HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`ZORTRESS® (everolimus) safely and effectively. See full prescribing
`
`
`information for ZORTRESS.
`
`
`ZORTRESS (everolimus) tablets for oral use
`
`
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`
`
`Initial U.S. Approval: 2010
`
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`•
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`•
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`•
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`•
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`1/2015
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`WARNING: MALIGNANCIES AND SERIOUS INFECTIONS,
`
`
`KIDNEY GRAFT THROMBOSIS; NEPHROTOXICITY; AND
`
`MORTALITY IN HEART TRANSPLANTATION
`
`
`See Full Prescribing Information for Complete Boxed Warning.
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`
`
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`• Only physicians experienced in immunosuppressive therapy and
`
`
`management of transplant patients should use Zortress. (5.1)
`
`
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`Increased susceptibility to infection and the possible development of
`
`
`malignancies may result from immunosuppression. (5.2, 5.3)
`
`
`Increased incidence of kidney graft thrombosis. (5.4)
`
`
`Reduced doses of cyclosporine are required for use in combination
`
`
`with Zortress in order to reduce nephrotoxicity. (2.4, 2.5, 5.6, 12.7,
`
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`12.8)
`
`Increased mortality in a heart transplant clinical trial. Use in heart
`
`
`
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`transplantation is not recommended. (5.7)
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`---------------------------RECENT MAJOR CHANGES---------------------------
`Dosage and Administration (2)
`1/2015
`
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`Warnings and Precautions, Management of
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`
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`Immunosuppression (5.1)
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`Warnings and Precautions, Interstitial Lung Disease/
`
`
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`11/2015
`Non-Infectious Pneumonitis (5.10)
`
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`---------------------------INDICATIONS AND USAGE----------------------------
`
`• Zortress is indicated for the prophylaxis of organ rejection in adult patients:
`
`
`
`
`• Kidney transplant: at low-moderate immunologic risk. Use in combination
`
`
`
`with basiliximab, cyclosporine (reduced doses) and corticosteroids. (1.1)
`
`
`
`
`
`
`• Liver transplant: Administer no earlier than 30 days post-transplant. Use in
`
`
`
`combination with tacrolimus (reduced doses) and corticosteroids. (1.2, 5.5)
`
`
`Limitations of Use (1.3)
`
`Safety and efficacy has not been established in the following:
`
`
`
`
`• Kidney transplant patients at high immunologic risk.
`
`
`
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`• Recipients of transplanted organs other than kidney or liver
`
`
`
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`• Pediatric patients (<18 years)
`
`
`-------------------------DOSAGE AND ADMINISTRATION---------------------
`• Kidney transplantation: starting oral dose of 0.75 mg twice daily as soon as
`
`
`possible after transplantation. (2.1)
`
`
`• Liver transplantation: starting oral dose of 1.0 mg twice daily starting 30
`
`
`
`
`days after transplantation. (2.2)
`
`
`• Monitor everolimus concentrations: Adjust maintenance dose to achieve
`
`
`
`trough concentrations within the 3-8 ng/mL target range (using LC/MS/MS
`
`
`
`assay method (2.1, 2.2, 2.3)
`
`
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`• Administer consistently with or without food at the same time as
`
`
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`
`
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`cyclosporine or tacrolimus. (2.6, 12.3)
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`• Mild hepatic impairment: Reduce initial daily dose by one-third (2.7)
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`
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`
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`• Moderate or Severe hepatic impairment: Reduce initial daily dose by one-
`
`half. (2.7, 12.6)
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`
`-------------------------DOSAGE FORMS AND STRENGTHS------------------
`Zortress is available as 0.25 mg, 0.5 mg, and 0.75 mg tablets. (3)
`
`
`
`
`
`
`
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`----------------------------------CONTRAINDICATIONS---------------------------
`• Hypersensitivity to everolimus, sirolimus, or to components of the drug
`
`
`
`
`
`
`
`product. (4)
`
`
`----------------------------WARNINGS AND PRECAUTIONS-------------------
`• Angioedema (increased risk with concomitant ACE inhibitors): Monitor for
`
`
`
`
`symptoms and treat promptly. (5.8)
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`
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`• Delayed Wound Healing/Fluid Accumulation: Monitor symptoms; treat
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`
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`promptly to minimize complications. (5.9)
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`• Interstitial Lung Disease/Non-Infectious Pneumonitis: Monitor for
`
`
`symptoms or radiologic changes; manage by dose reduction or discontinuation
`
`
`
`until symptoms resolve; consider use of corticosteroids. (5.10)
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`• Hyperlipidemia (elevations of serum cholesterol and triglycerides): Monitor
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`
`and consider anti-lipid therapy. (5.11)
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`
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`• Proteinuria (increased risk with higher trough concentrations): Monitor urine
`
`
`
`protein. (5.12)
`
`• Polyoma Virus Infections (activation of latent viral infections; BK- virus
`
`
`
`
`associated nephropathy): Consider reducing immunosuppression. (5.13)
`
`
`
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`• TMA/TTP/HUS (concomitant use with cyclosporine may increase risk):
`
`
`
`Monitor for hematological changes or symptoms. (5.15)
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`
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`• New Onset Diabetes After Transplantation: Monitor serum glucose. (5.16)
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`• Male Infertility: Azospermia or oligospermia may occur. (5.17, 13.1)
`
`
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`• Immunizations: Avoid live vaccines. (5.18)
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`
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`----------------------------------ADVERSE REACTIONS---------------------------
`Most common adverse reactions were as follows:
`
`
`
`Kidney transplantation (incidence ≥20%): peripheral edema, constipation,
`
`hypertension, nausea, anemia, UTI, and hyperlipidemia. (6.1);
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`Liver transplantation (incidence>10%): diarrhea, headache, peripheral edema,
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`
`
`hypertension, nausea, pyrexia, abdominal pain, and leukopenia (6.1)
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`
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`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
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`
`
`1088 or www.fda.gov/medwatch.
`
`
`-----------------------------------DRUG INTERACTIONS--------------------------
`
`Strong-moderate CYP3A4 inhibitors (e.g., cyclosporine, ketoconazole,
`
`
`erythromycin, verapamil) and CYP3A4 inducers (e.g., rifampin) may affect
`
`
`
`
`everolimus concentrations. (7.1) Consider Zortress dose adjustment (5.14)
`
`
`---------------------------USE IN SPECIFIC POPULATIONS--------------------
`• Pregnancy: Based on animal data may cause fetal harm. (8.1)
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`
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`• Nursing Mothers: Discontinue drug or nursing. (8.3)
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`
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`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
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`Guide
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`Revised: 11/2015
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`4.1 Hypersensitivity Reactions
`
`
`5 WARNINGS AND PRECAUTIONS
`
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`5.1 Management of Immunosuppression
`
`
`Lymphomas and Other Malignancies
`5.2
`
`
`5.3
`Serious Infections
`
`
`5.4 Kidney Graft Thrombosis
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`5.5 Hepatic Artery Thrombosis
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`5.6
`Zortress and Calcineurin Inhibitor-Induced Nephrotoxicity
`
`
`5.7 Heart Transplantation
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`
`5.8 Angioedema
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`5.9 Wound Healing and Fluid Accumulation
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`
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`5.10
`Interstitial Lung Disease/Non-Infectious Pneumonitis
`
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`5.11 Hyperlipidemia
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`5.12 Proteinuria
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`
`5.13 Polyoma Virus Infections
`
`
`5.14
`Interaction with Strong Inhibitors and Inducers of CYP3A4
`
`5.15 Thrombotic Microangiopathy/Thrombotic Thrombocytopenic
`
`
`Purpura/Hemolytic Uremic Syndrome (TMA/TTP/HUS)
`
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`5.16 New Onset Diabetes After Transplant
`
`
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`5.17 Male Infertility
`
`
`5.18
`Immunizations
`
`
`2
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: MALIGNANCIES AND SERIOUS INFECTIONS,
`
`KIDNEY GRAFT THROMBOSIS; NEPHROTOXICITY; AND
`
`MORTALITY IN HEART TRANSPLANTATION
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`Prophylaxis of Organ Rejection in Kidney Transplantation
`1.1
`
`
`
`Prophylaxis of Organ Rejection in Liver Transplantation
`1.2
`
`
`
`
`1.3
`Limitations of Use
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosage in Adult Kidney Transplant Patients
`
`
`
`2.2 Dosage in Adult Liver Transplant Patients
`
`
`2.3
`Therapeutic Drug Monitoring - Everolimus
`
`
`
`2.4
`Therapeutic Drug Monitoring- Cyclosporine in Kidney
`
`
`
`
`Transplant Patients
`
`2.5
`Therapeutic Drug Monitoring- Tacrolimus in Liver Transplant
`
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`
`
`Patients
`
`
`2.6 Administration
`
`
`2.7 Hepatic Impairment
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`
`3
`
`4
`
`Reference ID: 3843376
`
`NOVARTIS EXHIBIT 2055
`Par v Novartis, IPR 2016-00084
`Page 1 of 32
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`6
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`7
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`8
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`
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`Interaction with Grapefruit Juice
`5.19
`
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`5.20 Patients with Hereditary Disorders/Other
`
`ADVERSE REACTIONS
`
`
`Serious and Otherwise Important Adverse Reactions
`6.1
`
`
`
`6.2 Clinical Studies Experience
`
`
`
`6.3
`Postmarketing Experience
`
`DRUG INTERACTIONS
`
`Interactions with Strong Inhibitors or Inducers of CYP3A4 and P-
`7.1
`
`
`glycoprotein
`
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`7.2 Cyclosporine (CYP3A4/P-gp Inhibitor and CYP3A4 Substrate)
`
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`7.3 Ketoconazole and Other Strong CYP3A4 Inhibitors
`
`
`
`7.4
`Erythromycin (Moderate CYP3A4 Inhibitor)
`
`
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`7.5 Verapamil (CYP3A4 and P-gp Substrate)
`
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`7.6 Atorvastatin (CYP3A4 substrate) and Pravastatin (P-gp substrate)
`
`
`
`7.7
`Simvastatin and Lovastatin
`
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`7.8 Rifampin (Strong CYP3A4/P-gp Inducers)
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`7.9 Midazolam (CYP3A4/5 substrate)
`
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`7.10 Other Possible Interactions
`
`
`7.11 Octreotide
`
`
`7.12 Tacrolimus
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
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`8.6 Hepatic Impairment
`
`
`8.7 Renal Impairment
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.3 Pharmacokinetics
`
`
`12.5 Drug-Drug Interactions
`
`
`12.6 Specific Populations
`
`12.7 Everolimus Whole Blood Concentrations Observed in Kidney
`
`
`and in Liver Transplant Patients
`
`
`12.8 Cyclosporine Concentrations Observed in Kidney Transplant
`
`
`Patients
`
`
`12.9 Tacrolimus Concentrations in Liver Transplant
`
`
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`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Prevention of Organ Rejection after Renal Transplantation
`
`
`
`14.2 Prevention of Organ Rejection after Liver Transplantation
`
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`
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`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the full prescribing information are
`
`not listed
`
`
`Reference ID: 3843376
`
`NOVARTIS EXHIBIT 2055
`Par v Novartis, IPR 2016-00084
`Page 2 of 32
`
`

`
`
`•
`
`
` FULL PRESCRIBING INFORMATION
` WARNING: MALIGNANCIES AND SERIOUS INFECTIONS, KIDNEY GRAFT THROMBOSIS;
`
`
`NEPHROTOXICITY; AND MORTALITY IN HEART TRANSPLANTATION
`
`
`Malignancies and Serious Infections
`
`• Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe
`
`
`
`
`Zortress. 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)]
`
`
`
`
`Increased susceptibility to infection and the possible development of malignancies such as lymphoma and skin cancer
`
`
`may result from immunosuppression. [See Warnings and Precautions (5.2 and 5.3)]
`
`
`
`Kidney Graft Thrombosis
`
`• An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, was reported, mostly within the
`
`
`first 30 days post-transplantation. [See Warnings and Precautions (5.4)]
`
`
`Nephrotoxicity
`
`Increased nephrotoxicity can occur with use of standard doses of cyclosporine in combination with Zortress.
`•
`
`
`
`
`
`Therefore reduced doses of cyclosporine should be used in combination with Zortress in order to reduce renal
`
`
`
`dysfunction. It is important to monitor the cyclosporine and everolimus whole blood trough concentrations. [See
`
`
`
`
`Dosage and Administration (2.4 and 2.5) and Warnings and Precautions (5.6) and Clinical Pharmacology (12.7 and
`
`
`
`
`
`
`12.8)]
`
`Mortality in Heart Transplantation
`
`
` Increased mortality, often associated with serious infections, within the first three months post-transplantation was
`
`
`
`•
`observed in a clinical trial of de novo heart transplant patients receiving immunosuppressive regimens with or without
`
`
`
`
`
`induction therapy. Use in heart transplantation is not recommended. [See Warnings and Precautions (5.7)]
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`Prophylaxis of Organ Rejection in Kidney Transplantation
`1.1
`
`
`
`
`
`
`Zortress is indicated for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a
`
`
`kidney transplant. [See Clinical Studies (14.1)] Zortress is to be administered in combination with basiliximab induction
`
`
`and concurrently with reduced doses of cyclosporine and with corticosteroids. Therapeutic drug monitoring of everolimus
`
`
`
`
`
`and cyclosporine is recommended for all patients receiving these products. [See Dosage and Administration (2.2 and 2.3)]
`
`
`
`
`
`
`
`Prophylaxis of Organ Rejection in Liver Transplantation
`1.2
`
`
`
`
`Zortress is indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Zortress is to be
`
`
`
`
`
`administered no earlier than 30 days post-transplant concurrently in combination with reduced doses of tacrolimus and
`
`
`
`
`with corticosteroids [See Warnings and Precautions (5.5) and Clinical Studies (14.2)]. Therapeutic drug monitoring of
`
`
`
`everolimus and tacrolimus is recommended for all patients receiving these products. [See Dosage and Administration (2.3
`
`
`and 2.5)]
`
`Limitations of Use
`1.3
`
`
`
`The safety and efficacy of Zortress has not been established in the following populations:
`
`
`
`
`Kidney transplant patients at high immunologic risk
`
`
`Recipients of transplanted organs other than kidney and liver [See Warnings and Precautions (5.7)]
`
`
`
`
`
`Pediatric patients (<18 years).
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`Patients receiving Zortress may require dose adjustments based on everolimus blood concentrations achieved, tolerability,
`
`
`individual response, change in concomitant medications and the clinical situation. Optimally, dose adjustments of Zortress
`
`
`should be based on trough concentrations obtained 4 or 5 days after a previous dosing change. Dose adjustment is
`
`
`required if the trough concentration is below 3 ng/mL. The total daily dose of Zortress should be doubled using the
`
`available tablet strengths (0.25 mg, 0.5 mg or 0.75 mg). Dose adjustment is also required if the trough concentration is >8
`
`
`
`
`
`
`Reference ID: 3843376
`
`NOVARTIS EXHIBIT 2055
`Par v Novartis, IPR 2016-00084
`Page 3 of 32
`
`

`
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` ng/mL on 2 consecutive measures; the dose of Zortress® should be decreased by 0.25 mg b.i.d. [See Therapeutic Drug
`Monitoring (2.3) and Clinical Pharmacology (12.3)]
`
`Dosage in Adult Kidney Transplant Patients
`2.1
`
`
`
`
`
`An initial Zortress dose of 0.75 mg orally twice daily (1.5 mg per day) is recommended for adult kidney transplant
`
`
`
`
`
`
`
`
`
`
`
`patients in combination with reduced dose cyclosporine, administered as soon as possible after transplantation. [See
`
`
`
`Therapeutic Drug Monitoring (2.3, 2.4), Clinical Studies (14.1)]
`
`
`
`
`Oral prednisone should be initiated once oral medication is tolerated. Steroid doses may be further tapered on an
`
`
`individualized basis depending on the clinical status of patient and function of graft.
`
`
`
`
`Dosage in Adult Liver Transplant Patients
`2.2
`
`
`
`
`Start Zortress at least 30 days post-transplant. An initial dose of 1.0 mg orally twice daily (2.0 mg per day) is
`
`
`
`
`recommended for adult liver transplant patients in combination with reduced dose tacrolimus. [See Therapeutic Drug
`
`
`Monitoring (2.3 and 2.5), Clinical Studies (14.2)]
`
`Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of
`
`
`graft.
`Therapeutic Drug Monitoring - Everolimus
`2.3
`
`
`
`Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients. The
`
`
`
`
`
`
`recommended everolimus therapeutic range is 3 to 8 ng/mL. [See Clinical Pharmacology (12.7)] Careful attention should
`
`
`be made to clinical signs and symptoms, tissue biopsies, and laboratory parameters. It is important to monitor everolimus
`
`
`
`blood concentrations, in patients with hepatic impairment, during concomitant administration of CYP3A4 inducers or
`
`
`
`inhibitors, when switching cyclosporine formulations and/or when cyclosporine dosing is reduced according to
`
`
`
`recommended target concentrations. [See Clinical Pharmacology (12.7, 12.8)]
`
`
`
`
`There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if
`
`
`
`
`
`
`
`cyclosporine exposure is reduced. There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and thus,
`
`
`everolimus concentrations do not decrease if the tacrolimus exposure is reduced. [See Drug Interactions (7.2)]
`
`
`
`The everolimus recommended therapeutic range of 3 to 8 ng/mL is based on an LC/MS/MS assay method. Currently in
`clinical practice, everolimus whole blood trough concentrations may be measured by chromatographic or immunoassay
`
`
`
`methodologies. Because the measured everolimus whole blood trough concentrations depend on the assay used, individual
`
`
`
`patient sample concentration values from different assays may not be interchangeable. Consideration of assay results must
`
`
`be made with knowledge of the specific assay used. Therefore, communication should be maintained with the laboratory
`
`
`performing the assay.
`
`Therapeutic Drug Monitoring- Cyclosporine in Kidney Transplant Patients
`2.4
`
`
`
`
`
`
`Both cyclosporine doses and the target range for whole blood trough concentrations should be reduced, when given in a
`
`
`
`regimen with Zortress, in order to minimize the risk of nephrotoxicity. [See Warnings and Precautions (5.6), Drug
`
`
`
`
`
`Interactions (7.2), Clinical Pharmacology (12.8)]
`
`
`The recommended cyclosporine therapeutic ranges when administered with Zortress are 100 to 200 ng/mL through Month
`
`1 post-transplant, 75 to 150 ng/mL at Months 2 and 3 post-transplant, 50 to 100 ng/mL at Month 4 post-transplant, and 25
`
`to 50 ng/mL from Month 6 through Month 12 post-transplant. The median trough concentrations observed in the clinical
`
`
`
`trial ranged between 161 to 185 ng/mL through Month 1 post-transplant and between 111 to 140 ng/mL at Months 2 and 3
`
`
`post-transplant. The median trough concentration was 99 ng/mL at Month 4 post-transplant and ranged between 46 to 75
`
`ng/mL from Months 6 through Month 12 post-transplant. [See Clinical Pharmacology (12.8) and Clinical Studies (14.1)]
`
`
`
`
`Cyclosporine, USP Modified is to be administered as oral capsules twice daily unless cyclosporine oral solution or
`
`
`
`
`
`
`intravenous administration of cyclosporine cannot be avoided. Cyclosporine, USP Modified should be initiated as soon as
`
`
`
`
`
`possible - and no later than 48 hours - after reperfusion of the graft and dose adjusted to target concentrations from Day 5
`
`
`
`
`
`
`onwards.
`
`If impairment of renal function is progressive the treatment regimen should be adjusted. In renal transplant patients, the
`
`
`
`cyclosporine dose should be based on cyclosporine whole blood trough concentrations. [See Clinical Pharmacology
`
`
`
`(12.8)]
`
`In renal transplantation, there are limited data regarding dosing Zortress with reduced cyclosporine trough concentrations
`
`
`
`
`of 25 to 50 ng/mL after 12 months. Zortress has not been evaluated in clinical trials with other formulations of
`
`
`
`
`
`
`Reference ID: 3843376
`
`NOVARTIS EXHIBIT 2055
`Par v Novartis, IPR 2016-00084
`Page 4 of 32
`
`

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`
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` cyclosporine. Prior to dose reduction of cyclosporine it should be ascertained that steady-state everolimus whole blood
` trough concentration is at least 3 ng/mL. There is an interaction of cyclosporine on everolimus, and consequently,
`
`
` everolimus concentrations may decrease if cyclosporine exposure is reduced. [See Drug Interactions (7.2)]
`
`
`
` Therapeutic Drug Monitoring- Tacrolimus in Liver Transplant Patients
`
`
`
`
` 2.5
`
` Both tacrolimus doses and the target range for whole blood trough concentrations should be reduced, when given in a
`
`
` regimen with Zortress, in order to minimize the potential risk of nephrotoxicity. [See Warnings and Precautions (5.6),
`
`
`Clinical Pharmacology (12.9)]
`
` The recommended tacrolimus therapeutic range when administered with Zortress are whole blood trough (C-0h)
`
`
`
`
`
`
` concentrations of 3 to 5 ng/mL by three weeks after the first dose of Zortress (approximately Month 2) and through Month
`
` 12 post transplant.
` The median tacrolimus trough concentrations observed in the clinical trial ranged between 8.6 to 9.5 ng/mL at Weeks 2
`
`
`
`
` and 4 post-transplant (prior to initiation of everolimus). The median tacrolimus trough concentrations ranged between 7 to
`8.1 ng/mL at Weeks 5 and 6 post-transplant, between 5.2 to 5.6 ng/mL at Months 2 and 3 post-transplant, and between 4.3
`
`
` to 4.9 ng/mL between Months 4 and 12 post-transplant. [See Clinical Pharmacology (12.9), Clinical Studies (14.2)]
`
` Tacrolimus is to be administered as oral capsules twice daily unless intravenous administration of tacrolimus cannot be
`
`
`avoided.
`
`In liver transplant patients, the tacrolimus dose should be based on tacrolimus whole blood trough concentrations. [See
`
`
`
`Clinical Pharmacology (12.9)]
`
`In liver transplantation, there are limited data regarding dosing Zortress with reduced tacrolimus trough concentrations of
`
`
`
`3 to 5 ng/mL after 12 months. Prior to dose reduction of tacrolimus it should be ascertained that the steady-state
`
`
`
`
`everolimus whole blood trough concentration is at least 3 ng/mL. Unlike the interaction between cyclosporine and
`everolimus, tacrolimus does not affect everolimus trough concentrations, and consequently, everolimus concentrations do
`
`not decrease if the tacrolimus exposure is reduced.
`
`2.6
`Administration
`
`
`Zortress tablets should be swallowed whole with a glass of water and not crushed before use.
`
`
`
`
`Administer Zortress consistently approximately 12 hours apart with or without food to minimize variability in absorption
`
`
`
`
`and at the same time as cyclosporine or tacrolimus. [See Clinical Pharmacology (12.3)]
`
`
`
`
`
`2.7
`Hepatic Impairment
`
`
`Whole blood trough concentrations of everolimus should be closely monitored in patients with impaired hepatic function.
`
`
`
`For patients with mild hepatic impairment (Child-Pugh Class A), the initial daily dose should be reduced by
`
`
`
`approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic
`
`
`impairment (Child-Pugh B or C), the initial daily dose should be reduced to approximately one-half of the normally
`
`
`
`
`recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough
`
`
`
`concentration of everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3
`
`
`to 8 ng/mL. [See Clinical Pharmacology (12.6)]
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`Zortress is available as 0.25 mg, 0.5 mg, and 0.75 mg tablets.
`
`Table 1. Description of Zortress (everolimus) Tablets
`
`
`
`
`
`
` Dosage Strength
`
` Appearance
`
` Imprint
`
`
` 0.75 mg
` 0.5 mg
`
`
` 0.25 mg
`
`
` White to yellowish, marbled, round, flat tablets with bevelled edge
`
`“CL” on one side and
` “CH” on one side and
`“C” on one side and “NVR”
`
`
` on the other
`
`
` “NVR” on the other
` “NVR” on the other
` 4
`
`
` CONTRAINDICATIONS
` 4.1
` Hypersensitivity Reactions
`
`
`
` Zortress is contraindicated in patients with known hypersensitivity to everolimus, sirolimus, or to components of the drug
`
` product.
`
`
`
`
`
`Reference ID: 3843376
`
`
`
`NOVARTIS EXHIBIT 2055
`Par v Novartis, IPR 2016-00084
`Page 5 of 32
`
`

`
` 5
`
`
` WARNINGS AND PRECAUTIONS
`
` 5.1 Management of Immunosuppression
`
`Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe
`Zortress. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and
`
`
`
`
`supportive medical resources. The physician responsible for the maintenance therapy should have complete information
`
`
`
`
`
`requisite for the follow-up of the patient. In limited data with the complete elimination of CNI (calcineurin inhibition),
`
`
`
`
`
`
`
`there was an increased risk of acute rejection.
`Lymphomas and Other Malignancies
`5.2
`
`
`
`
`Patients receiving immunosuppressants, including Zortress, are at increased risk of developing lymphomas and other
`
`
`
`
`malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression
`
`
`
`rather than to the use of any specific agent.
`
`
`
`
`As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by
`
`
`
`
`
`wearing protective clothing and using a sunscreen with a high protection factor.
`
`5.3
`Serious Infections
`
`
`Patients receiving immunosuppressants, including Zortress, are at increased risk of developing bacterial, viral, fungal, and
`
`protozoal infections, including opportunistic infections. [See Warnings and Precautions (5.13), Adverse Reactions (6.1,
`
`
`
`6.2)] These infections may lead to serious, including fatal, outcomes. Because of the danger of over immunosuppression,
`
`
`
`
`
`which can cause increased susceptibility to infection, combination immunosuppressant therapy should be used with
`
`caution.
`
`Antimicrobial prophylaxis for Pneumocystis jiroveci (carinii) pneumonia and prophylaxis for cytomegalovirus (CMV) is
`
`
`
`
`
`
`recommended in transplant recipients.
`
`
`Kidney Graft Thrombosis
`5.4
`
`
`
`An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, usually within the
`
`first 30 days post-transplantation. [See Boxed Warning]
`
`
`5.5
`Hepatic Artery Thrombosis
`
`
`Mammalian target of rapamycin (mTOR) inhibitors are associated with an increase in hepatic artery thrombosis (HAT).
`
`
`
`
`
`
`Reported cases mostly have occurred within the first 30 days post-transplant and most also lead to graft loss or death.
`
`
`
`Therefore, Zortress should not be administered earlier than 30 days after liver transplant.
`
`
`
`Zortress and Calcineurin Inhibitor-Induced Nephrotoxicity
`5.6
`
`
`In kidney transplant recipients, Zortress with standard dose cyclosporine increases the risk of nephrotoxicity resulting in a
`
`
`
`lower glomerular filtration rate. Reduced doses of cyclosporine are required for use in combination with Zortress in order
`
`
`
`
`
`
`to reduce renal dysfunction. [See Boxed Warning, Indications and Usage (1.1), Clinical Pharmacology (12.8)]
`
`
`In liver transplant recipients, Zortress has not been studied with standard dose tacrolimus. Reduced doses of tacrolimus
`
`
`
`
`should be used in combination with Zortress in order to minimize the potential risk of nephrotoxicity. [See Indications and
`
`
`
`
`Usage (1.2), Clinical Pharmacology (12.9)]
`
`Renal function should be monitored during the administration of Zortress. Consider switching to other
`
`
`
`
`
`immunosuppressive therapies if renal function does not improve after dose adjustments or if the dysfunction is thought to
`
`
`
`
`be drug related. Caution should be exercised when using other drugs which are known to impair renal function.
`
`
`5.7
`Heart Transplantation
`
`
`In a clinical trial of de novo heart transplant patients, Zortress in an immunosuppressive regimen with or without induction
`
`
`
`therapy, resulted in an increased mortality often associated with serious infections within the first three months post-
`
`
`transplantation compared to the control regimen. Use of Zortress in heart transplantation is not recommended.
`
`
`
`
`Angioedema
`5.8
`
`
`Zortress has been associated with the development of angioedema. The concomitant use of Zortress with other drugs
`
`
`
`
`
`known to cause angioedema, such as angiotensin converting enzyme (ACE) inhibitors may increase the risk of developing
`
`
`
`
`angioedema.
`
`
`Reference ID: 3843376
`
`NOVARTIS EXHIBIT 2055
`Par v Novartis, IPR 2016-00084
`Page 6 of 32
`
`

`
`
`
`
`
` 5.9 Wound Healing and Fluid Accumulation
`
`
`
`
` Zortress increases the risk of delayed wound healing and increases the occurrence of wound-related complications like
`
`
`
`
` wound dehiscence, wound infection, incisional hernia, lymphocele and seroma. These wound-related complications may
`
`
` require more surgical intervention. Generalized fluid accumulation, including peripheral edema (e.g., lymphoedema) and
`
`
` other types of localized fluid collection, such as pericardial and pleural effusions and ascites have also been reported.
`
`
` Interstitial Lung Disease/Non-Infectious Pneumonitis
`
`
` 5.10
`
`
` A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with
`
`infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug
`
`
`
`causes have been ruled-out through appropriate investigations. Cases of ILD, implying lung intraparenchymal
`
`inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, some reported with pulmonary hypertension
`
`
`
`
`(including pulmonary arterial hypertension [PAH]) as a secondary event, have occurred in patients receiving rapamycins
`
`and their derivatives, including Zortress. Most cases generally resolve on drug interruption with or without glucocorticoid
`therapy. However, fatal cases have also occurred.
`
`5.11 Hyperlipidemia
`
`
`Increased serum cholesterol and triglycerides, requiring the need for anti-lipid therapy, have been reported to occur
`
`
`
`following initiation of Zortress and the risk of hyperlipidemia is increased with higher everolimus whole blood trough
`
`
`
`concentrations. [See Adverse Reactions (6.2)] Use of anti-lipid therapy may not normalize lipid levels in patients receiving
`
`
`
`
`Zortress.
`
`Any patient who is administered Zortress 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. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an
`
`
`
`immunosuppressive regimen containing Zortress. Similarly, the risk/benefit of continued Zortress therapy should be re-
`
`
`
`evaluated in patients with severe refractory hyperlipidemia. Zortress has not been studied in patients with baseline
`
`cholesterol levels >350 mg/dL.
`
`Due to an interaction with cyclosporine, clinical trials of Zortress and cyclosporine in kidney transplant patients strongly
`
`
`discouraged patients from receiving the HMG-CoA reductase inhibitors simvastatin and lovastatin. During Zortress
`
`therapy with cyclosporine, 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. [See Drug Interactions (7.7)]
`
`5.12
`Proteinuria
`
`
`The use of Zortress in transplant patients has been associated with increased proteinuria. The risk of proteinuria increased
`
`
`
`with higher everolimus whole blood trough concentrations. Patients receiving Zortress should be monitored for
`
`
`
`proteinuria. [See Adverse Reactions (6.2)]
`
`
`
`Polyoma Virus Infections
`5.13
`
`
`Patients receiving immunosuppressants, including Zortress, are at increased risk for opportunistic infections; including
`
`
`polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal,
`
`
`
`
`
`outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus
`
`
`
`associated progressive multiple leukoencephalopathy (PML). PVAN has been observed in patients receiving
`
`
`
`immunosuppressants, including Zortress. PVAN is associated with serious outcomes; including deteriorating renal
`
`
`
`function and kidney graft loss. [See Adverse Reactions (6.2)] Patient monitoring may help detect patients at risk for
`
`
`
`
`
`PVAN. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML.
`
`
`Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.
`
`
`5.14
`Interaction with Strong Inhibitors and Inducers of CYP3A4
`
`
`Co-administration of Zortress with strong CYP3A4-inhibitors (e.g., ketoconazole, itraconazole, voriconazole,
`clarithromycin, telithromycin