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
`RAPAMUNE (sirolimus) tablets, for oral use
`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 for prophylaxis of organ rejection
`in patients receiving renal transplants.
`• 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).
`
`
` --------------------------- RECENT MAJOR CHANGES-------------------------
`Warnings and Precautions, Angioedema (5.5) 4/2017
`
`------------------------------INDICATIONS AND USAGE------------------------
`Rapamune is an mTOR inhibitor immunosuppressant 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 CsA 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).
`Rapamune is an mTOR inhibitor indicated for the treatment of patients with
`lymphangioleiomyomatosis (1.3).
`
`-------------------------DOSAGE AND ADMINISTRATION--------------------
`Renal Transplant Patients:
`Administer once daily by mouth, consistently with or without food (2).
`•
`Administer the initial dose as soon as possible after transplantation
`•
`and 4 hours after CsA (2.1, 7.1).
`Adjust the Rapamune maintenance dose to achieve sirolimus trough
`concentrations within the target-range (2.5).
`Hepatic impairment: Reduce maintenance dose in patients with
`hepatic impairment (2.7, 8.6, 12.3.)
`In renal transplant patients at low-to moderate-immunologic risk:
`Rapamune and CsA Combination Therapy: One loading dose of 6 mg
`•
`on day 1, followed by daily maintenance doses of 2 mg (2.2).
`Rapamune Following CsA Withdrawal: 2-4 months
`post-transplantation, withdraw CsA over 4-8 weeks (2.2).
`In renal transplant patients at high-immunologic risk:
`Rapamune and CsA 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 (2.3).
`
`
`•
`
`•
`
`•
`
`Lymphangioleiomyomatosis Patients:
`• Administer once daily by mouth, consistently with or without food (2).
`• Recommended initial Rapamune dose is 2 mg/day (2.4).
`• Adjust the Rapamune dose to achieve sirolimus trough concentrations
`between 5-15 ng/mL (2.4).
`• Hepatic impairment: Reduce maintenance dose in patients with hepatic
`impairment (2.7, 8.6, 12.3).
`
`
`Therapeutic drug monitoring is recommended for all patients (2.5, 5.15).
`
`---------------------DOSAGE FORMS AND STRENGTHS--------------------
`• Oral Solution: 60 mg per 60 mL in amber glass bottle (3.1).
`• Tablets: 0.5 mg, 1 mg, 2 mg (3.2).
`
`-----------------------------CONTRAINDICATIONS------------------------------
`Hypersensitivity to Rapamune (4).
`
`------------------------WARNINGS AND PRECAUTIONS---------------------
`• Hypersensitivity Reactions (5.4)
`• Angioedema (5.5)
`• Fluid Accumulation and Impairment of Wound Healing (5.6)
`• Hyperlipidemia (5.7)
`• Decline in Renal Function (5.8)
`• Proteinuria (5.9)
`• Latent Viral Infections (5.10)
`Interstitial Lung Disease/Non-Infectious Pneumonitis (5.11)
`•
`• De Novo Use Without Cyclosporine (5.12)
`Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic
`•
`
`Syndrome/ Thrombotic Thrombocytopenic Purpura/ Thrombotic
` Microangiopathy (5.13)
`
`------------------------------ADVERSE REACTIONS-----------------------------
`Prophylaxis of organ rejection in patients receiving renal transplants: Most
`common adverse reactions (incidence ≥ 30%) are peripheral edema,
`hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine
`increased, abdominal pain, diarrhea, headache, fever, urinary tract infection,
`anemia, nausea, arthralgia, pain, and thrombocytopenia (6).
`
`Lymphangioleiomyomatosis: Most common adverse reactions (incidence ≥
`20%) are stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis,
`acne, chest pain, peripheral edema, upper respiratory tract infection,
`headache, dizziness, myalgia, and hypercholesterolemia (6.6).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
`1-800-438-1985 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).
`• See full prescribing information for complete list of clinically significant
`drug interactions (12.3).
`
`------------------------USE IN SPECIFIC POPULATIONS---------------------
`• Pregnancy: Use only if the potential benefit outweighs the potential risk
`to the embryo/fetus (8.1).
`
`See 17 for PATIENT COUNSELING INFORMATION and the
`FDA-approved Medication Guide
`
`Revised: 4/2017
`
`
`
`
`Reference ID: 4087386
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS *
`
`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 in Renal Transplantation
`1.3 Treatment of Patients with Lymphangioleiomyomatosis
`2 DOSAGE AND ADMINISTRATION
`2.1 General Dosing Guidance for Renal Transplant Patients
`2.2 Renal Transplant Patients at Low- to Moderate-Immunologic Risk
`2.3 Renal Transplant Patients at High-Immunologic Risk
`2.4 Dosing in Patients with Lymphangioleiomyomatosis
`2.5 Therapeutic Drug Monitoring
`2.6 Patients with Low Body Weight
`2.7 Patients with Hepatic Impairment
`2.8 Patients with Renal Impairment
`2.9 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
`5.3 Lung Transplantation – Bronchial Anastomotic Dehiscence
`5.4 Hypersensitivity Reactions
`5.5 Angioedema
`5.6 Fluid Accumulation and Impairment of Wound Healing
`5.7 Hyperlipidemia
`5.8 Decline in Renal Function
`5.9 Proteinuria
`5.10 Latent Viral Infections
`5.11 Interstitial Lung Disease/Non-Infectious Pneumonitis
`5.12 De Novo Use Without Cyclosporine
`5.13 Increased Risk of Calcineurin Inhibitor-Induced Hemolytic
`Uremic Syndrome/Thrombotic Thrombocytopenic
`Purpura/Thrombotic Microangiopathy
`5.14 Antimicrobial Prophylaxis
`5.15 Different Sirolimus Trough Concentrations Reported between
`Chromatographic and Immunoassay Methodologies
`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 Renal Transplant Patients
`6.4 Conversion from Calcineurin Inhibitors to Rapamune in
`Maintenance Renal Transplant Population
`6.5 Pediatric Renal Transplant Patients
`6.6 Patients with Lymphangioleiomyomatosis
`6.7 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 Weak and Moderate 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 in Renal Transplant Patients
`14.2 Cyclosporine Withdrawal Study in Renal Transplant Patients
`14.3 High-Immunologic Risk Renal Transplant 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 Pediatric Renal Transplant Patients
`14.7 Lymphangioleiomyomatosis Patients
`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: 4087386
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`
`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® for prophylaxis of organ
`rejection in patients receiving renal transplants. 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)].
`
`1
`
`INDICATIONS AND USAGE
`
`1.1
`
`Prophylaxis of Organ Rejection in Renal Transplantation
`
`
`Reference ID: 4087386
`
`3
`
`

`

`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 [see Dosage and Administration (2.2)].
`
`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 (2.3), Clinical Studies (14.3)].
`
`1.2
`
`Limitations of Use in Renal Transplantation
`
`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)].
`
`1.3
`
`Treatment of Patients with Lymphangioleiomyomatosis
`
`Rapamune (sirolimus) is indicated for the treatment of patients with
`lymphangioleiomyomatosis (LAM).
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Rapamune is to be administered orally once daily, consistently with or without food [see
`Dosage and Administration (2.5), Clinical Pharmacology (12.3)].
`
`
`Reference ID: 4087386
`
`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.
`
`2.1 General Dosing Guidance for Renal Transplant Patients
`
`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, at this dose these two formulations are
`interchangeable. 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)].
`
`2.2
`
`Renal Transplant 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 (2.5)].
`
`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 (2.5)]. 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: 4087386
`
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`
`

`

`2.3
`
`Renal Transplant 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 (2.5)].
`
`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 (2.5)]. Prednisone should be administered at a minimum of
`5 mg/day.
`
`Antibody induction therapy may be used.
`
`2.4
`
`Dosing in Patients with Lymphangioleiomyomatosis
`
`For patients with lymphangioleiomyomatosis, the initial Rapamune dose should be 2 mg/day.
`Sirolimus whole blood trough concentrations should be measured in 10-20 days, with dosage
`adjustment to maintain concentrations between 5-15 ng/mL [see Dosage and Administration
`(2.5)].
`
`In most patients, dose adjustments can be based on simple proportion: new Rapamune
`dose = current dose x (target concentration/current concentration). Frequent Rapamune dose
`adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or under
`dosing 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. Once a stable dose is achieved, therapeutic
`drug monitoring should be performed at least every three months.
`
`2.5
`
`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.
`
`
`Reference ID: 4087386
`
`6
`
`

`

`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
`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)].
`
`2.6
`
`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.
`
`2.7
`
`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 Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
`2.8
`
`Patients with Renal Impairment
`
`Dosage adjustment is not needed in patients with impaired renal function [see Use in Specific
`Populations (8.7)].
`
`2.9
`
`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
`
`
`Reference ID: 4087386
`
`7
`
`

`

`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.
`• 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 for prophylaxis of organ
`rejection in patients receiving renal transplants. 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
`
`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%
`
`
`Reference ID: 4087386
`
`8
`
`

`

`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)].
`
`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 (6.7)].
`
`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 angiotensin-converting
`enzyme (ACE) inhibitors, may increase the risk of developing angioedema. Elevated sirolimus
`levels (with/without concomitant ACE inhibitors) may also potentiate angioedema [see Drug
`Interactions (7.2)]. In some cases, the angioedema has resolved upon discontinuation or dose
`reduction of Rapamune.
`
`5.6
`
`Fluid Accumulation and Impairment of 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.
`
`
`Reference ID: 4087386
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`

`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.
`
`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 reactions 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
`
`Decline in 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
`
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`Reference ID: 4087386
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`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 k