RAPAMUNE (sirolimus)

Rapamune is contraindicated in patients with a hypersensitivity to sirolimus or its derivatives or any ingredient in the formulation, including any non-medicinal ingredient or component of the container. For a complete listing, see 6 Dosage Forms, STRENGTHS, Composition and Packaging.

4.1 Dosing Considerations

• In patients at low to moderate immunological risk, it is recommended that Rapamune should be used initially in a regimen with cyclosporine and corticosteroids. Cyclosporine withdrawal is recommended 2 to 4 months after transplantation in patients at low to moderate immunologic risk.  
• In patients at high immunologic risk, it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation (See 4 Dosage and Administration and 14 Clinical Trials). 
• To minimize the variability of exposure to Rapamune, this drug should be taken once daily, preferably at the same time of day, and consistently with or without food. 
• Cyclosporine microemulsion enhances absorption of Rapamune (See 9 Drug Interactions). It is recommended that sirolimus be taken 4 hours after cyclosporine microemulsion administration. 
• A daily dose of 2 mg Rapamune Tablets has been demonstrated to be clinically equivalent to 2 mg Rapamune Oral Solution. However, it is not known if higher doses of Rapamune tablets and oral solution are clinically equivalent on a mg-to-mg basis.  (See 10 Clinical Pharmacology). 
• It is recommended that a sirolimus trough concentration be taken 1 or 2 weeks after switching Rapamune formulations or tablet strengths or altering the total daily dose to confirm that the trough concentration is within the recommended target range (see 7 Warnings And Precautions – Monitoring and Laboratory Tests – Blood Concentration Monitoring). 
• Blood sirolimus trough levels should be monitored:
  • In patients receiving concentration-controlled Rapamune.
  • In pediatric patients
  • In patients with hepatic impairment.
  • During concurrent administration of inhibitors and inducers of CYP3A4 and P-glycoprotein.
  • If the cyclosporine dose is markedly reduced, or if cyclosporine is discontinued.
• The Rapamune dosage need not be adjusted because of impaired renal function (See 3 Pharmcokinetics - Special Populations and Conditions - Renal Insufficiency). 
• It is recommended that the maintenance dose of Rapamune be reduced by approximately one third to one-half in patients with hepatic impairment. It is not necessary to modify the Rapamune loading dose.  (See 10.3 Pharmacokinetics - Special Populations and Conditions - Hepatic Insufficiency). In patients with hepatic impairment, it is recommended that sirolimus whole blood trough levels be monitored.  
• Based on the finding that blood clearance decreases linearly with age, consideration should be given to reducing the Rapamune dose in patients 65 years of age and over. (See 10.3 Pharmacokinetics, Special populations and Conditions, Geriatrics).
• The safety and efficacy of Rapamune in pediatric patients below the age of 13 years have not been established. The initial loading dose should be 3 mg/m² in patients ≥ 13 years who weigh less than 40 kg.  The maintenance dose should be adjusted, based on body surface area, to 1 mg/m²/day. It is recommended that sirolimus whole blood trough levels be monitored. 
• The bioavailability of sirolimus (oral solution or tablet) is altered by concomitant food intake after administration. Rapamune should be taken consistently, either with or without food to minimize blood level variability. 
• Bioavailability has not been determined for tablets after they have been crushed, chewed, or split and therefore this cannot be recommended. Patients unable to take the tablets should be prescribed the oral solution and instructed in its use. 
• Rapamune oral solution contains up to 3.17 vol % ethanol (alcohol). A 6 mg loading dose contains up to 150 mg of alcohol which is equivalent to 3.80 mL beer or 1.58 mL wine. This dose could potentially be harmful for those suffering from alcoholism and should be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy. Maintenance doses of 4 mg or less contain small amounts of ethanol (100 mg or less) that are likely to be too low to be harmful. 

4.2 Recommended Dose and Dosage Adjustment

Patients at Low to Moderate Immunological Risk 

Rapamune and Cyclosporine Combination Therapy: The initial dose of Rapamune should be administered as soon as possible after transplantation.  For de novo transplant recipients, a loading dose of Rapamune corresponding to 3 times the maintenance dose should be given.  For most patients, the maintenance dose is 2 mg/day, with a loading dose of 6 mg.  

Although a maintenance dose of 5 mg/day, with a loading dose of 15 mg, was used in clinical trials of the oral solution and was shown to be safe and effective, no efficacy advantage over the 2 mg dose could be established for renal transplant patients.  Patients receiving 2 mg of Rapamune oral solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of Rapamune oral solution per day.  

It is recommended that Rapamune oral solution and 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 immunologic risk, and the Rapamune dose should be increased to reach recommended blood concentrations (See Rapamune Maintenance Regimen). 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 14 Clinical Trials).

It is recommended that Rapamune be taken 4 hours after cyclosporine microemulsion [(cyclosporine, USP) MODIFIED] administration.  

Rapamune Maintenance Regimen (RMR, Rapamune following cyclosporine withdrawal):

Initially, patients considered for cyclosporine withdrawal 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 were close to these ranges (See 7 Warnings And Precautions – Monitoring and Laboratory Tests – Blood Concentration Monitoring). 

Patients at High Immunological Risk 

Rapamune Combination Therapy:  It is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation in patients at high immunologic risk (defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high-panel reactive antibodies [PRA; peak PRA level > 80%]) (See 14 Clinical Trials). 

The safety and efficacy of these combinations in high-risk patients have not been studied beyond one year. Therefore, after the first year following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient. 

For patients receiving Rapamune with cyclosporine, Rapamune therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of Rapamune should thereafter be adjusted to achieve whole blood trough sirolimus concentrations of 10-15 ng/mL. 

The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses, and the dose should subsequently be adjusted to achieve whole blood trough concentrations of 200-300 ng/mL through week 2, 150-200 ng/mL from week 2 to week 26, and 100-150 ng/mL from week 26 to week 52. Prednisone should be administered at a minimum of 5 mg/day.

Antibody induction therapy may be used (See 14 Clinical Trials). 

Pediatrics (<13 years of age): The safety and efficacy of Rapamune in pediatric patients below the age of 13 years has not been established; therefore, Health Canada has not authorized an indication for patients under the age of 13 years.

Rapamune Dosage Adjustment 

Therapeutic drug monitoring should not be the sole basis for adjusting Rapamune therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory parameters (See 9 Drug Interactions). 

Cyclosporine inhibits the metabolism and transport of sirolimus, and consequently, whole blood 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 with cyclosporine (approximately 2-fold increase) and the augmented immunosuppressive requirement in the absence of cyclosporine (approximately 2-fold increase). 

Sirolimus has a long half-life; therefore frequent Rapamune dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing. Once the Rapamune maintenance dose is adjusted, patients should be retained on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with trough concentration monitoring. 

In most patients dose adjustments can be based on simple proportion: 

New Rapamune dose = Current Dose x (Target Concentration ) Current Concentration)

A loading dose should be considered in addition to a new maintenance dose when it is necessary to considerably increase sirolimus trough concentrations: 

Rapamune Loading Dose = 3 x (New Maintenance Dose - Current Maintenance Dose)

The maximum Rapamune dose administered on any day should not exceed 40 mg. If an estimated daily dose would exceed 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

4.4 Administration

Instructions for Dilution and Administration of Rapamune Oral Solution:

The amber oral dose syringe should be used to withdraw the prescribed amount of Rapamune from the bottle.  Empty the correct amount of Rapamune from the syringe into a glass or plastic container holding at least two (2) ounces (¼ cup; 60 mL) of water or orange juice.  No other liquids, including grapefruit juice, should be used for dilution.  Stir vigorously and drink at once.  Rinse the container with an additional volume (minimum of four [4] ounces; ½ cup; 120 mL) of water or orange juice, stir vigorously, and drink at once.

Rapamune oral solution contains polysorbate-80, which is known to increase the rate of di-(2- ethylhexyl) phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of Rapamune oral solution. It is important that the recommendations in this section be followed closely.

Instructions for Rapamune Tablets:

Rapamune tablets should be taken with orange juice or water only.  Rapamune tablets should not be taken with grapefruit juice.

4.5 Missed Dose

A missed dose should be taken as soon as remembered, but not within 4 hours of the next dose of cyclosporine.  Medicines can then be taken as usual. If a dose is missed completely, a double dose should not be taken to make up for a forgotten dose.

Availability of Dosage Forms

Oral Solution:

Rapamune (sirolimus oral solution) is supplied at a concentration of 1 mg/mL in:

• Amber glass bottles of 60 mL

The bottles are supplied with an oral syringe adapter for fitting into the neck of the bottle and 30 disposable amber oral syringes and 30 caps for daily dosing. 

Tablets:

Rapamune (sirolimus tablets) is available as:

• a white, triangular-shaped tablet containing 1 mg sirolimus marked “RAPAMUNE 1 mg” on one side;
• a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus marked “RAPAMUNE 2 mg” on one side, and;
• a tan, triangular-shaped tablet containing 5 mg sirolimus marked “RAPAMUNE 5 mg” on one side. 

The tablets are supplied in:

• Bottles of 100 tablets
• Unit dose cartons of 100 tablets (10 blister cards of 10 tablets each)

8.1 Adverse Reaction Overview

• Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.
• Clostridium difficile enterocolitis has been reported in patients receiving sirolimus.
• Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions.  The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Rapamune and cyclosporine combination therapy: 

Rapamune Oral Solution: The incidence of adverse reactions was determined in two randomized, double-blind, multicentre controlled trials (Studies 1 and 2) in which 499 renal transplant patients received Rapamune (sirolimus oral solution) 2 mg/day, 477 received Rapamune oral solution 5 mg/day, 160 received azathioprine 2-3 mg/kg/day, and 124 received placebo.  All patients were treated with cyclosporine and corticosteroids.  

Adverse reactions associated with the administration of Rapamune which occurred at a significantly higher frequency than placebo or azathioprine control group include arthralgia, hirsutism, diarrhea, hypertension, hypokalemia, lymphocele, peripheral edema, rash, tachycardia, and some infections.  In general, adverse events related to administration of Rapamune were dependent on dose/concentration.  Dose related elevations of triglycerides and cholesterol and decreases in platelets and hemoglobin have occurred in patients receiving Rapamune. 

The data presented by study group in Table 2 show the adverse reactions that occurred in any treatment group with an incidence of ≥10%.

Table 3 summarizes the incidence rates at 6 months for clinically important opportunistic or common transplant-related infections across treatment groups Studies 1 and 2.  There were no significant differences in incidence rates between 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.

Table 4 summarizes the incidence of malignancies in Studies 1 and 2.  At 12 months following transplantation there was a very low incidence of malignancies and there were no significant differences between treatment groups.

The following reactions (listed alphabetically by body system) were reported with a ≥1% incidence in patients treated with Rapamune in combination with cyclosporine and corticosteroids: 

In general, adverse events related to administration of Rapamune were dependent on dose/concentration.

Rapamune Tablets:

The incidence of adverse reactions through 12 months was determined in a randomized, multicentre, controlled trial (Study 3) in which 229 renal transplant patients received Rapamune Oral Solution 2 mg once daily and 228 patients received Rapamune Tablets 2 mg once daily. All patients were treated with cyclosporine and corticosteroids. 

The adverse reactions that occurred in either treatment group with an incidence of ≥ 10% in Study 3 were similar to those reported for Studies 1 and 2. There was no notable difference in the incidence of these adverse events between treatment groups (oral solution versus tablets) in Study 3, with the exception of acne and pharyngitis, which occurred more frequently in the oral solution group, and liver function abnormal and tremor which occurred more frequently in the tablet group. 

The adverse events that occurred in patients with an incidence of ≥3% and <10% in either treatment group in Study 3 were similar to those reported in Studies 1 and 2. There was no notable difference in the incidence of these adverse events between treatment groups (oral solution versus tablets) in Study 3, with the exception of hypertonia and urinary incontinence, which occurred more frequently in the oral solution group and cataract, acidosis, ascites, and dysphagia which occurred more frequently in the tablet group.  In Study 3 alone, menorrhagia, metrorrhagia, and polyuria occurred with an incidence of ≥3% and <10%. 

The clinically important opportunistic or common transplant-related infections were identical in all three studies and the incidences of these infections were similar in Study 3 compared with Studies 1 and 2. The incidence rates of these infections were not significantly different between the oral solution and tablet treatment groups in Study 3. 

In Study 3, there were two cases of lymphoma or lymphoproliferative disorder in the oral solution treatment group (0.8%) and two reported cases of lymphoma or lymphoproliferative disorder in the tablet treatment group (0.8%). These differences were not statistically significant and were similar to the incidences observed in Studies 1 and 2. 

Rapamune Maintenance Regimen (RMR): The incidence of adverse reactions was determined through 60 months in a randomized, multicentre controlled trial (Study 4). This study compared 430 renal transplant patients who were administered Rapamune, cyclosporine and corticosteroids for the first 3 months after transplantation (pre-randomization period) followed by a 1:1 randomization at 3 months ± 2 weeks to the withdrawal of cyclosporine (Rapamune maintenance regimen) or the continuation of the Rapamune, cyclosporine and steroid regimen.  The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2 mg Rapamune groups in Studies 1, 2, and 3. 

Patients who had cyclosporine eliminated from their immunosuppressive therapy at 3 months ± 2 weeks 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, hyperkalemia, hyperuricemia, gout, benign skin neoplasm and gum hyperplasia was significantly higher in patients who remained on a Rapamune plus cyclosporine regimen. Mean systolic and diastolic blood pressure improved significantly following cyclosporine withdrawal. 

The incidence of Herpes zoster infection (at 60 months) was significantly lower in patients receiving Rapamune following cyclosporine withdrawal compared with patients who continued to receive Rapamune and cyclosporine. 

The incidence of malignancies in at 60 months post-transplant following cyclosporine withdrawal, is presented in Table 5. The incidence of lymphoma or 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 receiving Rapamune as part of the Rapamune maintenance regimen as compared with patients receiving Rapamune and cyclosporine (10.7% versus 15.8%, respectively; p=0.155).

High-Risk Patients Study:  Safety was assessed in a controlled trial (Study 5) (See 14 Clinical Trials) in 224 patients who 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. The incidence of malignancy was 1.3% at 12 months. 

Table 6 shows the adverse reactions that occurred with an incidence of ≥10%.

The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have 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  6 months – 10 years post-transplant, 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 10.2 Pharmacodynamics). 

The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy. 

In patients with delayed graft function, Rapamune may delay recovery of renal function (See 7 WARNINGS AND PRECAUTIONS, Renal function).

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Safety was assessed in a controlled clinical trial in pediatric (< 18 years of age) renal transplant patients considered high immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including but not limited to increased serum triglycerides and cholesterol), and urinary tract infections.

8.3 Less Common Clinical Trial Adverse Reactions

Less frequently occurring adverse events included: pancreatitis, lymphoma/post-transplant lymphoproliferative disorder, pancytopenia, melanoma, exfoliative dermatitis (See 7 WARNINGS AND PRECAUTIONS), nephrotic syndrome, pulmonary hemorrhage, and pericardial effusion (including hemodynamically significant effusions in children and adults).

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Abnormal hematologic and clinical chemistry findings are included in Clinical Trials Adverse Reactions (see 8.2 Clinical Trial Adverse Reactions).

8.5 Post-Market Adverse Reactions

Reporting rates determined on the basis of spontaneously reported post-marketing adverse events are generally presumed to underestimate the risks associated with drug treatments. 

The following adverse events have been reported spontaneously during post-marketing experience with Rapamune.  A causal relationship to Rapamune cannot be excluded for spontaneously reported events. 

Body as a Whole: Lymphedema, tuberculosis 

Cardiovascular System: Pericardial effusion (including hemodynamically significant effusions in children and adults). 

Digestive: Ascites reports have been common. Clostridium difficile enterocolitis has been reported in patients receiving sirolimus. 

Hemic and Lymphatic System: Pancytopenia 

Hepatobiliary Disorders: Hepatotoxicity has been reported, including fatal hepatic necrosis with elevated trough sirolimus concentrations (i.e., exceeding therapeutic levels). 

Immune System:  Hypersensitivity reactions, including anaphylactic /anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus (see 7 Warnings And Precautions). 

Metabolic and Nutritional: Fluid accumulation reports have been common. 

Musculoskeletal: Rhabdomyolysis has been reported in patients administered Rapamune with HMG-CoA reductase inhibitors, with or without cyclosporine (See 7 Warnings and Precautions - Musculoskeletal). 

Nerve system disorders: There have been cases of posterior reversible encephalopathy syndrome (PRES) reported with the use of immunosuppressants, including sirolimus. 

Respiratory System: 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 sirolimus trough concentration increases. Occurrence of pulmonary hemorrhage coincident with sirolimus administration has been reported in selected patients. Symptomatic improvement or resolution were seen after withdrawal of sirolimus. Pleural effusion reports have been common. Rare reports of alveolar proteinosis have been received. 

Skin and Appendages: Abnormal healing following transplant surgery has been reported, including fascial dehiscence, incisional hernia and anastomotic disruption (e.g., wound, vascular, airway, ureteral, biliary). 

Urogenital System: Azoospermia reports have been uncommon. Azoospermia reported with the use of Rapamune has been reversible upon discontinuation of Rapamune in most cases (see 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity, Mutagenicity, and Reproductive and Developmental Toxicology). Focal segmental glomerulosclerosis (frequency unknown) has been reported.

10.1 Mechanism of Action

Rapamune is a potent immunosuppressive agent.  Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus.  Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, IL-7, 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.  Unlike cyclosporine and tacrolimus, the sirolimus:FKBP-12 complex has no effect on calcineurin activity.  Rather, this complex binds to and inhibits the activation of a specific cell cycle regulatory protein called the mammalian Target Of Rapamycin (mTOR).  mTOR is a key regulatory kinase and its inhibition by sirolimus suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.

10.2 Pharmacodynamics

In in vitro studies, sirolimus inhibits proliferation of T lymphocytes, B lymphocytes, and vascular and bronchial smooth muscle cells induced by cytokines and growth factors.  Because sirolimus affects lymphocyte activation by a different mechanism, activation stimuli that resist inhibition by cyclosporine and tacrolimus have been shown to be sensitive to sirolimus.  Sirolimus also affects B cell activation and antibody production.  These effects contribute to the immunosuppressive properties of sirolimus. 

Sirolimus prolongs allograft survival in animal models of transplantation, ranging from rodents to primates, both for solid organ and for cellular allografts. In mice, sirolimus prolongs the survival of heart, skin and islet allografts.  Sirolimus prevents acute rejection of heart, kidney, small bowel, and pancreatico-duodenal grafts in rats and induces long-term tolerance.  In rats, sirolimus reverses ongoing acute rejection of heart, kidney, and pancreas allografts, and suppresses accelerated heart allograft rejection in presensitized hosts.  Sirolimus also prevents acute rejection of kidney allografts in dogs, pigs and baboons, as well as pancreatic islet cell rejection in dogs.  Although in animals, sirolimus improves allograft survival as a single agent, it is synergistic with cyclosporine and is effective in combination with tacrolimus. 

In animal 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. 

In rodents and primates, sirolimus mitigates the progression of chronic rejection by reducing the vascular intimal proliferation that is characteristic of chronic vascular rejection.  In a pig model of coronary restenosis after angioplasty, sirolimus reduces the vascular proliferative response to mechanical vascular injury. 

Animal studies have shown that sirolimus-mediated immunosuppression is reversible. 

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%).

10.3 Pharmacokinetics

Sirolimus pharmacokinetic activity has been determined following oral administration in healthy subjects, pediatric dialysis patients, hepatically impaired patients and renal transplant patients.  Sirolimus is rapidly absorbed and undergoes extensive metabolism to seven major metabolites that do not contribute significantly to the pharmacological effect. 

Absorption:

Following administration of Rapamune oral solution, sirolimus is rapidly absorbed, with a time to peak concentration (t_max) of 1 hour in healthy subjects and 2-3 hours in renal transplant recipients.  Following administration of Rapamune 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 is approximately 14% after the administration of Rapamune Oral Solution.  The mean bioavailability of sirolimus after administration of the Rapamune tablet is about 22% higher relative to the oral solution. Sirolimus tablets are not bioequivalent to the oral solution; however, clinical equivalence has been demonstrated at the 2 mg dose level over a 12-month period in renal allograft recipients, where clinical equivalence was measured as the rate of occurrence of the composite endpoint of first biopsy-proven acute rejection, graft loss, or death in the first 3 months after transplantation.  (See 14 Clinical Trials – Rapamune Tablets and 4 Dosage And Administration).  Sirolimus concentrations are dose proportional between 3 and 12 mg/m² following the administration of Rapamune oral solution to stable renal transplant patients, and between 5 and 40 mg after administration of Rapamune tablets in healthy volunteers.  Upon repeated administration to stable renal transplant patients, the average blood concentration of sirolimus was increased approximately 3-fold. 

Bioequivalence testing of the various sirolimus tablet strengths in healthy volunteers (n = 22) showed that 10 mg doses of the 1 mg, 2 mg, and 5 mg tablets were equivalent with respect to C_max, AUC_0-72h and AUC_0-inf (see 14.3 Comparative Bioavailability Studies).  

Food effects:  In 22 healthy volunteers receiving Rapamune oral solution, a high fat breakfast (861.8 kcal, 54.9% kcal from fat) altered the bioavailability characteristics of sirolimus.  Compared with fasting, a 34% decrease in the peak blood sirolimus concentration (C_max), a 3.5-fold increase in the time to peak concentration (t_max), and a 35% increase in total exposure (AUC) was observed.  The change in bioavailability is not clinically important.  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 multicentre controlled trial comparing Rapamune oral solution to tablets, supports that the differences in absorption rate 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 (See 4 Dosage And Administration).  Bioequivalence testing based on AUC and C_max showed that Rapamune administered with orange juice is equivalent to administration with water.  Therefore, orange juice and water may be used interchangeably as administration liquids for Rapamune (See 4 Dosage And Administration).  Grapefruit juice reduces CYP3A4-mediated drug metabolism and potentially enhances P-glycoprotein-mediated drug counter-transport from enterocytes of the small intestine.  Grapefruit juice must not be taken with Rapamune tablets or oral solution or be used for oral solution dilution. 

Distribution: 

The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 17.9 in stable renal allograft recipients after administration of Rapamune oral solution, indicating that sirolimus is extensively partitioned into formed blood elements.  The mean volume of distribution (V_ss/F) of sirolimus by Rapamune oral solution is 12 ± 7.52 L/kg.  Sirolimus is extensively bound (approximately 92%) to human plasma proteins.  In man, the binding of sirolimus was shown mainly to be associated with serum albumin (97%), 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 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.  The combined demethyl and hydroxy metabolites show ≤30% of the in vitro immunosuppressive activity of sirolimus. 

Elimination:

After a single dose of [¹⁴C] sirolimus by 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 (t½) of sirolimus after multiple dosing by Rapamune oral solution in stable renal transplant patients was estimated to be 62 ± 16 hours.  

Pharmacokinetics in renal transplant patients 

Rapamune and cyclosporine combination therapy:

Rapamune Oral Solution:  Mean (± SD) pharmacokinetic parameters for Rapamune oral solution given daily in combination with cyclosporine and corticosteroids in renal transplant patients were determined at months 1, 3, and 6 after transplantation (Study 1; See 14 Clinical Trials). There were no significant differences in any of these parameters with respect to treatment group or month. Whole blood sirolimus trough concentrations (mean ± SD) for the 2 mg/day and 5 mg/day dose groups were 8.6 ± 4.0 ng/mL (n=226) and 17.3 ± 7.4 ng/mL (n=219), respectively. Whole blood trough sirolimus concentrations were significantly correlated (r²=0.95) with AUC_τ,ss.  The table below provides a summary of these sirolimus pharmacokinetic parameters.  

Rapamune Tablets: Pharmacokinetic parameters for Rapamune tablets administered daily in combination with cyclosporine and corticosteroids in renal transplant patients are summarized below based on data collected at months 1 and 3 after transplantation (Study 3; See 14 Clinical Trials).

Whole blood sirolimus trough concentrations, (mean ± SD), as measured by immunoassay, for 2 mg of oral solution and 2 mg of tablets over 6 months, were 8.9 ± 4.4 ng/mL (n = 172) and 9.5 ±

3.9 ng/mL (n = 179), respectively.  Whole blood trough sirolimus concentrations, as measured by

LC/MS/MS, were significantly correlated (r² = 0.85) with AUC_τ,ss. Mean whole blood sirolimus trough concentrations in patients receiving either Rapamune Oral Solution or Rapamune Tablets with a loading dose of three times the maintenance dose achieved steady-state concentrations within 24 hours after the start of dose administration. 

Use of Rapamune without concomitant cyclosporine administration:

Average Rapamune doses and sirolimus whole blood trough concentrations for Rapamune tablets administered daily in combination with cyclosporine and following cyclosporine withdrawal, in combination with corticosteroids in renal transplant patients (Study 4; See 14 Clinical Trials) are summarized in the table below.

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

Pharmacokinetics in high-risk patients:

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

Special Populations and Conditions 

Pediatrics (<13 years of age): 

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.

The table below summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically impaired renal function receiving Rapamune by oral solution.

Geriatrics (>65 years of age): 

A decrease in CL/F of approximately 13% per decade was observed in population analyses.  Clinical studies of Rapamune did not include a sufficient number of patients > 65 years of age to determine whether they will respond differently than younger patients. After the administration of Rapamune oral solution, sirolimus trough concentration data in 35 renal transplant patients > 65 years of age were similar to those in the adult population (n=822) 18 to 65 years of age. Similar results were obtained after the administration of Rapamune tablets to 12 renal transplant patients > 65 years of age compared with adults (n=167) 18 to 65 years of age. 

Sex:

The pharmacokinetic differences between males and females are relatively small. Rapamune oral dose clearance after Rapamune oral solution 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. 

Ethnic Origin: 

In large phase 3 trials (Studies 1 and 2) using Rapamune and cyclosporine (microemulsion, Neoral^®), there were no significant differences in mean trough sirolimus concentrations or AUC over time between black (n=139) and non-black (n=724) patients during the first 6 months after transplantation at Rapamune doses of 2 mg/day and 5 mg/day by oral solution.  Similarly, after administration of Rapamune Tablets (2 mg/day) in a phase 3 trial, mean sirolimus trough concentrations over 6 months were not significantly different among black (n=51) and non-black (n=128) patients.  There is limited information on black patients from a Phase 3 trial (Study 4) using Rapamune with cyclosporine elimination.  In a Phase 2 study of similar design to Study 4, mean dose-normalized sirolimus trough concentrations in the control group (sirolimus 2 mg/day + cyclosporine) over 12 months were significantly decreased by approximately 31% among black (n=17) patients compared with non-black (n=72) patients.  The mean dose-normalized sirolimus trough concentrations over 12 months in the Rapamune (concentration-controlled 10-20 ng/mL) with cyclosporine elimination group were significantly decreased by approximately 15% among black (n=15) patients compared with non-black (n=76) patients.  

Hepatic Insufficiency: 

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

Compared with the values in the normal hepatic group, the hepatic impairment group had higher mean values for sirolimus AUC  and t_½  and had lower mean values for sirolimus CL/F. Sirolimus absorption was not altered by hepatic disease, as evidenced by no changes in C_max and t _max values.  The initial 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.  In patients with hepatic impairment, it is recommended that sirolimus whole blood trough levels be monitored. However, hepatic diseases with varying etiologies may show different effects. 

Renal Insufficiency: 

There is minimal (2.2%) renal excretion of the drug or its metabolites.  The pharmacokinetics of sirolimus are very similar in various populations with renal function ranging from normal to absent (dialysis patients).