Rapamune Description

Rapamune® (sirolimus) is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus . The chemical name of sirolimus (also known as rapamycin) is (3 S ,6 R ,7 E ,9 R ,10 R ,12 R ,14 S ,15 E ,17 E ,19 E ,21 S ,23 S ,26 R ,27 R ,34a S )-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1 R )-2-[(1 S ,3 R ,4 R )-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3 H -pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4 H ,6 H ,31 H )-pentone. Its molecular formula is C51 H79 NO13 and its molecular weight is 914.2. The structural formula of sirolimus is shown below.

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

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

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

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

Rapamune Indications And Usage

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

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recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation and the Rapamune® dose should be increased to reach recommended blood concentrations (See DOSAGE AND ADMINISTRATION ).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

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

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

Rapamune Contraindications

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

Rapamune Side Effects

Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression (see ADVERSE REACTIONS ). Oversuppression of the immune system can also increase susceptibility to infection including opportunistic infections such as tuberculosis, fatal infections, and sepsis. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Rapamune. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

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

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

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

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

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

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

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

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

Liver Transplantation? Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT):

The use of sirolimus 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 sirolimus 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.

Lung Transplantation? Bronchial Anastomotic Dehiscence:

Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen.

The safety and efficacy of Rapamune® (sirolimus) as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended.

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

Rapamune Precautions

General

Rapamune is intended for oral administration only.

Fluid Accumulation and Wound Healing

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

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

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

Lipids

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

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

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

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

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

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

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

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

Renal Function

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

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

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

Proteinuria

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

De Novo Use Without Cyclosporine

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

Calcineurin Inhibitor-induced Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathy (Hus/Ttp/Tma)

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

Angioedema

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

Antimicrobial Prophylaxis

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

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

Interstitial Lung Disease

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

Information For Patients

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

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

Laboratory Tests

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

Drug Interactions

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

Cyclosporine Capsules Modified

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Drugs Which May Be Coadministered Without Dose Adjustment

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

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

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

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

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

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

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

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

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

Other Drug Interactions

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

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

Sirolimus is a substrate for the multidrug efflux pump, P-gp in the small intestine. Therefore, absorption of sirolimus may be influenced by drugs that affect P-gp.

Aside from those mentioned above, other drugs that increase sirolimus blood concentrations include (but are not limited to):

• Calcium channel blockers: nicardipine.
  Antifungal agents: clotrimazole, fluconazole.
  Antibiotics: troleandomycin.
  Gastrointestinal prokinetic agents: cisapride, metoclopramide.
  Other drugs: bromocriptine, cimetidine, danazol, HIV-protease inhibitors (e.g., ritonavir, indinavir).

Aside from those mentioned above, other drugs that decrease sirolimus concentrations include (but are not limited to):

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

Care should be exercised when drugs or other substances that are metabolized by CYP3A4 are administered concomitantly with Rapamune. Grapefruit juice reduces CYP3A4-mediated metabolism of Rapamune and must not be used for dilution (see DOSAGE AND ADMINISTRATION ).

Herbal Preparations

St. John's Wort ( hypericum perforatum ) induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. John's Wort in patients receiving Rapamune could result in reduced sirolimus concentrations.

Vaccination

Immunosuppressants may affect response to vaccination. Therefore, during treatment with Rapamune, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid.

Drug-laboratory Test Interactions

There are no studies on the interactions of sirolimus in commonly employed clinical laboratory tests.

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

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.

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 with controls. In a 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.

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.

Pregnancy

Pregnancy Category C: Sirolimus was embryo/feto toxic in rats at dosages of 0.1 mg/kg and above (approximately 0.2 to 0.5 the clinical doses adjusted for body surface area). Embryo/feto toxicity was manifested as mortality and reduced fetal weights (with associated delays in skeletal ossification). However, no teratogenesis was evident. In combination with cyclosporine, rats had increased embryo/feto mortality compared with Rapamune alone. There were no effects on rabbit development at the maternally toxic dosage of 0.05 mg/kg (approximately 0.3 to 0.8 times the clinical doses adjusted for body surface area). There are no adequate and well controlled studies in pregnant women. Effective contraception must be initiated before Rapamune therapy, during Rapamune therapy, and for 12 weeks after Rapamune therapy has been stopped. Rapamune should be used during pregnancy only if the potential benefit outweighs the potential risk to the embryo/fetus.

Use During Lactation

Sirolimus is excreted in trace amounts in milk of lactating rats. It is not known whether sirolimus is excreted in human milk. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Because many drugs are excreted in 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.

Pediatric Use

The safety and efficacy of Rapamune® in pediatric patients below the age of 13 years have not been established.

The safety and efficacy of Rapamune® Oral Solution and Rapamune® Tablets have been established in children aged 13 or older judged to be at low to moderate immunologic risk. Use of Rapamune® Oral Solution and Rapamune® Tablets in this subpopulation of children aged 13 or older is supported by evidence from adequate and well-controlled trials of Rapamune® Oral Solution in adults with additional pharmacokinetic data in pediatric renal transplantation recipients (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric ).

Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (< 18 years of age) renal transplant recipients judged to be at high immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of Rapamune® Oral Solution or Tablets in combination with calcineurin inhibitors and corticosteroids, due to the increased risk of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens, without increased benefit with respect to acute rejection, graft survival, or patient survival (see CLINICAL STUDIES, Pediatrics ).

Geriatric Use

Clinical studies of Rapamune Oral Solution or Tablets did not include sufficient numbers of patients aged 65 years and over to determine whether safety and efficacy differ in this population from younger patients. Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary.

Rapamune Overdosage

Reports of overdose with Rapamune have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the ADVERSE REACTIONS section (see 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 was greater than 800 mg/kg.

Rapamune Information For Patients

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

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