`
`Food and Drug Administration
`
`
`Silver Spring MD 20993
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`NDA APPROVAL
`
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`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`
`
`
` NDA 21560
`
`
`
`Novartis Pharmaceuticals Corporation
`Attention: Mr. Ronald G. Van Valen
`Director, Drug Regulatory Affairs
`One Health Plaza
`East Hanover, NJ 07936-1080
`
`Dear Mr. Van Valen:
`
`
`
`Please refer to your New Drug Application (NDA) dated December 19, 2002 and received
`December 20, 2002 submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Zortress (everolimus) Tablets, 0.25 mg, 0.5 mg, and 0.75 mg.
`
`We acknowledge receipt of your submissions dated:
`
`
`
`January 22, 2010
`February 3, 2010
`
`
`
`
`February19, 2010 March 31, 2010
`April 7, 2010
`
`
`April 2, 2010
`April 8, 2010
`March 19, 2010
`
`April 13, 2010
`
`
`The January 22, 2010 submission constituted a complete response to our December 23, 2009
`action letter.
`
`
`This new drug application provides for the use of Zortress (everolimus) Tablets for prophylaxis
`of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney
`transplant.
`
`
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`CONTENT OF LABELING
`
`
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format, as described
`at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling (text for the package insert and Medication Guide). For
`administrative purposes, please designate this submission, “SPL for approved NDA 21560.”
`
`
`
`Breckenridge Exhibit 1072
`Zortress Approval
`Page 001
`
`

`

`
`
` NDA 21560
`
`Page 2
`
` CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate container labels as soon as they are available, but no more than 30 days after they are
`printed. Please submit these labels electronically according to the guidance for industry titled
`Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product
`Applications and Related Submissions Using the eCTD Specifications (October 2005).
`Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
`heavy-weight paper or similar material. For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 21560.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`Marketing the product with labels that are not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
`
`
`
`LABELING
`
`
`Submit final printed labeling as soon as it is available, but no more than 30 days after it is
`printed. The final printed labeling (FPL) must be identical to the enclosed labeling (text for the
`package insert and Medication Guide), and must be in the “Drug Facts” format (21 CFR 201.66),
`where applicable.
`
`The final printed labeling should be submitted electronically according to the guidance for
`industry titled Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical
`Product Applications and Related Submissions Using the eCTD Specifications (October 2005).
`Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
`heavy-weight paper or similar material. For administrative purposes, designate this submission
`“Final Printed Labeling for approved NDA 21560.” Approval of this submission by FDA is
`not required before the labeling is used.
`
`Marketing the product with a package insert and Medication Guide that is not identical to the
`approved labeling text and Medication Guide in the required format may render the product
`misbranded and an unapproved new drug.
`
`
`
`
`WEBSITE POSTING
`
`
`
`We request that the labeling and Medication Guide approved today be available on your website
`within 10 days of receipt of this letter.
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`
`Breckenridge Exhibit 1072
`Zortress Approval
`Page 002
`
`

`

` NDA 21560
`
`Page 3
`
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for this application for patients from birth to 16
`years of age because this product does not represent a meaningful therapeutic benefit over
`existing therapies for pediatric patients and is unlikely to be used in a substantial number of
`pediatric patients.
`
`
`
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o) of the FDCA authorizes FDA to require holders of approved drug and biological
`
`product applications to conduct postmarketing studies and clinical trials for certain purposes, if
`FDA makes certain findings required by the statute (section 505(o)(3)(A)).
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess signals of the serious
`risks of wound healing complications, hyperlipidemia, proteinuria, and graft thromboses.
`
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess these serious
`risks.
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess signals of the serious risks of wound healing complications,
`hyperlipidemia, proteinuria, and graft thromboses.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`
`conduct the following:
`
`
`
`1624-1
`
`Trial RAD001A2309 “A 24-month, multicenter, randomized, open-label
`noninferiority study of efficacy and safety comparing concentration-controlled
`Certican™ in two doses (1.5 and 3.0 mg/day starting doses) with reduced Neoral®
`versus 1.44 g Myfortic® with standard dose Neoral in de novo renal transplant
`recipients” which contains the 24-month follow-up safety data on all patients enrolled
`in the trial.
`
`Completed; trial is ongoing
`
`
`August 18, 2009
`
`July 30, 2010
`
`
`
`
`Final protocol submission
`Trial Completion Date:
`
`Final Report Submission:
`
`
`
`
`
`Submit the final report to your NDA. Prominently identify the submission with the following
`wording in bold capital letters at the top of the first page of the submission, as appropriate:
`
`• REQUIRED POSTMARKETING FINAL REPORT UNDER 505(o)
`
`
`Breckenridge Exhibit 1072
`Zortress Approval
`Page 003
`
`

`

` NDA 21560
`
`Page 4
`
`• REQUIRED POSTMARKETING CORRESPONDENCE UNDER 505(o)
`
`
`
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21 CFR
`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We remind
`you that to comply with 505(o), your annual report must also include a report on the status of any
`study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an
`annual report for studies or clinical trials required under 505(o) on the date required will be
`considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
`
`
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`
`Section 505-1 of the FDCA authorizes FDA to require the submission of a Risk Evaluation and
`Mitigation Strategy (REMS) if FDA determines that such a strategy is necessary to ensure that
`
`the benefits of the drug outweigh the risks (section 505-1(a)). The details of the REMS
`requirements were described in our complete response letter dated December 23, 2009.
`
`Your proposed REMS, submitted on January 22, 2010, and amended on February 19, 2010,
`March 19, 2010, April 7, 2010, April 13, 2010, and appended to this letter, is approved. The
`REMS consists of a Medication Guide, a communication plan, and a timetable for submission of
`assessments of the REMS.
`
`
`The REMS assessment plan should include but is not limited to the following:
`
`
`a. A survey of healthcare providers’ and patients’ understanding of the serious risks of
`Zortress (everolimus).
`b. A report on periodic assessments of the distribution and dispensing of the Medication
`Guide in accordance with 21 CFR 208.24.
`c. A report on failures to adhere to distribution and dispensing requirements, and
`corrective actions taken to address noncompliance.
`
`
`
`
`Assessments of an approved REMS must include, under section 505-1(g)(3)(B) and (C),
`information on the status of any postapproval study or clinical trial required under section 505(o)
`or otherwise undertaken to investigate a safety issue. You can satisfy these requirements in your
`REMS assessments by referring to relevant information included in the most recent annual report
`
`
`
`Breckenridge Exhibit 1072
`Zortress Approval
`Page 004
`
`

`

` NDA 21560
`
`Page 5
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`required under section 506B and 21 CFR 314.81(b)(2)(vii) and including any updates to the
`status information since the annual report was prepared. Failure to comply with the REMS
`assessments provisions in section 505-1(g) could result in enforcement action.
`
`We remind you that in addition to the assessments submitted according to the timetable included
`in the approved REMS, you must submit a REMS assessment and may propose a modification to
`the approved REMS when you submit a supplemental application for a new indication for use as
`described in section 505-1(g)(2)(A) of FDCA.
`
`Prominently identify the submission containing the REMS assessments or proposed
`modifications with one of the following wording selections applicable to the specific submission
`in bold capital letters at the top of the first page of the submission:
`
`
`• NDA 021560 REMS ASSESSMENT
`
`
`• NEW SUPPLEMENT FOR NDA 021560
`
`
`PROPOSED REMS MODIFICATION
`
`REMS ASSESSMENT
`
`
`
`• NEW SUPPLEMENT (NEW INDICATION FOR USE)
`
`
`
`FOR NDA 021560
`
`REMS ASSESSMENT
`
`
`PROPOSED REMS MODIFICATION (if included)
`
`
`If you do not submit electronically, please send 5 copies of the REMS-related submissions.
`
`
`
`PROMOTIONAL MATERIALS
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
`
`information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), see
`
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`Breckenridge Exhibit 1072
`Zortress Approval
`Page 005
`
`

`

` NDA 21560
`
`Page 6
`
`
`
`
`
` LETTERS TO HEALTH CARE PROFESSIONALS
`
`If you issue a letter communicating important safety-related information about this drug product
`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
`
` the letter to both this NDA and to the following address:
`
`
`MedWatch
`
`Food and Drug Administration
`
`Suite 12B-05
`
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`
`
`
`REPORTING REQUIREMENTS
`
`
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Jacquelyn Smith, M.A., Regulatory Project Manager, at
`(301) 796-1600.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`
`
`
` M.D.
`
` Albrecht,
`Renata
`
`
`
`Director
`
`Division of Special Pathogen and Transplant
`Products Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
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`
`
`Enclosures: REMS Document
`
`Package Insert (including Medication Guide)
`
`Carton and Container Labels (including Physician’s Sample)
`
`
`
`
`
`
`
`Breckenridge Exhibit 1072
`Zortress Approval
`Page 006
`
`

`

`Application
`Type/Number
`--------------------
`NDA-21560
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`------------------------------------------
`--------------------
`Zortress (EVEROLIMUS)
`NOVARTIS
`PHARMACEUTICA TABLETS
`LS CORP
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RENATA ALBRECHT
`04/20/2010
`
`Breckenridge Exhibit 1072
`Zortress Approval
`Page 007
`
`

`

`• Serious infections: Increased risk of bacterial, viral, fungal and protozoal
`
`
`infections, including opportunistic infections: combination
`immunosuppression should be used with caution. (5.3)
`
`• Angioedema: Increased risk with concomitant ACE inhibitors; monitor for
`symptoms and treat promptly. (5.4)
`• Wound Healing/Fluid Accumulation: Increased risk for delayed wound
`
`healing. Monitor symptoms; treat promptly to minimize complications. (5.6)
`• Hyperlipidemia: Elevations of serum cholesterol and triglycerides are
`
`
`common. Monitoring is recommended; consider intervention including anti-
`
`lipid therapy. (5.7)
`• Proteinuria: Increased risk with higher trough concentrations; monitor urine
`protein. (5.9)
`
`• Polyoma Virus Infections: Risk of activation of latent viral infections; BK-
`virus associated nephropathy has been observed; consider reducing
`immunosuppression. (5.10)
`
`• Interactions with Strong Inhibitors and Inducers of CYP3A4: closely
`
`monitor everolimus trough concentrations with concomitant use. (5.11)
`
`• Non-Infectious Pneumonitis: Monitor for clinical symptoms or radiologic
`changes; fatal cases have occurred. Manage by dose reduction or
`
`
`discontinuation until symptoms resolve; consider use of corticosteroids. (5.12)
`•TMA/TTP/HUS: Concomitant use with cyclosporine may increase risk;.
`
`Monitor for hematological changes or clinical symptoms. (5.13)
`
`
`• New Onset Diabetes After Transplantation: Blood glucose elevations may
`
`
`occur in dose related manner. Monitor serum glucose. (5.14)
`
`• Male Infertility: Azospermia or oligospermia may occur. (5.15, 13.1)
`
`
`• Immunizations: Live vaccines should be avoided. (5.16)
`-------------------ADVERSE REACTIONS----------------------
`The most common (incidence ≥20%) adverse events are: peripheral edema,
`
`constipation, hypertension, nausea, anemia, UTI, and hyperlipidemia. (6.2)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
`1088 or www.fda.gov/medwatch.
`
`-------------------DRUG INTERACTIONS----------------------
`CYP3A4 inhibitors and inducers: Strong-moderate inhibitors (e.g.,
`
`cyclosporine, ketoconazole, erythromycin, verapamil) and inducers (e.g.,
`
`rifampin) may affect everolimus concentrations. Blood concentration
`monitoring is recommended; consider dose adjustment of everolimus. (7)
`
`
`-------------USE IN SPECIFIC POPULATIONS-------------
`• Pregnancy: Based on animal data may cause fetal harm. (8.1)
`
`
`• Nursing Mothers: Discontinue drug or nursing taking into consideration
`
`importance of drug to mother. (8.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`
`Revised: 03/2010
`
`
`
`
`5.8 Nephrotoxicity
`
`5.9 Proteinuria
`
`5.10 Polyoma Virus Infections
`
`5.11 Interaction with Strong Inhibitors and Inducers of CYP3A4
`
`5.12 Non-Infectious Pneumonitis
`5.13 Thrombotic Microangiopathy/ Thrombotic Thrombocytopenic
`
`Purpura/ Hemolytic Uremic Syndrome (TMA/TTP/HUS)
`
`5.14 New Onset Diabetes After Transplant
`5.15 Male Infertility
`5.16 Immunizations
`
`5.17 Interaction with Grapefruit Juice
`
`5.18 Patients with Hereditary Disorders / Other
`
`6 ADVERSE REACTIONS
`
`6.1 Serious and Otherwise Important Adverse Reactions
`
`6.2 Clinical Studies Experience
`
`6.3 Post Marketing Experience
`
`7 DRUG INTERACTIONS
`7.1 Interactions with Strong Inhibitors or Inducers of CYP3A4 and P-
`
`glycoprotein
`
`7.2 Cyclosporine (CYP3A4/P-gp inhibitor and CYP3A4 substrate)
`
`7.3 Ketoconazole (Strong CYP3A4 Inhibitor)
`
`7.4 Erythromycin (Moderate CYP3A4 Inhibitor)
`
`7.5 Verapamil (CYP3A4 and P-gp Substrate)
`
`7.6 Atorvastatin (CYP3A4 substrate) and Pravastatin (P-gp substrate)
`
`7.7 Simvastatin and Lovastatin
`
`7.8 Rifampin (Strong CYP3A4) Inducers
`
`
`
`
`
`
`
`
`
`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. Tablets for oral administration.
`
`
`Initial U.S. Approval: 2010
`WARNING: IMMUNOSUPPRESSION AND RENAL FUNCTION
`See Full Prescribing Information For Complete Boxed Warning
`
`• Only physicians experienced in immunosuppressive therapy and
`management of transplant patients should use everolimus. (5.1)
`
`• Increased susceptibility to infection and the possible development of
`malignancies may result from immunosuppression. (5.2, 5.3)
`
`• Reduced doses of cyclosporine are required for use in combination with
`everolimus in order to reduce nephrotoxicity. (5.8)
`
`
`• Increased incidence of kidney graft thrombosis. (5.5)
`
`
`--------------INDICATIONS AND USAGE---------------------
`• Prophylaxis of organ rejection in adult patients at low-moderate
`immunologic risk receiving a kidney transplant.
`• Use in combination with basiliximab and concurrently with reduced doses of
`cyclosporine and corticosteroids. (1.1)
`
`• Use in patients at high immunologic risk is not established. (1.2)
`
`• Use for prophylaxis in organs other than kidney is not established. (1.2)
`
`• Safety and efficacy in pediatric patients (<18 years) has not been established.
`(1.2)
`
`------------DOSAGE AND ADMINISTRATION-------------
`• Starting oral dose of 0.75 mg twice daily. Adjust maintenance dose to
`
`
`achieve everolimus trough concentrations within the 3-8 ng/mL target range.
`
`
`(2.1)
`
`Administer as soon as possible after transplantation.
`
`
`• Routine everolimus and cyclosporine therapeutic drug concentration
`
`monitoring is recommended. (2.2, 2.3)
`
`
`
`• Administer consistently with or without food (12) at the same time as
`
`cyclosporine. (2.4)
`
`
`• Moderate hepatic impairment: Reduce daily dose by half and monitor blood
`
`
`concentrations. (2.5)
`
`-----------DOSAGE FORMS AND STRENGTHS------------
`Zortress is available as 0.25 mg, 0.5 mg, and 0.75 mg tablets. (3)
`
`---------------------CONTRAINDICATIONS-------------------
`• Patients with known hypersensitivity to everolimus, sirolimus, or to
`
`components of the drug product. (4)
`
`---------------WARNINGS AND PRECAUTIONS------------
`• Lymphoma and Other Malignancies: Increased risk with all
`immunosuppressants; appears related to intensity and duration of use. Avoid
`prolonged exposure to UV light and sunlight. (5.2)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: IMMUNOSUPPRESSION AND RENAL FUNCTION
`See Full Prescribing Information For Complete Boxed Warning
`WARNING IMMUNOSUPPRESSION, RENAL FUNCTION,
`AND GRAFT THROMBOSIS
`1 INDICATIONS AND USAGE
`
`1.1 Prophylaxis of Organ Rejection in Renal Transplantation
`
`1.2 Limitations of Use
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosage in Adult Kidney Transplant Patients
`
`
`2.2 Therapeutic Drug Monitoring - Everolimus
`
`2.3 Therapeutic Drug Monitoring- Cyclosporine
`
`2.4 Administration
`
`2.5 Hepatic Impairment
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`4.1 Hypersensitivity Reactions
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Management of Immunosuppression
`5.2 Lymphomas and Other Malignancies
`
`5.3 Serious Infections
`
`5.4 Angioedema
`
`5.5 Graft Thrombosis
`
`5.6 Wound Healing and Fluid Accumulation
`
`5.7 Hyperlipidemia
`
`
`
`
`
`
`
`Breckenridge Exhibit 1072
`Zortress Approval
`Page 008
`
`

`

`
`
`
`
`
`7.9 Other Possible Interactions
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`
`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 Everolimus Whole Blood Concentrations Observed in Kidney
`
`
`
`
`Transplant Patients
`
`12.6 Cyclosporine Concentrations Observed in Kidney Transplant
`
`
`
`Patients
`
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`14.1 Prevention of Organ Rejection after Renal Transplantation
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`17.1 Administration
`
`
`17.2 Development of Lymphomas and Other Malignancies
`
`
`17.3 Increased Risk of Infection
`
`
`17.4 Nephrotoxicity
`
`
`17.5 Graft Thrombosis
`
`
`17.6 Pregnancy
`
`
`17.7 Angioedema
`
`
`17.8 Wound Healing Complications and Fluid Accumulation
`
`
`17.9 Hyperlipidemia
`
`
`17.10 Proteinuria
`
`
`17.11 Medications that Interfere with Zortress
`
`
`17.12 Non-Infectious Pneumonitis
`
`
`17.13 New Onset Diabetes
`
`
`17.14 Immunizations
`
`
`17.15 Patient with Hereditary Disorders
`
`
`* Sections or subsections omitted from the full prescribing information are not
`
`listed
`
`
`
`
`
`Breckenridge Exhibit 1072
`Zortress Approval
`Page 009
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`WARNING IMMUNOSUPPRESSION, RENAL FUNCTION, AND GRAFT THROMBOSIS
`• 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)]
`
`• 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 nephrotoxicity can occur with use of standard doses of cyclosporine in combination with everolimus.
`Therefore reduced doses of cyclosporine should be used in combination with everolimus in order to reduce renal
`dysfunction. It is important to monitor the cyclosporine and everolimus whole blood trough concentrations. [See Dosage
`and Administration (2.2 and 2.3) and Warnings and Precautions (5.8) and Clinical Pharmacology (12.5 and 12.6)]
`
`
`
`• 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 (5.5)]
`1 INDICATIONS AND USAGE
`1.1 Prophylaxis of Organ Rejection in Renal Transplantation
`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 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)]
`1.2 Limitations of Use
`• In patients at high immunologic risk, the safety and efficacy of everolimus has not been established.
`
`• Use of everolimus for the prophylaxis of organ rejection in transplanted organs other than kidney has not been
`established.
`• Standard doses of cyclosporine should be avoided with everolimus in order to reduce the risk of nephrotoxicity. [See
`Warnings and Precautions(5), and Adverse Reactions (6.2)]
`
`
`• The safety and efficacy of Zortress has not been established in pediatric patients (<18 years).
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosage in Adult Kidney Transplant Patients
`An initial everolimus dose of 0.75 mg orally twice daily (1.5 mg/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 (2.2 and 2.3), Clinical Studies (14.1)] Patients receiving everolimus may require dose adjustments based
`
`on everolimus blood concentrations achieved, tolerability, individual response, change in concomitant medications and
`
`the clinical situation. Dose adjustments can be made at 4-5 day intervals. [See Therapeutic Drug Monitoring (2.2)]
`
`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.
`2.2 Therapeutic Drug Monitoring - Everolimus
`Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients using
`appropriate assay methodology. The recommended everolimus therapeutic range is 3 to 8 ng/mL. [See Clinical
`Pharmacology (12.5)] 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 (12.5 and 12.6)]
`
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`Zortress Approval
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`Optimally, dose adjustments of everolimus should be based on trough concentrations obtained 4 or 5 days after a previous
`
`dosing change. There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may
`decrease if cyclosporine exposure is reduced. [See Drug Interactions (7.2)]
`2.3 Therapeutic Drug Monitoring- Cyclosporine
`Both cyclosporine doses and the target range for whole blood trough concentrations should be reduced, when given in a
`
`regimen with everolimus, in order to minimize the risk of nephrotoxicity. [See Warnings and Precautions (5.8) and Drug
`
`Interactions (7.2), Clinical Pharmacology (12.6)]
`The recommended cyclosporine therapeutic range when administered with everolimus 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 (12.6) and Clinical Studies
`
`
`(14.1)]
`Cyclosporine, USP Modified is to be administered as oral capsules twice daily unless cyclosporine oral solution or i.v.
`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
`(12.6)]
`
`In renal transplantation, there are limited data regarding dosing everolimus with reduced cyclosporine trough
`
`concentrations of 25 to 50 ng/mL after 12 months. Everolimus has not been evaluated in clinical trials with other
`
`formulations of 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)]
`
`2.4 Administration
`Everolimus tablets should be swallowed whole with a glass of water and not crushed before use.
`Administer everolimus consistently approximately 12 hours apart with or without food to minimize variability in
`absorption and at the same time as cyclosporine. [See Clinical Pharmacology (12.3)]
`
`
`2.5 Hepatic Impairment
`
`No dose adjustment is needed for patients with mild hepatic impairment (Child-Pugh Class A). In patients with moderate
`
`hepatic impairment (Child-Pugh Class B), the daily dose needs to be reduced by one-half the recommended initial daily
`dose and blood concentrations should be monitored to make further adjustments as necessary. There is no information on
`the effects of severe hepatic impairment (Child-Pugh Class C) on everolimus pharmacokinetics. [See Clinical
`Pharmacology (12.3)]
`3 DOSAGE FORMS AND STRENGTHS
`Zortress is available as 0.25 mg, 0.5 mg, and 0.75 mg tablets.
`
`
`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
`“C” on one side and “NVR”
`“CH” on one side and
`“CL” on one side and
`on the other
`“NVR” on the other
`“NVR” on the other
`
`
`
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`Zortress Approval
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`4 CONTRAINDICATIONS
`4.1 Hypersensitivity Reactions
`Zortress is contraindicated in patients with known hypersensitivity to everolimus, sirolimus, or to components of the drug
`product.
`
`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. [See Boxed Warning]
`5.2 Lymphomas and Other Malignancies
`Patients receiving immunosuppressants, including everolimus, are at increased risk of developing lymphomas and other
`malignancies, particularly of the skin. [See Boxed Warning] 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 everolimus, are at increased risk of developing bacterial, viral, fungal,
`
`and protozoal infections, including opportunistic infections. [See Warnings and Precautions (5.10) and Adverse Reactions
`(6.2)] These infections may lead to serious, including fatal,