los:;
`3.1
`2.2
`Death
`Lost to follow-up
`0
`Patients received cyclosporine and corticosteroids.
`
`a:
`
`19.2
`3.7
`2.7
`0
`
`41.5
`3.9
`2.3
`0
`
`!
`\
`
`208
`209
`210
`21 l
`212
`213
`214
`215
`216
`217
`218
`219
`220
`221
`222
`223
`224
`225
`226
`227
`228
`
`229
`
`230
`
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`Rapamune Prescribing Information
`Page 008
`
`

`

`.......
`,t._., 1
`232
`233
`234
`235
`
`Patient and graft survival at 1 year were co-primary endpoints. The table below shows graft
`and patient survival at 1 year in Study 1 and Study 2. The graft and patient survival rates at
`I year were similar in the Rapamune- and comparator-treated patients.
`
`Parameter
`
`I-YEAR GRAFT AND PATIENT SUR VIV AL (%)"
`Rapamuneit
`Rapamunelf
`Azathioprine
`. 2-3 mg/kg/day
`Oral Solution
`Oral Solution
`5 mg/day
`2 mg/day
`(n = 274)
`(n = 284)
`Study I
`94.7
`Graft survival
`92.7
`97 .2
`Patient survival
`96.0
`(n = 227)
`Study 2
`(n = 219)
`89.9
`Graft survival
`90.9
`95.0
`96.5
`Patient survival
`a: Patients received cyclosporine and corticosteroids.
`
`(n= 161)
`93.8
`98.l
`
`Placebo
`
`(o = 130)
`87.7
`94.6
`
`236
`The reduction in the incidence of first biopsy-confirmed acute rejection episodes in
`237
`238 Rapamune-treated patients compared to the control groups included a reduction in aH grades
`of rejection.
`239
`240
`
`PERCENT AGE OF EFFICACY FAIL URE BY RACE AT 6 MONTIIS
`Rapamune1
`Rapamune®
`Azathioprine
`Oral Solution
`2-3 mg/kg/day
`Oral Solution
`5 mg/day
`2 mg/day
`
`Parameter
`
`Placebo
`
`Study 1
`Black (n=l66)
`Nonblack (n=553)
`Study 2
`Black (n=66)
`Non-black (n=5 l 0)
`
`34.9 (n=63)
`14.0 (n=221)
`
`18.0 (n=61)
`16.4 ( n=213)
`
`33.3 (n=42)
`31.9(n=l19)
`
`30.8 (n=26)
`29.9 (n=201)
`
`33.7 (n=27)
`24.5 (n=l92)
`
`38.5 (n=13)
`48.7(n=l17)
`
`241
`In Study I, which was prospectively stratified by race within center, efficacy failure was
`242
`similar for Rapamune Oral Solution 2 mg/day and lower for Rapamune Oral Solution
`243
`5 mg/day compared to azathioprine in black patients. In Study 2, which was not
`244
`prospectively stratified by race, efficacy failure was similar for both Rapamune Oral
`245
`Solution doses compared to placebo in black patients. The decision to use the higher dose of
`246
`24 7 Rapamune Oral Solution in black patients must be weighed against the increased risk of
`dose-dependent adverse events that were observed with the Rapamune Oral Solution 5 mg
`248
`dose (see ADVERSE REACTIONS).
`249
`250
`
`West-Ward Exhibit 1058
`Rapamune Prescribing Information
`Page 009
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`

`(
`
`Parameter
`Study I
`Mean (SE)
`Study 2
`
`Mean (SE)
`
`(n=l 90)
`54.9 (1.26)
`
`OVERALL CALCULATED GLOMERULAR FILTRATION RA TES (CC/MIN) BY NANJUVELL
`EQUATION AT 12 MONTIIS POST TRANSPLANT
`Rapamune®
`Rapamune®
`Azathioprine
`2-3 mg/kg/day
`Oral Solution
`Oral Solution
`5 mg/day
`2 mg/day
`(n=233)
`(n=226)
`57.4 ( 1.28)
`55.1 (1.28)
`(n=175)
`52.9 (l.46)
`
`(n=J27)
`65.9 (J.69)
`
`Placebo
`
`(n=IOI)
`61.7 (J.81)
`
`251
`252
`253
`254
`255
`256
`257
`258
`259
`260
`261
`262
`263
`264
`265
`266
`267
`268
`269
`270
`271
`272
`273
`274
`275
`276
`277
`278
`279
`280
`281
`282
`283
`
`Mean glomerular filtration rates (GFR) at one year post transplant were caJculated by using
`the NankivelJ equation for alJ subjects in Studies 1 and 2 who had serum creatinine
`measured at 12 months. In Studies I and 2 mean GFR, at 12 months, were lower in patients
`treated with cycJosporine and Rapamune Oral Solution compared to those treated with
`cycJosporine and the respective azathioprine or placebo control.
`
`Within each treatment group in Studies l and 2, mean GFR at one year post transplant was
`lower in patients who experienced at least l episode of biopsy-proven acute rejection,
`compared to those who did not.
`
`Renal function should be monitored and appropriate adjustment of the immunosuppression
`regimen should be considered in patients with elevated serum creatinine levels (see
`PRECAUTIONS).
`
`Rapamune® Tablets: The safety and efficacy ofRapamune Oral Solution and Rapamune
`Tablets for the prevention of organ rejection following renal transplantation were compared
`in a randomized multicenter controJied trial (Study 3). This study compared a single dose
`level (2 mg, once daily) ofRapamune Oral Solution and Rapamune Tablets when
`administered in combination with cycJosporine and corticosteroids. The study was
`conducted at 30 centers in Australia, Canada, and the United States. Four hundred seventy(cid:173)
`seven (477) patients were enrolled in this study and randomized before transplantation; 238
`patients were randomized to receive Rapamune Oral Solution 2 mg/day and 239 patients
`were randomized to receive Rapamune Tablets 2 mg/day. In this study, the use of
`antilympr..ocyte antibody induction therapy was prohibited. The primary efficacy endpoint
`was the rate of efficacy failure in the first 3 months after transplantation. Efficacy failure
`was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft
`Joss, or death.
`
`The table below summarizes the result of the primary efficacy analysis at 3 months from this
`trial. The overa11 rate of efficacy failure in the tablet treatment group was equivalent to the
`rate in the oral solution treatment group.
`
`West-Ward Exhibit 1058
`Rapamune Prescribing Information
`Page 0010
`
`

`

`l
`
`INCIDENCE (%)OF THE PRJMARY ENDPOINT AT 3 MOJ\TTHS: STIJDY 31
`Rapamune
`Rapamune~
`Oral Solution
`Tablets
`(n = 239)
`(n = 238)
`
`Efficacy Failure at 3 months
`Components of efficacy failure
`Biopsy-proven acute rejection
`18.9
`Graft loss
`3.4
`1.3
`Death
`a: Patients received cyclosporine and corticosteroids.
`
`23.5
`
`24.7
`
`17.6
`6.3
`0.8
`
`284
`285
`286
`287
`
`The table below summarizes the results of the primary efficacy analysis at 6 months after
`transplantation.
`INCIDENCE(%) OF THE PRJMARY ENDPOINT AT 6 MONTHS: SlUDY 3"
`Rapamune1
`Rapamune®
`Oral Splution
`Tablets
`(n = 239)
`(n = 238)
`
`Efficacy Failure at 6 months
`Components of efficacy failure
`21.0
`Biopsy-proven acute rejection
`Graft loss
`3.4
`Death
`1.7
`a: Patients received cyclosporine and corticosteroids.
`
`26.1
`
`27.2
`
`19.2
`6.3
`1.7
`
`288
`289 Graft and patient survival at 12 months were co-primary efficacy endpoints. There was no
`290
`significant difference between the oral solution and tablet formulations for both graft and
`291
`patient survival. Graft survival was 92.0% and 88.7% for the oral solution and tablet
`292
`treatment groups, respectively. The patient survival rates in the oral solution and tablet
`293
`treatment groups were 95.8% and 96.2%, respectively.
`294
`295
`296
`297
`298
`299
`300
`
`The mean GFR at 12 months, calculated by the Nankivell equation, were not significantly
`different for the oral solution group and for the tablet group.
`
`fhe table below summarizes the mean GFR at one-year post-transplantation for all subjects
`in Study 3 who had serum creatinine measured at 12 months.
`
`OVERALL CALCULATED GLOMERULAR FILTRATION RA TES (CC/MIN) BY
`NANKIVELL EQUA TJON AT 12 MONTIIS POST TRANSPLANT: STIJDY 3
`Rapamune
`Rapamune
`Oral Solution
`Tablets
`58.3 (l.64)
`58.S (l.44)
`n=l~
`n=l~
`
`Mean (SE)
`
`301
`
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`Rapamune Prescribing Information
`Page 0011
`
`

`

`INDICATIONS AND USAGE
`Rapamune is indicated for the prophylaxis of organ rejection in patients receiving renal
`transplants. It is recommended that Rapamune be used in a regimen with cyclosporine and
`corticosteroids.
`
`3U2
`303
`304
`305
`306
`307
`308 CONTRAINDICATIONS
`309 Rapamune is contraindicated in patients with a hypersensitivity to sirolimus or its
`310
`derivatives or any component of the drug product.
`311
`312
`313 WARNINGS
`314
`. Increased susceptibiJity to infection and the possible development of lymphoma and other
`315 malignancies, particularly of the skin, may result from immunosuppression (see ADVERSE
`316 REACTIONS). Oversuppression of the immune system can also increase susceptibility to
`317
`infection including opportunistic infections, fatal infections, and sepsis. Only physicians
`318
`experienced in immunosuppressive therapy and management of organ transplant patients
`319
`should use Rapamune. Patients receiving the drug should be managed in facilities equipped
`320
`and staffed with adequate laboratory and supportive medical resources. The physician
`321
`responsible for maintenance therapy should have complete information requisite for the
`fo11ow-up of the patient.
`322
`323
`324 As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light
`325
`should be limited by wearing protective clothing and using a sunscreen with a high
`326
`protection factor.
`32i
`328
`329
`330
`331
`In phase III studies, mean serum creatinine was increased and mean glomerular filtration rate
`332
`333 was decreased in patients treated with Rapamune and cyclosporine compared to those treated
`334 with cyclosporine and placebo or azathioprine controls (see CLINJCAL STUDIES). Rc.nal
`335
`function should be monitored during the administration of maintenance immunosuppression
`336
`regimens including Rapamune in combination with cyclosporine, and appropriate
`337
`adjustment of the immunosuppression regimen should be considered in patients with
`elevated serum creatinine h:vels. Caution should be exercised when using agents which are
`338
`339
`known to impair renal function (see PRECAUTIONS).
`340
`341
`In clinical trials, Rapamune has been administered concurrently with corticosteroids and
`342
`343 with the following formulations of cyclosporine:
`344
`345
`346
`
`Increased serum cholesterol and triglycerides, that may require treatment, occurred more
`frequently in patients treated with Rapamune compared to azathioprine or placebo controls.
`(see PRECAUTIONS).
`
`Sandimmunc® Injection (cyclosporine injection)
`Sa.-idimmune~ Oral Solution (cyclosporine oral solution)
`
`West-Ward Exhibit 1058
`Rapamune Prescribing Information
`Page 0012
`
`

`

`Sandimmuneg Soft Gelatin Capsu]es (cyclosporine capsules)
`Neora]~ Soft Gelatin Capsules (cycJosporine capsules [MODIFIED])
`Neoral~ Oral Solution (cycJosporine ora] solution [MODIFIED])
`
`The efficacy and safety of the use of Raparnune in combination with other
`immunosuppressive agents has not been determined.
`
`347
`348
`349
`350
`351
`352
`353
`354
`355
`PRECAUTIONS
`356 General
`357 Raparnune is intended for ora] administration only.
`358
`· Lymphoce]e, a known surgical complication ofrena] transplantation, occurred significantly
`359
`360 more often in a dose-related fashion in Raparnune-treated patients. Appropriate post-
`361
`operative measures should be considered to minimize this complication.
`362
`363
`364
`365
`366
`367
`368
`369
`3 70
`3 71
`372
`In pnase III cJinica] tria]s, in de novo rena] transplant recipients who began the study with
`373
`normal, fasting, total serum triglycerides (fasting serum triglycerides< 200 mg/dL), there
`374
`375 was an increased incidence ofhypertrig]yceridemia (fasting serum triglycerides> 500
`376 mg/dL) in patients receiving Raparnune® 2 mg and Raparnune® 5 mg compared to
`377
`azathioprine and placebo controls.
`378
`379
`380
`381
`382
`383 Rena] transplant patients have a higher prevalence of clinically significant hyper1ipidemia.
`384 Accordingly, the risk/benefit should be carefully considered in patients with established
`385
`hyper1ipidemia before initiating an imrnunosuppressive regimen including Raparnune.
`386
`387 Any patient who is administered Raparnune should be monitored for hyperJipidemia using
`388
`laboratory tests and ifhyperlipidemia is detected, subsequent interventions such as diet, ·
`389
`exercise, and lipid-lowering agents, as outlined by the National Cho]estero] Education
`390
`Program guidelines, should be initiated.
`
`In phase III c1inical trials, in de novo renal transplant recipients who began the study with
`normal, fasting, total serum cho]estero] (fasting serum cholesterol< 200 mg/dL), there was
`an increased incidence of hypercholestero]emia (fasting serum cho1estero1 > 240 mg/dL) in
`patients receiving both Rapamune® 2 mg and Rapamune® 5 mg compared to azathioprine
`and placebo controls.
`
`Lipids
`The use ofRapamune® in renal transplant patients was associated with increased serum
`cho1estero1 and triglycerides that may require treatment.
`
`Treatment of new-onset hypercho1estero1emia with Jipid-Jowering agents was required in 42
`-52% of patients enrolled in the Raparnune arms of the study compared to 16% of patients in
`the placebo arm and 22% of patients in the azathioprine arm.
`
`West-Ward Exhibit 1058
`Rapamune Prescribing Information
`Page 0013
`
`

`

`Renal Function
`Patients treated with cyclosporine and Rapamune were noted to have higher serum creatinine
`levels and lower glomerular filtration rates compared to patients treated with cyclosporine
`and placebo or azathioprine controls. Renal function should be monitored during the
`administration of maintenance immunosuppression regimens including Rapamtine in
`combination with cyclosporine, and appropriate adjustment of the immunosuppression
`regimen should be considered in patients with elevated serum creatinine levels. Caution
`should be exercised when using agents (eg, aminoglycosides, and amphotericin B) that are
`known to have a deleterious effect on renal function.
`
`391
`In the limited number of patients studied, the concomitant administration ofRapamune and
`392
`393 HMG-CoA reductase inhibitors and/or fibrates appeared to be well tolerated. Nevertheless,
`394 . alJ patients administered Rapamune with cyclosporine, in conjunction with an HMG-CoA
`395
`reductase inhibitor, should be monitored for the development ofrhabdomyolysis.
`396
`397
`398
`399
`400
`401
`402
`403
`404
`405
`406
`407
`Antimicrobial Propltylaxis
`408 Cases