HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`Rapamune safely and effectively. See full prescribing information for
`Rapamune.
`
`RAPAMUNE (sirolimus) ORAL SOLUTION AND TABLETS
`Initial U.S. Approval: 1999
`
`WARNING: IMMUNOSUPPRESSION, USE IS NOT
`RECOMMENDED IN LIVER OR LUNG TRANSPLANT PATIENTS
`See Full Prescribing Information for complete Boxed Warning.
`
`Increased susceptibility to infection and the possible development of
`lymphoma and other malignancies may result from
`immunosuppression (5.1). Only physicians experienced in
`immunosuppressive therapy and management of renal transplant
`patients should use Rapamune.
` 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 (5.2, 5.3).
`Liver Transplantation – Excess mortality, graft loss, and
`
`hepatic artery thrombosis (5.2).
`Lung Transplantation – Bronchial anastomotic
`
`dehiscence (5.3).
`
`
`
`———————— INDICATIONS AND USAGE ————————
`Rapamune is an immunosuppressive agent indicated for the
`prophylaxis of organ rejection in patients aged ≥13 years receiving
`renal transplants.
`
`Patients at low- to moderate-immunologic risk: Use initially with
`cyclosporine (CsA) and corticosteroids. CsA withdrawal is
`recommended 2-4 months after transplantation (1.1).
`Patients at high-immunologic risk: Use in combination with
`cyclosporine and corticosteroids for the first 12 months following
`transplantation (1.1). Safety and efficacy of CsA withdrawal has not
`been established in high risk patients (1.1, 1.2, 14.3).
` Therapeutic drug monitoring is recommended for all patients (2.3,
`
`5.15).
`
`——————— DOSAGE AND ADMINISTRATION ——————
` Take once daily by mouth, consistently with or without food. Take the
`initial dose as soon as possible after transplantation and 4 hours after
`CsA (2, 7.1). Adjust the Rapamune maintenance dose to achieve
`sirolimus trough concentrations within the target-range (2.3).
`Patients at low- to moderate-immunologic risk
` Rapamune and Cyclosporine Combination Therapy: One loading dose
`of 6 mg on day 1, followed by daily maintenance doses of 2 mg (2.1).
` Rapamune Following Cyclosporine Withdrawal: 2-4 months post-
`transplantation, withdraw CsA over 4-8 weeks (2.2).
`Patients at high-immunologic risk
` Rapamune and Cyclosporine Combination Therapy (for the first 12
`months post-transplantation): One loading dose of up to 15 mg on day
`1, followed by daily maintenance doses of 5 mg (2.2).
`
`—————— DOSAGE FORMS AND STRENGTHS ——————
`
`Rapamune Oral Solution: 60 mg per 60 mL in amber glass bottle
`(3.1).
`
`Rapamune Tablets: 0.5 mg, tan; 1 mg, white; 2 mg, yellow-to-beige
`(3.2).
`
`————————— CONTRAINDICATIONS ————————
`Hypersensitivity to Rapamune (4).
`
`——————— WARNINGS AND PRECAUTIONS ——————
`
`Hypersensitivity Reactions (5.4)
`
`
`Angioedema (5.5)
`
`
`Fluid Accumulation and Wound Healing (5.6)
`
`
`Hyperlipidemia (5.7)
`
`
`Renal Function (5.8)
`
`
`Proteinuria (5.9)
`
`
`Latent Viral Infections (5.10)
`
`
`Interstitial Lung Disease (5.11)
`
`
`De Novo Use Without Cyclosporine (5.12)
`
`
`Increased Risk of Calcineurin Inhibitor-induced HUS/TTP/TMA
`
`(5.13)
`
`————————— ADVERSE REACTIONS —————————
`The most common (> 30%) adverse reactions are: peripheral edema,
`hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine
`increased, abdominal pain, diarrhea, headache, fever, urinary tract infection,
`anemia, nausea, arthralgia, pain, and thrombocytopenia (6).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Wyeth
`Pharmaceuticals Inc. at 1-800-934-5556 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`
`————————— DRUG INTERACTIONS —————————
`
`Avoid concomitant use with strong CYP3A4/P-gp inducers or strong
`CYP3A4/P-gp inhibitors that decrease or increase sirolimus
`concentrations (7.4, 12.3).
`Exercise caution when administering with drugs that are
`inhibitors/inducers of CYP3A4/P-gp (7.4, 12.3).
`
`
`
`——————— USE IN SPECIFIC POPULATIONS ——————
`
`Pregnancy: Use only if the potential benefit outweighs the potential
`risk to the embryo/fetus (8.1).
`
`Hepatic impairment: Reduce maintenance dose in patients with
`hepatic impairment (2.5, 8.6, 12.3).
`
`See 17 for PATIENT COUNSELING INFORMATION and the
`FDA-approved Medication Guide
`
`Revised: MM/YYYY
`
`Reference ID: 3711999
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS *
`
`BOX WARNING: IMMUNOSUPPRESSION, USE IS NOT
`RECOMMENDED IN LIVER OR LUNG TRANSPLANT PATIENTS
`1
`INDICATIONS AND USAGE
`1.1 Prophylaxis of Organ Rejection in Renal Transplantation
`
`1.2 Limitations of Use
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Patients at Low- to Moderate-Immunologic Risk
`
`2.2 Patients at High-Immunologic Risk
`
`2.3 Therapeutic Drug Monitoring
`
`2.4 Patients with Low Body Weight
`
`2.5 Patients with Hepatic Impairment
`
`2.6 Patients with Renal Impairment
`
`2.7
`Instructions for Dilution and Administration of Rapamune Oral
`
`Solution
`
`3 DOSAGE FORMS AND STRENGTHS
`3.1 Rapamune Oral Solution
`
`3.2 Rapamune Tablets
`
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Increased Susceptibility to Infection and the Possible
`
`Development of Lymphoma
`
`5.2 Liver Transplantation – Excess Mortality, Graft Loss, and
`
`Hepatic Artery Thrombosis (HAT)
`
`5.3 Lung Transplantation – Bronchial Anastomotic Dehiscence
`
`5.4 Hypersensitivity Reactions
`
`5.5 Angioedema
`
`5.6 Fluid Accumulation and Wound Healing
`
`5.7 Hyperlipidemia
`
`5.8 Renal Function
`
`5.9 Proteinuria
`
`5.10 Latent Viral Infections
`
`5.11 Interstitial Lung Disease
`
`5.12 De Novo Use Without Cyclosporine
`
`5.13 Increased Risk of Calcineurin Inhibitor-Induced Hemolytic
`
`Uremic Syndrome/Thrombotic Thrombocytopenic
`
`Purpura/Thrombotic Microangiopathy (HUS/TTP/TMA)
`
`5.14 Antimicrobial Prophylaxis
`
`5.15 Assay for Sirolimus Therapeutic Drug Monitoring
`
`5.16 Skin Cancer Events
`
`5.17 Interaction with Strong Inhibitors and Inducers of CYP3A4
`
`and/or P-gp
`
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience in Prophylaxis of Organ Rejection
`
`Following Renal Transplantation
`
`6.2 Rapamune Following Cyclosporine Withdrawal
`
`6.3 High-Immunologic Risk Patients
`
`
`6.4 Conversion from Calcineurin Inhibitors to Rapamune in
`
`Maintenance Renal Transplant Population
`
`6.5 Pediatrics
`
`6.6 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`7.1 Use with Cyclosporine
`
`7.2 Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp
`
`7.3 Grapefruit Juice
`
`7.4
`Inducers or Inhibitors of CYP3A4 and P-gp
`
`7.5 Vaccination
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Patients with Hepatic Impairment
`
`8.7 Patients with Renal Impairment
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`14.1 Prophylaxis of Organ Rejection
`
`14.2 Cyclosporine Withdrawal Study
`
`14.3 High-Immunologic Risk Patients
`
`14.4 Conversion from Calcineurin Inhibitors to Rapamune in
`
`Maintenance Renal Transplant Patients
`
`14.5 Conversion from a CNI-based Regimen to a Sirolimus-based
`
`Regimen in Liver Transplant Patients
`
`14.6 Pediatrics
`
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 Rapamune Oral Solution
`
`16.2 Rapamune Tablets
`
`17 PATIENT COUNSELING INFORMATION
`17.1 Dosage
`
`17.2 Skin Cancer Events
`
`17.3 Pregnancy Risks
`
`* Sections or subsections omitted from the full prescribing information are
`not listed
`
`Reference ID: 3711999
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`BOX WARNING: IMMUNOSUPPRESSION, USE IS NOT RECOMMENDED IN LIVER
`OR LUNG TRANSPLANT PATIENTS
`
`
`
`Increased susceptibility to infection and the possible development of lymphoma and
`other malignancies may result from immunosuppression
`
`Increased susceptibility to infection and the possible development of lymphoma may result
`from immunosuppression. Only physicians experienced in immunosuppressive therapy and
`management of renal 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 [see Warnings and
`Precautions (5.1)].
` 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 [see Warnings and Precautions (5.2, 5.3)].
` 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 patients. 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 patients, 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 [see Warnings and Precautions (5.2)].
` 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 [see Warnings and Precautions (5.3)].
`
`Reference ID: 3711999
`
`3
`
`

`

`1
`
`INDICATIONS AND USAGE
`
`1.1 Prophylaxis of Organ Rejection in Renal Transplantation
`
`Rapamune (sirolimus) is indicated for the prophylaxis of organ rejection in patients aged 13
`years or older receiving renal transplants. Therapeutic drug monitoring is recommended for all
`patients receiving Rapamune [see Dosage and Administration (2.3), Warnings and Precautions
`(5.15)].
`
`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 [see Dosage and Administration (2.1)].
`
`In patients at high-immunologic risk (defined as Black 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 Dosage and Administration (2.2), Clinical Studies (14.3)].
`
`1.2 Limitations of Use
`
`Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or
`vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those
`with serum creatinine > 4.5 mg/dL, Black patients, patients of multi-organ transplants,
`secondary transplants, or those with high levels of panel-reactive antibodies [see Clinical
`Studies (14.2)].
`
`In patients at high-immunologic risk, the safety and efficacy of Rapamune used in
`combination with cyclosporine and corticosteroids has not been studied beyond one year;
`therefore after the first 12 months following transplantation, any adjustments to the
`immunosuppressive regimen should be considered on the basis of the clinical status of the
`patient [see Clinical Studies (14.3)].
`
`In pediatric patients, the safety and efficacy of Rapamune have not been established in
`patients < 13 years old, or in pediatric (< 18 years) renal transplant patients considered at high-
`immunologic risk [see Adverse Reactions (6.5), Clinical Studies (14.6)]. The safety and
`efficacy of de novo use of Rapamune without cyclosporine have not been established in renal
`transplant patients [see Warnings and Precautions (5.12)].
`
`The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in
`maintenance renal transplant patients have not been established [see Clinical Studies (14.4)].
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Rapamune is to be administered orally once daily, consistently with or without food [see
`Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
`
`Reference ID: 3711999
`
`4
`
`
`

`

`Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be
`prescribed the solution and instructed in its use.
`
`The initial dose of Rapamune should be administered as soon as possible after transplantation.
`It is recommended that Rapamune be taken 4 hours after administration of cyclosporine oral
`solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [see Drug Interactions
`(7.2)].
`
`Frequent Rapamune dose adjustments based on non-steady-state sirolimus concentrations can
`lead to overdosing or underdosing because sirolimus has a long half-life. Once Rapamune
`maintenance dose is adjusted, patients should continue on the new maintenance dose for at least
`7 to 14 days before further dosage adjustment with 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 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 exceeds 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).
`
`Two milligrams (2 mg) of Rapamune Oral Solution have been demonstrated to be clinically
`
`equivalent to 2 mg Rapamune Tablets; hence, are interchangeable on a mg-to-mg basis.
`However, it is not known if higher doses of Rapamune Oral Solution are clinically equivalent
`to higher doses of Rapamune Tablets on a mg-to-mg basis [see Clinical Pharmacology (12.3)].
`
`2.1 Patients at Low- to Moderate-Immunologic Risk
`
`Rapamune and Cyclosporine Combination Therapy
`
`For de novo renal transplant patients, it is recommended that Rapamune Oral Solution and
`Tablets be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of
`Rapamune equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance
`dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring
`should be used to maintain sirolimus drug concentrations within the target-range [see Dosage
`and Administration (2.3)].
`
`Rapamune Following Cyclosporine Withdrawal
`
`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 sirolimus whole blood
`trough concentrations within the target-range [see Dosage and Administration (2.3)]. Because
`cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may
`
`decrease when cyclosporine is discontinued, unless the Rapamune dose is increased [see
`Clinical Pharmacology (12.3)].
`
`Reference ID: 3711999
`
`5
`
`
`

`

`2.2 Patients at High-Immunologic Risk
`
`In patients with high-immunologic risk, it is recommended that Rapamune be used in
`combination with cyclosporine and corticosteroids for the first 12 months following
`transplantation [see Clinical Studies (14.3)]. The safety and efficacy of this combination in
`high-immunologic risk patients has not been studied beyond the first 12 months. Therefore,
`after the first 12 months 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 [see Dosage and
`Administration (2.3)].
`
`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 target whole blood trough concentrations [see
`Dosage and Administration (2.3)]. Prednisone should be administered at a minimum of
`5 mg/day.
`
`Antibody induction therapy may be used.
`
`2.3 Therapeutic Drug Monitoring
`
`Monitoring of sirolimus trough concentrations is recommended for all patients, especially in
`those patients likely to have altered drug metabolism, in patients ≥ 13 years who weigh less
`than 40 kg, in patients with hepatic impairment, when a change in the Rapamune dosage form
`is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [see
`Drug Interactions (7)].
`
`Therapeutic drug monitoring should not be the sole basis for adjusting Rapamune therapy.
`Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and
`laboratory parameters.
`
`When used in combination with cyclosporine, sirolimus trough concentrations should be
`maintained within the target-range [see Clinical Studies (14), Clinical Pharmacology (12.3)].
`Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic
`risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year
`following transplantation. Thereafter, the target sirolimus concentrations should be 12 to
`20 ng/mL.
`
`The above recommended 24-hour trough concentration ranges for sirolimus are based on
`chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations
`are being measured by both chromatographic and immunoassay methodologies. Because the
`measured sirolimus whole blood concentrations depend on the type of assay used, the
`concentrations obtained by these different methodologies are not interchangeable [see
`Warnings and Precautions (5.15), Clinical Pharmacology (12.3)]. Adjustments to the targeted
`range should be made according to the assay utilized to determine sirolimus trough
`
`Reference ID: 3711999
`
`6
`
`
`

`

`concentrations. Since results are assay and laboratory dependent, and the results may change
`over time, adjustments to the targeted therapeutic range must be made with a detailed
`knowledge of the site-specific assay used. Therefore, communication should be maintained
`with the laboratory performing the assay. A discussion of different assay methods is contained
`in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see References (15)].
`
`2.4 Patients with Low Body Weight
`
`The initial dosage in patients ≥ 13 years who weigh less than 40 kg should be adjusted, based
`on body surface area, to 1 mg/m2/day. The loading dose should be 3 mg/m2 .
`
`2.5 Patients with Hepatic Impairment
`
`It is recommended that the maintenance dose of Rapamune be reduced by approximately one
`third in patients with mild or moderate hepatic impairment and by approximately one half in
`patients with severe hepatic impairment. It is not necessary to modify the Rapamune loading
`dose [see Clinical Pharmacology (12.3)].
`
`2.6 Patients with Renal Impairment
`
`Dosage adjustment is not needed in patients with impaired renal function [see Use in Specific
`Populations (8.7)].
`
`2.7
`
`Instructions for Dilution and Administration of Rapamune Oral Solution
`
`The amber oral dose syringe should be used to withdraw the prescribed amount of Rapamune
`Oral Solution from the bottle. Empty the correct amount of Rapamune from the syringe into
`only a glass or plastic container holding at least two (2) ounces (1/4 cup, 60 mL) of water or
`orange juice. No other liquids, including grapefruit juice, should be used for dilution [see Drug
`Interactions (7.3), Clinical Pharmacology (12.3)]. Stir vigorously and drink at once. Refill the
`container with an additional volume [minimum of four (4) ounces (1/2 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 these recommendations be followed closely.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`3.1 Rapamune Oral Solution
` 60 mg per 60 mL in amber glass bottle.
`3.2 Rapamune Tablets
` 0.5 mg, tan, triangular-shaped tablets marked “RAPAMUNE 0.5 mg” on one side.
` 1 mg, white, triangular-shaped tablets marked “RAPAMUNE 1 mg” on one side.
`
`Reference ID: 3711999
`
`7
`
`
`

`

` 2 mg, yellow-to-beige triangular-shaped tablets marked “RAPAMUNE 2 mg” on one
`side.
`
`4
`
`CONTRAINDICATIONS
`
`Rapamune is contraindicated in patients with a hypersensitivity to Rapamune [see Warnings
`and Precautions (5.4)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1
`
`Increased Susceptibility to Infection and the Possible Development of Lymphoma
`
`Increased susceptibility to infection and the possible development of lymphoma and other
`malignancies, particularly of the skin, may result from immunosuppression. The rates of
`lymphoma/lymphoproliferative disease observed in Studies 1 and 2 were 0.7-3.2% (for
`Rapamune-treated patients) versus 0.6-0.8% (azathioprine and placebo control) [see Adverse
`Reactions (6.1) and (6.2)]. 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.
`
`5.2 Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery
`Thrombosis (HAT)
`
`The safety and efficacy of Rapamune as immunosuppressive therapy have not been established
`in liver transplant patients; therefore, such use is not recommended. The use of Rapamune has
`been associated with adverse outcomes in patients following liver transplantation, including
`excess mortality, graft loss and Hepatic Artery Thrombosis (HAT).
`
`In a study in de novo liver transplant patients, the use of Rapamune in combination with
`tacrolimus was associated with excess mortality and graft loss (22% in combination versus 9%
`on tacrolimus alone). 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 patients, the use of Rapamune in
`combination with cyclosporine or tacrolimus was associated with an increase in HAT (7% in
`combination versus 2% in the control arm); most cases of HAT occurred within 30 days post-
`transplantation, and most led to graft loss or death.
`
`In a clinical study in stable liver transplant patients 6-144 months post-liver transplantation and
`receiving a CNI-based regimen, an increased number of deaths was observed in the group
`converted to a Rapamune-based regimen compared to the group who was continued on a CNI-
`based regimen, although the difference was not statistically significant (3.8% versus 1.4%) [see
`Clinical Studies (14.5)].
`
`Reference ID: 3711999
`
`8
`
`
`

`

`5.3 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.
`
`The safety and efficacy of Rapamune as immunosuppressive therapy have not been established
`in lung transplant patients; therefore, such use is not recommended.
`
`5.4 Hypersensitivity Reactions
`
`Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema,
`exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the
`administration of Rapamune [see Adverse Reactions (6.6)].
`
`5.5 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.
`
`5.6 Fluid Accumulation and Wound Healing
`
`There have been reports of impaired or delayed wound healing in patients receiving Rapamune,
`including lymphocele and wound dehiscence [see Adverse Reactions (6.1)]. 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. Lymphocele, a
`known surgical complication of renal transplantation, occurred significantly more often in a
`dose-related fashion in patients treated with Rapamune [see Adverse Reactions (6.1)].
`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, ascites, and pericardial effusions (including hemodynamically significant
`effusions and tamponade requiring intervention in children and adults), in patients receiving
`Rapamune.
`
`5.7 Hyperlipidemia
`
`Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in
`patients treated with Rapamune compared with azathioprine or placebo controls in Studies 1
`and 2 [see Adverse Reactions (6.1)]. There were increased incidences of hypercholesterolemia
`(43-46%) and/or hypertriglyceridemia (45-57%) in patients receiving Rapamune compared
`with placebo controls (each 23%). The risk/benefit should be carefully considered in patients
`with established hyperlipidemia before initiating an immunosuppressive regimen including
`Rapamune.
`
`Reference ID: 3711999
`
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`
`
`

`

`Any patient who is administered Rapamune should be monitored for hyperlipidemia. If
`detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as
`outlined by the National Cholesterol Education Program guidelines.
`
`In clinical trials of patients receiving Rapamune plus cyclosporine or Rapamune after
`cyclosporine withdrawal, up to 90% of patients required treatment for hyperlipidemia and
`hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid
`management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and
`triglycerides above recommended target levels. The concomitant administration of Rapamune
`and HMG-CoA reductase inhibitors resulted in adverse events such as CPK elevations (3%),
`myalgia (6.7%) and rhabdomyolysis (<1%). In these trials, the number of patients was too
`small and duration of follow-up too short to evaluate the long-term impact of Rapamune on
`cardiovascular mortality.
`
`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.
`
`5.8 Renal Function
`
`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. 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.
`
`Appropriate adjustment of the immunosuppressive regimen, including discontinuation of
`Rapamune and/or cyclosporine, should be considered in patients with elevated or increasing
`serum creatinine levels. 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. 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.
`
`5.9 Proteinuria
`
`Periodic quantitative monitoring of urinary protein excretion is recommended. In a study
`
`evaluating conversion from calcineurin inhibitors (CNI) to Rapamune 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 compared with
`CNI continuation [see Clinical Studies (14.4), Adverse Reactions (6.4)]. Patients with the
`greatest amount of urinary protein excretion prior to Rapamune conversion were those whose
`protein excretion increased the most after conversion. New onset nephrosis (nephrotic
`
`Reference ID: 3711999
`
`10
`
`
`

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`syndrome) was also reported as a treatment-emergent adverse event in 2.2% of the Rapamune
`conversion group patients in comparison to 0.4% in the CNI continuation group of patients.
`Nephrotic range proteinuria (defined as urinary protein to creatinine ratio > 3.5) was also
`reported in 9.2% in the Rapamune conversion group of patients in comparison to 3.7% in the
`CNI continuation group of patients. In some patients, 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 Rapamune in maintenance renal
`transplant patients have not been established.
`
`5.10 Latent Viral Infections
`
`Immunosuppressed patients are at increased risk for opportunistic infections, including
`activation of latent viral infections. These include BK virus-associated nephropathy, which has
`been observed in patients receiving immunosuppressants, including Rapamune. This infection
`may be associated with serious outcomes, including deteriorating renal function and renal graft
`loss [see Adverse Reactions (6.6)]. Patient monitoring may help detect patients at risk for BK
`virus-associated nephropathy. Reduction in immunosuppression should be considered for
`patients who develop evidence of BK virus-associated nephropathy.
`
`Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been
`reported in patients treated with immunosuppressants, including Rapamune. PML commonly
`
`presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for
`PML include treatment with immunosuppressant therapies and impairment of immune
`function. In immunosuppressed patients, physicians should consider PML in the differential
`diagnosis in patients reporting neurological symptoms and consultation with a neurologist
`should be considered as clinically indicated. Consideration should be given to reducing the
`amount of immunosuppression in patients who develop PML. In transplant patients, physicians
`should also consider the risk that reduced immunosuppression represents to the graft.
`
`5.11 Interstitial Lung Disease
`
`Cases of interstitial lung disease (including pneumonitis, 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 concentration increases [see
`Adverse Reactions (6.6)].
`
`5.12 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 multicenter c