Rapamune

Composition and Pharmaceutical Characteristics: Rapamune is available for administration as a white, triangular-shaped tablet containing 1 mg.
Rapamune (sirolimus) is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus.
Chemical Name: 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.
Molecular Formula: Its molecular formula is C₅₁H₇₉NO₁₃.
Molecular Weight: Its molecular weight is 914.2.
Physical Characteristics: Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.
Excipients/Inactive Ingredients: The inactive ingredients in Rapamune Tablets include sucrose, lactose monohydrate, polyethylene glycol 8000 powdered, calcium sulfate anhydrous, microcrystalline cellulose, pharmaceutical glaze (shellac solution 4# cut), talc, titanium dioxide, magnesium stearate, povidone (K29/32), poloxamer 188, polyethylene glycol (macrogol) type 20,000, glyceryl monooleate (60%), carnauba wax, vitamin E (dl-alpha tocopherol), alcohol denatured 23A*, water purified*, mineral spirits odorless, ink-red opacode S-1-15095, and water for injection*.
*Removed during processing. Does not appear in the finished dosage form.

Pharmacotherapeutic Group: Immunosuppressant. ATC code: L04AA10.
Pharmacology: Pharmacodynamics: 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 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, dogs, 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.
Clinical Trials Data on Efficacy: 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 as follows 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. (See Table 1.)

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Graft and patient survival at 12 months were co-primary efficacy 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 as follows summarizes the mean GFR at one-year post-transplantation for all patients in Study 3 who had serum creatinine measured at 12 months. (See Table 2.)

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Rapamune maintenance regimen with cyclosporine withdrawal: The safety and efficacy of Rapamune as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months post-renal transplantation. In a randomized multi-centre 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 (pre-randomization 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 through month 60). 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 93 Grade III 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-confirmed 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, 36, 48 and 60 months for this trial. At 12, 24, and 36 months, graft and patient survival were similar for both groups. (See Table 3.)

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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 acute 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. (See Table 4.)

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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 3.0%). 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 4 (cyclosporine withdrawal study). (See Table 5.)

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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 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 Rapamune with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR.
In an open-label, randomized, comparative, multicenter study where renal transplant patients were either converted from tacrolimus to sirolimus 3 to 5 months post-transplant or remained on tacrolimus, there was no significant difference in renal function at 2 years. There were more adverse events (99.2% versus 91.1%, p=0.002) and more discontinuations from the treatment due to adverse events (26.7% versus 4.1%, p<0.001) in the group converted to sirolimus compared to the tacrolimus group. The incidence of biopsy confirmed acute rejection was higher (p=0.020) for patients in the sirolimus group (11, 8.4%) compared to the tacrolimus group (2, 1.6%) through 2 years; most rejections were mild in severity (8 of 9 [89%] T-cell BCAR, 2 of 4 [50%] antibody mediated BCAR) in the sirolimus group. Patients who had both antibody-mediated rejection and T-cell-mediated rejection on the same biopsy were counted once for each category. More patients converted to sirolimus developed new onset diabetes mellitus 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 after randomization (18.3% versus 5.6%, p=0.025). A lower incidence of squamous cell carcinoma of the skin was observed in the sirolimus group (0% versus 4.9%).
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 by tablet, sirolimus t_max was approximately 3 hours after single doses in healthy volunteers and multiple doses in renal transplant patients. 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 Trials Data on Efficacy as previously mentioned and Dosage & Administration.)
Sirolimus concentrations, are dose proportional between 5 and 40 mg after administration of Rapamune tablets to healthy volunteers.
Food effects: After administration of Rapamune Tablets and a high-fat meal in 24 healthy volunteers, C_max, t_max, and AUC showed increases of 65%, 32%, and 23%, respectively. Thus, a high-fat meal produced differences in the two formulations with respect to rate of absorption but not in extent of absorption. Evidence from a large randomized multicenter controlled trial comparing Rapamune oral solution to tablets supports that the differences in absorption rates do not affect the efficacy of the drug.
To minimize variability, both Rapamune Oral Solution and Tablets should be taken consistently with or without food. Bioequivalence testing based on AUC and C_max showed that sirolimus administered with orange juice is equivalent to administration with water. Grapefruit juice reduces CYP3A4 mediated drug metabolism and potentially enhances P-gp mediated drug counter-transport from enterocytes of the small intestine and must not be used for dilution or taken with Rapamune. (See Interactions and Dosage & Administration).
Distribution: The mean (±SD) blood-to-plasma ratio of sirolimus was 36 (±17.9) 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 (V_ss/F) of sirolimus is 12 ± 7.52 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins. In human whole blood, the binding of sirolimus was shown mainly to be associated with serum albumin (97%), α₁-acid glycoprotein, and lipoproteins.
Metabolism: Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. 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. The 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.
Elimination: After a single dose of [¹⁴C] sirolimus by oral solution in healthy subjects, 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 by Rapamune oral solution in stable renal transplant patients was estimated to be about 62 ± 16 hours.
Pharmacokinetics in Renal Transplant Patients: Mean (±SD) pharmacokinetic parameters for sirolimus oral solution given daily in combination with cyclosporine and corticosteroids in renal transplant patients were determined at months 1, 3, and 6 after transplantation. There were no significant differences in C_max, t_max, AUC, or CL/F with respect to treatment group or month. After daily administration of Rapamune in renal transplant patients by oral solution and tablet, estimates of C_max, AUC, and CL/F did not appear to be different; but t_max was significantly different.
Upon repeated twice daily administration of Rapamune oral solution without an initial loading dose in a multiple-dose study, the average trough concentration of sirolimus increased approximately 2- to 3-fold over the initial 6 days of therapy at which time steady state was reached. Mean whole blood sirolimus trough concentrations in patients receiving either Rapamune by oral solution or tablet with a loading dose of three times the maintenance dose achieved steady-state concentrations within 24 hours after the start of dose administration.
The pharmacokinetic parameters of sirolimus in adult renal transplant patients following multiple dosing with Rapamune 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in the following table. (See Table 6.)

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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.
Sirolimus Concentrations (Chromatographic Equivalent) Observed in Phase 3 Clinical Studies: The following sirolimus concentrations (chromatographic equivalent) were observed in phase III clinical studies (see Clinical Trials Data on Efficacy as previously mentioned). (See Table 7.)

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Average Rapamune doses and sirolimus whole blood trough concentrations for tablets administered daily in combination with cyclosporine or tacrolimus and corticosteroids in high-risk renal transplant patients (Study 5; see Clinical Trials Data on Efficacy as previously mentioned) are summarized in the table as follows. (See Table 8.)

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Patients treated with the combination of Rapamune and tacrolimus required larger Rapamune doses to achieve the target sirolimus concentrations than patients treated with the combination of Rapamune and cyclosporine.
Special Populations: Patients with Renal Impairment: There is minimal renal excretion of drug or its metabolites. The pharmacokinetics of sirolimus are very similar in various populations with renal function ranging from normal to absent (dialysis patients).
Patients with Hepatic Impairment: Sirolimus oral solution (15 mg) 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) primary hepatic impairment.
Compared with the values in the normal hepatic function group, the patients with mild, moderate, or severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, and t_½ with no significant differences in mean C_max. As the severity of hepatic impairment increased, there were steady increases in mean sirolimus t_½, and decreases in the mean sirolimus clearance normalized for body weight (CL/F/kg).
The maintenance dose of Rapamune 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 based on decreased clearance (see Dosage & Administration). In patients with hepatic impairment, it is necessary that sirolimus whole blood trough levels be monitored. In patients with severe hepatic impairment, consideration should be given to monitoring every 5 to 7 days for a longer period of time after dose adjustment or after loading dose due to the delay in reaching steady state because of the prolonged half-life.
Children: 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. (See Table 9.)

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The Table as follows summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically impaired renal function receiving Rapamune by oral solution. (See Table 10.)

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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) from 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 t_½ 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 t_½ was observed after the administration of Rapamune Tablets. Dose adjustments based on gender are not recommended.
Race: In large phase III trials using Rapamune Oral Solution and cyclosporine oral solution (e.g., Neoral Oral Solution) and/or cyclosporine capsules (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.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenicity: Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at dosages of 0, 12.5, 25 and 50/6 (dosage lowered from 50 to 6 mg/kg/day at week 31 due to infection secondary to immunosuppression) there was a statistically significant increase in malignant lymphoma at all dose levels (approximately 16 to 135 times the clinical doses adjusted for body surface area) compared to controls.
In the second mouse study at dosages of 0, 1, 3 and 6 mg/kg (approximately 3 to 16 times the clinical dose adjusted for body surface area), hepatocellular adenoma and carcinoma (males), were considered Rapamune related. In the 104-week rat study at dosages of 0, 0.05, 0.1 and 0.2 mg/kg/day (approximately 0.4 to 1 times the clinical dose adjusted for body surface area), there was a statistically significant increased incidence of testicular adenoma in the 0.2 mg/kg/day group.
Mutagenicity: Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.
Reproductive Toxicology: There was no effect on fertility in female rats following the administration of sirolimus at dosages up to 0.5 mg/kg (approximately 1 to 3 times the clinical doses adjusted for body surface area). In male rats, there was no significant difference in fertility rate compared to controls at a dosage of 2 mg/kg (approximately 4 to 11 times the clinical doses adjusted for body surface area). Reductions in testicular weights and/or histological lesions (e.g., tubular atrophy and tubular giant cells) were observed in rats following dosages of 0.65 mg/kg (approximately 1 to 3 times the clinical doses adjusted for body surface area) and above and in a monkey study at 0.1 mg/kg (approximately 0.4 to 1 times the clinical doses adjusted for body surface area) and above. Sperm counts were reduced in male rats following the administration of sirolimus for 13 weeks at a dosage of 6 mg/kg (approximately 12 to 32 times the clinical doses adjusted for body surface area), but showed improvement by 3 months after dosing was stopped.

Rapamune (sirolimus) is indicated for the prophylaxis of organ rejection in patients 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 & Administration). Cyclosporine withdrawal has not been studied in patients with Banff 93 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, renal re-transplants, multi-organ transplants, or patients with high-panel reactive antibodies (see Pharmacology: Pharmacodynamics: Clinical Trials Data on Efficacy under Actions).

Dosage: Bioavailability has not been determined for tablets after they have been crushed, chewed, or split and therefore, this cannot be recommended.
Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe 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.
Patients at Low to Moderate Immunologic Risk: It is recommended that Rapamune tablets be used initially in a regimen with cyclosporine and corticosteroids. Cyclosporine should be withdrawn 2 to 4 months after renal transplantation in patients at low to moderate immunological risk, and the Rapamune dose should be increased to reach recommended blood concentrations. Cyclosporine withdrawal has not been studied in patients with Banff 93 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 Indications/Uses and Pharmacology: Pharmacodynamics: Clinical Trials Data on Efficacy under Actions).
Adults: Rapamune with Cyclosporine Therapy: The usual dosage regimen for Rapamune is a 6 mg oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily. The Rapamune dose should then be individualized, to obtain whole blood trough levels of 4 to 12 ng/mL.
Rapamune is to be administered orally once daily.
Rapamune Maintenance Regimen with Cyclosporine Withdrawal: Initially, patients should be receiving Rapamune and cyclosporine combination therapy. At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks and the Rapamune dose should be adjusted to obtain whole blood trough concentrations within the range of 16 to 24 ng/mL (chromatographic method) for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL (chromatographic method). The actual observations at year 1 and 5 (see as follows) were close to these ranges (see Sirolimus whole blood trough level monitoring as follows). Therapeutic drug monitoring should not be the sole basis for adjusting Rapamune therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy, and laboratory parameters. Cyclosporine inhibits the metabolism and transport of sirolimus, and consequently, sirolimus concentrations will decrease when cyclosporine is discontinued unless the Rapamune dose is increased. The Rapamune dose will need to be approximately 4-fold higher to account for both the absence of the pharmacokinetic interaction (approximately 2-fold increase) and the augmented immunosuppressive requirement in the absence of cyclosporine (approximately 2-fold increase).
Patients at High Immunologic Risk: It is recommended that Rapamune be taken 4 hours after cyclosporine microemulsion [cyclosporine, USP] administration.
Use in Children: Safety and efficacy of Rapamune in pediatric patients below the age of 13 years have not been established. It is recommended that sirolimus whole blood trough levels be monitored if used in pediatric patients <13 years of age.
Use in Elderly Patient: No dose adjustment is required in elderly patients.
Clinical studies of Rapamune did not include sufficient number of patients aged 65 and over to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age.
Patients with Renal Impairment: No dosage adjustment is required.
Patients with Hepatic Impairment: In patients with hepatic impairment, it is recommended that the maintenance dose of Rapamune be reduced by approximately one-third to one-half. It is not necessary to modify the Rapamune loading dose.
The pharmacokinetics of Rapamune has not been studied in patients with severe hepatic impairment.
In patients with hepatic impairment, it is recommended that sirolimus whole blood trough levels be monitored.
Sirolimus whole blood trough level monitoring: Blood sirolimus trough levels should be monitored: (1) in patients with hepatic impairment; (2) in patients receiving concentration-controlled Rapamune; (3) in pediatric patients; (4) during concurrent administration of inhibitors and inducers of CYP3A4 and P-glycoprotein (P-gp); (5) if cyclosporine dosing is markedly reduced, or if cyclosporine is discontinued.
Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory parameters.
It is recommended that patients switched from the solution to the tablet formulation on a mg per mg basis have a trough concentration taken 1 or 2 weeks after switching formulations to confirm that the trough concentration is within the recommended target range.
Assay Methodology: The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Several assay methodologies have been used to measure the whole blood concentrations of sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. The concentration values obtained by these different methodologies are not interchangeable. Adjustments to the targeted range should be made according to the assay being utilized to determine the sirolimus trough concentration. Since results are assay and laboratory dependent, and the results may change over time, adjustments to the target therapeutic range must be made with a detailed knowledge of the site-specific assay used. A discussion of the different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000.
Mode of administration: Rapamune is intended for oral administration only.
Rapamune must be taken consistently with or without food to minimize variation in drug absorption.
It is important that the recommendations in Dosage & Administration be followed closely.

There is limited experience with overdose. In general, the adverse effects of overdose are consistent with those listed in the Adverse Reactions. General supportive measures should be followed in all cases of overdose. Based on the poor 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 lethal dose (LD₅₀) was greater than 800 mg/kg.

Rapamune is contraindicated in patients with a hypersensitivity to sirolimus or its derivatives or any excipients in the formulation.

Immunosuppression increases the susceptibility to infection and the development of lymphoma and other malignancies, particularly of the skin, (see Adverse Reactions). Oversuppression of the immune system can also increase susceptibility to opportunistic infections, sepsis, and fatal infections. 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).
The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended.
Liver Transplantation: Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT): The use of Rapamune in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant recipients. Many of these patients had evidence of infection at or near the time of death. In this and another study in de novo liver transplant recipients, the use of Rapamune in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death.
A clinical study in liver transplant patients randomized to conversion to a sirolimus-based regimen versus continuation of a calcineurin inhibitors (CNI)-based regimen 6-144 months post-liver transplantation demonstrated an increased number of deaths in the sirolimus conversion group compared to the CNI continuation group, although the difference was not statistically significant (see Pharmacology: Pharmacodynamics: Clinical Trials Data on Efficacy under Actions).
Lung Transplantation: Bronchial Anastomotic Dehiscence: Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen.
Drug-Drug Interactions: Co-administration of Rapamune 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. Sirolimus is extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver. Inhibitors of CYP3A4 decrease the metabolism of sirolimus and increase sirolimus levels. Inducers of CYP3A4 increase the metabolism of sirolimus and decrease sirolimus levels (see Interactions).
There have been reports of increased blood levels of sirolimus during concomitant use with cannabidiol. Caution should be used when cannabidiol and Rapamune are co-administered, closely monitor sirolimus blood levels and for adverse events suggestive of sirolimus toxicity (see Sirolimus whole blood trough level monitoring under Dosage & Administration and Cannabidiol under Interactions).
Renal Function: 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 Pharmacology: Pharmacodynamics: Clinical Trials Data on Efficacy under Actions). 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. Renal function should also be closely monitored during the co-administration of Rapamune with tacrolimus. Appropriate adjustment of the immunosuppression regimen, including discontinuation of Rapamune and/or cyclosporine and/or tacrolimus, 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 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); Neoral Oral Solution (cyclosporine oral solution).
The efficacy and safety of the use of Rapamune in combination with other immunosuppressive agents has not been determined.
General: Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in Rapamune-treated patients. Appropriate post-operative measures should be considered to minimize this complication.
Wound Healing and Fluid Accumulation: 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. There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence. 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.
Skin Malignancies: Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin. Therefore, patients taking Rapamune should limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protective factor (see Adverse Reactions).
Hyperlipidemia: The use of Rapamune may lead to more frequently increased serum cholesterol and triglycerides that may require treatment compared with azathioprine or placebo controls. Patients must be monitored for hyperlipidemia.
In phase III clinical trials, in de novo renal transplant recipients who began the study with normal, fasting, total serum triglycerides (fasting serum triglycerides <200 mg/dL), there was an increased incidence of hypertriglyceridemia (fasting serum triglycerides >500 mg/dL) in patients receiving Rapamune 2 mg and Rapamune 5 mg compared to 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 the study compared to 16% of patients in the placebo arm and 22% of patients in the azathioprine arm.
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.
Rhabdomyolysis: In clinical trials, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors and/or fibrates was well tolerated. During Rapamune therapy with or without cyclosporine, patients should be monitored for elevated lipids, and 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.
Rapamune following Cyclosporine Withdrawal: In a study that compared a regimen of Rapamune and cyclosporine to one in which cyclosporine was withdrawn 2-4 months post-transplantation, those in whom cyclosporine was not withdrawn had significantly higher serum creatinine levels and significantly lower glomerular filtration rates at 12 months through 60 months, and significantly lower graft survival at 48 months, the point at which it was decided by the sponsor to discontinue subjects from assigned therapy in the Rapamune and cyclosporine arm. When the protocol was amended all subjects had reached 48 months and some completed the 60 months of the study.
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 individual patients.
In patients with delayed graft function, Rapamune may delay recovery of renal function.
Proteinuria: Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluation conversion from CNI to Rapamune in maintenance renal transplant patients 6 - 120 months post-transplant, increased urinary protein excretion was commonly observed from the 6 through 24 month after conversion of Rapamune compared with CNI continuation (23.6% versus 12.8%, respectively) (see Adverse Reactions and Pharmacology: Pharmacodynamics: Clinical Trials Data on Efficacy under Actions). Those patients in the highest quartile of urinary protein excretion prior to Rapamune conversion (urinary protein to creatinine ratio ≥0.27) were those whose protein excretion increased the most after conversion. New-onset nephrosis (nephrotic syndrome) was also reported in 2% of the patients in the study. Reduction in the degree of urinary protein excretion was observed for individual patients following discontinuation of Rapamune. The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established.
Conversion to Rapamune in Patients with Glomerular Filtration Rate <40 mL/min: In a study evaluating conversion from CNI to Rapamune in maintenance renal transplant patients 6-120 months post-transplant (see Pharmacology: Pharmacodynamics: Clinical Trials Data on Efficacy under Actions), in a stratum of the Rapamune treatment arm with a calculated glomerular filtration rate of less than 40 mL/min, there was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death. The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established.
De Novo Use without Calcineurin Inhibitor (CNI): The safety and efficacy of de novo use of Rapamune without a calcineurin inhibitor (CNI) is not established in renal transplant patients. In two multi-center clinical studies, 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 a calcineurin inhibitor, MMF, steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal function, was not apparent in the treatment arms with de novo use of Rapamune without a CNI. It should be noted that an abbreviated schedule of administration of daclizumab was employed in one of the studies.
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: The concomitant administration of Rapamune and angiotensin-converting enzyme (ACE) inhibitors has resulted in angioneurotic edema-type reactions.
Elevated sirolimus levels (with/without concomitant ACE inhibitors) may also potentiate angioedema (see Inhibitors and inducers of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) under Interactions). In some cases, the angioedema has resolved upon discontinuation or dose reduction of Rapamune.
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 sirolimus levels increases (see Interstitial Lung Disease under Adverse Reactions).
Latent Viral Infections: Patients treated with immunosuppressants, including Rapamune, are at increased risk for opportunistic infections, including activation of latent viral infections. Among these conditions is BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal outcomes, including graft loss. Physicians should consider latent viral infections in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms (see Latent Viral Infections under Adverse Reactions).
Antimicrobial Prophylaxis: 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 infection.
Contraception: Women of childbearing potential should be informed of the potential risks during pregnancy and that effective contraception must be initiated before Rapamune therapy, and maintained during Rapamune therapy and for 12 weeks after Rapamune therapy has been stopped.
Use in High-Risk Patients: The safety and efficacy of cyclosporine withdrawal in high-risk renal transplant patients have not been adequately studied and such use is therefore, not recommended. This includes patients with Banff 93 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, renal re-transplants, multi-organ transplants, and patients with a high panel of reactive antibodies (see Indications/Uses and Pharmacology: Pharmacodynamics: Clinical Trials Data on Efficacy under Actions).
Laboratory Tests: Whole blood sirolimus levels should be monitored in all patients. It is prudent to monitor blood sirolimus levels 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 Interactions).
Abuse and dependence: Rapamune has no potential for abuse. There is no evidence of dependence on Rapamune.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.

Pregnancy: There are no studies of Rapamune use in pregnant women. In animal studies, embryo/fetal toxicity was manifested as mortality and reduced fetal weights (with associated delays in skeletal ossification) (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Rapamune should be used during pregnancy only if the potential benefit outweighs the potential risk to the embryo/fetus (see Precautions).
Lactation: Rapamune is excreted in trace amounts in milk of lactating rats. It is not known whether sirolimus is excreted in human milk. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from sirolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Rapamune Oral Solution: The incidence of adverse reactions was determined in two randomized, double-blind, multicenter controlled trials in which 499 renal transplant patients received Rapamune Oral Solution 2 mg/day, 477 received Rapamune Oral Solution 5 mg/day, 160 received azathioprine, and 124 received placebo. All patients were treated with cyclosporine and corticosteroids. Data (≥12 months post-transplant) presented in the table as follows show the adverse reactions that occurred in any treatment group with an incidence of ≥20%.
Specific adverse reactions associated with the administration of Rapamune Oral Solution occurred at a significantly higher frequency than in the respective control group. For both Rapamune Oral Solution 2 mg/day and 5 mg/day these include hypercholesterolemia, hyperlipemia, hypertension, and rash; for Rapamune Oral Solution 2 mg/day acne; and for Rapamune Oral Solution 5 mg/day anemia, arthralgia, diarrhea, hypokalemia, and thrombocytopenia. The elevations of triglycerides and cholesterol and decreases in platelets and hemoglobin occurred in a dose-related manner in patients receiving Rapamune.
Patients maintained on Rapamune Oral Solution 5 mg/day, when compared with patients on Rapamune Oral Solution 2 mg/day, demonstrated an increased incidence of the following adverse events: anemia, leukopenia, thrombocytopenia, hypokalemia, hyperlipemia, fever, and diarrhea.
In general, adverse events related to the administration of Rapamune were dependent on dose/concentration. (See Table 11.)

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At 12 months, there were no significant differences in incidence rates for clinically important opportunistic or common transplant-related infections across treatment groups, with the exception of mucosal infections with Herpes simplex, which occurred at a significantly greater rate in patients treated with Rapamune 5 mg/day than in both of the comparator groups.
Among the adverse events that were reported at a rate of ≥3% and <20%, the following were more prominent in patients maintained on Rapamune 5 mg/day, when compared to patients on Rapamune 2 mg/day; epistaxis, lymphocele, insomnia, thrombotic thrombocytopenic purpura (hemolytic-uremic syndrome), skin ulcer, increased LDH, hypotension, facial edema.
The frequency of adverse reactions listed in the following table includes reactions reported in patients treated with Rapamune-based regimens.
In general, adverse events related to administration of Rapamune were dependent on dose/concentration.
The adverse reactions in the table as follows are listed in the MedDRA frequency categories. (See Table 12.)

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Rapamune following cyclosporine withdrawal: The incidence of adverse reactions was determined through 60 months in a randomized, multicenter controlled trial in which 215 renal transplant patients received Rapamune as a maintenance regimen following cyclosporine withdrawal, and 215 patients received Rapamune with cyclosporine therapy. All patients were treated with corticosteroids. The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2-mg Rapamune groups in studies of Rapamune in combination with cyclosporine. Following randomization (at 3 months), patients who had cyclosporine eliminated from their therapy experienced significantly higher incidences of increased AST/SGOT and increased ALT/SGPT, liver damage, hypokalemia, thrombocytopenia, abnormal healing, acne, ileus, and joint disorder. Conversely, the incidence of acidosis, hypertension, cyclosporine toxicity, increased creatinine, abnormal kidney function, toxic nephropathy, edema, hyperuricemia, gout, and gum hyperplasia was significantly higher in patients who remained on cyclosporine than those who had cyclosporine withdrawn from therapy. Mean systolic and diastolic blood pressure improved significantly following cyclosporine withdrawal.
Following cyclosporine withdrawal, (at 60 months), the incidence of Herpes zoster infection was significantly lower in patients receiving Rapamune following cyclosporine withdrawal, compared with patients who continued to receive Rapamune and cyclosporine.
The incidence of malignancies following cyclosporine withdrawal, based upon distinct categories, is presented in the following table. The incidence of lymphoma/lymphoproliferative disease was similar in all treatment groups. The overall incidence of malignancy, based upon the number of patients who had one or more malignancy, was lower in patients who had cyclosporine withdrawn than in patients receiving Rapamune plus cyclosporine (10.7% versus 15.8%, respectively). (See Table 13.)

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By 60 months, the incidence of non-skin malignancies (lymphoma/lymphoproliferative disease plus other malignancy from the previous table) was significantly higher in the cohort who continued cyclosporine as compared with the cohort who had cyclosporine withdrawn (8.4% versus 3.8%, respectively). For skin cancer, the median time to first occurrence was significantly delayed (491 versus 1126 days) and when taking into account that a patient may have multiple skin cancers the relative risk (RR = 0.346) for developing skin cancer was significantly lowered in the cyclosporine withdrawal group as compared with the group that continued cyclosporine.
Safety was assessed in a controlled trial (see Pharmacology: Pharmacodynamics: Clinical Trials Data on Efficacy under Actions) involving 448 patients who received at least one dose of study drug (safety population): 224 patients received at least one dose of sirolimus with tacrolimus, and 224 patients received at least one dose of sirolimus with cyclosporine. Overall, the incidence and nature of adverse events was similar to those seen in previous combination studies with Rapamune. Diarrhea and herpes simplex occurred significantly more frequently in patients who received sirolimus and tacrolimus, whereas, hypertension, cardiomegaly, lymphocele, increased creatinine, acne, urinary tract disorder, ovarian cyst, and calcineurin inhibitor toxicity occurred at a significantly higher rate in patients who received sirolimus and cyclosporine. The incidence of malignancy was low (1.3% in each group).
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients has not been established.
In a study evaluating the safety and efficacy of conversion (6 to 120 months after transplantation) from calcineurin inhibitors to Rapamune (sirolimus target levels of 12-20 ng/mL by chromatographic assay) in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n=90) with a baseline glomerular filtration rate of less than 40 mL/min. There was a higher rate of serious adverse events including pneumonia, acute rejection, graft loss and death in this Rapamune treatment arm (n=60, median time post-transplant 36 months).
In a study evaluating the safety and efficacy of conversion from tacrolimus to Rapamune 3 to 5 months post renal transplant, a higher rate of acute rejection and new onset diabetes mellitus was observed following conversion to Rapamune (see Pharmacology: Pharmacodynamics: Clinical Trials Data on Efficacy under Actions).
The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA (see Precautions).
In patients with delayed graft function, Rapamune may delay recovery of renal function (see Renal Function under Precautions).
Other Clinical Experience: Azoospermia has been reported with the use of Rapamune and has been reversible upon discontinuation of Rapamune in most cases (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Clostridium difficile enterocolitis has been reported in patients receiving sirolimus.
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 sirolimus level increases. (See Interstitial Lung Disease under Precautions.)
Latent Viral Infections: BK virus associated nephropathy and progressive multifocal leukoencephalopathy (PML) have been observed in patients receiving immunosuppressants, including Rapamune. These infection may be associated with serious or fatal outcomes, including renal graft loss (see Latent Viral Infections under Precautions).
Hepatotoxicity: Hepatotoxicity has been reported, including fatal hepatic necrosis with elevated trough sirolimus levels (i.e., exceeding therapeutic levels).
Abnormal Healing: Abnormal healing following transplant surgery has been reported, including fascial dehiscence, incisional hernia and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary).

Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-glycoprotein (P-gp). The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed as follows. Drug interaction studies have not been conducted with drugs other than those described as follows.
Inhibitors and inducers of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp): Co-administration of Rapamune with strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) or inducers of CYP3A4 (such as rifampin or rifabutin) is not recommended. Sirolimus is extensively metabolized by the CYP3A4 isoenzyme intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine by the P-glycoprotein (P-gp) drug-efflux pump. Therefore, absorption and the subsequent elimination of systemically absorbed sirolimus may be influenced by drugs that affect these proteins. Inhibitors of CYP3A4 and P-gp may increase sirolimus levels. Inducers of CYP3A4 and P-gp may decrease sirolimus levels. In patients in whom strong inhibitors or inducers of CYP3A4 and P-gp are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 and P-gp should be considered.
Substances that inhibit CYP3A4 include but are not limited to: Calcium channel blockers: diltiazem, nicardipine, verapamil.
Antifungal agents: clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole.
Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin.
Gastrointestinal prokinetic agents: cisapride, metoclopramide.
Other drugs: bromocriptine, cimetidine, cyclosporine, danazol, letermovir, protease inhibitors (e.g., for HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir).
Grapefruit juice.
Substances that induce CYP3A4 include but are not limited to: Anticonvulsants: carbamazepine, phenobarbital, phenytoin.
Antibiotics: rifabutin, rifampicin, rifapentine.
Herbal preparations: St. John's Wort (Hypericum perforatum, hypericin).
The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed as follows. Drug interaction studies have been conducted with the following: Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus levels should be monitored and a dose reduction may be necessary if diltiazem is co-administered.
The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly increased 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.
Verapamil: Verapamil is an inhibitor of CYP3A4 and P-gp. Sirolimus levels should be monitored and appropriate dose reduction of both medications should be considered.
Multiple-dose administration of verapamil and Rapamune oral solution significantly affected the rate and extent of absorption of both drugs. In a study of 25 healthy volunteers, whole blood sirolimus C_max, t_max, and AUC were increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil C_max and AUC were both increased 1.5-fold, and t_max was decreased 24%.
Erythromycin: Erythromycin is an inhibitor of CYP3A4 and P-gp. Sirolimus levels should be monitored and appropriate dose reductions of both medications should be considered.
Multiple-dose administration of erythromycin ethylsuccinate and Rapamune oral solution significantly increased the rate and extent of absorption of both drugs. In a study of 24 healthy volunteers, whole blood sirolimus C_max, t_max, and AUC were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The C_max, t_max, and AUC of plasma erythromycin base were increased 1.6-fold, 1.3-fold, and 1.7-fold, respectively.
Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 and P-gp. Co-administration of Rapamune and ketoconazole is not recommended.
In a study of 24 healthy volunteers, it was found that 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 C_max, t_max, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively. However, the terminal t_½ of sirolimus was not changed. Single-dose Rapamune did not affect steady-state 12-hour plasma ketoconazole concentrations.
Rifampicin: Rifampin is a strong inducer of CYP3A4 and P-gp. Co-administration of Rapamune and rifampin is not recommended.
Pretreatment of 14 healthy volunteers with multiple doses of rifampicin (600 mg daily for 14 days) followed by a single 20 mg-dose of Rapamune oral solution, greatly increased sirolimus oral-dose clearance by 5.5-fold (range = 2.8 to 10), which represents mean decreases in AUC and C_max of about 82% and 71%, respectively.
Non-interactions: Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed as follows. A synopsis of the type of study performed for each drug is provided. Sirolimus and these drugs may be co-administered 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.
Prednisone: 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).
Cyclosporine: Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp.
Patients administered sirolimus with cyclosporine together with HMG-CoA reductase inhibitor and/or fibrate should be monitored for the development of rhabdomyolysis (see Precautions).
Cyclosporine microemulsion (cyclosporine, USP): It is recommended that Rapamune be taken 4 hours after cyclosporine microemulsion (cyclosporine, USP) administration.
In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg Rapamune oral solution either simultaneously or 4 hours after a 300 mg dose of cyclosporine microemulsion (cyclosporine, USP). For simultaneous administration, the mean C_max and AUC of sirolimus were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine microemulsion (cyclosporine, USP) administration, sirolimus C_max and AUC were increased by 37% and 80%, respectively, compared to administration of Rapamune alone.
In an otherwise identical study, Rapamune was administered as a 10 mg dose by tablet. For simultaneous administration, mean C_max and AUC were increased by 6.1-fold and 2.5-fold, respectively, relative to administration of Rapamune alone. However, when given 4 hours after cyclosporine microemulsion (cyclosporine, USP) administration, sirolimus C_max and AUC were both increased by only 33% compared with administration of Rapamune alone.
After multiple-dose administration of Rapamune by oral solution given 4 hours after cyclosporine microemulsion (cyclosporine, USP) in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of cyclosporine microemulsion (cyclosporine, USP) were needed to maintain target cyclosporine concentrations.
Rapamune Oral Solution: In a single dose drug-drug interaction study, 24 healthy volunteers were administered 5 mg Rapamune either simultaneously or 2 hours before and after a 300 mg dose of cyclosporine microemulsion (cyclosporine, USP). For simultaneous administration, the mean C_max and AUC of sirolimus were increased by 117% and 183%, respectively, relative to administration of Rapamune alone. When given 2 hours after cyclosporine microemulsion (cyclosporine, USP) administration, sirolimus C_max and AUC were increased by 126% and 141%, respectively, compared to administration of Rapamune alone. When given 2 hours before cyclosporine microemulsion (cyclosporine, USP) administration, sirolimus C_max and AUC were not affected.
Sandimmune Soft Gelatin Capsules (cyclosporine capsules) are not bioequivalent to Neoral Soft Gelatin Capsules (cyclosporine capsules) and should not be used interchangeably.
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), and should not be used interchangeably. Although there is no published data comparing Sandimmune Oral Solution (cyclosporine oral solution) to SandCya Oral Solution (cyclosporine oral solution), they should not be used interchangeably.
Cannabidiol: There have been reports of increased blood levels of sirolimus during concomitant use with cannabidiol. Caution should be used when cannabidiol and Rapamune are co-administered, closely monitor sirolimus blood levels and for adverse events suggestive of sirolimus toxicity (see Sirolimus whole blood trough level monitoring under Dosage & Administration and Precautions).
HMG-CoA reductase inhibitors, fibrates: Patients administered Rapamune with HMG-CoA reductase inhibitors and/or fibrates should be monitored for the development of rhabdomyolysis (see Precautions).
Calcineurin inhibitors: Calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been reported in patients receiving sirolimus with a calcineurin inhibitor (see Precautions).
Vaccination: Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants, including Rapamune, vaccination may be less effective. The use of live vaccines should be avoided during treatment with Rapamune.
Food: The bioavailability of sirolimus is affected by concomitant food intake after administration by either Rapamune oral solution or tablet. Rapamune should be taken consistently with or without food to minimize blood level variability.
Grapefruit juice reduces CYP3A4-mediated drug metabolism and potentially enhances P-gp-mediated drug counter-transport from enterocytes of the small intestines. This juice must not be taken with Rapamune tablets or oral solution or be used for oral solution dilution (see Mode of Administration under Dosage & Administration).
Interference with laboratory and other diagnostic tests: There are no studies on the interactions of Rapamune in commonly employed clinical laboratory tests.

Special precautions for disposal and other handling: Since Rapamune is not absorbed through the skin, there are no special precautions. However, if direct contact with the skin or mucous membranes occurs, wash thoroughly with soap and water; rinse eyes with plain water.

Rapamune Tablet 1 mg should be stored below 30°C. Use cartons to protect blister cards and strips from light. Dispense in a tight, light-resistant container as defined in the USP.

Immunosuppressants

L04AH01 - sirolimus ; Belongs to the class of mammalian target of rapamycin (mTOR) kinase inhibitors. Used as immunosuppressants.

POM