EVEROLIMUS

Everolimus is a kinase inhibitor. The chemical name of everolimus is (1 R ,9 S ,12 S ,15 R ,16 E ,18 R ,19 R ,21 R ,23 S ,24 E ,26 E ,28 E ,30 S ,32 S ,35 R )-1,18-dihydroxy-12-{(1 R )-2-[(1 S ,3 R ,4 R )-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.0 4,9 ]-hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. The molecular formula is C 53 H 83 NO 14 and the molecular weight is 958.22 g/mol. The structural formula is: Everolimus tablets for oral administration contains 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus, USP and the following inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, and magnesium stearate. chem-structure-everolimus-usp-05-18-2024.jpg

Everolimus is a kinase inhibitor indicated for the treatment of: • 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 ) 1.3 Renal Cell Carcinoma (RCC) Everolimus is indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib. 1.4 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma Everolimus is indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery.

Everolimus is available in tablets for oral administration 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 ) RCC: • 10 mg orally once daily ( 2.4 ) TSC-Associated Renal Angiomyolipoma: • 10 mg orally once daily. ( 2.5 ) 2.1 Important Dosage Information • 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 ( 2.11 , 2.12 )] . 2.4 Recommended Dosage for Renal Cell Carcinoma (RCC) The recommended dosage of Everolimus 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 is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of Everolimus for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus 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 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 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 discontinue. Stomatitis [see Warnings and Precautions ( 5.5 )] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. If recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions ( 5.9 )] Grade 3 Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Other non-hematologic toxicities Grade 2 If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1. Resume at same dose. If toxicity recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 3 Withhold until improvement to Grade 0 or 1. Consider resuming at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If recurs at Grade 3, permanently discontinue. Grade 4 Permanently discontinue. Thrombocytopenia [see Warnings and Precautions ( 5.10 )] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. Grade 3 OR Grade 4 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Neutropenia [see Warnings and Precautions ( 5.10 )] Grade 3 Withhold until improvement to Grade 0, 1, or 2. Resume at same dose. Grade 4 Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Febrile neutropenia [see Warnings and Precautions ( 5.10 )] Grade 3 Withhold until improvement to Grade 0, 1, or 2, and no fever. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. 2.10 Dosage Modifications for Hepatic Impairment The recommended dosages of Everolimus for patients with hepatic impairment are described in Table 3 [see Use in Specific Populations ( 8.6 )] : Table 3: Recommended Dosage Modifications for Patients with Hepatic Impairment Indication Dose Modification for Everolimus RCC and TSC-Associated Renal Angiomyolipoma • Mild hepatic impairment (Child-Pugh class A) – 7.5 mg orally once daily; decrease the dose to 5 mg orally once daily if a dose of 7.5 mg once daily is not tolerated. • Moderate hepatic impairment (Child-Pugh class B) – 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if a dose of 5 mg once daily is not tolerated. • Severe hepatic impairment (Child-Pugh class C) – 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed a dose of 2.5 mg once daily. Abbreviations: RCC, Renal Cell Carcinoma; TSC, Tuberous Sclerosis Complex. 2.11 Dosage Modifications for P-gp and CYP3A4 Inhibitors • Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Drug Interactions ( 7.1 )] . • Avoid ingesting grapefruit and grapefruit juice. • Reduce the dose for patients taking Everolimus with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4 [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . Table 4: Recommended Dosage Modifications for Concurrent Use of Everolimus with a P-gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for Everolimus RCC and TSC-Associated Renal Angiomyolipoma • Reduce dose to 2.5 mg once daily. • May increase dose to 5 mg once daily if tolerated. • Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. 2.12 Dosage Modifications for P-gp and CYP3A4 Inducers • Avoid concomitant use of St. John’s Wort (Hypericum perforatum). • Increase the dose for patients taking Everolimus with a P-gp and strong CYP3A4 inducer as recommended in Table 5 [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . Table 5: Recommended Dosage Modifications for Concurrent Use of Everolimus with P-gp and Strong CYP3A4 Inducers Indication Dose Modification for Everolimus RCC and TSC-Associated Renal Angiomyolipoma • Avoid coadministration where alternatives exist. • If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required. • Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days. 2.13 Administration and Preparation • Administer Everolimus at the same time each day. • Administer Everolimus consistently either with or without food [see Clinical Pharmacology ( 12.3 )] . • If a dose of Everolimus is missed, it can be administered up to 6 hours after the time it is normally administered. After more than 6 hours, the dose should be skipped for that day. The next day, Everolimus should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed. • Everolimus should be swallowed whole with a glass of water. Do not break or crush tablets.

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 )

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 ( 6.2 )]. • 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 ) • TSC-Associated Renal Angiomyolipoma: Most common adverse reaction (incidence ≥ 30%) is stomatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 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. The data described below reflect exposure to Everolimus (n=274) and placebo (n=137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (27 to 85 years), 88% were white, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving Everolimus. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3 to 4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3 to 4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Everolimus arm. The rate of adverse reactions resulting in permanent discontinuation was 14% for the Everolimus group. The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during Everolimus treatment were for infections, anemia, and stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus vs. placebo are presented in Table 12. Laboratory abnormalities are presented in Table 13. Table 12: Adverse Reactions Reported in ≥ 10% of Patients with RCC and at a Higher Rate in the Everolimus Arm than in the Placebo Arm in RECORD-1 Everolimus N = 274 Placebo N = 137 All Grades Grades 3-4 All Grades Grades 3-4 % % % % Gastrointestinal Stomatitis Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. 44 4 8 0 Diarrhea 30 2 No Grade 4 adverse reactions were reported. 7 0 Nausea 26 2 19 0 Vomiting 20 2 12 0 Infections Includes all reported infections including, but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections. 37 10 18 2 General Asthenia 33 4 23 4 Fatigue 31 6 27 4 Edema peripheral 25 <1 8 <1 Pyrexia 20 <1 9 0 Mucosal inflammation 19 2 1 0 Respiratory, Thoracic and Mediastinal Cough 30 <1 16 0 Dyspnea 24 8 15 3 Epistaxis 18 0 0 0 Pneumonitis Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. 14 4 4 0 0 Skin and Subcutaneous Tissue Rash 29 1 7 0 Pruritus 14 < 1 7 0 Dry skin 13 < 1 5 0 Metabolism and Nutrition Anorexia 25 2 14 <1 Nervous System Headache 19 1 9 <1 Dysgeusia 10 0 2 0 Musculoskeletal and Connective Tissue Pain in extremity 10 1 7 0 Grading according to NCI CTCAE Version 3.0. Other notable adverse reactions occurring more frequently with Everolimus than with placebo, but with an incidence of <10% include: Gastrointestinal : Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General : Weight loss (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, Thoracic and Mediastinal : Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and Subcutaneous Tissue : Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema (<1%) Metabolism and Nutrition : Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric : Insomnia (9%) Nervous System : Dizziness (7%), paresthesia (5%) Ocular: Eyelid edema (4%), conjunctivitis (2%) Vascular : Hypertension (4%), deep vein thrombosis (<1%) Renal and Urinary : Renal failure (3%) Cardiac : Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and Connective Tissue : Jaw pain (3%) Hematologic : Hemorrhage (3%) Table 13: Selected Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the Everolimus Arm Than the Placebo Arm in RECORD-1 Laboratory Parameter Everolimus N = 274 Placebo N = 137 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. Anemia 92 13 79 6 Lymphopenia 51 18 28 5 No Grade 4 laboratory abnormalities were reported. Thrombocytopenia 23 1 2 < 1 Neutropenia 14 < 1 4 0 Chemistry Hypercholesterolemia 77 4 35 0 Hypertriglyceridemia 73 < 1 34 0 Hyperglycemia 57 16 25 2 Increased creatinine increased 50 2 34 0 Hypophosphatemia 37 6 8 0 Increased AST 25 1 7 0 Increased ALT 21 1 4 0 Hyperbilirubinemia 3 1 2 0 Grading according to NCI CTCAE Version 3.0. Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of Everolimus in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The median age of patients was 31 years (18 to 61 years), 89% were white, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving Everolimus. The most common adverse reaction reported for Everolimus (incidence ≥ 30%) was stomatitis. The most common Grade 3 to 4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3 to 4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia. The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the Everolimus-treated patients. Adverse reactions leading to permanent discontinuation in the Everolimus arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of Everolimus-treated patients. The most common adverse reaction leading to Everolimus dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus and occurring more frequently with Everolimus than with placebo are presented in Table 14. Laboratory abnormalities are presented in Table 15. Table 14: Adverse Reactions Reported in ≥ 10% of Everolimus-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus N = 79 Placebo N = 39 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitis 78 6 No Grade 4 adverse reactions were reported 23 0 Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. Vomiting 15 0 5 0 Diarrhea 14 0 5 0 General Peripheral edema 13 0 8 0 Infections Upper respiratory tract infection 11 0 5 0 Musculoskeletal and Connective Tissue Arthralgia 13 0 5 0 Respiratory, Thoracic and Mediastinal Cough 20 0 13 0 Skin and Subcutaneous Tissue Acne 22 0 5 0 Grading according to NCI CTCAE Version 3.0 Amenorrhea occurred in 15% of Everolimus-treated females (8 of 52). Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%). The following additional adverse reactions occurred in less than 10% of Everolimus-treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), ovarian cyst (3%), pneumonitis (1%), and angioedema (1%). Table 15: Selected Laboratory Abnormalities Reported in Everolimus-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus N = 79 Placebo N = 39 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology Anemia 61 0 49 0 Leukopenia 37 0 21 0 Neutropenia 25 1 26 0 Lymphopenia 20 1 No Grade 4 laboratory abnormalities were reported. 8 0 Thrombocytopenia 19 0 3 0 Chemistry Hypercholesterolemia 85 1 46 0 Hypertriglyceridemia 52 0 10 0 Hypophosphatemia 49 5 15 0 Increased alkaline phosphatase 32 1 10 0 Increased AST 23 1 8 0 Increased ALT 20 1 15 0 Hyperglycemia (fasting) 14 0 8 0 Grading according to NCI CTCAE Version 3.0 Updated safety information from 112 patients treated with Everolimus for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), urinary tract infection (31%), proteinuria (18%), abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Everolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: • Blood and lymphatic disorders: Thrombotic microangiopathy • Cardiac: Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event • Gastrointestinal: Acute pancreatitis • Hepatobiliary: Cholecystitis and cholelithiasis • Infections: Sepsis and septic shock • Nervous System: Reflex sympathetic dystrophy • Vascular: Arterial thrombotic events, lymphedema • Injury, poisoning and procedural complications: Radiation Sensitization and Radiation Recall

• 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 )] .