In renal transplant 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 (2.3).
`
`
`
`
` In lymphangioleiomyomatosis patients
`
`
`
` • Take once daily by mouth, consistently with or without food. The
`
`
` initial Rapamune dose should be 2 mg/day. Adjust the Rapamune
`
`
`
`
` dose to achieve sirolimus trough concentrations between
`
`
`
`
`
`
` 5-15 ng/mL (2.4).
`
`
`
` ——————DOSAGE FORMS AND STRENGTHS——————
`
` • Rapamune Oral Solution: 60 mg per 60 mL in amber glass bottle
`
`
`
`
` (3.1).
`
` • Rapamune Tablets: 0.5 mg, tan; 1 mg, white; 2 mg, yellow-to-beige
`
` (3.2).
` —————————CONTRAINDICATIONS————————
`
`
` Hypersensitivity to Rapamune (4).
` ——————— WARNINGS AND PRECAUTIONS ——————
`
`
` • Hypersensitivity Reactions (5.4)
`
`
`
` • Angioedema (5.5)
`
`
`
`
` • Fluid Accumulation and Wound Healing (5.6)
`
` • Hyperlipidemia (5.7)
`
`
`
` • Renal Function (5.8)
`
`
`
` • Proteinuria (5.9)
`
`
`
` • Latent Viral Infections (5.10)
`
`
`
`
`•
` Interstitial Lung Disease/Non-Infectious Pneumonitis (5.11)
`
` • De Novo Use Without Cyclosporine (5.12)
`
`
`
`
`•
`
` Increased Risk of Calcineurin Inhibitor-induced HUS/TTP/TMA (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.
`
`
` 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).
`
`
` • 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 (2.7, 8.6, 12.3).
`
`
` See 17 for PATIENT COUNSELING INFORMATION and the
` FDA-approved Medication Guide
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Revised: 11/2015
`
`
`
`
`
` 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 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 ————————
`
`Indications and Usage, Treatment of Patients with
`
`
`
`
`
`5/2015
`Lymphangioleiomyomatosis (1.3)
`
`
`5/2015
`Dosing in Patients with Lymphangioleiomyomatosis (2.4)
`
`
`
`Warnings and Precautions, Interstitial Lung Disease/Non-Infectious
`
`
`
`
`
`Pneumonitis (5.11)
`11/2015
`
`
`
`———————— INDICATIONS AND USAGE ————————
`
`
`Rapamune is indicated:
`
` • As 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
`
`
`
`
`
` (2.5,5.15).
`
`
` • For the treatment of patients with lymphangioleiomyomatosis.
`
` − Therapeutic drug monitoring is recommended for all patients
`
`
`
`
`
`
` (2.5,5.15).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ——————— DOSAGE AND ADMINISTRATION ——————
` In renal transplant patients
`
`
`
` • 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 (2.5).
`
`
`
` In renal transplant 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 (2.2).
`
`
`
` • Rapamune Following Cyclosporine Withdrawal: 2-4 months
`
`
` post-transplantation, withdraw CsA over 4-8 weeks (2.2).
`
`
`
`
`
`
`
`
`Reference ID: 3843454
`
`
`
` 1
`
`NOVARTIS EXHIBIT 2053
`Par v Novartis, IPR 2016-00084
`Page 1 of 56
`
`

`
`
`
` 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 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
`
`
`
`Increased Susceptibility to Infection and the Possible
`
`5.1
`
`
`
`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/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 (HUS/TTP/TMA)
`
`
`
`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 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 (LAM) 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: 3843454
`
`
`
` 2
`
`NOVARTIS EXHIBIT 2053
`Par v Novartis, IPR 2016-00084
`Page 2 of 56
`
`

`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`BOX WARNING: IMMUNOSUPPRESSION, USE IS NOT RECOMMENDED IN LIVER
`OR LUNG TRANSPLANT PATIENTS
`
`
`
`•
`
`Increased susceptibility to infection and the possible development of lymphoma and
`
` other malignancies may result from immunosuppression
`
`
` Increased susceptibility to infection and the possible development of lymphoma may result
`
`
`
`
` from immunosuppression. Only physicians experienced in immunosuppressive therapy and
`
` management of renal transplant patients should use Rapamune® 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
`
` 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
`
`
`
`
`Reference ID: 3843454
`
`
`
` 3
`
`NOVARTIS EXHIBIT 2053
`Par v Novartis, IPR 2016-00084
`Page 3 of 56
`
`

`
`all patients receiving Rapamune [see Dosage and Administration (2.5), 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 (2.2)].
`
`
`
`
`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.
`
`Therapeutic drug monitoring is recommended for all patients receiving Rapamune [see Dosage
`
`
`
`and Administration (2.5), Warnings and Precautions (5.15)].
`
`
`
`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: 3843454
`
`
`
` 4
`
`NOVARTIS EXHIBIT 2053
`Par v Novartis, IPR 2016-00084
`Page 4 of 56
`
`

`
`
`
` 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, 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)].
`
`
`
`
` 2.2
`
`
`
` 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: 3843454
`
`
`
` 5
`
`
`NOVARTIS EXHIBIT 2053
`Par v Novartis, IPR 2016-00084
`Page 5 of 56
`
`

`
`
`
` 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)].
`
`
`
`
`
`
`
`
`Reference ID: 3843454
`
`
`
` 6
`
`
`NOVARTIS EXHIBIT 2053
`Par v Novartis, IPR 2016-00084
`Page 6 of 56
`
`

`
`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)].
`
`
`
`2.6
`
`
`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 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
`
`
`
`
`Reference ID: 3843454
`
`
`
` 7
`
`
`NOVARTIS EXHIBIT 2053
`Par v Novartis, IPR 2016-00084
`Page 7 of 56
`
`

`
`
`
` 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
`
`
`
` 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.
`
`
`
`
`
`Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery
`5.2
`
`Thrombosis (HAT)
`
`
`
`The safety and efficacy of Rapamune as immunosuppressive therapy have not been established
`
`in liver transplant patients; therefore, such use is not recommended. The use of Rapamune has
`
`
`Reference ID: 3843454
`
`
`
` 8
`
`
`NOVARTIS EXHIBIT 2053
`Par v Novartis, IPR 2016-00084
`Page 8 of 56
`
`

`
` 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)].
`
`
`
`5.5
`
`
`Angioedema
`
`
`
`Rapamune has been associated with the development of angioedema. The concomitant use of
`
`
`Rapamune with other drugs known to cause angioedema, such as ACE-inhibitors, may increase
`
`the risk of developing angioedema.
`
`
`5.6
`
`
`Fluid Accumulation and Wound Healing
`
`
`There have been reports of impaired or delayed wound healing in patients receiving Rapamune,
`including lymphocele and wound dehiscence [see Adverse Reactions (6.1)]. mTOR inhibitors
`
`
`
`
`such as sirolimus have been shown in vitro to inhibit production of certain growth factors that
`
`
`may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphocele, a
`
`known surgical complication of renal transplantation, occurred significantly more often in a
`
`dose-related fashion in patients treated with Rapamune [see Adverse Reactions (6.1)].
`Appropriate measures should be considered to minimize such complications. Patients with a
`
`
`
`
`
`Reference ID: 3843454
`
`
`
` 9
`
`
`NOVARTIS EXHIBIT 2053
`Par v Novartis, IPR 2016-00084
`Page 9 of 56
`
`

`
` 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 Natio