sirolimus Dailymed

10 Overdosage

Reports of overdose with sirolimus have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those uled in the adverse reactions section [see Adverse Reactions (6)].

General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD₅₀ was greater than 800 mg/kg. 

11 Description

Sirolimus is an mTOR inhibitor 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 illustrated as follows.

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

Sirolimus tablets are available as a grey to greenish grey colored film-coated, round shaped beveled edge standard convex tablet containing 0.5 mg sirolimus; as a white to off-white colored film-coated, round shaped beveled edge standard convex tablet containing 1 mg sirolimus; and as a yellow to orange yellow colored film-coated, round shaped beveled edge standard convex tablet containing 2 mg sirolimus. Sirolimus tablets, 2 mg contains FD&C yellow No. 6 as a color additive.

The inactive ingredients in sirolimus tablets include: croscarmellose sodium, dl-alpha tocopherol, edetate disodium, glyceryl behenate, hypromellose, lactose monohydrate, microcrystalline cellulose, poloxamer 188, polyethylene glycol, sucrose and titanium dioxide. Additionally, the 0.5 mg dosage strength also contains: iron oxide black, iron oxide yellow and iron oxide red and the 2 mg dosage strength also contains: D&C yellow #10, FD&C yellow #6 and FD&C blue #2.

12 Clinical Pharmacology

12.1 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. Mammalian target of rapamycin (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.

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.

Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.

12.2 Pharmacodynamics

Orally-administered sirolimus, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at 6 months following transplantation compared with either azathioprine or placebo [see Clinical Studies (14.1)]. There was no demonstrable efficacy advantage of a daily maintenance dose of 5 mg with a loading dose of 15 mg over a daily maintenance dose of 2 mg with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range [see Dosage and Administration (2.5)].

12.3 Pharmacokinetics

Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients. 

The pharmacokinetic parameters of sirolimus in low- to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in Table 4. 

TABLE 4: MEAN ± SD STEADY STATE SIROLIMUS PHARMACOKINETIC PARAMETERS IN LOW-TO MODERATE-IMMUNOLOGIC RISK ADULT RENAL TRANSPLANT PATIENTS FOLLOWING SIROLIMUS 2 MG DAILY^a,b

	Multiple Dose (daily dose)
	Solution	Tablets
a: In presence of cyclosporine administered 4 hours before sirolimus dosing.
b: Based on data collected at months 1 and 3 post-transplantation.
c: Average Cmin over 6 months.
Cmax (ng/mL)	14.4 ± 5.3	15 ± 4.9
tmax (hr)	2.1 ± 0.8	3.5 ± 2.4
AUC (ng•h/mL)	194 ± 78	230 ± 67
Cmin (ng/mL)c	7.1 ± 3.5	7.6 ± 3.1
CL/F (mL/h/kg)	173 ± 50	139 ± 63

Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUC_τ,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 [see Dosage and Administration (2.3, 2.5), Warning and Precautions (5.17)].

Absorption

Following administration of sirolimus oral solution, the mean times to peak concentration (t_max) of sirolimus are approximately 1 hour and 2 hours in healthy subjects and renal transplant patients, respectively. The systemic availability of sirolimus is low, and was estimated to be approximately 14% after the administration of sirolimus oral solution. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of sirolimus oral solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m².

Food Effects

To minimize variability in sirolimus concentrations, both sirolimus oral solution and tablets should be taken consistently with or without food [see Dosage and Administration (2)]. In healthy subjects, a high-fat meal (861.8 kcal, 54.9% kcal from fat) increased the mean total exposure (AUC) of sirolimus by 23 to 35%, compared with fasting. The effect of food on the mean sirolimus C_max was inconsistent depending on the sirolimus dosage form evaluated. 

Distribution

The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft patients, 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, mainly serum albumin (97%), α₁-acid glycoprotein, and lipoproteins.

Metabolism

Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations [see Warnings and Precautions (5.20) and Drug Interactions (7)]. 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. 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. The mean ± SD terminal elimination half-life (t_½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours. 

Sirolimus Concentrations (Chromatographic Equivalent) Observed in Phase 3 Clinical Studies

The following sirolimus concentrations (chromatographic equivalent) were observed in phase 3 clinical studies for prophylaxis of organ rejection in de novo renal transplant patients [see Clinical Studies (14)].

TABLE 5: SIROLIMUS WHOLE BLOOD TROUGH CONCENTRATIONS OBSERVED IN RENAL TRANSPLANT PATIENTS ENROLLED IN PHASE 3 STUDIES

Patient Population (Study number)	Treatment	Year 1		Year 3
		Mean  (ng/mL)	10th to 90th  percentiles  (ng/mL)	Mean  (ng/mL)	10th to 90th  percentiles  (ng/mL)
a: Months 4 through 12
b: Up to Week 2; observed CsA Cmin was 217 (56 to 432) ng/mL
c: Week 2 to Week 26; observed CsA Cmin range was 174 (71 to 288) ng/mL
d: Week 26 to Week 52; observed CsA Cmin was 136 (54.5 to 218) ng/mL
Low-to-moderate risk (Studies 1 & 2)	Sirolimus (2 mg/day) + CsA	7.2	3.6 to 11	–	–
	Sirolimus (5 mg/day) + CsA	14	8 to 22	–	–
Low-to-moderate risk (Study 3)	Sirolimus + CsA	8.6	5 to 13a	9.1	5.4 to 14
	Sirolimus alone	19	14 to 22a	16	11 to 22
High risk (Study 4)	Sirolimus + CsA	15.711.811.5	5.4 to 27.3b 6.2 to 16.9c 6.3 to 17.3d	-	-

The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state required approximately 6 weeks. Following cyclosporine withdrawal, larger sirolimus doses were required due to the absence of the inhibition of sirolimus metabolism and transport by cyclosporine and to achieve higher target sirolimus trough concentrations during concentration-controlled administration [see Dosage and Administration (2.1), Drug Interactions (7.1)].

Lymphangioleiomyomatosis

In a clinical trial of patients with lymphangioleiomyomatosis, the median whole blood sirolimus trough concentration after 3 weeks of receiving sirolimus tablets at a dose of 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to 9 ng/mL; n = 37).

Pharmacokinetics in Specific Populations

Hepatic Impairment

Sirolimus was administered as a single, oral dose to subjects with normal hepatic function and to patients with Child-Pugh classification A (mild), B (moderate), or C (severe) hepatic impairment. Compared with the values in the normal hepatic function group, the patients with mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, with no statistically significant differences in mean C_max. As the severity of hepatic impairment increased, there were steady increases in mean sirolimus t_1/2, and decreases in the mean sirolimus clearance normalized for body weight (CL/F/kg).

The maintenance dose of sirolimus should be reduced by approximately one third in patients with mild-to-moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment [see Dosage and Administration (2.5)]. It is not necessary to modify the sirolimus loading dose in patients with mild, moderate, and severe hepatic impairment. Therapeutic drug monitoring is necessary in all patients with hepatic impairment [see Dosage and Administration (2.7)].

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 in healthy volunteers. The loading and the maintenance doses of sirolimus need not be adjusted in patients with renal impairment [see Dosage and Administration (2.6)].

Pediatric Renal Transplant Patients

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 to 20 ng/mL for the 21 children receiving tablets, or 5 to 15 ng/mL for the one child receiving oral solution. The children aged 6 to 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 to 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. See Table 6 below.

TABLE 6: 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)
6 to 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 to 18	14	52 ± 15	34.5 ± 12.2	2.7 ± 1.5	14.7 ± 8.6	466 ± 236	136 ± 57	4.7 ± 1.9

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).

Table 7 below summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically impaired renal function.
450 ± 232

TABLE 7: SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC PATIENTS WITH END-STAGE KIDNEY DISEASE 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/WT (mL/h/kg)
5 to 11	9	1.1 ± 0.5	71 ± 40	580 ± 450
12 to 18	11	0.79 ± 0.17	55 ± 18

*All subjects received sirolimus oral solution.

Geriatric

Clinical studies of sirolimus 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 sirolimus oral solution or tablets, sirolimus trough concentration data in renal transplant patients > 65 years of age were similar to those in the adult population 18 to 65 years of age.

Gender

Sirolimus clearance in males was 12% lower than that in females; male subjects had a significantly longer t_1/2 than did female subjects (72.3 hours versus 61.3 hours). Dose adjustments based on gender are not recommended. 

Race

In the phase 3 trials for the prophylaxis of organ rejection following renal transplantation using sirolimus solution or tablets and cyclosporine oral solution [MODIFIED] (e.g., Neoral^® Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral^® Soft Gelatin Capsules) [see Clinical Studies (14)], there were no significant differences in mean trough sirolimus concentrations over time between Black (n = 190) and non-Black (n = 852) patients during the first 6 months after transplantation. 

Drug-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: Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). Sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased [see Dosage and Administration (2.2), Drug Interactions (7.1)].

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

In a single dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus oral solution either simultaneously or 4 hours after a 300 mg dose of Neoral^® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean C_max and AUC of sirolimus, following simultaneous administration 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 C_max and AUC were increased by only 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 oral solution 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 C_max and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean C_max and AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone. 

Mean cyclosporine C_max and AUC were not significantly affected when sirolimus oral solution 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. 

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% to 165%) than those from previous studies. 

Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary [see Drug Interactions (7.4)]. 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 C_max, t_max, 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 and Precautions (5.20), Drug Interactions (7.2)]. 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 C_max and AUC were increased 4.4- and 4.2-fold respectively and t_max was increased by 0.4 hr. Erythromycin C_max and AUC were increased 1.6- and 1.7-fold, respectively, and t_max 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 and Precautions (5.20), Drug Interactions (7.2)]. Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of sirolimus oral solution, as reflected by increases in sirolimus C_max, t_max, and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal t_½ 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. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered [see Warnings and Precautions (5.20), Drug Interactions (7.2)]. 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 decreased sirolimus AUC and C_max by about 82% and 71%, respectively.

Verapamil: Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary; [see Drug Interactions ( 7.4 )]. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady state to 25 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus C_max and AUC were increased 2.3- and 2.2-fold, respectively, without substantial change in t_max. The C_max and AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and t_max was decreased by 1.2 hr.

Drugs Which May Be Co-administered Without Dose Adjustment

Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs uled below. Sirolimus and these drugs may be co-administered without dose adjustments. 

• •Acyclovir
• •Atorvastatin
• •Digoxin
• •Glyburide
• •Nifedipine
• •Norgestrel/ethinyl estradiol (Lo/Ovral^®)
• •Prednisolone
• •Sulfamethoxazole/trimethoprim (Bactrim^®)

Other Drug-Drug Interactions

Co-administration of sirolimus with other known strong inhibitors of CYP3A4 and/or P-gp (such as voriconazole, itraconazole, telithromycin, or clarithromycin) or other known strong inducers of CYP3A4 and/or P-gp (such as rifabutin) is not recommended [see Warnings and Precautions (5.20), Drug Interactions (7.2)]. 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.

Care should be exercised when drugs or other substances that are substrates and/or inhibitors or inducers of CYP3A4 are administered concomitantly with sirolimus. Other drugs that have the potential to increase sirolimus blood concentrations include (but are not limited to): 

• •Calcium channel blockers: nicardipine.
• •Antifungal agents: clotrimazole, fluconazole. 
• •Antibiotics: troleandomycin. 
• •Gastrointestinal prokinetic agents: cisapride, metoclopramide. 
• •Other drugs: bromocriptine, cimetidine, danazol, letermovir, protease inhibitors (e.g., for HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir).

Other drugs that have the potential to decrease sirolimus concentrations include (but are not limited to):

• •Anticonvulsants: carbamazepine, phenobarbital, phenytoin.
• •Antibiotics: rifapentine.

Other Drug-Food Interactions

Grapefruit juice reduces CYP3A4-mediated drug metabolism. Grapefruit juice must not be taken with or used for dilution of sirolimus [see Drug Interactions (7.3)].

Drug-Herb Interactions

St. John’s Wort (Hypericum perforatum) induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. John’s Wort in patients receiving sirolimus could result in reduced sirolimus concentrations [see Drug Interactions (7.4)].

14.1 Prophylaxis of Organ Rejection in Renal Transplant Patients

Sirolimus Oral Solution

The safety and efficacy of sirolimus 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 sirolimus 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 sirolimus oral solution 2 mg/day; 274 were randomized to receive sirolimus oral solution 5 mg/day, and 161 to receive azathioprine 2 to 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 sirolimus oral solution 2 mg/day; 219 were randomized to receive sirolimus 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. Sirolimus 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.
Biopsy-proven acute rejectionGraft lossDeathLost to follow-upBiopsy-proven acute rejectionGraft lossDeathLost to follow-up

TABLE 8: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 24 MONTHS FOR STUDY 1^a,b

Parameter	Sirolimus Oral Solution 2 mg/day (n = 284)	Sirolimus Oral Solution 5 mg/day (n = 274)	Azathioprine 2 to 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
16.5	11.3	29.2
1.1	2.9	2.5
0.7	1.8	0
0.4	0.7	0.6
Efficacy failure at 24 months	32.8	25.9	36
Components of efficacy failure
23.6	17.5	32.3
3.9	4.7	3.1
4.2	3.3	0
1.1	0.4	0.6

Biopsy-proven acute rejectionGraft lossDeathLost to follow-upBiopsy-proven acute rejectionGraft lossDeathLost to follow-up

TABLE 9: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 36 MONTHS FOR STUDY 2^a,b

Parameter	Sirolimus Oral Solution 2 mg/day (n = 227)	Sirolimus 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	25.6	47.7
Components of efficacy failure
24.7	19.2	41.5
3.1	3.7	3.9
2.2	2.7	2.3
0	0	0
Efficacy failure at 36 months	44.1	41.6	54.6
Components of efficacy failure
32.2	27.4	43.9
6.2	7.3	4.6
5.7	5.9	5.4
0	0.9	0.8

Patient and graft survival at 1 year were co-primary endpoints. The following table 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 sirolimus and comparator-treated patients.
Month 12 Month 24 Month 12 Month 24 Month 12 Month 36 Month 12 Month 36 

TABLE 10: GRAFT AND PATIENT SURVIVAL (%) FOR STUDY 1 (12 AND 24 MONTHS) AND STUDY 2 (12 AND 36 MONTHS)^a,b

Parameter	Sirolimus Oral Solution 2 mg/day	Sirolimus Oral Solution 5 mg/day	Azathioprine 2 to 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
94.7	92.7	93.8
85.2	89.1	90.1
Patient survival
97.2	96	98.1
92.6	94.9	96.3
Study 2	(n = 227)	(n = 219)		(n = 130)
Graft survival
89.9	90.9		87.7
81.1	79.9		80.8
Patient survival
96.5	95		94.6
90.3	89.5		90.8

The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with sirolimus 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 sirolimus oral solution 2 mg/day and lower for sirolimus 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 sirolimus oral solution doses compared with placebo in Black patients. The decision to use the higher dose of sirolimus oral solution in Black patients must be weighed against the increased risk of dose-dependent adverse events that were observed with the sirolimus oral solution 5-mg dose [see Adverse Reactions (6.1)].
Black (n = 166)Non-Black (n = 553)Black (n = 66) Non-Black (n = 510) 

TABLE 11: PERCENTAGE OF EFFICACY FAILURE BY RACE AT 6 MONTHS^a,b

a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment.
Parameter	SirolimusOral Solution2 mg/day	SirolimusOral Solution5 mg/day	Azathioprine2 to 3 mg/kg/day	Placebo
Study 1
34.9 (n = 63)	18 (n = 61)	33.3 (n = 42)
14 (n = 221)	16.4 (n = 213)	31.9 (n = 119)
Study 2
30.8 (n = 26)	33.7 (n = 27)		38.5 (n = 13)
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 sirolimus oral solution compared with those treated with cyclosporine and the respective azathioprine or placebo control.
Month 12 Month 24 Month 12 Month 36 

TABLE 12: OVERALL CALCULATED GLOMERULAR FILTRATION RATES (Mean ± SEM, cc/min) BY NANKIVELL EQUATION POST-TRANSPLANT^a,b

Parameter	Sirolimus Oral Solution 2 mg/day	Sirolimus Oral Solution 5 mg/day	Azathioprine 2 to 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.
Study 1
57.4 ± 1.3(n = 269)	54.6 ± 1.3(n = 248)	64.1 ± 1.6(n = 149)
58.4 ± 1.5(n = 221)	52.6 ± 1.5(n = 222)	62.4 ± 1.9(n = 132)
Study 2
52.4 ± 1.5(n = 211)	51.5 ± 1.5(n = 199)		58 ± 2.1(n = 117)
48.1 ± 1.8(n = 183)	46.1 ± 2(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 one episode of biopsy-proven acute rejection, compared with those who did not.

Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels [see Warnings and Precautions (5.8)].

Sirolimus Tablets

The safety and efficacy of sirolimus oral solution and sirolimus tablets for the prevention of organ rejection following renal transplantation were demonstrated to be clinically equivalent in a randomized, multicenter, controlled trial [see Clinical Pharmacology (12.3)].

14.2 Cyclosporine Withdrawal Study in Renal Transplant Patients

The safety and efficacy of sirolimus as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months after renal transplantation. Study 3 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 sirolimus, cyclosporine, and corticosteroids continuously with patients who received this same standardized therapy for the first 3 months after transplantation (pre-randomization period) followed by the withdrawal of cyclosporine. During cyclosporine withdrawal, the sirolimus 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). At 3 months, 430 patients were equally randomized to either continue sirolimus with cyclosporine therapy or to receive sirolimus as a maintenance regimen following cyclosporine withdrawal.

Eligibility for randomization included no Banff Grade 3 acute rejection or vascular rejection episode 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 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.

TABLE 13: GRAFT AND PATIENT SURVIVAL (%): STUDY 3^a

Parameter	Sirolimus with Cyclosporine Therapy (n = 215)	Sirolimus 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
Month 36d	87	91.6
Patient Survival
Month 12	97.2	98.1
Month 24	94.4	95.8
Month 36d	91.6	94

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 rates between the two groups after randomization and through 12 months. Most of the post-randomization acute rejections occurred in the first 3 months following randomization.

TABLE 14: INCIDENCE OF FIRST BIOPSY-PROVEN ACUTE REJECTION (%) BY TREATMENT GROUP AT 36 MONTHS: STUDY 3^a,b

Period	Sirolimus with Cyclosporine Therapy (n = 215)	Sirolimus 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.
Pre-randomizationc	9.3	10.2
Post-randomization through 12 monthsc	4.2	9.8
Post-randomization from 12 to 36 months	1.4	0.5
Post-randomization 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% versus 3%). Patients receiving renal allografts with ≤ 3 HLA mismatches demonstrated similar rates of acute rejection between treatment groups (6.8% versus 7.7%) following randomization. 

The following table summarizes the mean calculated GFR in Study 3 (cyclosporine withdrawal study).
Mean ± SEM Mean ± SEM Mean ± SEM 

TABLE 15: CALCULATED GLOMERULAR FILTRATION RATES (mL/min) BY NANKIVELL EQUATION AT 12, 24, AND 36 MONTHS POST-TRANSPLANT: STUDY 3^a,b,c

Parameter	Sirolimus with  Cyclosporine Therapy	Sirolimus 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.
c: All patients received corticosteroids.
Month 12
53.2 ± 1.5(n = 208)	59.3 ± 1.5(n = 203)
Month 24
48.4 ± 1.7(n = 203)	58.4 ± 1.6(n = 201)
Month 36
47 ± 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 sirolimus as a maintenance regimen following cyclosporine withdrawal than for those in the sirolimus 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 sirolimus with cyclosporine group. There was no significant difference in GFR between groups for patients who experienced acute rejection post-randomization.

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 sirolimus with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR. 

14.3 High-Immunologic Risk Renal Transplant Patients

Sirolimus was studied in a one-year, clinical trial in high risk patients (Study 4) who were defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reasons 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. The sirolimus dose was adjusted to achieve target whole blood trough sirolimus concentrations of 10 to 15 ng/mL (chromatographic method) throughout the 12-month study period. The cyclosporine dose was adjusted to achieve target whole blood trough concentrations of 200 to 300 ng/mL through week 2, 150 to 200 ng/mL from week 2 to week 26, and 100 to 150 ng/mL from week 26 to week 52 [see Clinical Pharmacology (12.3)] for the observed trough concentrations ranges. 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 result of these endpoints. 

TABLE 16: EFFICACY FAILURE, GRAFT LOSS OR DEATH AND CALCULATED GLOMERULAR FUNCTION RATES (mL/min) BY NANKIVELL EQUATION AT 12 MONTHS POST-TRANSPLANT: STUDY 4

Parameter	Sirolimus 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. 

14.4 Conversion from Calcineurin Inhibitors to Sirolimus in Maintenance Renal Transplant Patients

Conversion from calcineurin inhibitors (CNI) to sirolimus was assessed in maintenance renal transplant patients 6 months to 10 years post-transplant (Study 5). This study was a randomized, multicenter, controlled trial conducted at 111 centers globally, including US and Europe, and was intended to show that renal function was improved by conversion from CNI to sirolimus. Eight hundred thirty (830) patients were enrolled and stratified by baseline calculated glomerular filtration rate (GFR, 20 to 40 mL/min versus greater than 40 mL/min). In this trial there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the sirolimus conversion arm. In addition, enrollment of patients with baseline calculated GFR less than 40 mL/min was discontinued due to a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death [see Adverse Reactions (6.4)].

This study compared renal transplant patients (6 to 120 months after transplantation) who were converted from calcineurin inhibitors to sirolimus, with patients who continued to receive calcineurin inhibitors. Concomitant immunosuppressive medications included mycophenolate mofetil (MMF), azathioprine (AZA), and corticosteroids. Sirolimus was initiated with a single loading dose of 12 to 20 mg, after which dosing was adjusted to achieve a target sirolimus whole blood trough concentration of 8 to 20 ng/mL (chromatographic method). The efficacy endpoint was calculated GFR at 12 months post-randomization. Additional endpoints included biopsy-confirmed acute rejection, graft loss, and death. Findings in the patient stratum with baseline calculated GFR greater than 40 mL/min (Sirolimus conversion, n = 497; CNI continuation, n = 246) are summarized below. There was no clinically or statistically significant improvement in Nankivell GFR compared to baseline. 

TABLE 17: RENAL FUNCTION IN STABLE RENAL TRANSPLANT PATIENTS IN PATIENTS WITH BASELINE GFR > 40 mL/min THE SIROLIMUS CONVERSION STUDY (STUDY 5)

Parameter	Sirolimus conversion N = 496	CNI continuation  N = 245	Difference (95% CI)
GFR mL/min (Nankivell) at 1 year	59	57.7	1.3 (-1.1, 3.7)
GFR mL/min (Nankivell) at 2 year	53.7	52.1	1.6 (-1.4, 4.6)

The rates of acute rejection, graft loss, and death were similar at 1 and 2 years. Treatment-emergent adverse events occurred more frequently during the first 6 months after sirolimus conversion. The rates of pneumonia were significantly higher for the sirolimus conversion group. 

While the mean and median values for urinary protein to creatinine ratio were similar between treatment groups at baseline, significantly higher mean and median levels of urinary protein excretion were seen in the sirolimus conversion arm at 1 year and at 2 years, as shown in the table below [see Warnings and Precautions (5.9)]. In addition, when compared to patients who continued to receive calcineurin inhibitors, a higher percentage of patients had urinary protein to creatinine ratios > 1 at 1 and 2 years after sirolimus conversion. This difference was seen in both patients who had a urinary protein to creatinine ratio ≤ 1 and those who had a protein to creatinine ratio > 1 at baseline. More patients in the sirolimus conversion group developed nephrotic range proteinuria, as defined by a urinary protein to creatinine ratio > 3.5 (46/482 [9.5%] versus 9/239 [3.8%]), even when the patients with baseline nephrotic range proteinuria were excluded. The rate of nephrotic range proteinuria was significantly higher in the sirolimus conversion group compared to the calcineurin inhibitor continuation group with baseline urinary protein to creatinine ratio > 1 (13/29 versus 1/14), excluding patients with baseline nephrotic range proteinuria.

TABLE 18: MEAN AND MEDIAN VALUES FOR URINARY PROTEIN TO CREATININE RATIO (mg/mg) BETWEEN TREATMENT GROUPS AT BASELINE, 1 AND 2 YEARS IN THE STRATUM WITH BASELINE CALCULATED GFR > 40 mL/min

Study period	Sirolimus Conversion			CNI Continuation
	N	Mean ± SD	Median	N	Mean ± SD	Median	p-value
Baseline	410	0.35 ± 0.76	0.13	207	0.28 ± 0.61	0.11	0.381
1 year	423	0.88 ± 1.61	0.31	203	0.37 ± 0.88	0.14	<0.001
2 years	373	0.86 ± 1.48	0.32	190	0.47 ± 0.98	0.13	<0.001

The above information should be taken into account when considering conversion from calcineurin inhibitors to sirolimus in stable renal transplant patients due to the lack of evidence showing that renal function improves following conversion, and the finding of a greater increment in urinary protein excretion, and an increased incidence of treatment-emergent nephrotic range proteinuria following conversion to sirolimus. This was particularly true among patients with existing abnormal urinary protein excretion prior to conversion.

In an open-label, randomized, comparative, multicenter study where kidney transplant patients were either converted from tacrolimus to sirolimus 3 to 5 months post-transplant (sirolimus group) or remained on tacrolimus, there was no significant difference in renal function at 2 years post-transplant. Overall, 44/131 (33.6%) discontinued treatment in the sirolimus group versus 12/123 (9.8%) in the tacrolimus group. More patients reported adverse events 130/131 (99.2%) versus 112/123 (91.1%) and more patients reported discontinuations from the treatment due to adverse events 28/131 (21.4%) versus 4/123 (3.3%) in the sirolimus group compared to the tacrolimus group.

The incidence of biopsy-confirmed acute rejection was higher for patients in the sirolimus group 11/131 (8.4%) compared to the tacrolimus group 2/123 (1.6%) through 2 years post-transplant. The rate of new-onset diabetes mellitus post-randomization, defined as 30 days or longer of continuous or at least 25 days non-stop (without gap) use of any diabetic treatment after randomization, a fasting glucose ≥126 mg/dL or a non-fasting glucose ≥200 mg/dL, was higher in the sirolimus group 15/82 (18.3%) compared to the tacrolimus group 4/72 (5.6%). A greater incidence of proteinuria, was seen in the sirolimus group 19/131 (14.5%) versus 2/123 (1.6%) in the tacrolimus group.

14.5 Conversion from a CNI-based Regimen to a Sirolimus-based Regimen in Liver Transplant Patients

Conversion from a CNI-based regimen to a sirolimus-based regimen was assessed in stable liver transplant patients 6 to 144 months post-transplant. The clinical study was a 2:1 randomized, multi-center, controlled trial conducted at 82 centers globally, including the US and Europe, and was intended to show that renal function was improved by conversion from a CNI to sirolimus without adversely impacting efficacy or safety. A total of 607 patients were enrolled.

The study failed to demonstrate superiority of conversion to a sirolimus-based regimen compared to continuation of a CNI-based regimen in baseline-adjusted GFR, as estimated by Cockcroft-Gault, at 12 months (62 mL/min in the sirolimus conversion group and 63 mL/min in the CNI continuation group). The study also failed to demonstrate non-inferiority, with respect to the composite endpoint consisting of graft loss and death (including patients with missing survival data) in the sirolimus conversion group compared to the CNI continuation group (6.6% versus 5.6%). The number of deaths in the sirolimus conversion group (15/393, 3.8%) was higher than in the CNI continuation group (3/214, 1.4%), although the difference was not statistically significant. The rates of premature study discontinuation (primarily due to adverse events or lack of efficacy), adverse events overall (infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the sirolimus conversion group compared to the CNI continuation group.

14.6 Pediatric Renal Transplant Patients

Sirolimus 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 patients 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 sirolimus (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 sirolimus 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 sirolimus group compared to 44% in the control group, and did not demonstrate superiority. There was one death in each group. The use of sirolimus 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 [see Warnings and Precautions (5.8)]. This study does not support the addition of sirolimus to calcineurin-inhibitor-based immunosuppressive therapy in this subpopulation of pediatric renal transplant patients.

14.7 Lymphangioleiomyomatosis Patients

The safety and efficacy of sirolimus for treatment of lymphangioleiomyomatosis (LAM) were assessed in a randomized, double-blind, multicenter, controlled trial. This study compared sirolimus (dose-adjusted to maintain blood trough concentrations between 5 to 15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observation period. Eighty-nine (89) patients were enrolled; 43 patients were randomized to receive placebo and 46 patients to receive sirolimus. The primary endpoint was the difference between the groups in the rate of change (slope) per month in forced expiratory volume in 1 second (FEV1). During the treatment period, the FEV1 slope was -12±2 mL per month in the placebo group and 1±2 mL per month in the sirolimus group (treatment difference = 13 mL (95% CI: 7, 18). The absolute between-group difference in the mean change in FEV1 during the 12-month treatment period was 153 mL, or approximately 11% of the mean FEV1 at enrollment. Similar improvements were seen for forced vital capacity (FVC). After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group (see Figure 1).

FIGURE 1: CHANGE IN FORCED EXPIRATORY VOLUME IN 1 SECOND (FEV1) DURING THE TREATMENT AND OBSERVATION PHASES OF THE STUDY IN LAM PATIENTS

The rate of change over 12 months of vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor which has been shown to be elevated in patients with LAM, was significantly different in the sirolimus-treated group (-88 ± 16.6 pg/mL/month) compared to placebo (-2.42 ± 17.2 pg/mL/month) with a treatment difference of -86 pg/mL/month (95% CI: -133, -39). The absolute between-group difference in the mean change in VEGF-D during the 12-month treatment period was -1017.2, or approximately 50% of the mean VEGF-D at enrollment.