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
`Warnings and Precautions, Embryo-Fetal Toxicity (5.15) 1/2018
`
`------------------------------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, 5.16).
`
`---------------------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)
`• Embryo-Fetal Toxicity (5.15, 8.1)
`
`------------------------------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: Based on animal data may cause fetal harm (5.15, 8.1).
`
`See 17 for PATIENT COUNSELING INFORMATION and the
`FDA-approved Medication Guide
`
`Revised: 01/2018
`
`
`
`
`Reference ID: 4206874
`
`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 Embryo-Fetal Toxicity
`5.16 Different Sirolimus Trough Concentrations Reported between
`Chromatographic and Immunoassay Methodologies
`5.17 Skin Cancer Events
`5.18 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: 4206874
`
`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)].
`
`
`
`
`Reference ID: 4206874
`
`3
`
`

`

`1
`
`1.1
`
`INDICATIONS AND USAGE
`
`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.
`
`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)].
`
`Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the
`solution and instructed in its use.
`
`
`Reference ID: 4206874
`
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`
`

`

`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)].
`
`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
`
`
`Reference ID: 4206874
`
`5
`
`

`

`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.
`
`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 (5.16), 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)].
`
`
`Reference ID: 4206874
`
`6
`
`

`

`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 considered
`during the preparation and administration of Rapamune Oral Solution. It is important that these
`recommendations be followed closely.
`
`3
`
`3.1
`
`DOSAGE FORMS AND STRENGTHS
`
`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)].
`
`
`Reference ID: 4206874
`
`7
`
`

`

`5
`
`5.1
`
`WARNINGS AND PRECAUTIONS
`
`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% 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)].
`
`
`Reference ID: 4206874
`
`8
`
`

`

`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)]. Mammalian target of rapamycin (mTOR)
`inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may
`affect angiogenesis, fibroblast proliferation, and vascular permeability. 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.
`
`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.
`
`
`Reference ID: 4206874
`
`9
`
`

`

`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 be considered when the benefits outweigh the risks of this combination
`for the individual patients. Caution should be exercised w