Generic Name: (Sirolimus)
Dosage Type: tablet, sugar coated

Generic Name: (Sirolimus)
Dosage Type: solution
Organization: Wyeth Pharmaceuticals, Inc.

Rx only

DESCRIPTION

Rapamune® (sirolimus) is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone. Its molecular formula is C51H79NO13 and its molecular weight is 914.2. The structural formula of sirolimus is shown below.

Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.

Rapamune® is available for administration as an oral solution containing 1 mg/mL sirolimus. Rapamune is also available as a white, triangular-shaped tablet containing 1-mg sirolimus, and as a yellow to beige triangular-shaped tablet containing 2-mg sirolimus.

The inactive ingredients in Rapamune® Oral Solution are Phosal 50 PG® (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Rapamune Oral Solution contains 1.5% - 2.5% ethanol.

The inactive ingredients in Rapamune® Tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl-alpha tocopherol, and other ingredients. The 2 mg dosage strength also contains iron oxide yellow 10 and iron oxide brown 70.

CLINICAL PHARMACOLOGY

Mechanism Of Action

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 is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.

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 prolongs the graft survival in presensitized rats. In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen specific.

In 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.

Pharmacokinetics

Sirolimus pharmacokinetic activity has been determined following oral administration in healthy subjects, pediatric patients, hepatically-impaired patients, and renal transplant patients.

Absorption

Following administration of Rapamune® Oral Solution, sirolimus is rapidly absorbed, with a mean time-to-peak concentration (tmax) 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 (861.8 kcal, 54.9% kcal from fat) altered the bioavailability characteristics of sirolimus. Compared with fasting, a 34% decrease in the peak blood sirolimus concentration (Cmax), a 3.5-fold increase in the time-to-peak concentration (tmax), and a 35% increase in total exposure (AUC) was observed. After administration of Rapamune Tablets and a high-fat meal in 24 healthy volunteers, Cmax, tmax, 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 ADMINISTRATION).

Distribution

The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft recipients after administration of oral solution, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (Vss/F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins. In man, the binding of sirolimus was shown mainly to be associated with serum albumin (97%), a1-acid glycoprotein, and lipoproteins.

Metabolism

Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein (P-gp). Sirolimus is extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-gp drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Therefore, absorption and subsequent elimination of systemically absorbed sirolimus may be influenced by drugs that affect these proteins. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations. (See WARNINGS and PRECAUTIONS, Drug Interactions and Other drug interactions). Sirolimus is extensively metabolized by O-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 [14C]sirolimus oral solution in healthy volunteers, the majority (91%) of radioactivity was recovered from the feces, and only a minor amount (2.2%) was excreted in urine.

Pharmacokinetics In Renal Transplant Patients

Rapamune Oral Solution: Pharmacokinetic parameters for sirolimus oral solution given daily in combination with cyclosporine and corticosteroids in renal transplant patients are summarized below based on data collected at months 1, 3, and 6 after transplantation (Studies 1 and 2; see CLINICAL STUDIES). There were no significant differences in any of these parameters with respect to treatment group or month.

SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN RENAL TRANSPLANT PATIENTS (MULTIPLE DOSE ORAL SOLUTION)a,b

		Cmax,ssc	tmax,ss	AUCt,ssc	CL/F/WTd
N	Dose	(ng/mL)	(h)	(ng•h/mL)	(mL/h/kg)
a: Sirolimus administered four hours after cyclosporine oral solution (MODIFIED) (e.g., Neoral® Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g., Neoral® Soft Gelatin Capsules). b: As measured by the Liquid Chromatographic/Tandem Mass Spectrometric Method (LC/MS/MS). c: These parameters were dose normalized prior to the statistical comparison. d: CL/F/WT = oral dose clearance.
19	2 mg	12.2 ± 6.2	3.01 ± 2.40	158 ± 70	182 ± 72
23	5 mg	37.4 ± 21	1.84 ± 1.30	396 ± 193	221 ± 143

Whole blood sirolimus trough concentrations (mean ± SD), expressed as chromatographic assay values, for the 2 mg/day and 5 mg/day dose groups were 6.9 ± 3.2 ng/mL (n = 226) and 13.8 ± 5.9 ng/mL (n = 219), respectively (see DOSAGE AND ADMINISTRATION). Whole blood trough sirolimus concentrations, as measured by LC/MS/MS, were significantly correlated (r2 = 0.96) with AUCt,ss. Upon 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 initial 6 days of therapy at which time steady state is reached. A loading dose of 3 times the maintenance dose will provide near steady-state concentrations within 1 day in most patients. The mean ± SD terminal elimination half life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours.

Rapamune Tablets: Pharmacokinetic parameters for sirolimus tablets administered daily in combination with cyclosporine and corticosteroids in renal transplant patients are summarized below based on data collected at months 1 and 3 after transplantation (Study 3; see CLINICAL STUDIES).

SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN RENAL TRANSPLANT PATIENTS (MULTIPLE DOSE TABLETS)a,b

	Dose	Cmax,ssc	tmax,ss	AUCt,ssc	CL/F/WTd
n	(2 mg/day)	(ng/mL)	(h)	(ng•h/mL)	(mL/h/kg)
a: Sirolimus administered four hours after cyclosporine oral solution (MODIFIED) (e.g., Neoral® Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g., Neoral® Soft Gelatin Capsules). b: As measured by the Liquid Chromatographic/Tandem Mass Spectrometric Method (LC/MS/MS). c: These parameters were dose normalized prior to the statistical comparison. d: CL/F/WT = oral dose clearance.
17	Oral solution	14.4 ± 5.3	2.12 ± 0.84	194 ± 78	173 ± 50
13	Tablets	15.0 ± 4.9	3.46 ± 2.40	230 ± 67	139 ± 63

Whole blood sirolimus trough concentrations (mean ± SD), expressed as chromatographic assay values, for 2 mg of oral solution and 2 mg of tablets over 6 months, were 7.1 ± 3.5 ng/mL (n = 172) and 7.6 ± 3.1 ng/mL (n = 179), respectively (see DOSAGE AND ADMINISTRATION). Whole blood trough sirolimus concentrations, as measured by LC/MS/MS, were significantly correlated (r2 = 0.85) with AUCt,ss. Mean whole blood sirolimus trough concentrations in patients receiving either Rapamune Oral Solution or Rapamune Tablets with a loading dose of three times the maintenance dose achieved steady-state concentrations within 24 hours after the start of dose administration.

Average Rapamune doses and sirolimus whole blood trough concentrations for tablets administered daily in combination with cyclosporine and following cyclosporine withdrawal, in combination with corticosteroids in renal transplant patients (Study 4; see CLINICAL STUDIES) are summarized in the table below.

AVERAGE RAPAMUNE DOSES AND SIROLIMUS TROUGH CONCENTRATIONS (MEAN ± SD) IN LOW- TO MODERATE- RISK RENAL TRANSPLANT PATIENTS AFTER MULTIPLE DOSE TABLET ADMINISTRATION

	Rapamune with Cyclosporine Therapya	Rapamune Following Cyclosporine Withdrawala
a: 215 patients were randomized to each group. b: Expressed as chromatographic assay values and equivalence.
Rapamune Dose (mg/day)
Months 4 to 12	2.1 ± 0.7	8.2 ± 4.2
Months 12 to 24	2.0 ± 0.8	6.4 ± 3.0
Months 24 to 36	2.0 ± 0.8	5.3 ± 2.5
Sirolimus Cmin, (ng/mL)b
Months 4 to 12	8.6 ± 3.0	18.6 ± 4.0
Months 12 to 24	9.0 ± 3.3	18.0 ± 3.8
Months 24 to 36	9.1 ± 3.4	16.3 ± 4.3

The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state required approximately 6 weeks. Larger Rapamune® doses were required due to the absence of the inhibition of sirolimus metabolism and transport by cyclosporine and to achieve higher target concentrations during concentration-controlled administration following cyclosporine withdrawal.

Average Rapamune doses and sirolimus whole blood trough concentrations for tablets administered daily in combination with cyclosporine and corticosteroids in high-risk renal transplant patients (Study 5; see CLINICAL STUDIES) are summarized in the table below.

AVERAGE RAPAMUNE DOSES AND SIROLIMUS TROUGH CONCENTRATIONS (MEAN ± SD) IN HIGH-RISK RENAL TRANSPLANT PATIENTS AFTER MULTIPLE-DOSE TABLET ADMINISTRATION

	Rapamune with Cyclosporine Therapy
a: Expressed by chromatography b: n=109 c: n=113 d: n=127
Rapamune Dose (mg/day)
Months 3 to 6	5.1 ± 2.4
Months 6 to 9	5.1 ± 2.3
Months 9 to 12	5.0 ± 2.3
Sirolimus Cmin (ng/mL)a
Months 3 to 6b	11.8 ± 4.2
Months 6 to 9c	11.3 ± 5.2
Months 9 to 12d	11.2 ± 3.8

Special Populations

Hepatic impairment: Sirolimus oral solution (15 mg) was administered as a single oral dose to 18 subjects with normal hepatic function and to 18 patients with Child-Pugh classification A or B hepatic impairment, in which hepatic impairment was primary and not related to an underlying systemic disease. Shown below are the mean ± SD pharmacokinetic parameters following the administration of sirolimus oral solution.

SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN 18 HEALTHY SUBJECTS AND 18 PATIENTS WITH HEPATIC IMPAIRMENT (15 MG SINGLE DOSE – ORAL SOLUTION)

Population	Cmax,ssa	tmax	AUC0-8	CL/F/WT
	(ng/mL)	(h)	(ng•h/mL)	(mL/h/kg)
a: As measured by LC/MS/MS.
Healthy subjects	78.2 ± 18.3	0.82 ± 0.17	970 ± 272	215 ± 76
Hepatic impairment	77.9 ± 23.1	0.84 ± 0.17	1567 ± 616	144 ± 62

Compared with the values in the normal hepatic group, the hepatic impairment group had higher mean values for sirolimus AUC (61%) and t1/2 (43%) and had lower mean values for sirolimus CL/F/WT (33%). The mean t1/2 increased from 79 ± 12 hours in subjects with normal hepatic function to 113 ± 41 hours in patients with impaired hepatic function. The rate of absorption of sirolimus was not altered by hepatic disease, as evidenced by Cmax and tmax values. However, hepatic diseases with varying etiologies may show different effects and the pharmacokinetics of sirolimus in patients with severe hepatic dysfunction is 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: Sirolimus pharmacokinetic data were collected in concentration-controlled trials of pediatric renal transplant patients who were also receiving cyclosporine and corticosteroids. The target ranges for trough concentrations were either 10-20 ng/mL for the 21 children receiving tablets, or 5-15 ng/mL for the one child receiving oral solution. The children aged 6-11 years (n = 8) received mean ± SD doses of 1.75 ± 0.71 mg/day (0.064 ± 0.018 mg/kg, 1.65 ± 0.43 mg/m2). The children aged 12-18 years (n = 14) received mean ± SD doses of 2.79 ± 1.25 mg/day (0.053 ± 0.0150 mg/kg, 1.86 ± 0.61 mg/m2). At the time of sirolimus blood sampling for pharmacokinetic evaluation, the majority (80%) of these pediatric patients received the sirolimus dose at 16 hours after the once daily cyclosporine dose.

SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC RENAL TRANSPLANT PATIENTS (MULTIPLE DOSE CONCENTRATION CONTROL)a,b

Age (y)	n	Body weight (kg)	Cmax,ss (ng/mL)	tmax,ss (h)	Cmin,ss (ng/mL)	AUCt,ss (ng•h/mL)	CL/Fc (mL/h/kg)	CL/Fc (L/h/m2)
a: Sirolimus co-administered with cyclosporine oral solution (MODIFIED) (e.g., Neoral Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g., Neoral Soft Gelatin Capsules). b: As measured by Liquid Chromatographic/Tandem Mass Spectrometric Method (LC/MS/MS). c: Oral-dose clearance adjusted by either body weight (kg) or body surface area (m2).
6-11	8	27 ± 10	22.1 ± 8.9	5.88 ± 4.05	10.6 ± 4.3	356 ± 127	214 ± 129	5.4 ± 2.8
12-18	14	52 ± 15	34.5 ± 12.2	2.7 ± 1.5	14.7 ± 8.6	466 ± 236	136 ± 57	4.7 ± 1.9

The table below summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically impaired renal function.

SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC PATIENTS WITH STABLE CHRONIC RENAL FAILURE MAINTAINED ON HEMODIALYSIS OR PERITONEAL DIALYSIS (1, 3, 9, 15 MG/M2 SINGLE DOSE)*

Age Group (y)	n	tmax (h)	t1/2 (h)	CL/F (mL/h/kg)
* All subjects received sirolimus oral solution
5-11	9	1.1 ± 0.5	71 ± 40	580 ± 450
12-18	11	0.79 ± 0.17	55 ± 18	450 ± 232

Geriatric: Clinical studies of Rapamune did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. After 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 (n = 822) 18 to 65 years of age. Similar results were obtained after the administration of Rapamune Tablets to 12 renal transplant patients >65 years of age compared with adults (n = 167) 18 to 65 years of age.

Gender: After the administration of Rapamune Oral Solution, sirolimus oral dose clearance in males was 12% lower than that in females; male subjects had a significantly longer t1/2 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 t1/2 was observed after the administration of Rapamune Tablets. Dose adjustments based on gender are not recommended.

Race: In large phase 3 trials (Studies 1 and 2) using Rapamune Oral Solution and cyclosporine oral solution (MODIFIED) (e.g., 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 III trial, mean sirolimus trough concentrations over 6 months were not significantly different among black (n = 51) and non-black (n = 128) patients.

CLINICAL STUDIES

Rapamune® Oral Solution: The safety and efficacy of Rapamune® Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials. These studies compared two dose levels of Rapamune Oral Solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids. Study 1 was conducted in the United States at 38 sites. Seven hundred nineteen (719) patients were enrolled in this trial and randomized following 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 Australia, 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 (confirmed 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 (statistically significant at the<0.025 level; nominal significance level adjusted for multiple [2] dose comparisons) at 6 months following transplantation compared with both azathioprine and placebo.

INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 24 MONTHS FOR STUDY 1a,b

Parameter	Rapamune® Oral Solution 2 mg/day (n = 284)	Rapamune® Oral Solution 5 mg/day (n = 274)	Azathioprine 2-3 mg/kg/day (n = 161)
a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment. c: Primary endpoint.
Efficacy failure at 6 monthsc	18.7	16.8	32.3
Components of efficacy failure
Biopsy-proven acute rejection	16.5	11.3	29.2
Graft loss	1.1	2.9	2.5
Death	0.7	1.8	0
Lost to follow-up	0.4	0.7	0.6
Efficacy failure at 24 months	32.8	25.9	36.0
Components of efficacy failure
Biopsy-proven acute rejection	23.6	17.5	32.3
Graft loss	3.9	4.7	3.1
Death	4.2	3.3	0
Lost to follow-up	1.1	0.4	0.6

INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 36 MONTHS FOR STUDY 2a,b

Parameter	Rapamune® Oral Solution 2 mg/day (n = 227)	Rapamune® Oral Solution 5 mg/day (n = 219)	Placebo (n = 130)
a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment. c: Primary endpoint.
Efficacy failure at 6 monthsc	30.0	25.6	47.7
Components of efficacy failure
Biopsy-proven acute rejection	24.7	19.2	41.5
Graft loss	3.1	3.7	3.9
Death	2.2	2.7	2.3
Lost to follow-up	0	0	0
Efficacy failure at 36 months	44.1	41.6	54.6
Components of efficacy failure
Biopsy-proven acute rejection	32.2	27.4	43.9
Graft loss	6.2	7.3	4.6
Death	5.7	5.9	5.4
Lost to follow-up	0	0.9	0.8

Patient and graft survival at 1 year were co-primary endpoints. The table below shows graft and patient survival at 1 and 2 years in Study 1 and 1 and 3 years in Study 2. The graft and patient survival rates were similar in patients treated with Rapamune and comparator-treated patients.

GRAFT AND PATIENT SURVIVAL (%) FOR STUDY 1 (12 AND 24 MONTHS) AND STUDY 2 (12 AND 36 MONTHS)a,b

Parameter	Rapamune® Oral Solution 2 mg/day	Rapamune® Oral Solution 5 mg/day	Azathioprine 2-3 mg/kg/day	Placebo
a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment.
Study 1	(n = 284)	(n = 274)	(n = 161)
Graft survival
Month 12	94.7	92.7	93.8
Month 24	85.2	89.1	90.1
Patient survival
Month 12	97.2	96.0	98.1
Month 24	92.6	94.9	96.3
Study 2	(n = 227)	(n = 219)		(n = 130)
Graft survival
Month 12	89.9	90.9		87.7
Month 36	81.1	79.9		80.8
Patient survival
Month 12	96.5	95.0		94.6
Month 36	90.3	89.5		90.8

The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with Rapamune compared with the control groups included a reduction in all grades of rejection.

In Study 1, which was prospectively stratified by race within center, efficacy failure was similar for Rapamune Oral Solution 2 mg/day and lower for Rapamune Oral Solution 5 mg/day compared with azathioprine in black patients. In Study 2, which was not prospectively stratified by race, efficacy failure was similar for both Rapamune Oral Solution doses compared with placebo in black patients. The decision to use the higher dose of 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 dose (see ADVERSE REACTIONS).

PERCENTAGE OF EFFICACY FAILURE BY RACE AT 6 MONTHSa,b

Parameter	Rapamune® Oral Solution 2 mg/day	Rapamune® Oral Solution 5 mg/day	Azathioprine 2-3 mg/kg/day	Placebo
a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment.
Study 1
Black (n = 166)	34.9 (n = 63)	18.0 (n = 61)	33.3 (n = 42)
Non-black (n = 553)	14.0 (n = 221)	16.4 (n = 213)	31.9 (n = 119)
Study 2
Black (n = 66)	30.8 (n = 26)	33.7 (n = 27)		38.5 (n = 13)
Non-black (n = 510)	29.9 (n = 201)	24.5 (n = 192)		48.7 (n = 117)

Mean glomerular filtration rates (GFR) post transplant were calculated by using the Nankivell equation at 12 and 24 months for Study 1, and 12 and 36 months for Study 2. Mean GFR was lower in patients treated with cyclosporine and Rapamune Oral Solution compared with those treated with cyclosporine and the respective azathioprine or placebo control.

OVERALL CALCULATED GLOMERULAR FILTRATION RATES (Mean ± SEM, cc/min) BY NANKIVELL EQUATION POST TRANSPLANTa,b

Parameter	Rapamune® Oral Solution 2 mg/day	Rapamune® Oral Solution 5 mg/day	Azathioprine 2-3 mg/kg/day	Placebo
a: Includes patients who prematurely discontinued treatment. b: Patients who had a graft loss were included in the analysis with GFR set to 0.0.
Study 1
Month 12	57.4 ± 1.3 (n = 269)	54.6 ± 1.3 (n = 248)	64.1 ± 1.6) (n = 149)
Month 24	58.4 ± 1.5 (n = 221)	52.6 ± 1.5 (n = 222)	62.4 ± 1.9 (n = 132)
Study 2
Month 12	52.4 ± 1.5 (n = 211)	51.5 ± 1.5 (n = 199)		58.0 ± 2.1 (n = 117)
Month 36	48.1 ± 1.8 (n = 183)	46.1 ± 2.0 (n = 177)		53.4 ± 2.7 (n = 102)

Within each treatment group in Studies 1 and 2, mean GFR at one year post transplant was lower in patients who experienced at least 1 episode of biopsy-proven acute rejection, compared with those who did not.

Renal function should be monitored and appropriate adjustment of the immunosuppression regimen should be considered in patients with elevated or increasing serum creatinine levels (see PRECAUTIONS).

Rapamune® Tablets: The safety and efficacy of Rapamune Oral Solution and Rapamune Tablets for the prevention of organ rejection following renal transplantation were compared in a randomized multicenter controlled trial (Study 3). This study compared a single dose level (2 mg, once daily) of Rapamune Oral Solution and Rapamune Tablets when administered in combination with cyclosporine and corticosteroids. The study was conducted at 30 centers in Australia, Canada, and the United States. Four hundred seventy-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 antilymphocyte 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 loss, or death.

The table below summarizes the result of the efficacy failure analysis at 3 and 6 months from this trial. The overall rate of efficacy failure at 3 months, the primary endpoint, in the tablet treatment group was equivalent to the rate in the oral solution treatment group.

INCIDENCE (%) OF EFFICACY FAILURE AT 3 AND 6 MONTHS: STUDY 3a,b

	Rapamune® Oral Solution (n = 238)	Rapamune® Tablets (n = 239)
a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment. c: Efficacy failure at 3 months was the primary endpoint.
Efficacy Failure at 3 monthsc	23.5	24.7
Components of efficacy failure
Biopsy-proven acute rejection	18.9	17.6
Graft loss	3.4	6.3
Death	1.3	0.8
Efficacy Failure at 6 months	26.1	27.2
Components of efficacy failure
Biopsy-proven acute rejection	21.0	19.2
Graft loss	3.4	6.3
Death	1.7	1.7

Graft and patient survival at 12 months were co-primary endpoints. There was no significant difference between the oral solution and tablet formulations for both graft and patient survival. Graft survival was 92.0% and 88.7% for the oral solution and tablet treatment groups, respectively. The patient survival rates in the oral solution and tablet treatment groups were 95.8% and 96.2%, respectively.

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.

The table below summarizes the mean GFR at one-year post-transplantation for all patients in Study 3 who had serum creatinine measured at 12 months.

OVERALL CALCULATED GLOMERULAR FILTRATION RATES (CC/MIN) BY NANKIVELL EQUATION AT 12 MONTHS POST TRANSPLANT: STUDY 3a,b

	Rapamune® Oral Solution	Rapamune® Tablets
a: Includes patients who prematurely discontinued treatment. b: Patients who had a graft loss were included in the analysis with GFR set to 0.0.
Mean ± SEM	53.1 ± 1.7 (n = 229)	51.7 ± 1.7 (n = 225)

In Study 4 (cyclosporine withdrawal study), the safety and efficacy of Rapamune as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months post renal transplantation. Study 4 was a randomized, multicenter, controlled trial conducted at 57 centers in Australia, Canada, and Europe. Five hundred twenty-five (525) patients were enrolled. All patients in this study received the tablet formulation. This study compared patients who were administered Rapamune, cyclosporine, and corticosteroids continuously with patients who received the same standardized therapy for the first 3 months after transplantation (prerandomization period) followed by the withdrawal of cyclosporine. During cyclosporine withdrawal the Rapamune dosages were adjusted to achieve targeted sirolimus whole blood trough concentration ranges (16 to 24 ng/mL until month 12, then 12 to 20 ng/mL thereafter, expressed as chromatographic assay values; see DOSAGE AND ADMINISTRATION). At 3 months, 430 patients were equally randomized to either Rapamune with cyclosporine therapy or Rapamune as a maintenance regimen following cyclosporine withdrawal.

Eligibility for randomization included no Banff Grade 3 acute rejection episode or vascular rejection in the 4 weeks before random assignment; serum creatinine = 4.5 mg/dL; and adequate renal function to support cyclosporine withdrawal (in the opinion of the investigator). The primary efficacy endpoint was graft survival at 12 months after transplantation. Secondary efficacy endpoints were the rate of biopsy-confirmed acute rejection, patient survival, incidence of efficacy failure (defined as the first occurrence of either biopsy-proven acute rejection, graft loss, or death), and treatment failure (defined as the first occurrence of either discontinuation, acute rejection, graft loss, or death).

The safety and efficacy of cyclosporine withdrawal in high-risk patients have not been adequately studied and it is therefore not recommended. This includes patients with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, serum creatinine > 4.5 mg/dL, black patients, re-transplants, multi-organ transplants, or patients with high panel of reactive antibodies (See INDICATIONS AND USAGE).

The following table summarizes the resulting graft and patient survival at 12, 24, and 36 months for this trial. At 12, 24, and 36 months, graft and patient survival were similar for both groups.

GRAFT AND PATIENT SURVIVAL (%): STUDY 4 (CYCLOSPORINE WITHDRAWAL STUDY)a

Parameter	Rapamune with Cyclosporine Therapy (n = 215)	Rapamune Following Cyclosporine Withdrawal (n = 215)
a: Includes patients who prematurely discontinued treatment. b: Primary efficacy endpoint. c. Survival including loss to follow-up as an event. d. Initial planned duration of the study.
Graft Survival
Month 12b	95.3c	97.2
Month 24	91.6	94.0
Month 36d	87.0	91.6
Patient Survival
Month 12	97.2	98.1
Month 24	94.4	95.8
Month 36d	91.6	94.0

The following table summarizes the results of first biopsy-proven acute rejection at 12 and 36 months. There was a significant difference in first biopsy-proven rejection between the two groups during post-randomization through 12 months. Most of the post-randomization acute rejections occurred in the first 3 months following randomization.

INCIDENCE OF FIRST BIOPSY-PROVEN ACUTE REJECTION (%) BY TREATMENT GROUP AT 36 MONTHS: STUDY 4 (CYCLOSPORINE WITHDRAWAL STUDY)a,b

Period	Rapamune with Cyclosporine Therapy (n = 215)	Rapamune Following Cyclosporine Withdrawal (n = 215)
a: Includes patients who prematurely discontinued treatment. b: All patients received corticosteroids. c: Randomization occurred at 3 months ± 2 weeks.
Prerandomizationc	9.3	10.2
Postrandomization through 12 monthsc	4.2	9.8
Postrandomization from 12 to 36 months	1.4	0.5
Postrandomization through 36 months	5.6	10.2
Total at 36 months	14.9	20.5

Patients receiving renal allografts with = 4 HLA mismatches experienced significantly higher rates of acute rejection following randomization to the cyclosporine withdrawal group compared with patients who continued cyclosporine (15.3% vs 3.0%). Patients receiving renal allografts with = 3 HLA mismatches, demonstrated similar rates of acute rejection between treatment groups (6.8% vs 7.7%) following randomization.

The following table summarizes the mean calculated GFR in Study 4 (cyclosporine withdrawal study).

CALCULATED GLOMERULAR FILTRATION RATES (mL/min) BY NANKIVELL EQUATION AT 12, 24, and 36 MONTHS POST TRANSPLANT: STUDY 4 (CYCLOSPORINE WITHDRAWAL STUDY)a, b, c

Parameter	Rapamune with Cyclosporine Therapy	Rapamune Following Cyclosporine Withdrawal
a: Includes patients who prematurely discontinued treatment. b: Patients who had a graft loss were included in the analysis and had their GFR set to 0.0. c: All patients received corticosteroids.
Month 12
Mean ± SEM	53.2 ± 1.5 n = 208	59.3 ± 1.5 n = 203
Month 24
Mean ± SEM	48.4 ± 1.7 n = 203	58.4 ± 1.6 n = 201
Month 36
Mean ± SEM	47.0 ± 1.8 (n = 196)	58.5 ± 1.9 (n = 199)

The mean GFR at 12, 24, and 36 months, calculated by the Nankivell equation, was significantly higher for patients receiving Rapamune as a maintenance regimen following cyclosporine withdrawal than for those in the Rapamune with cyclosporine therapy group. Patients who had an acute rejection prior to randomization had a significantly higher GFR following cyclosporine withdrawal compared to those in the Rapamune with cyclosporine group. There was no significant difference in GFR between groups for patients who experienced acute rejection postrandomization.

Although the initial protocol was designed for 36 months, there was a subsequent amendment to extend this study. The results for the cyclosporine withdrawal group at months 48 and 60 were consistent with the results at month 36. Fifty-two percent (112/215) of the patients in the Rapamune® with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR.

High-Risk Patients: Rapamune was studied in a one-year, clinical trial in high-risk patients (Study 5) who were defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high-panel reactive antibodies (PRA; peak PRA level > 80%). Patients received concentration-controlled sirolimus and cyclosporine (MODIFIED), and corticosteroids per local practice. Antibody induction was allowed per protocol as prospectively defined at each transplant center, and was used in 88.4% of patients. The study was conducted at 35 centers in the United States. A total of 224 patients received a transplant and at least one dose of sirolimus and cyclosporine and was comprised of 77.2% Black patients, 24.1% repeat renal transplant recipients, and 13.5% patients with high PRA. Efficacy was assessed with the following endpoints, measured at 12 months: efficacy failure (defined as the first occurrence of biopsy-confirmed acute rejection, graft loss, or death), first occurrence of graft loss or death, and renal function as measured by the calculated GFR using the Nankivell formula. The table below summarizes the results of these endpoints.

EFFICACY FAILURE, GRAFT LOSS OR DEATH AND CALCULATED GLOMERULAR FUNCTION RATES (mL/min) BY NANKIVELL EQUATION AT 12 MONTHS POST-TRANSPLANT: STUDY 5

Parameter	Rapamune with Cyclosporine, Corticosteroids (n = 224)
a: Calculated glomerular filtration rate by Nankivell equation b: Patients who had graft loss were included in this analysis with GFR set to 0.
Efficacy Failure (%)	23.2
Graft Loss or Death (%)	9.8
Renal Function (mean ± SEM)a,b	52.6 ± 1.6 (n = 222)

Patient survival at 12 months was 94.6%. The incidence of biopsy-confirmed acute rejection was 17.4% and the majority of the episodes of acute rejection were mild in severity.

Pediatrics: Rapamune® was evaluated in a 36-month, open-label, randomized, controlled clinical trial at 14 North American centers in pediatric (aged 3 to < 18 years) renal transplant recipients considered to be at high immunologic risk for developing chronic allograft nephropathy, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. Seventy-eight (78) subjects were randomized in a 2:1 ratio to Rapamune® (sirolimus target concentrations of 5 to 15 ng/mL, by chromatographic assay, n = 53) in combination with a calcineurin inhibitor and corticosteroids or to continue calcineurin-inhibitor-based immunosuppressive therapy (n = 25). The primary endpoint of the study was efficacy failure as defined by the first occurrence of biopsy confirmed acute rejection, graft loss, or death, and the trial was designed to show superiority of Rapamune® added to a calcineurin-inhibitor-based immunosuppressive regimen compared to a calcineurin-inhibitor-based regimen. The cumulative incidence of efficacy failure up to 36 months was 45.3% in the Rapamune® group compared to 44.0% in the control group, and did not demonstrate superiority. There was one death in each group. The use of Rapamune® in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including but not limited to increased serum triglycerides and cholesterol), and urinary tract infections. This study does not support the addition of Rapamune® to calcineurin-inhibitor-based immunosuppressive therapy in this subpopulation of pediatric renal transplant patients.

INDICATIONS AND USAGE

Rapamune® (sirolimus) is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants.

In patients at low to moderate immunologic risk, it is recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation and the Rapamune® dose should be increased to reach recommended blood concentrations (See DOSAGE AND ADMINISTRATION). Cyclosporine withdrawal has not been studied in patients with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, or with serum creatinine > 4.5 mg/dL, Black patients, re-transplants, multi-organ transplants, or patients with high-panel reactive antibodies (see CLINICAL STUDIES).

In patients at high immunologic risk (defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high-panel reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation (see CLINICAL STUDIES, DOSAGE AND ADMINISTRATION). The safety and efficacy of this combination in high-risk patients have not been studied beyond one year; therefore, after the first year following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient.

In pediatric patients, the safety and efficacy of Rapamune® have not been established in patients less than 13 years old, or in pediatric (< 18 years) renal transplant recipients considered at high immunologic risk (see PRECAUTIONS, Pediatric use, and CLINICAL STUDIES, Pediatrics).

CONTRAINDICATIONS

Rapamune is contraindicated in patients with a hypersensitivity to sirolimus or its derivatives or any component of the drug product.

WARNINGS

Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression (see ADVERSE REACTIONS). Oversuppression of the immune system can also increase susceptibility to infection including opportunistic infections, fatal infections, and sepsis. Only physicians experienced in immunosuppressive therapy and management of organ 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.

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus (see ADVERSE REACTIONS).

As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Increased serum cholesterol and triglycerides, that may require treatment, occurred more frequently in patients treated with Rapamune compared with azathioprine or placebo controls (see PRECAUTIONS).

In Studies 1 and 2, from month 6 through months 24 and 36, respectively, mean serum creatinine was increased and mean glomerular filtration rate was decreased in patients treated with Rapamune and cyclosporine compared with those treated with cyclosporine and placebo or azathioprine controls. The rate of decline in renal function was greater in patients receiving Rapamune and cyclosporine compared with control therapies (see CLINICAL STUDIES).

Renal function should be closely monitored during the co-administration of Rapamune® with cyclosporine because long-term administration of the combination has been associated with deterioration of renal function. Appropriate adjustment of the immunosuppression regimen, including discontinuation of Rapamune and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels. Caution should be exercised when using other drugs which are known to impair renal function. In patients at low to moderate immunologic risk continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when the benefits outweigh the risks of this combination for the individual patients (see PRECAUTIONS).

In clinical trials, Rapamune has been administered concurrently with corticosteroids and with cyclosporine. The formulations of cyclosporine include:

 

Sandimmune® Injection (cyclosporine injection)
Sandimmune® Oral Solution (cyclosporine oral solution)
Sandimmune® Soft Gelatin Capsules (cyclosporine capsules)
Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED])
Neoral® Oral Solution (cyclosporine oral solution [MODIFIED])

The efficacy and safety of the use of Rapamune in combination with other immunosuppressive agents has not been determined.

Co-administration of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) is not recommended (see CLINICAL PHARMACOLOGY, Metabolism, and PRECAUTIONS, Drug Interactions and Other drug interactions).

PRECAUTIONS

General

Rapamune is intended for oral administration only.

Fluid Accumulation and Wound Healing

mTOR inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability.

There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence (see Adverse Reactions, Other clinical experience). Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in patients treated with Rapamune. Appropriate measures should be considered to minimize such complications. Patients with a body mass index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature.

There have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion and pericardial effusions (including hemodynamically significant effusions in children and adults), in patients receiving Rapamune.

Lipids

The use of Rapamune® in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment.

In Studies 1 and 2, in de novo renal transplant recipients who began the study with normal, fasting, total serum cholesterol (<200 mg/dL) or normal, fasting, total serum triglycerides (<200 mg/dL), there was an increased incidence of hypercholesterolemia (fasting serum cholesterol >240 mg/dL) or hypertriglyceridemia (fasting serum triglycerides >500 mg/dL), respectively, in patients receiving both Rapamune® 2 mg and Rapamune® 5 mg compared with azathioprine and placebo controls.

Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42 - 52% of patients enrolled in the Rapamune arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm.

In Study 4 (cyclosporine withdrawal study) during the prerandomization period, mean fasting serum cholesterol and triglyceride values rapidly increased, and peaked at 2 months with mean cholesterol values > 240 mg/dL and triglycerides > 250 mg/dL. After randomization mean cholesterol and triglyceride values remained higher in the cyclosporine withdrawal arm compared to the Rapamune® and cyclosporine combination.

Renal transplant patients have a higher prevalence of clinically significant hyperlipidemia. Accordingly, the risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune.

Any patient who is administered Rapamune should be monitored for hyperlipidemia using laboratory tests and if hyperlipidemia is detected, subsequent interventions such as diet, exercise, and lipid-lowering agents, as outlined by the National Cholesterol Education Program guidelines, should be initiated.

In clinical trials, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors and/or fibrates appeared to be well tolerated.

During Rapamune therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects as described in the respective labeling for these agents.

Renal Function

Patients treated with cyclosporine and Rapamune were noted to have higher serum creatinine levels and lower glomerular filtration rates compared with patients treated with cyclosporine and placebo or azathioprine controls (Studies 1 and 2). The rate of decline in renal function in these studies was greater in patients receiving Rapamune and cyclosporine compared with control therapies. In patients at low to moderate immunologic risk (See CLINICAL STUDIES) continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when the benefits outweigh the risks of this combination for the individual patients. (see WARNINGS).

Renal function should be monitored during the administration of Rapamune® in combination with cyclosporine. Appropriate adjustment of the immunosuppression regimen, including discontinuation of Rapamune and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels. Caution should be exercised when using agents (e.g., aminoglycosides, and amphotericin B) that are known to have a deleterious effect on renal function.

In patients with delayed graft function, Rapamune may delay recovery of renal function.

Proteinuria

In a study evaluating conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients 6-120 months post-transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to Rapamune. In general, those patients with the greatest amount of urinary protein excretion prior to sirolimus conversion were those whose protein excretion increased the most after conversion. New onset of nephrotic proteinuria was also reported. Reduction in the degree of urinary protein excretion was observed following discontinuation of sirolimus. Periodic quantitative monitoring of urinary protein excretion is recommended. The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant population has not been established.

De Novo Use Without Cyclosporine

The safety and efficacy of de novo use of Rapamune without cyclosporine is not established in renal transplant patients. In a multi-center clinical study, de novo renal transplant patients treated with Rapamune, MMF, steroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of Rapamune without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial.

Calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA)

The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA.

Angioedema

Rapamune has been associated with the development of angioedema. The concomitant use of Rapamune with other drugs known to cause angioedema, such as ACE-inhibitors, may increase the risk of developing angioedema.

Antimicrobial Prophylaxis

Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for 1 year following transplantation.

Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.

Interstitial Lung Disease

Cases of interstitial lung disease (including pneumonitis, and infrequently bronchiolitis obliterans organizing pneumonia [BOOP] and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the trough Rapamune concentration increases (see ADVERSE REACTIONS, Other clinical experience).

Information for Patients

Patients should be given complete dosage instructions (see Patient Instructions). Women of childbearing potential should be informed of the potential risks during pregnancy and that they should use effective contraception prior to initiation of Rapamune therapy, during Rapamune therapy and for 12 weeks after Rapamune therapy has been stopped (see PRECAUTIONS: Pregnancy).

Patients should be told that exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer (see WARNINGS).

Laboratory Tests

Whole blood sirolimus concentrations should be monitored in patients receiving concentration-controlled Rapamune. Monitoring is also necessary in patients likely to have altered drug metabolism, in patients=13 years who weigh less than 40 kg, in patients with hepatic impairment, and during concurrent administration of potent CYP3A4 inducers and inhibitors (see PRECAUTIONS: Drug Interactions).

Drug Interactions

Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below.

Cyclosporine capsules MODIFIED:

Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp.

Because of the effect of cyclosporine capsules (MODIFIED), it is recommended that sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED) (see DOSAGE AND ADMINISTRATION).

Studies assessing the effect of concomitant administration of cyclosporine capsules (MODIFIED) with sirolimus oral solution and with sirolimus tablets are summarized below.

Rapamune Oral Solution: In a single dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus either simultaneously or 4 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean Cmax and AUC of sirolimus were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus Cmax and AUC were increased by 37% and 80%, respectively, compared with administration of sirolimus alone.

In a single-dose cross-over drug-drug interaction study, 33 healthy volunteers received 5 mg sirolimus alone, 2 hours before, and 2 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). When given 2 hours before Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus Cmax and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean Cmax and AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone.

Mean cyclosporine Cmax and AUC were not significantly affected when sirolimus was given simultaneously or when administered 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after Neoral® in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were needed to maintain target cyclosporine concentration.

Rapamune Tablets: In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus (Rapamune Tablets) either simultaneously or 4 hours after a 300-mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, mean Cmax and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimus Cmax and AUC were both increased by only 33% compared with administration of sirolimus alone.

Cyclosporine oral solution: In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5, 1.5, and 3 mg/m2/day was administered simultaneously with Sandimmune® Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (%CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune® Oral Solution (cyclosporine oral solution) administration. However, the %CV was higher (range 85.9% - 165%) than those from previous studies.

Sandimmune® Oral Solution (cyclosporine oral solution) is not bioequivalent to Neoral® Oral Solution (cyclosporine oral solution MODIFIED), and should not be used interchangeably. Although there is no published data comparing Sandimmune® Oral Solution (cyclosporine oral solution) to SangCya® Oral Solution (cyclosporine oral solution [MODIFIED]), they should not be used interchangeably. Likewise, Sandimmune® Soft Gelatin Capsules (cyclosporine capsules) are not bioequivalent to Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) and should not be used interchangeably.

Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary. The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem.

Erythromycin: Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and erythromycin is not recommended (see WARNINGS). The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 800 mg q 8h of erythromycin as erythromycin ethylsuccinate tablets at steady state to 24 healthy volunteers significantly affected the bioavailability of sirolimus and erythromycin. Sirolimus Cmax and AUC were increased 4.4- and 4.2-fold respectively and tmax was increased by 0.4 hr. Erythromycin Cmax and AUC were increased 1.6- and 1.7-fold, respectively, and tmax was increased by 0.3 hr.

Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and ketoconazole is not recommended (see WARNINGS). Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of Rapamune® Oral Solution, as reflected by increases in sirolimus Cmax, tmax, and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal t1/2 of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations.

Rifampin: Rifampin is a strong inducer of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and rifampin is not recommended (see WARNINGS). Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20-mg dose of sirolimus oral solution, greatly increased sirolimus oral-dose clearance by 5.5-fold (range = 2.8 to 10), which represents mean decreases in AUC and Cmax of about 82% and 71%, respectively. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered.

Verapamil: Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady state to 26 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus Cmax and AUC were increased 2.3- and 2.2-fold, respectively, without substantial change in tmax. The Cmax and AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and tmax was decreased by 1.2 hr.

Drugs which may be coadministered without dose adjustment

Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. A synopsis of the type of study performed for each drug is provided. Sirolimus and these drugs may be coadministered without dose adjustments.

Acyclovir: Acyclovir, 200 mg, was administered once daily for 3 days followed by a single 10-mg dose of sirolimus oral solution on day 3 in 20 adult healthy volunteers.

Atorvastatin: Atorvastatin, 20 mg, was given daily for 10 days to 23 healthy volunteers, followed by a combined regimen of sirolimus oral solution, 2 mg, and atorvastatin, 20 mg, for 5 days.

Digoxin: Digoxin, 0.25 mg, was administered daily for 8 days and a single 10-mg dose of sirolimus oral solution was given on day 8 to 24 healthy volunteers.

Glyburide: A single 5-mg dose of glyburide and a single 10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Sirolimus did not affect the hypoglycemic action of glyburide.

Nifedipine: A single 60-mg dose of nifedipine and a single 10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers.

Norgestrel/ethinyl estradiol (Lo/Ovral®): Sirolimus oral solution, 2 mg, was given daily for 7 days to 21 healthy female volunteers on norgestrel/ethinyl estradiol.

Prednisolone: Pharmacokinetic information was obtained from 42 stable renal transplant patients receiving daily doses of prednisone (5-20 mg/day) and either single or multiple doses of sirolimus oral solution (0.5-5 mg/m2 q 12h).

Sulfamethoxazole/trimethoprim (Bactrim®): A single oral dose of sulfamethoxazole (400 mg)/trimethoprim (80 mg) was given to 15 renal transplant patients receiving daily oral doses of sirolimus (8 to 25 mg/m2).

Other Drug Interactions

Co-administration of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) is not recommended (see WARNINGS). Sirolimus is extensively metabolized by the CYP3A4 isoenzyme in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-gp drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Therefore, absorption and the subsequent elimination of systemically absorbed sirolimus may be influenced by drugs that affect these proteins. Strong inhibitors of CYP3A4 and P-gp significantly decrease the metabolism of sirolimus and increase sirolimus concentrations, while strong inducers of CYP3A4 and P-gp significantly increase the metabolism of sirolimus and decrease sirolimus concentrations.

In patients in whom strong inhibitors or inducers of CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 should be considered.

Sirolimus is a substrate f