NDA 21-083/S-046
`NDA 21-110/S-056
`Page 4
`
`
`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).
`
`
`
`
`
`
`
`•
`
`
`———————— RECENT MAJOR CHANGES ————————
`
`
`
`Dosage and Administration
`
`•
`
`
` Therapeutic Drug Monitoring (2.3)
`
`04/2010
`
`09/2009
`
`04/2010
`
`06/2010
`
`04/2010
`
`
`Warnings and Precautions
`
`•
`
` Liver Transplantation (5.2)
`
`•
`
`•
`
`• Assay for Sirolimus Therapeutic Drug
`
`
`
`Monitoring (5.15)
`
`
`
`
` Fluid Accumulation and Wound Healing (5.6)
`
`Latent Viral infections (5.10)
`
`
`
`
`
`
`
`
`
`———————— 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)
`
`
`
`
`4
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`

`

`NDA 21-083/S-046
`NDA 21-110/S-056
`Page 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 FDA-approved patient labeling
`
`
`
`
`
`
`
` Revised: 04/2010
`
`
`
`
`
`5
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`

`

`NDA 21-083/S-046
`NDA 21-110/S-056
`Page 6
`
`
`
`
` 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
`
`
`17.4 FDA-Approved Patient Labeling
`
`
`
`
`
`
`* Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`6
`
`

`

`NDA 21-083/S-046
`NDA 21-110/S-056
`Page 7
`
`
`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)].
`
`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)].
`
`
`
`7
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`

`NDA 21-083/S-046
`NDA 21-110/S-056
`Page 8
`
`
`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)].
`
`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
`
`
`
`
`
`
`8
`
`

`

`NDA 21-083/S-046
`NDA 21-110/S-056
`Page 9
`
`
`
`sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the Rapamune dose is
`increased [see Clinical Pharmacology (12.3)].
`
` 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 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)].
`
`
`
`9
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`

`NDA 21-083/S-046
`NDA 21-110/S-056
`Page 10
`
`
` 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.
`
`• 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
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` 5.1 Increased Susceptibility to Infection and the Possible Development of
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`Lymphoma
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` Increased susceptibility to infection and the possible development of lymphoma and other malignancies,
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` 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
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`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
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`Rapamune. Patients receiving the drug should be managed in facilities equipped and staffed with adequate
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`laboratory and supportive medical resources. The physician responsible for maintenance therapy should have
`complete information requisite for the follow-up of the patient.
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` 5.2 Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery
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`Thrombosis (HAT)
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`The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver transplant
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`patients; therefore, such use is not recommended. The use of Rapamune has been associated with adverse
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`outcomes in patients following liver transplantation, including excess mortality, graft loss and Hepatic Artery
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`Thrombosis (HAT).
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`In a study in de novo liver transplant patients, the use of Rapamune in combination with tacrolimus was associated
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`with excess mortality and graft loss (22% in combination versus 9% on tacrolimus alone). Many of these patients
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`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
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`cyclosporine or tacrolimus was associated with an increase in HAT (7% in combination versus 2% in the control
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`arm); most cases of HAT occurred within 30 days post-transplantation, and most led to graft loss or death.
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`In a clinical study in stable liver transplant patients 6-144 months post-liver transplantation and receiving a CNI-
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`based regimen, an increased number of deaths was observed in the group converted to a Rapamune-based regimen
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`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)].
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` 5.3 Lung Transplantation – Bronchial Anastomotic Dehiscence
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`Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients
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` when Rapamune has been used as part of an immunosuppressive regimen.
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` The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in lung transplant
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` patients; therefore, such use is not recommended.
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` 5.4 Hypersensitivity Reactions
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` Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and
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` hypersensitivity vasculitis, have been associated with the administration of Rapamune [see Adverse Reactions
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`(6.6)].
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`5.5 Angioedema
`Rapamune has been associated with the development of angioedema. The concomitant use of Rapamune with
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`other drugs known to cause angioedema, such as ACE-inhibitors, may increase the risk of developing angioedema.
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`5.6 Fluid Accumulation and Wound Healing
`There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including
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`lymphocele and wound dehiscence [see Adverse Reactions (6.1)]. mTOR inhibitors such as sirolimus have been
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`shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation,
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`and vascular permeability. Lymphocele, a known surgical complication of renal transplantation, occurred
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`significantly more often in a dose-related fashion in patients treated with Rapamune [see Adverse Reactions (6.1)].
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`Appropriate measures should be considered to minimize such complications. Patients with a body mass index
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`(BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical
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`literature.
`There have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion,
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`ascites, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring
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`intervention in children and adults), in patients receiving Rapamune.
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`5.7 Hyperlipidemia
`Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with
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`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
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`receiving Rapamune compared with placebo controls (each 23%). The risk/benefit should be carefully considered
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`in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune.
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`Any patient who is administered Rapamune should be monitored for hyperlipidemia. If detected, interventions
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`such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol
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`Education Program guidelines.
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`In clinical trials, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors and/or fibrates
`appeared to be well-tolerated.
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`During Rapamune therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or
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`fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as
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`described in the respective labeling for these agents.
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`5.8 Renal Function
`Renal function should be closely monitored during the co-administration of Rapamune with cyclosporine, because
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`long-term administration of the combination has been associated with deterioration of renal function. Patients
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`treated with cyclosporine and Rapamune were noted to have higher serum creatinine levels and lower glomerular
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`filtration rates compared with patients treated with cyclosporine and placebo or azathioprine controls (Studies 1
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`and 2). The rate of decline in renal function in these studies was greater in patients receiving Rapamune and
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`cyclosporine compared with control therapies.
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`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
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`low- to moderate-immunologic risk, continuation of combination therapy with cyclosporine beyond 4 months
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`following transplantation should only be considered when the benefits outweigh the risks of this combination for
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`the individual patients. Caution should be exercised when using agents (e.g., aminoglycosides and amphotericin B)
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`that are known to have a deleterious effect on renal function.
`In patients with delayed graft function, Rapamune may delay recovery of renal function.
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`5.9 Proteinuria
`Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion
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`from calcineurin inhibitors (CNI) to Rapamune in maintenance renal transplant patients 6-120 months post-
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`transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after
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`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
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`protein excretion increased the most after conversion. New onset nephrosis (nephrotic syndrome) was also
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`reported as a treatment-emergent adverse event in 2.2% of the Rapamune conversion group patients in comparison
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`to 0.4% in the CNI continuation group of patients. Nephrotic range proteinuria (defined as urinary protein to
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`creatinine ratio > 3.5) was also reported in 9.2% in the Rapamune conversion group of patients in comparison to
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`3.7% in the CNI continuation group of patients. In some patients, reduction in the degree of urinary protein
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`excretion was observed for individual patients following discontinuation of Rapamune. The safety and efficacy of
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`conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been
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`established.
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`5.10 Latent Viral Infections
`Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral
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`infections. These include BK virus-associated nephropathy, which has been observed in patients receiving
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`immunosuppressants, including Rapamune. This infection may be associated with serious outcomes, including
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`deteriorating renal function and renal graft loss [see Adverse Reactions (6.6)]. Patient monitoring may help detect
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`patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for
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`patients who develop evidence of BK virus-associated nephropathy.
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`Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients
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`treated with immunosuppressants, including Rapamune. PML commonly presents with hemiparesis, apathy,
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`confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant
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`therapies and impairment of immune function. In immunosuppressed patients, physicians shoul