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-------------------------­
`
`
`Warnings and Precautions, Angioedema (5.3)
`1/2015
`
`----------------------------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)
`
`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. The effectiveness of AFINITOR in the
`treatment of renal angiomyolipoma is based on an analysis of durable
`objective responses in patients treated for a median of 8.3 months. Further
`
`follow-up of patients is required to determine long-term outcomes. (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. The
`effectiveness is based on demonstration of durable objective response, as
`evidenced by reduction in SEGA tumor volume. Improvement in disease-
`related symptoms and overall survival in patients with SEGA and TSC has
`
`not been demonstrated. (1.5)
`
`------------------------DOSAGE AND ADMINISTRATION--------------------­
`Advanced HR+ BC, advanced PNET, 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 with no score
`(3.1)
`
`
`
`
`
`
`
`AFINITOR DISPERZ (everolimus tablets for oral suspension): 2 mg, 3 mg,
`
`
`and 5 mg tablets for oral suspension with no score (3.2)
`-------------------------------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: Fetal harm can occur when administered to a
`
`
`pregnant woman. Apprise women of potential harm to the fetus. (5.12, 8.1)
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`Advanced HR+ BC, advanced PNET, 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-----------------------­
` Nursing mothers: Discontinue drug or nursing, taking into consideration
`the importance of drug to the mother. (8.3)
` Hepatic impairment: For advanced HR+ BC, advanced PNET, 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 09/2015
`
`
`
`
`
`
`
`
`Reference ID: 3822070
`
`NOVARTIS EXHIBIT 2048
`Par v Novartis, IPR 2016-00084
`Page 1 of 44
`
`

`
`
`
`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 of Pancreatic Origin (PNET)
` 
` 
`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 PNET, Advanced RCC,
` 
`and Renal Angiomyolipoma with TSC
` 
`2.2 Dose Modifications in Advanced Hormone Receptor-Positive,
`HER2-Negative Breast Cancer, Advanced PNET, 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 (everolimus) Tablets
`
` 
` 
`3.2 AFINITOR DISPERZ (everolimus tablets for oral suspension)
` 
` 
`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 Pancreatic 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
` 
` 
`8.3 Nursing Mothers
` 
` 
`8.4 Pediatric Use
` 
` 
`8.5 Geriatric Use
` 
` 
`8.6 Females and Males of Reproductive Potential
` 
` 
`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: 3822070
`
`NOVARTIS EXHIBIT 2048
`Par v Novartis, IPR 2016-00084
`Page 2 of 44
`
`

`
`
`
`
`
` 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.
`
`
`1.2
`Advanced Neuroendocrine Tumors of Pancreatic Origin (PNET)
`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 not indicated for the treatment of patients with functional carcinoid tumors.
`
`
`
`Advanced Renal Cell Carcinoma (RCC)
`1.3
`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.
`The effectiveness of AFINITOR in the treatment of renal angiomyolipoma is based on an analysis of durable objective
`responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term
`outcomes.
`
`1.5
`Subependymal Giant Cell Astrocytoma (SEGA) with Tuberous Sclerosis Complex (TSC)
`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.
`
`The effectiveness of AFINITOR Tablets and AFINITOR DISPERZ is based on demonstration of durable objective
`response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall
`
`survival in patients with SEGA and TSC has not been demonstrated [see Clinical Studies (14.5)].
`
`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
`2.1
`PNET, 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.
`
`
`
`
`
`Reference ID: 3822070
`
`NOVARTIS EXHIBIT 2048
`Par v Novartis, IPR 2016-00084
`Page 3 of 44
`
`

`
`
`Dose Modifications in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced
`2.2
`PNET, 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
`Severitya
`AFINITOR Dose Adjustmentb and Management
`
`Adverse Reaction
`Recommendations
`No dose adjustment required.
`Initiate appropriate monitoring.
`
`Non-infectious
`pneumonitis
`
`
`
`
`
`
`
`Stomatitis
`
`
`
`
`
`
`
`Reference ID: 3822070
`
`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
`
`
`NOVARTIS EXHIBIT 2048
`Par v Novartis, IPR 2016-00084
`Page 4 of 44
`
`

`
`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
`
`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.
`
`
`
`Grade 3
`
`Grade 4
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`
`
`
`
`Metabolic events
`(e.g. hyperglycemia,
`dyslipidemia)
`
`
`
`
`
`
`
`
`
`Reference ID: 3822070
`
`NOVARTIS EXHIBIT 2048
`Par v Novartis, IPR 2016-00084
`Page 5 of 44
`
`

`
`
`
`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)].
`
`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).
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` 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.
`
`
`
`
`
`
`
`2.5
`Dose Modifications in SEGA with TSC
`
`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)].
`
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`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.
`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.
`
`2.7
`Administration and Preparation of AFINITOR DISPERZ in SEGA with TSC
`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
`
`
`AFINITOR (everolimus) Tablets
`3.1
`2.5 mg tablet
`White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “LCL” on one side and
`
`“NVR” on the other.
`
`
`
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`Reference ID: 3822070
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`5 mg tablet
`
`White to slightly yellow, elongated tablets with a bevelled edge and no score, 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 no score, engraved with “7P5” on one side and
`“NVR” on the other.
`10 mg tablet
`
`White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE” on one side and
`“NVR” on the other.
`
`
`
`AFINITOR DISPERZ (everolimus tablets for oral suspension)
`3.2
`2 mg tablet for oral suspension
`
`White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D2” on one side and
`“NVR” on the other.
`3 mg tablet for oral suspension
`
`White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D3” on one side and
`“NVR” on the other.
`5 mg tablet for oral suspension
`
`White to slightly yellowish, round, flat tablets with a bevelled edge an