-------------------------------CONTRAINDICATIONS-----------------------------­
`
`
`
`Hypersensitivity to everolimus, to other rapamycin derivatives, or to any of
`
`
`the excipients (4)
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`• Non-infectious pneumonitis: Monitor for clinical symptoms or radiological
`
`
`changes; fatal cases have occurred. Manage by dose reduction or
`
`
`
`discontinuation until symptoms resolve, and consider use of
`
`corticosteroids. (5.1)
`
`
`
`• Infections: Increased risk of infections, some fatal. Monitor for signs and
`
`
`
`symptoms, and treat promptly. (5.2)
`
`
`
`
`
`• Angioedema: Patients taking concomitant ACE inhibitor therapy may be at
`
`
`increased risk for angioedema. (5.3)
`
`
`
`• Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis are common.
`
`
`
`Management includes mouthwashes and topical treatments. (5.4)
`• Renal failure: Cases of renal failure (including acute renal failure), some
`
`
`
`with a fatal outcome, have been observed. (5.5)
`
`• Impaired wound healing: Increased risk of wound-related complications.
`
`
`
`
`Monitor signs and symptoms. Exercise caution in the peri-surgical period.
`
`(5.6)
`
`
`• Laboratory test alterations: Elevations of serum creatinine, urinary protein,
`
`
`
`blood glucose, and lipids may occur. Decreases in hemoglobin, neutrophils,
`
`
`
`
`and platelets may also occur. Monitor renal function, blood glucose, lipids,
`
`
`
`
`and hematologic parameters prior to treatment and periodically thereafter.
`
`(5.8)
`
`• Vaccinations: Avoid live vaccines and close contact with those who have
`
`
`received live vaccines. (5.11)
`
`
`
`• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
`
`
`
`
`
`reproductive potential of the potential risk to a fetus and to use effective
`
`
`contraception during treatment with AFINITOR and for 8 weeks after final
`
`dose. (5.12, 8.1, 8.3)
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
`
`
`Advanced HR+ BC, advanced NET, advanced RCC: Most common adverse
`reactions (incidence ≥30%) include stomatitis, infections, rash, fatigue,
`
`
`diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache and
`
`decreased appetite. (6.1, 6.2, 6.3)
`
`Renal angiomyolipoma with TSC: Most common adverse reaction (incidence
`
`≥ 30%) is stomatitis. (6.4)
`
`
`SEGA with TSC: Most common adverse reactions (incidence ≥ 30%) are
`
`stomatitis and respiratory tract infection. (6.5)
`
`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------------------------------­
`
`
`• Strong CYP3A4/PgP inhibitors: Avoid concomitant use. (2.2, 2.5, 5.9, 7.1)
`
`
`
`
`
`• Moderate CYP3A4/PgP inhibitors: If combination is required, use caution
`
`and reduce dose of AFINITOR. (2.2, 2.3, 2.5, 5.9, 7.1)
`
`
`
`
`• Strong CYP3A4/PgP inducers: Avoid concomitant use. If combination
`
`
`
`
`cannot be avoided, increase dose of AFINITOR. (2.2, 2.3, 2.5, 5.9, 7.2)
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`
`
`
`
`• Lactation: Breast feeding not recommended. (8.2)
`
`
`
`• Females and Males of Reproductive Potential: May impair fertility. (8.3)
`
`
`
`• Hepatic impairment: For advanced HR+ BC, advanced NET, advanced
`
`
`
`
`RCC, or renal angiomyolipoma with TSC patients with hepatic impairment,
`
`reduce AFINITOR dose. For SEGA patients with severe hepatic
`
`impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR
`
`DISPERZ. (2.2, 2.3, 2.5, 5.10, 8.8)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling
`
`
`
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`
`
`
`AFINITOR safely and effectively. See full prescribing information for
`
`
`AFINITOR.
`AFINITOR® (everolimus) tablets for oral administration
`
`
`
`AFINITOR® DISPERZ (everolimus tablets for oral suspension)
`
`
`
`
`
`
`Initial U.S. Approval: 2009
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`
`Indications and Usage (1.2, 1.4)
`2/2016
`
`
`Indications and Usage (1.5)
`1/2016
`
`
`
`Warnings and Precautions, Non-infectious Pneumonitis (5.1)
`6/2016
`
`
`
`Warnings and Precautions, Embryo-Fetal Toxicity (5.12)
`2/2016
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`
`AFINITOR is a kinase inhibitor indicated for the treatment of:
`
`• postmenopausal women with advanced hormone receptor-positive, HER2­
`
`
`
`negative breast cancer (advanced HR+ BC) in combination with
`
`
`exemestane after failure of treatment with letrozole or anastrozole. (1.1)
`
`
`• adults with progressive neuroendocrine tumors of pancreatic origin (PNET)
`
`
`
`
`
`and adults with progressive, well-differentiated, non-functional
`
`neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that
`
`
`are unresectable, locally advanced or metastatic. AFINITOR is not
`
`
`
`indicated for the treatment of patients with functional carcinoid tumors.
`
`(1.2)
`
`• adults with advanced renal cell carcinoma (RCC) after failure of treatment
`
`
`with sunitinib or sorafenib. (1.3)
`
`• adults with renal angiomyolipoma and tuberous sclerosis complex (TSC),
`
`
`
`
`not requiring immediate surgery. (1.4)
`
`
`AFINITOR and AFINITOR DISPERZ are kinase inhibitors indicated for the
`
`treatment of:
`• pediatric and adult patients with tuberous sclerosis complex (TSC) who
`
`
`have subependymal giant cell astrocytoma (SEGA) that requires
`
`
`
`
`therapeutic intervention but cannot be curatively resected. (1.5)
`
`------------------------DOSAGE AND ADMINISTRATION--------------------­
`
`
`
`Advanced HR+ BC, advanced NET, advanced RCC, or renal angiomyolipoma
`
`with TSC:
`
`
`• 10 mg once daily with or without food. (2.1)
`
`
`
`
`
`• For patients with hepatic impairment, reduce the AFINITOR dose. (2.2)
`
`
`• If moderate inhibitors of CYP3A4/P-glycoprotein (PgP) are required,
`
`
`
`reduce the AFINITOR dose to 2.5 mg once daily; if tolerated, consider
`
`
`increasing to 5 mg once daily. (2.2)
`
`
`
`• If strong inducers of CYP3A4 are required, consider doubling the daily
`
`
`
`
`
`
`
`dose of AFINITOR using increments of 5 mg or less. (2.2)
`
`SEGA with TSC:
`• 4.5 mg/m2 once daily; adjust dose to attain trough concentrations of 5-15
`
`
`
`
`
`ng/mL. (2.3)
`
`• Assess trough concentrations approximately 2 weeks after initiation of
`
`
`
`treatment, a change in dose, a change in co-administration of CYP3A4/PgP
`
`
`
`
`
`inducers or inhibitors, a change in hepatic function, or a change in dosage
`
`
`form between AFINITOR Tablets and AFINITOR DISPERZ. (2.3, 2.4)
`
`
`
`
`• For patients with severe hepatic impairment reduce the starting dose of
`
`
`AFINITOR Tablets or AFINITOR DISPERZ. (2.3, 2.5)
`
`• If concomitant use of moderate inhibitors of CYP3A4/PgP is required,
`
`
`reduce the dose of AFINITOR Tablets or AFINITOR DISPERZ by 50%.
`
`(2.3, 2.5)
`
`
`
`
`• If concomitant use of strong inducers of CYP3A4/PgP is required, double
`
`
`the dose of AFINITOR Tablets or AFINITOR DISPERZ. (2.3, 2.5)
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`
`
`
`
`AFINITOR Tablets: 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets (3.1)
`
`
`
`
`
`
`
`AFINITOR DISPERZ Tablets, for oral suspension: 2 mg, 3 mg, and 5 mg
`
`
`tablets (3.2)
`
`
`
`Reference ID: 3944879
`
`
`
`
`
`Revised: 6/2016
`
`Breckenridge Exhibit 1071
`Afinitor PI 6-14-2016
`Page 001
`
`

`

`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Advanced Hormone Receptor-Positive, HER2-Negative Breast
`
`
`Cancer (Advanced HR+ BC)
`
`
`
`1.2 Advanced Neuroendocrine Tumors (NET)
`
`
`
`
`1.3 Advanced Renal Cell Carcinoma (RCC)
`
`
`
`1.4 Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC)
`
`
`1.5 Subependymal Giant Cell Astrocytoma (SEGA) with Tuberous
`
`
`
`
`
`Sclerosis Complex (TSC)
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dose in Advanced Hormone Receptor-Positive,
`
`
`HER2-Negative Breast Cancer, Advanced NET, Advanced RCC,
`
`
`and Renal Angiomyolipoma with TSC
`
`
`
`
`2.2 Dose Modifications in Advanced Hormone Receptor-Positive,
`
`HER2-Negative Breast Cancer, Advanced NET, Advanced RCC,
`
`
`
`and Renal Angiomyolipoma with TSC
`
`
`
`
`2.3 Recommended Dose in SEGA with TSC
`
`
`
`2.4 Therapeutic Drug Monitoring in SEGA with TSC
`
`
`
`
`
`2.5 Dose Modifications in SEGA with TSC
`
`
`
`
`2.6 Administration of AFINITOR Tablets in SEGA with TSC
`
`
`
`2.7 Administration and Preparation of AFINITOR DISPERZ in SEGA
`
`
`
`with TSC
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`3.1 AFINITOR Tablets
`
`
`
`3.2 AFINITOR DISPERZ
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Non-infectious Pneumonitis
`
`
`
`5.2
`Infections
`
`
`5.3 Angioedema with Concomitant Use of Angiotensin-Converting
`
`
`Enzyme (ACE) Inhibitors
`
`
`
`
`5.4 Oral Ulceration
`
`
`
`5.5 Renal Failure
`
`
`
`5.6
`Impaired Wound Healing
`
`
`
`5.7 Geriatric Patients
`
`
`
`5.8 Laboratory Tests and Monitoring
`
`
`
`
`
`5.9 Drug-Drug Interactions
`
`
`
`5.10 Hepatic Impairment
`
`
`
`5.11 Vaccinations
`
`
`
`5.12 Embryo-Fetal Toxicity
`
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Study Experience in Advanced Hormone Receptor-
`
`
`Positive, HER2-Negative Breast Cancer
`
`
`
`6.2 Clinical Study Experience in Advanced Neuroendocrine Tumors
`
`
`
`
`6.3 Clinical Study Experience in Advanced Renal Cell Carcinoma
`
`
`
`6.4 Clinical Study Experience in Renal Angiomyolipoma with
`
`
`
`Tuberous Sclerosis Complex
`
`
`6.5 Clinical Study Experience in Subependymal Giant Cell
`
`
`Astrocytoma with Tuberous Sclerosis Complex
`
`
`
`6.6 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Agents That May Increase Everolimus Blood Concentrations
`
`
`
`
`
`7.2 Agents That May Decrease Everolimus Blood Concentrations
`
`
`
`7.3 Drugs That May Have Their Plasma Concentrations Altered by
`
`
`
`Everolimus
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.2 Lactation
`
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.7 Renal Impairment
`
`
`
`8.8 Hepatic Impairment
`
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`
`12.6 QT/QTc Prolongation Potential
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`
`
`14 CLINICAL STUDIES
`
`14.1 Advanced Hormone Receptor-Positive, HER2-Negative Breast
`
`
`
`Cancer
`
`
`
`14.2 Advanced Neuroendocrine Tumors
`
`
`
`14.3 Advanced Renal Cell Carcinoma
`
`
`
`
`14.4 Renal Angiomyolipoma with Tuberous Sclerosis Complex
`
`
`14.5 Subependymal Giant Cell Astrocytoma with Tuberous Sclerosis
`
`
`
`
`
`Complex
`
`
`
`15 REFERENCES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the full prescribing information are
`
`not listed
`
`
`Reference ID: 3944879
`
`Breckenridge Exhibit 1071
`Afinitor PI 6-14-2016
`Page 002
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
` 1.1
` Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC)
`
`
`
`
`AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2­
`
`
`
`
`
`
`negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or
`
`anastrozole.
`
`
`
`Advanced Neuroendocrine Tumors (NET)
`1.2
`AFINITOR® is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin
`
`
`
`
`
`(PNET) with unresectable, locally advanced or metastatic disease.
`AFINITOR® is indicated for the treatment of adult patients with progressive, well-differentiated, non-functional
`
`
`
`
`neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic
`
`
`
`disease.
`
` AFINITOR® is not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2)].
`
`
`
`
`
`
`
`
` 1.3
`
`
` Advanced Renal Cell Carcinoma (RCC)
` AFINITOR® is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of
`
`
`treatment with sunitinib or sorafenib.
`
`
`
`
`
`
`
`
`
`
`
`Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC)
`1.4
`
`
`
`AFINITOR® is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex
`
`
`
`(TSC), not requiring immediate surgery.
`
`
`Subependymal Giant Cell Astrocytoma (SEGA) with Tuberous Sclerosis Complex (TSC)
`1.5
`
`
`
`
`AFINITOR® Tablets and AFINITOR® DISPERZ are indicated in pediatric and adult patients with tuberous sclerosis
`
`
`
`
`
`
`complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention
`
`
`
`
`
`but cannot be curatively resected.
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`AFINITOR is available in two dosage forms: tablets (AFINITOR Tablets) and tablets for oral suspension (AFINITOR
`
`
`
`
`
`DISPERZ).
`
`• AFINITOR Tablets may be used for all approved indications.
`
`
`
`
`• AFINITOR DISPERZ is approved for the treatment of patients with subependymal giant cell astrocytoma
`
`
`
`
`
`(SEGA) and tuberous sclerosis complex (TSC).
`
`
`Recommended Dose in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced
`
`
`NET, Advanced RCC, and Renal Angiomyolipoma with TSC
`
`The recommended dose of AFINITOR Tablets is 10 mg, to be taken once daily at the same time every day. Administer
`
`
`
`
`
`
`either consistently with food or consistently without food [see Clinical Pharmacology (12.3)]. AFINITOR Tablets should
`
`
`
`be swallowed whole with a glass of water. Do not break or crush tablets.
`
`Continue treatment until disease progression or unacceptable toxicity occurs.
`
`
`2.1
`
`
`Reference ID: 3944879
`
`Breckenridge Exhibit 1071
`Afinitor PI 6-14-2016
`Page 003
`
`

`

`
`
`
`
`
`
` Grade 1
`
`
`Asymptomatic,
`
`
` radiographic findings
`
`only
`
`
` Grade 2
`
`
` Symptomatic,
`
`
`not interfering with
`
`ADLc
`
`
`
`Grade 3
`
`Symptomatic,
`interfering with ADLc;
`
`
`
`O2 indicated
`
`
`Grade 4
`
`Life-threatening,
`
`ventilatory support
`
` indicated
`Grade 1
`
`Minimal symptoms,
`
`
`normal diet
`
`
`Grade 2
`
`
`Symptomatic but can eat
`
`and swallow modified
`
`diet
`
`
`
`Grade 3
`
`
`Symptomatic and unable
`
`
`to adequately aliment or
`
`
`hydrate orally
`
`
`
`
`
` Consider interruption of therapy, rule out infection and consider
`
`
`
`
` treatment with corticosteroids until symptoms improve to ≤ Grade
`1.
`
`
`Re-initiate AFINITOR at a lower dose.
`
`
`
`
`Discontinue treatment if failure to recover within 4 weeks.
`
`
`
`
`Interrupt AFINITOR until symptoms resolve to ≤ Grade 1.
`
`
`Rule out infection, and consider treatment with corticosteroids.
`
`Consider re-initiating AFINITOR at a lower dose. If toxicity
`
`
`recurs at Grade 3, consider discontinuation.
`
`
`
`Discontinue AFINITOR, rule out infection, and consider treatment
`
`with corticosteroids.
`
`
`No dose adjustment required.
`
`
`Manage with non-alcoholic or salt water (0.9%) mouth wash
`
`
`several times a day.
`
`
`Temporary dose interruption until recovery to Grade ≤1.
`
`
`
`Re-initiate AFINITOR at the same dose.
`
`
`If stomatitis recurs at Grade 2, interrupt dose until recovery to
`
`
`
`Grade ≤1. Re-initiate AFINITOR at a lower dose.
`
`
`Manage with topical analgesic mouth treatments (e.g., benzocaine,
`
`
`
`butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol)
`
`
`
`with or without topical corticosteroids (i.e., triamcinolone oral
`
`
`
`paste).d
`
`
`
`Temporary dose interruption until recovery to Grade ≤1.
`
`
`
`
`Re-initiate AFINITOR at a lower dose.
`
`
`
`
`Manage with topical analgesic mouth treatments (i.e., benzocaine,
`
`
`
`butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol)
`
`
`
`with or without topical corticosteroids (i.e., triamcinolone oral
`
`
` paste).d
`
`
`
`
` Dose Modifications in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced
`
`
` NET, Advanced RCC, and Renal Angiomyolipoma with TSC
`
` Adverse Reactions
`
`
` Management of severe or intolerable adverse reactions may require temporary dose interruption (with or without a dose
`
` reduction of AFINITOR therapy) or discontinuation. If dose reduction is required, the suggested dose is approximately
`
`
`
`
`
`
`
` 50% lower than the daily dose previously administered [see Warnings and Precautions (5)].
`
`
`
` Table 1 summarizes recommendations for dose reduction, interruption or discontinuation of AFINITOR in the
`
`
`
`
` management of adverse reactions. General management recommendations are also provided as applicable. Clinical
`
` judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk
`
`
` assessment.
`
` Table 1: AFINITOR Dose Adjustment and Management Recommendation for Adverse Reactions
`
`
`
`AFINITOR Dose Adjustmentb and Management
` Severitya
`
`
` Adverse Reaction
`
`
` Recommendations
` No dose adjustment required.
`
`
` Initiate appropriate monitoring.
`
`
`
` 2.2
`
`
`
` Non-infectious
`
` pneumonitis
`
`
`
`
`
`
`
`Stomatitis
`
`
`
`
`
`
`Reference ID: 3944879
`
`Breckenridge Exhibit 1071
`Afinitor PI 6-14-2016
`Page 004
`
`

`

`
`
` Discontinue AFINITOR and treat with appropriate medical
`
` therapy.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Other non-
`hematologic toxicities
`
`(excluding metabolic
`
`events)
`
`
` Grade 4
`
`
` Symptoms associated
`
` with life-threatening
`
` consequences
`Grade 1
`
`
`Grade 2
`
`
`
`
`
`
` Metabolic events
`
`(e.g. hyperglycemia,
`
`dyslipidemia)
`
`
`
`
`
`Grade 3
`
`
`
`
` Grade 4
`
`
`
` Grade 1
`
`Grade 2
`
`
`
`
` Grade 3
`
`
`
` Grade 4
`
`If toxicity is tolerable, no dose adjustment required.
`
`
`
` Initiate appropriate medical therapy and monitor.
`If toxicity is tolerable, no dose adjustment required.
`
`Initiate appropriate medical therapy and monitor.
`
`
`If toxicity becomes intolerable, temporary dose interruption until
`
`recovery to Grade ≤1. Reinitiate AFINITOR at the same dose.
`
`
`If toxicity recurs at Grade 2, interrupt AFINITOR until recovery to
`
`Grade ≤1. Reinitiate AFINITOR at a lower dose.
`
`
`Temporary dose interruption until recovery to Grade ≤1.
`
`Initiate appropriate medical therapy and monitor.
`
`Consider reinitiating AFINITOR at a lower dose. If toxicity recurs
`
`
`
` at Grade 3, consider discontinuation.
` Discontinue AFINITOR and treat with appropriate medical
`
` therapy.
`
` No dose adjustment required.
` Initiate appropriate medical therapy and monitor.
`
`No dose adjustment required.
`
`
` Manage with appropriate medical therapy and monitor.
`
` Temporary dose interruption.
` Reinitiate AFINITOR at a lower dose.
`
`
`
`
` Manage with appropriate medical therapy and monitor.
` Discontinue AFINITOR and treat with appropriate medical
`
`
` therapy.
`a Severity grade description: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening
`
`
`
`symptoms.
`
`
`b If dose reduction is required, the suggested dose is approximately 50% lower than the dose previously administered.
`
`
`
`
`c Activities of daily living (ADL)
`
`
`d Avoid using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis
`
`
`
`
` as they may worsen mouth ulcers.
`
`
`
` Hepatic Impairment
`
` Hepatic impairment will increase the exposure to everolimus [see Warnings and Precautions (5.10) and Use in Specific
` Populations (8.8)]. Dose adjustments are recommended:
`
` • Mild hepatic impairment (Child-Pugh class A) – The recommended dose is 7.5 mg daily; the dose may be decreased
`
`
`
` to 5 mg if not well tolerated.
`
` • Moderate hepatic impairment (Child-Pugh class B) – The recommended dose is 5 mg daily; the dose may be
`
`
`
`
`
` decreased to 2.5 mg if not well tolerated.
`
` • Severe hepatic impairment (Child-Pugh class C) – If the desired benefit outweighs the risk, a dose of 2.5 mg daily
`
`
` may be used but must not be exceeded.
` Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment.
`
`
` CYP3A4/P-glycoprotein (PgP) Inhibitors
`
` Avoid the use of strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone,
`
` saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) [see Warnings and Precautions (5.9) and Drug
`
`
`
` Interactions (7.1)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3944879
`
`Breckenridge Exhibit 1071
`Afinitor PI 6-14-2016
`Page 005
`
`

`

`
`
`Use caution when co-administered with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant,
`
`
`erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4/PgP
`
`
`inhibitor, reduce the AFINITOR dose to 2.5 mg daily. The reduced dose of AFINITOR is predicted to adjust the area
`
`
`
`
`
`
`under the curve (AUC) to the range observed without inhibitors. An AFINITOR dose increase from 2.5 mg to 5 mg may
`
`
`
`be considered based on patient tolerance. If the moderate inhibitor is discontinued, a washout period of approximately 2 to
`
`
`
`
`
`3 days should be allowed before the AFINITOR dose is increased. If the moderate inhibitor is discontinued, the
`
`
`
`AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor.
`
`
`
`Grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity may increase
`
`
`everolimus exposures and should be avoided during treatment.
`
`Strong CYP3A4/PgP Inducers
`
`
`
`Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin,
`
`
`
`
`
`rifapentine, phenobarbital). If patients require co-administration of a strong CYP3A4/PgP inducer, consider doubling the
`
`
`
`
`
`daily dose of AFINITOR using increments of 5 mg or less. This dose of AFINITOR is predicted, based on
`
`
`
`
`pharmacokinetic data, to adjust the AUC to the range observed without inducers. However, there are no clinical data with
`
`
`
`
`this dose adjustment in patients receiving strong CYP3A4/PgP inducers. If the strong inducer is discontinued, consider a
`
`
`
`
`
`
`
`washout period of 3 to 5 days, before the AFINITOR dose is returned to the dose used prior to initiation of the strong
`
`
`
`
`CYP3A4/PgP inducer [see Warnings and Precautions (5.9) and Drug Interactions (7.2)].
`
`St. John’s Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided.
`
`
`
`
`
`Recommended Dose in SEGA with TSC
`2.3
`The recommended starting dose is 4.5 mg/m2, once daily. The recommended starting dose for patients with severe hepatic
`
`
`
`
`impairment (Child-Pugh class C) or requiring moderate CYP3A4/PgP inhibitors is 2.5 mg/m2, once daily [see Dosage and
`
`
`
`
`Administration (2.5)]. The recommended starting dose for patients requiring a concomitant strong CYP3A4 inducer is
`
`
`
`
`9 mg/m2, once daily [see Dosage and Administration (2.5)]. Round dose to the nearest strength of either AFINITOR
`
`
`
`
`
`
`
`Tablets or AFINITOR DISPERZ.
`
`
`
`
`
`Do not combine AFINITOR Tablets and AFINITOR DISPERZ to achieve the desired total dose.
`Use therapeutic drug monitoring to guide subsequent dosing [see Dosage and Administration (2.4)]. Adjust dose at 2
`
`
`
`
`week intervals as needed to achieve and maintain trough concentrations of 5 to 15 ng/mL [see Dosage and Administration
`
`
`
`(2.4, 2.5)].
`
`
`
`
`
`
`Continue treatment until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown.
`
`
`
`
`
`Therapeutic Drug Monitoring in SEGA with TSC
`2.4
`
`
`
`
`Monitor everolimus whole blood trough levels routinely in all patients. When possible, use the same assay and laboratory
`
`
`
`for therapeutic drug monitoring throughout treatment.
`
`
`
`
`Assess trough concentrations approximately 2 weeks after initiation of treatment, a change in dose, a change in co­
`
`
`
`
`administration of CYP3A4/PgP inducers and/or inhibitors, a change in hepatic function, or a change in dosage form
`
`
`
`
`between AFINITOR Tablets and AFINITOR DISPERZ. Once a stable dose is attained, monitor trough concentrations
`
`
`every 3 to 6 months in patients with changing body surface area or every 6 to 12 months in patients with stable body
`
`surface area for the duration of treatment.
`
`
`
`Titrate the dose to attain trough concentrations of 5 to 15 ng/mL.
`
` • For trough concentrations less than 5 ng/mL, increase the daily dose by 2.5 mg (in patients taking AFINITOR
`
`
`
` Tablets) or 2 mg (in patients taking AFINITOR DISPERZ).
`
`
`
`
` • For trough concentrations greater than 15 ng/mL, reduce the daily dose by 2.5 mg (in patients taking AFINITOR
`
`
`
` Tablets) or 2 mg (in patients taking AFINITOR DISPERZ).
`
`
`
` If dose reduction is required for patients receiving the lowest available strength, administer every other day.
`
`
`
`
`
`•
`
`Reference ID: 3944879
`
`
`
`
`
`
`
`
`
`
`
`Breckenridge Exhibit 1071
`Afinitor PI 6-14-2016
`Page 006
`
`

`

`
`
`Dose Modifications in SEGA with TSC
`2.5
`
`
`Adverse Reactions
`
`Temporarily interrupt or permanently discontinue AFINITOR Tablets or AFINITOR DISPERZ for severe or intolerable
`
`
`
`
`
`adverse reactions. If dose reduction is required when reinitiating therapy, reduce the dose by approximately 50% [see
`
`
`
`
`
`Dosage and Administration (2.2) and Warnings and Precautions (5)]. If dose reduction is required for patients receiving
`
`
`
`
`
`the lowest available strength, administer every other day.
`
`
`Hepatic Impairment
`
`
` • Reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% in patients with
`
`
`
`
`
` SEGA who have severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2.3)].
` Adjustment to the starting dose for patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-
`
` Pugh class B) hepatic impairment may not be needed. Subsequent dosing should be based on therapeutic drug
`
`
`
`
` monitoring.
`
` • Assess everolimus trough concentrations approximately 2 weeks after commencing treatment, a change in dose, or
`
`
` any change in hepatic function [see Dosage and Administration (2.3, 2.4)].
`
`
`CYP3A4/P-glycoprotein (PgP) Inhibitors
`
`
`
`
`Avoid the use of concomitant strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir,
`
`
`nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving AFINITOR
`
`Tablets or AFINITOR DISPERZ [see Warnings and Precautions (5.9) and Drug Interactions (7.1)].
`
`
`
`
`For patients who require treatment with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant,
`
`erythromycin, fluconazole, verapamil, diltiazem):
`
` • Reduce the AFINITOR Tablets or AFINITOR DISPERZ dose by approximately 50%. Administer every other day if
`
`
`
` dose reduction is required for patients receiving the lowest available strength and maintain trough concentrations of 5
`
`
`
` to 15 ng/mL [see Dosage and Administration (2.3, 2.4)].
`
`
` • Assess everolimus trough concentrations approximately 2 weeks after dose reduction [see Dosage and Administration
`
`
`
` (2.3, 2.4)].
`
`
` • Resume the dose that was used prior to initiating the CYP3A4/PgP inhibitor 2 to 3 days after discontinuation of a
`
` moderate inhibitor. Assess the everolimus trough concentration approximately 2 weeks later [see Dosage and
`
`
`
`
` Administration (2.3, 2.4)].
` Do not ingest foods or nutritional supplements (e.g., grapefruit, grapefruit juice) that are known to inhibit cytochrome
`
`
` P450 or PgP activity.
`
`
` Strong CYP3A4/PgP Inducers
`
` Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin,
`
`
` rifapentine, phenobarbital) if alternative therapy is available [see Warnings and Precautions (5.9) and Drug Interactions
`
`
` (7.2)]. For patients who require treatment with a strong CYP3A4/PgP inducer:
`
`
` • Double the dose of AFINITOR Tablets or AFINITOR DISPERZ and assess tolerability [see Dosage and
`
`
`
`
`
` Administration (2.3)].
`
`
`
` • Assess the everolimus trough concentration 2 weeks after doubling the dose and adjust the dose if necessary to
`
` maintain a trough concentration of 5 to 15 ng/mL [see Dosage and Administration (2.3, 2.4)].
`
`
`
`
` • Return the AFINITOR Tablets or AFINITOR DISPERZ dose to that used prior to initiating the strong CYP3A4/PgP
`
`
` inducer if the strong inducer is discontinued, and assess the everolimus trough concentrations approximately 2 weeks
`
`
`
`
`
`
` later [see Dosage and Administration (2.3, 2.4)].
`
`
` Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce
`
`
` cytochrome P450 activity.
`
`
`
`
` Administration of AFINITOR Tablets in SEGA with TSC
`
` 2.6
` Do not combine the 2 dosage forms (AFINITOR Tablets and AFINITOR DISPERZ) to achieve the desired total dose. Use
`
`
` one dosage form or the other.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3944879
`
`Breckenridge Exhibit 1071
`Afinitor PI 6-14-2016
`Page 007
`
`

`

`
`
`Administer AFINITOR Tablets orally once daily at the same time every day. Administer either consistently with food or
`
`consistently without food [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`AFINITOR Tablets should be swallowed whole with a glass of water. Do not break or crush tablets.
`
`
`Administration and Preparation of AFINITOR DISPERZ in SEGA with TSC
`2.7
`
`
`Wear gloves to avoid possible contact with everolimus when preparing suspensions of AFINITOR DISPERZ for another
`
`
`person.
`
`
`
`
`
`
`Do not combine the 2 dosage forms (AFINITOR Tablets and AFINITOR DISPERZ) to achieve the desired total dose. Use
`
`
`one dosage form or the other.
`
`Administer AFINITOR DISPERZ (everolimus tablets for oral suspension) as a suspension only.
`
`
`
`
`
`Administer AFINITOR DISPERZ orally once daily at the same time every day. Administer either consistently with food
`
`
`
`
`or consistently without food [see Clinical Pharmacology (12.3)].
`
`
`Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after
`
`
`
`
`preparation.
`
`
`
`Prepare suspension in water only.
`
`Using an oral syringe:
`
` Place the prescribed dose of AFINITOR DISPERZ into a 10-mL syringe. Do not exceed a total of 10 mg per syringe.
`
`•
`
`
`
` If higher doses are required, prepare an additional syringe. Do not break or crush tablets.
` • Draw approximately 5 mL of water and 4 mL of air into the syringe.
`
`
`
`
`
`
` Place the filled syringe into a container (tip up) for 3 minutes, until the AFINITOR DISPERZ tablets are in
`
`
`
`
`•
`
` suspension.
`
`
`
` • Gently invert the syringe 5 times immediately prior to administration.
`
`
`
` • After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into the same
`
`
`
` syringe, and swirl the contents to suspend remaining particles. Administer the entire contents of the syringe.
`
`
`
` Using a small drinking glass:
` Place the prescribed dose of AFINITOR DISPERZ into a small drinking glass (maximum size 100 mL) containing
`
`
`
`•
`
`
` approximately 25 mL of water. Do not exceed a total of 10 mg of AFINITOR DISPERZ per glass. If higher doses are
` required, prepare an additional glass. Do not break or crush tablets.
`
`
` • Allow 3 minutes for suspension to occur.
`
` Stir the contents gently with a spoon, immediately prior to drinking.
`
`
`•
`
` • After administration of the prepared suspension, add 25 mL of water and stir with the same spoon to re-suspend
`
` remaining particles. Administer the entire contents of the glass.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
` 3.1
` AFINITOR Tablets
`
`
` 2.5 mg tablet
` White to slightly yellow, elongated tablets with a bevelled edge and engraved with “LCL” on one side and “NVR” on the
`
`
` other.
`
` 5 mg tablet
` White to slightly yellow, elongated tablets with a bevelled edge and engraved with “5” on one side and “NVR” on the
`
`
` other.
`
` 7.5 mg tablet
` White to slightly yellow, elongated tablets with a bevelled edge and engraved with “7P5”