everolimus

1 INDICATIONS AND USAGE Everolimus tablets are a kinase inhibitor indicated for the treatment of: Postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. ( 1.1 ) Adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Limitations of Use: Everolimus tablets are not indicated for the treatment of patients with functional carcinoid tumors. ( 1.2 ) Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. ( 1.4 ) Everolimus tablets are a kinase inhibitor indicated for the treatment of adult and pediatric patients aged 1 year and older with TSC who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. ( 1.5 ) 1.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer Everolimus tablets are indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. 1.2 Neuroendocrine Tumors (NET) Everolimus tablets are indicated for the treatment of adult patients with progressive, well-differentiated, non-functional NET of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. Limitations of Use: Everolimus tablets are not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2) ]. 1.4 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma Everolimus tablets are indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery. 1.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) Everolimus tablets are indicated in adult and pediatric patients aged 1 year and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected.

2 DOSAGE AND ADMINISTRATION Do not combine everolimus tablets and AFINITOR DISPERZ to achieve the total daily dose. ( 2.1 ) Modify the dose for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4. ( 2.1 ) Breast Cancer: 10 mg orally once daily. ( 2.2 ) NET: 10 mg orally once daily. ( 2.3 ) TSC-Associated Renal Angiomyolipoma: 10 mg orally once daily. ( 2.5 ) TSC-Associated SEGA: 4.5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5 ng/mL to 15 ng/mL. ( 2.6 , 2.8 ) 2.1 Important Dosage Information Do not combine everolimus tablets and AFINITOR DISPERZ to achieve the total dose. Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4 [see Dosage and Administration (2.10 , 2.11 , 2.12 )]. 2.2 Recommended Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for Neuroendocrine Tumors (NET) The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.5 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.6 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of everolimus tablets is 4.5 mg/m 2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8) ] . 2.8 Therapeutic Drug Monitoring (TDM) and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) Monitor everolimus whole blood trough concentrations at time points recommended in Table 1. Titrate the dose to attain trough concentrations of 5 ng/mL to 15 ng/mL. Adjust the dose using the following equation: New dose* = current dose x (target concentration divided by current concentration) *The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough concentration. When possible, use the same assay and laboratory for TDM throughout treatment. Table 1: Recommended Timing of Therapeutic Drug Monitoring Abbreviation: P-gp, P-glycoprotein. Event When to Assess Trough Concentrations After Event Initiation of everolimus tablets 1 week to 2 weeks Modification of everolimus tablets dose 1 week to 2 weeks Switch between everolimus tablets and AFINITOR DISPERZ 1 week to 2 weeks Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor 2 weeks Initiation or discontinuation of P-gp and strong CYP3A4 inducer 2 weeks Change in hepatic function 2 weeks Stable dose with changing body surface area (BSA) Every 3 months to 6 months Stable dose with stable BSA Every 6 months to 12 months 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of everolimus tablets for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus Tablets for Adverse Reactions Adverse Reaction Severity Dosage Modification Non-infectious pneumonitis [see Warnings and Precautions (5.1) ] Grade 2 Withhold until improvement to Grade 0 or Grade 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks. Grade 3 Withhold until improvement to Grade 0 or Grade 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If toxicity recurs at Grade 3, permanently discontinue. Grade 4 Permanently discon…

5 WARNINGS AND PRECAUTIONS Non-Infectious Pneumonitis: Monitor for clinical symptoms or radiological changes. Withhold or permanently discontinue based on severity. ( 2.9 , 5.1 ) Infections: Monitor for signs and symptoms of infection. Withhold or permanently discontinue based on severity. ( 2.9 , 5.2 ) Severe Hypersensitivity Reactions: Permanently discontinue for clinically significant hypersensitivity. ( 5.3 ) Angioedema: Patients taking concomitant angiotensin-converting-enzyme (ACE) inhibitors may be at increased risk for angioedema. Permanently discontinue for angioedema. ( 5.4 , 7.2 ) Stomatitis: Initiate dexamethasone alcohol-free mouthwash when starting treatment. ( 5.5 , 6.1 ) Renal Failure: Monitor renal function prior to treatment and periodically thereafter. ( 5.6 ) Risk of Impaired Wound Healing: Withhold for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment after resolution of wound healing complications has not been established. ( 5.7 ) Geriatric Patients: Monitor and adjust dose for adverse reactions. ( 5.8 ) Metabolic Disorders: Monitor serum glucose and lipids prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. ( 2.9 , 5.9 ) Myelosuppression: Monitor hematologic parameters prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. ( 2.9 , 5.10 ) Risk of Infection or Reduced Immune Response with Vaccination: Avoid live vaccines and close contact with those who have received live vaccines. Complete recommended childhood vaccinations prior to starting treatment. ( 5.11 ) Radiation Sensitization and Radiation Recall: Severe radiation reactions may occur. ( 5.12 , 6.2 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.13 , 8.1 , 8.3 ) 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to 19% of patients treated with everolimus in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Grade 3 and Grade 4 non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions (6.1) ]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms. Consider opportunistic infections, such as pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms. Continue everolimus without dose alteration in patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis. For Grade 2 to Grade 4 non-infectious pneumonitis, withhold or permanently discontinue everolimus based on severity [see Dosage and Administration (2.9) ] . Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose. 5.2 Infections Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1) ] . Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP), and viral infections (e.g., reactivation of hepatitis B virus) have occurred. Some of these infections have been severe (e…

4 CONTRAINDICATIONS Everolimus is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives [see Warnings and Precautions (5.3) ] . Clinically significant hypersensitivity to everolimus or to other rapamycin derivatives. ( 4 )

7 DRUG INTERACTIONS P-gp and strong CYP3A4 inhibitors: Avoid concomitant use. ( 2.11 , 7.1 ) P-gp and moderate CYP3A4 inhibitors: Reduce the dose as recommended. ( 2.11 , 7.1 ) P-gp and strong CYP3A4 inducers: Increase the dose as recommended. ( 2.12 , 7.1 ) 7.1 Effect of Other Drugs on Everolimus Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Dosage and Administration (2.11) , Clinical Pharmacology (12.3) ]. Reduce the dose for patients taking everolimus with a P-gp and moderate CYP3A4 inhibitor as recommended [see Dosage and Administration (2.11) , Clinical Pharmacology (12.3) ]. Inducers Increase the dose for patients taking everolimus with a P-gp and strong CYP3A4 inducer as recommended [see Dosage and Administration (2.12) , Clinical Pharmacology (12.3) ]. 7.2 Effects of Combination Use of Angiotensin Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitors with everolimus may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with everolimus [see Warnings and Precautions (5.4) ] .

8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)] , everolimus can cause fetal harm when administered to a pregnant woman. There are limited case reports of everolimus use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of everolimus 10 mg orally once daily (see Data) . Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Data Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m 2 ) with resulting exposures of approximately 4% of the human exposure at the recommended dose of everolimus 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m 2 ), approximately 1.6 times the recommended dose of everolimus 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA). The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m 2 ), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Non-Infectious Pneumonitis [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Severe Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Angioedema with Concomitant Use of ACE inhibitors [see Warnings and Precautions (5.4) ] Stomatitis [see Warnings and Precautions (5.5) ] Renal Failure [see Warnings and Precautions (5.6) ] Impaired Wound Healing [see Warnings and Precautions (5.7) ] Metabolic Disorders [see Warnings and Precautions (5.9) ] Myelosuppression [see Warnings and Precautions (5.10) ] Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.12) ] Breast cancer, NET: 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 ) TSC-Associated Renal Angiomyolipoma: Most common adverse reaction (incidence ≥ 30%) is stomatitis. ( 6.1 ) TSC-Associated SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novugen Pharma (USA) LLC at 1-888-966-8843 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Hormone Receptor-Positive, HER2-Negative Breast Cancer The safety of everolimus (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (28 years to 93 years), and 75% were white. The median follow-up was approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3 to Grade 4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3 to Grade 4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypokalemia, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred in 2% of patients who received everolimus. The rate of adverse reactions resulting in permanent discontinuation was 24% for the everolimus arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the everolimus arm. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus vs. placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with everolimus was 23.9 weeks; 33% were exposed to everolimus for a period of ≥ 32 weeks. Table 6: Adverse Reactions Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2 Everolimus with Exemestane N = 482 Placebo with Exemestane N = 238 All Grades % Grade 3 to Grade 4 % All Grades % Grade 3 to Grade 4 % Gastrointestinal Stomatitis a 67 8 d 11 0.8 Diarrhea 33 2 18 0.8 Nausea 29 0.4 28 1 Vomiting 17 1 12 0.8 Constipation 14 0.4 d 13 0.4 Dry mouth 11 0 7 0 General Fatigue 36 4 27 1 d Edema peripheral 19 1 d 6 0.4 d Pyrexia 15 0.2 d 7 0.4 d Asthenia 13 2 4 0 Infections Infections b 50 6 25 2 d Investigations Weight loss 25 1 d 6 0 Metabolism and nutrit…