Everolimus

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) ] TSC-Associated SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. ( 6.1 ) TSC-Associated Partial-Onset Seizures: Most common adverse reaction (incidence ≥ 30%) is stomatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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. TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA) The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-1) of AFINITOR in 117 patients with SEGA and TSC. The median age of patients was 9.5 years (0.8 to 26 years), 93% were white, and 57% were male. The median duration of blinded study treatment was 52 weeks (24 to 89 weeks) for patients receiving AFINITOR. The most common adverse reactions reported for AFINITOR (incidence ≥ 30%) were stomatitis and respiratory tract infection. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was neutropenia. There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are reported in Table 16. Laboratory abnormalities are presented in Table 17. Table 16: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1 Grading according to NCI CTCAE Version 3.0. AFINITOR N = 78 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Gastrointestinal Stomatitis Includes mouth ulceration, stomatitis, and lip ulceration. 62 9 No Grade 4 adverse reactions were reported. 26 3 Vomiting 22 1 13 0 Diarrhea 17 0 5 0 Constipation 10 0 3 0 Infections Respiratory tract infection Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral. 31 3 23 0 Gastroenteritis Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection. 10 5 3 0 Pharyngitis streptococcal 10 0 3 0 General Pyrexia 23 6 18 3 Fatigue 14 0 3 0 Psychiatric Anxiety, aggression or other behavioral disturbance Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder. 21 5 3 0 Skin and subcutaneous tissue Rash Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria. 21 0 8 0 Acne 10 0 5 0 Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18). For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%). The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%), and pneumonitis (1%). Table 17: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1 Grading according to NCI CTCAE Version 3.0. AFINITOR N = 78 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Hematology Elevated partial thromboplastin time 72 3 No Grade 4 laboratory abnormalities were reported. 44 5 Neutropenia 46 9 41 3 Anemia 41 0 21 0 Chemistry Hypercholesterolemia 81 0 39 0 Elevated AST 33 0 0 0 Hypertriglyceridemia 27 0 15 0 Elevated ALT 18 0 3 0 Hypophosphatemia 9 1 3 0 Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional notable adverse reactions and selected laboratory abnormalities: decreased appetite (14%), hyperglycemia (13%), hypertension (11%), urinary tract infection (9%), decreased fibrinogen (8%), cellulitis (6%), abdominal pain (5%), decreased weight (5%), elevated creatinine (5%), and azoospermia (1%). TSC-Associated Partial-Onset Seizures The data described below are based on the 18-week Core phase of a randomized, double-blind, multicenter, three-arm trial (EXIST-3) comparing two everolimus trough levels (3-7 ng/mL and 9-15 ng/mL) to placebo as adjunctive antiepileptic therapy in patients with TSC-associated partial-onset seizures. A total of 366 patients were randomized to everolimus tablets for oral suspension low trough (LT) (n = 117), everolimus tablets for oral suspension high trough (HT) (n = 130), or placebo (n = 119). The median age of patients was 10 years (2.2 to 56 years; 28% were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years), 65% were white, and 52% were male. Patients received between one and three concomitant antiepileptic drugs. The most common adverse reaction reported for everolimus tablets for oral suspension in both arms (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pneumonia, and irregular menstruation. The most common laboratory abnormality (incidence ≥ 50%) was hypercholesterolemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 2%) was neutropenia. Adverse reactions leading to study drug discontinuation occurred in 5% and 3% of patients in the LT and HT arms, respectively. The most common adverse reaction (incidence ≥ 1%) leading to discontinuation was stomatitis. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 24% and 35% of patients in the LT and HT arms, respectively. The most common adverse reactions (incidence ≥ 3%) leading to dose adjustments in the everolimus tablets for oral suspension arms were stomatitis, pneumonia, and pyrexia. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets for oral suspension are presented in Table 18. Laboratory abnormalities are presented in Table 19. Table 18: Adverse Reactions Reported in ≥ 10% of Everolimus Tablets for Oral Suspension-Treated Patients With TSC-Associated Partial-Onset Seizures in EXIST-3 Grading according to NCI CTCAE version 4.03. Everolimus Tablets for Oral Suspension Placebo Target of 3-7 ng/mL N = 117 Target of 9-15 ng/mL N = 130 N = 119 All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 % Gastrointestinal Stomatitis Includes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain. 55 3 No Grade 4 adverse reactions were reported. 64 4 9 0 Diarrhea 17 0 22 0 5 0 Vomiting 12 0 10 2 9 0 Infections Nasopharyngitis 14 0 16 0 16 0 Upper respiratory tract infection 13 0 15 0 13 0.8 General Pyrexia 20 0 14 0.8 5 0 Respiratory, thoracic and mediastinal Cough 11 0 10 0 3 0 Skin and subcutaneous tissue Rash 6 0 10 0 3 0 The following additional adverse reactions occurred in < 10% of everolimus tablets for oral suspension treated patients (% everolimus tablets for oral suspension LT, % everolimus tablets for oral suspension HT): decreased appetite (9%, 7%), pneumonia (2%, 4%), aggression (2%, 0.8%), proteinuria (0%, 2%), menorrhagia (0.9%, 0.8%), and pneumonitis (0%, 0.8%). Table 19: Selected Laboratory Abnormalities Reported in ≥ 10% Everolimus Tablets for Oral Suspension-Treated Patients With TSC-Associated Partial-Onset Seizures Grading according to NCI CTCAE version 4.03. Everolimus Tablets for Oral Suspension Placebo Target of 3-7 ng/mL N = 117 Target of 9-15 ng/mL N = 130 N = 119 All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 % Hematology Neutropenia 25 4 No Grade 4 laboratory abnormalities were reported. 37 6 23 7 Anemia 27 0.9 30 0 21 0.8 Thrombocytopenia 12 0 15 0 6 0 Chemistry Hypercholesterolemia 86 0 85 0.8 58 0 Hypertriglyceridemia 43 2 39 2 22 0 Increased ALT 17 0 22 0 6 0 Increased AST 13 0 19 0 4 0 Hyperglycemia 19 0 18 0 17 0 Increased alkaline phosphatase 24 0 16 0 29 0 Hypophosphatemia 9 0.9 16 2 3 0 Updated safety information from 357 patients treated with everolimus tablets for oral suspension for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of everolimus tablets for oral suspension. 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

4 CONTRAINDICATIONS Everolimus tablets for oral suspension are 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 )

11 DESCRIPTION Everolimus tablets for oral suspension are a kinase inhibitor. The chemical name of everolimus is (3 S ,6 R ,7 E ,9 R ,10 R ,12 R ,14 S ,15 E ,17 E ,19 E ,21 S ,23 S ,26 R ,27 R ,34a S )-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1 R )-2-[(1 S ,3 R ,4 R )-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3 H -pyrido[2,1- c ][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4 H ,6 H ,31 H )-pentone. The molecular formula is C 53 H 83 NO 14 and the molecular weight is 958.2 g/mol. The structural formula is: Everolimus tablets for oral suspension contain 2 mg, 3 mg, or 5 mg of everolimus and the following inactive ingredients: anhydrous lactose, butylated hydroxytoluene, croscarmellose sodium, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose and silicon dioxide. Everolimus Structural Formula

2 DOSAGE AND ADMINISTRATION Do not combine AFINITOR ® and everolimus tablets for oral suspension 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 ) TSC-Associated SEGA: • 4.5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. ( 2.6 , 2.8 ) TSC-Associated Partial-Onset Seizures: • 5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. ( 2.7 , 2.8 ) 2.1 Important Dosage Information • Do not combine AFINITOR and everolimus tablets for oral suspension 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) ]. 2.6 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of everolimus tablets for oral suspension is 4.5 mg/m 2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8) ] . 2.7 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures The recommended starting dosage of everolimus tablets for oral suspension is 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) and TSC-Associated Partial-Onset Seizures • 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 Event When to Assess Trough Concentrations After Event Initiation of everolimus tablets for oral suspension 1 to 2 weeks Modification of everolimus tablets for oral suspension dose 1 to 2 weeks Switch between AFINITOR and everolimus tablets for oral suspension 1 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 to 6 months Stable dose with stable BSA Every 6 to 12 months Abbreviation: P-gp, P-glycoprotein. 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of everolimus tablets for oral suspension for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus Tablets for Oral Suspension 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 tablets for oral suspension 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 Tablets for Oral Suspension TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures • Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m 2 orally once daily. • Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8) ]. Abbreviations: SEGA, Subependymal Giant Cell Astrocytoma; 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 tablets for oral suspension 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 Tablets for Oral Suspension With a P-gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for Everolimus Tablets for Oral Suspension TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures • Reduce the daily dose by 50%. • Change to every other day dosing if the reduced dose is lower than the lowest available strength. • Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. • Assess trough concentrations when initiating and discontinuing the inhibitor [see Dosage and Administration (2.8) ]. 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 tablets for oral suspension 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 Tablets for Oral Suspension With P-gp and Strong CYP3A4 Inducers Indication Dose Modification for Everolimus Tablets for Oral Suspension TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures • Double the daily dose using increments of 5 mg or less. Multiple increments may be required. • Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification. • Assess trough concentrations when initiating and discontinuing the inducer [see Dosage and Administration (2.8) ]. • Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days. 2.13 Administration and Preparation • Administer everolimus tablets for oral suspension at the same time each day. • Administer everolimus tablets for oral suspension consistently either with or without food [see Clinical Pharmacology (12.3) ] . • If a dose of everolimus tablets for oral suspension 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 tablets for oral suspension should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed. Everolimus Tablets for Oral Suspension: • Wear gloves to avoid possible contact with everolimus when preparing suspensions of everolimus tablets for oral suspension for another person. • Administer as a suspension only. • Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after preparation. • Prepare suspension in water only. Using an Oral Syringe to Prepare Oral Suspension: • Place the prescribed dose 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 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 to Prepare Oral Suspension: • Place the prescribed dose into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total of 10 mg 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.

1 INDICATIONS AND USAGE Everolimus tablets for oral suspension 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 ) Everolimus tablets for oral suspension are a kinase inhibitor indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. ( 1.6 ) 1.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) Everolimus tablets for oral suspension 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. 1.6 Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures Everolimus tablets for oral suspension are indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

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 Tablets for Oral Suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with everolimus tablets for oral suspension [see Warnings and Precautions (5.4) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC). Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies. Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 ( TSC1 , TSC2 ). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body as well as seizures and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death. 12.2 Pharmacodynamics Exposure-Response Relationship In patients with TSC-associated subependymal giant cell astrocytoma (SEGA), the magnitude of the reduction in SEGA volume was correlated with the everolimus trough concentration. In patients with TSC-associated partial-onset seizures, the magnitude of the reduction in absolute seizure frequency was correlated with the everolimus trough concentration. Cardiac Electrophysiology In a randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered a single oral dose of AFINITOR (20 mg and 50 mg) and placebo. AFINITOR at single doses up to 50 mg did not prolong the QT/QTc interval. 12.3 Pharmacokinetics Absorption In patients with TSC-associated SEGA, everolimus C min was approximately dose-proportional within the dose range from 1.35 mg/m 2 to 14.4 mg/m 2 . Effect of Food In healthy subjects who received 9 mg of everolimus tablets for oral suspension, high-fat meals (containing approximately 1000 calories and 55 grams of fat) reduced everolimus AUC by 12% and C max by 60% and low-fat meals (containing approximately 500 calories and 20 grams of fat) reduced everolimus AUC by 30% and C max by 50%. Relative Bioavailability The AUC inf of everolimus was equivalent between everolimus tablets for oral suspension and AFINITOR; the C max of everolimus in the everolimus tablets for oral suspension dosage form was 20% to 36% lower than that of AFINITOR. The predicted trough concentrations at steady-state were similar after daily administration. Distribution The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in patients given AFINITOR 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. Elimination The mean elimination half-life of everolimus is approximately 30 hours. Metabolism Everolimus is a substrate of CYP3A4. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself. Excretion No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. Specific Populations No relationship was apparent between oral clearance and age or sex in patients. Patients with Renal Impairment No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus. Patients with Hepatic Impairment Compared to normal subjects, there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively. In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function [see Dosage and Administration (2.10) , Use in Specific Populations (8.6) ] . Pediatric Patients In patients with TSC-associated SEGA or TSC-associated partial-onset seizures, the mean C min values normalized to mg/m 2 dose in pediatric patients (< 18 years of age) were lower than those observed in adults, suggesting that everolimus clearance adjusted to BSA was higher in pediatric patients as compared to adults. Race or Ethnicity Based on a cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose. Oral clearance (CL/F) is on average 20% higher in black patients than in white patients. Drug Interaction Studies Effect of CYP3A4 and P-glycoprotein (P-gp) Inhibitors on Everolimus Everolimus exposure increased when AFINITOR was coadministered with: • ketoconazole (a P-gp and strong CYP3A4 inhibitor) - C max and AUC increased by 3.9- and 15-fold, respectively. • erythromycin (a P-gp and moderate CYP3A4 inhibitor) - C max and AUC increased by 2- and 4.4-fold, respectively. • verapamil (a P-gp and moderate CYP3A4 inhibitor) - C max and AUC increased by 2.3- and 3.5-fold, respectively. Effect of CYP3A4 and P-gp Inducers on Everolimus The coadministration of AFINITOR with rifampin, a P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and C max by 58% compared to AFINITOR alone [see Dosage and Administration (2.12) ] . Effect of Everolimus on CYP3A4 Substrates No clinically significant pharmacokinetic interactions were observed between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate). The coadministration of an oral dose of midazolam (sensitive CYP3A4 substrate) with AFINITOR resulted in a 25% increase in midazolam C max and a 30% increase in midazolam AUC 0-inf . Effect of Everolimus on Antiepileptic Drugs (AEDs) Everolimus increased pre-dose concentrations of the carbamazepine, clobazam, oxcarbazepine, and clobazam’s metabolite N-desmethylclobazam by about 10%. Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin.

12.1 Mechanism of Action Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC). Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies. Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 ( TSC1 , TSC2 ). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body as well as seizures and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death.

12.2 Pharmacodynamics Exposure-Response Relationship In patients with TSC-associated subependymal giant cell astrocytoma (SEGA), the magnitude of the reduction in SEGA volume was correlated with the everolimus trough concentration. In patients with TSC-associated partial-onset seizures, the magnitude of the reduction in absolute seizure frequency was correlated with the everolimus trough concentration. Cardiac Electrophysiology In a randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered a single oral dose of AFINITOR (20 mg and 50 mg) and placebo. AFINITOR at single doses up to 50 mg did not prolong the QT/QTc interval.

12.3 Pharmacokinetics Absorption In patients with TSC-associated SEGA, everolimus C min was approximately dose-proportional within the dose range from 1.35 mg/m 2 to 14.4 mg/m 2 . Effect of Food In healthy subjects who received 9 mg of everolimus tablets for oral suspension, high-fat meals (containing approximately 1000 calories and 55 grams of fat) reduced everolimus AUC by 12% and C max by 60% and low-fat meals (containing approximately 500 calories and 20 grams of fat) reduced everolimus AUC by 30% and C max by 50%. Relative Bioavailability The AUC inf of everolimus was equivalent between everolimus tablets for oral suspension and AFINITOR; the C max of everolimus in the everolimus tablets for oral suspension dosage form was 20% to 36% lower than that of AFINITOR. The predicted trough concentrations at steady-state were similar after daily administration. Distribution The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in patients given AFINITOR 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. Elimination The mean elimination half-life of everolimus is approximately 30 hours. Metabolism Everolimus is a substrate of CYP3A4. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself. Excretion No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. Specific Populations No relationship was apparent between oral clearance and age or sex in patients. Patients with Renal Impairment No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus. Patients with Hepatic Impairment Compared to normal subjects, there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively. In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function [see Dosage and Administration (2.10) , Use in Specific Populations (8.6) ] . Pediatric Patients In patients with TSC-associated SEGA or TSC-associated partial-onset seizures, the mean C min values normalized to mg/m 2 dose in pediatric patients (< 18 years of age) were lower than those observed in adults, suggesting that everolimus clearance adjusted to BSA was higher in pediatric patients as compared to adults. Race or Ethnicity Based on a cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose. Oral clearance (CL/F) is on average 20% higher in black patients than in white patients. Drug Interaction Studies Effect of CYP3A4 and P-glycoprotein (P-gp) Inhibitors on Everolimus Everolimus exposure increased when AFINITOR was coadministered with: • ketoconazole (a P-gp and strong CYP3A4 inhibitor) - C max and AUC increased by 3.9- and 15-fold, respectively. • erythromycin (a P-gp and moderate CYP3A4 inhibitor) - C max and AUC increased by 2- and 4.4-fold, respectively. • verapamil (a P-gp and moderate CYP3A4 inhibitor) - C max and AUC increased by 2.3- and 3.5-fold, respectively. Effect of CYP3A4 and P-gp Inducers on Everolimus The coadministration of AFINITOR with rifampin, a P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and C max by 58% compared to AFINITOR alone [see Dosage and Administration (2.12) ] . Effect of Everolimus on CYP3A4 Substrates No clinically significant pharmacokinetic interactions were observed between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate). The coadministration of an oral dose of midazolam (sensitive CYP3A4 substrate) with AFINITOR resulted in a 25% increase in midazolam C max and a 30% increase in midazolam AUC 0-inf . Effect of Everolimus on Antiepileptic Drugs (AEDs) Everolimus increased pre-dose concentrations of the carbamazepine, clobazam, oxcarbazepine, and clobazam’s metabolite N-desmethylclobazam by about 10%. Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin.

20230515

3

3 DOSAGE FORMS AND STRENGTHS Everolimus Tablets for Oral Suspension are available containing 2 mg, 3 mg, or 5 mg of everolimus. • The 2 mg tablets are white to slightly yellow, round, unscored tablets debossed with M on one side of the tablet and EVD over 2 on the other side. • The 3 mg tablets are white to slightly yellow, round, unscored tablets debossed with M on one side of the tablet and EVD over 3 on the other side. • The 5 mg tablets are white to slightly yellow, round, unscored tablets debossed with M on one side of the tablet and EVD over 5 on the other side. Everolimus tablets for oral suspension: 2 mg, 3 mg, and 5 mg tablets ( 3 )

Everolimus Everolimus EVEROLIMUS EVEROLIMUS ANHYDROUS LACTOSE BUTYLATED HYDROXYTOLUENE CROSCARMELLOSE SODIUM CROSPOVIDONE HYPROMELLOSE 2910 (3 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE 102 SILICON DIOXIDE white to slightly yellow M;EVD;2 Everolimus Everolimus EVEROLIMUS EVEROLIMUS ANHYDROUS LACTOSE BUTYLATED HYDROXYTOLUENE CROSCARMELLOSE SODIUM CROSPOVIDONE HYPROMELLOSE 2910 (3 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE 102 SILICON DIOXIDE white to slightly yellow M;EVD;3 Everolimus Everolimus EVEROLIMUS EVEROLIMUS ANHYDROUS LACTOSE BUTYLATED HYDROXYTOLUENE CROSCARMELLOSE SODIUM CROSPOVIDONE HYPROMELLOSE 2910 (3 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE 102 SILICON DIOXIDE white to slightly yellow M;EVD;5

13.2 Animal Toxicology and/or Pharmacology In juvenile rat toxicity studies, dose-related delayed attainment of developmental landmarks, including delayed eye-opening, delayed reproductive development in males and females and increased latency time during the learning and memory phases were observed at doses as low as 0.15 mg/kg/day.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding, respectively to 3.9 and 0.2 times the estimated human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily. Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1500 mg/m 2 /day, approximately 255-fold the recommended dose of AFINITOR 10 mg orally once daily, and approximately 200-fold the median dose administered to patients with TSC-associated SEGA and TSC-associated partial-onset seizures, based on the BSA), administered as 2 doses, 24 hours apart. Based on non-clinical findings, everolimus tablets for oral suspension may impair male fertility. In a 13-week male fertility study in rats, testicular morphology was affected at doses of 0.5 mg/kg and above. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. The exposures at these doses (52 ng•hr/mL and 414 ng•hr/mL, respectively) were within the range of human exposure at the recommended dose of AFINITOR 10 mg orally once daily (560 ng•hr/mL) and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at AUC 0-24h values 10% to 81% lower than human exposure at the recommended dose of AFINITOR 10 mg orally once daily. After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60%. Oral doses of everolimus in female rats at doses ≥ 0.1 mg/kg (approximately 4% the human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding, respectively to 3.9 and 0.2 times the estimated human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily. Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1500 mg/m 2 /day, approximately 255-fold the recommended dose of AFINITOR 10 mg orally once daily, and approximately 200-fold the median dose administered to patients with TSC-associated SEGA and TSC-associated partial-onset seizures, based on the BSA), administered as 2 doses, 24 hours apart. Based on non-clinical findings, everolimus tablets for oral suspension may impair male fertility. In a 13-week male fertility study in rats, testicular morphology was affected at doses of 0.5 mg/kg and above. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. The exposures at these doses (52 ng•hr/mL and 414 ng•hr/mL, respectively) were within the range of human exposure at the recommended dose of AFINITOR 10 mg orally once daily (560 ng•hr/mL) and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at AUC 0-24h values 10% to 81% lower than human exposure at the recommended dose of AFINITOR 10 mg orally once daily. After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60%. Oral doses of everolimus in female rats at doses ≥ 0.1 mg/kg (approximately 4% the human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility. 13.2 Animal Toxicology and/or Pharmacology In juvenile rat toxicity studies, dose-related delayed attainment of developmental landmarks, including delayed eye-opening, delayed reproductive development in males and females and increased latency time during the learning and memory phases were observed at doses as low as 0.15 mg/kg/day.

ANDA210130

Everolimus

Everolimus

0378-0006

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL – 2 mg NDC 0378-0005-85 Everolimus Tablets for Oral Suspension 2 mg TABLETS MUST BE DISPERSED IN WATER. TABLETS MUST NOT BE SWALLOWED WHOLE, CHEWED, OR CRUSHED. Each tablet contains everolimus, 2 mg Rx only 28 Tablets for Oral Suspension (carton contains 4 individual blister cards of 7 tablets) For oral use. Usual Dosage: See accompanying prescribing information. See enclosed everolimus tablets for oral suspension Instructions for Use. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Store in the original container; protect from light and moisture. Keep this and all medication out of the reach of children. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in India Code No. MP/DRUGS/25/1/2014 MXI:0005:28C:R1 Mylan.com Everolimus Tablets for Oral Suspension 2 mg Carton Label

Warnings and Precautions, Radiation Sensitization and Radiation Recall ( 5.12 ) 4/2021

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Non-infectious Pneumonitis: Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions (5.1) ] . Infections: Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infections to their healthcare provider [see Warnings and Precautions (5.2) ] . Hypersensitivity Reactions: Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction, including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications (4) , Warnings and Precautions (5.3) ] . Angioedema with Concomitant Use of ACE Inhibitors: Advise patients to avoid ACE inhibitors and to promptly contact their healthcare provider or seek emergency care for signs or symptoms of angioedema [see Warnings and Precautions (5.4) ] . Stomatitis: Advise patients of the risk of stomatitis and to use alcohol-free mouthwashes during treatment [see Warnings and Precautions (5.5) ] . Renal Impairment: Advise patients of the risk of developing kidney failure and the need to monitor their kidney function periodically during treatment [see Warnings and Precautions (5.6) ] . Risk of Impaired Wound Healing: Advise patients that everolimus tablets for oral suspension may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.7) ] . Metabolic Disorders: Advise patients of the risk of metabolic disorders and the need to monitor glucose and lipids periodically during therapy [see Warnings and Precautions (5.9) ] . Myelosuppression: Advise patients of the risk of myelosuppression and the need to monitor CBCs periodically during therapy [see Warnings and Precautions (5.10) ] . Risk of Infection or Reduced Immune Response With Vaccination: Advise patients to avoid the use of live vaccines and close contact with those who have received live vaccines [see Warnings and Precautions (5.11) ] . Embryo-Fetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 8 weeks after the last dose. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 weeks after the last dose [see Warnings and Precautions (5.13 ), Use in Specific Populations (8.1 , 8.3) ] . Radiation Sensitization and Radiation Recall: Radiation sensitization and recall can occur in patients treated with radiation prior to, during, or subsequent to everolimus tablets for oral suspension treatment. Advise patients to inform their healthcare provider if they have had or are planning to receive radiation therapy [see Warnings and Precautions (5.12) ] . Lactation: Advise women not to breastfeed during treatment with everolimus tablets for oral suspension and for 2 weeks after the last dose [see Use in Specific Populations (8.2) ]. Infertility: Advise males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3) ] . The brands listed are trademarks of their respective owners.

14 CLINICAL STUDIES 14.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) EXIST-1 A randomized (2:1), double-blind, placebo-controlled trial (EXIST-1, NCT00789828) of AFINITOR was conducted in 117 pediatric and adult patients with SEGA and TSC. Eligible patients had at least one SEGA lesion ≥ 1 cm in longest diameter on MRI based on local radiology assessment and one or more of the following: serial radiological evidence of SEGA growth, a new SEGA lesion ≥ 1 cm in longest diameter, or new or worsening hydrocephalus. Patients randomized to the treatment arm received AFINITOR at a starting dose of 4.5 mg/m 2 daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 to 15 ng/mL as tolerated. AFINITOR or matched placebo continued until disease progression or unacceptable toxicity. MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks, and annually thereafter. The main efficacy outcome measure was SEGA response rate based on independent central radiology review. SEGA response was defined as a ≥ 50% reduction in the sum of SEGA volume relative to baseline, in the absence of unequivocal worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm, and new or worsening hydrocephalus. The primary analysis of SEGA response rate was limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The analysis of SEGA response rate was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no). Of the 117 patients enrolled, 78 were randomized to AFINITOR and 39 to placebo. The median age was 9.5 years (0.8 to 26 years); a total of 20 patients were < 3 years, 54 patients were 3 to < 12 years, 27 patients were 12 to < 18 years, and 16 patients were ≥ 18 years; 57% were male, and 93% were white. At baseline, 18% of patients were receiving EIAEDs. Based on central radiology review at baseline, 98% of patients had at least one SEGA lesion ≥ 1.0 cm in longest diameter, 79% had bilateral SEGAs, 43% had ≥ 2 target SEGA lesions, 26% had growth in or into the inferior surface of the ventricle, 9% had evidence of growth beyond the subependymal tissue adjacent to the ventricle, and 7% had radiographic evidence of hydrocephalus. The median values for the sum of all target SEGA lesions at baseline were 1.63 cm 3 (0.18 to 25.15 cm 3 ) and 1.30 cm 3 (0.32 to 9.75 cm 3 ) in the AFINITOR and placebo arms, respectively. Eight (7%) patients had prior SEGA-related surgery. The median duration of follow-up was 8.4 months (4.6 to 17.2 months) at the time of primary analysis. The SEGA response rate was statistically significantly higher in AFINITOR-treated patients (Table 25). At the time of the primary analysis, all SEGA responses were ongoing and the median duration of response was 5.3 months (2.1 to 8.4 months). With a median follow-up of 8.4 months, SEGA progression was detected in 15.4% of the 39 patients randomized to receive placebo and none of the 78 patients randomized to receive AFINITOR. No patient in either treatment arm required surgical intervention. Table 25: Subependymal Giant Cell Astrocytoma Response Rate in TSC-Associated SEGA in EXIST-1 AFINITOR N = 78 Placebo N = 39 p-value Primary analysis SEGA response rate Per independent central radiology review. - (%) 35 0 < 0.0001 95% CI 24, 46 0, 9 Patients randomized to placebo were permitted to receive AFINITOR at the time of SEGA progression or after the primary analysis, whichever occurred first. After the primary analysis, patients treated with AFINITOR underwent additional follow-up MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 111 patients (78 patients randomized to AFINITOR and 33 patients randomized to placebo) received at least one dose of AFINITOR. Median duration of AFINITOR treatment and follow-up was 3.9 years (0.2 to 4.9 years). By four years after the last patient was enrolled, 58% of the 111 patients treated with AFINITOR had a ≥ 50% reduction in SEGA volume relative to baseline, including 27 patients identified at the time of the primary analysis and 37 patients with a SEGA response after the primary analysis. The median time to SEGA response was 5.3 months (2.5 to 33.1 months). Twelve percent of the 111 patients treated with AFINITOR had documented disease progression by the end of the follow-up period and no patient required surgical intervention for SEGA during the study. Study 2485 Study 2485 (NCT00411619) was an open-label, single-arm trial conducted to evaluate the antitumor activity of AFINITOR 3 mg/m 2 /orally once daily in patients with SEGA and TSC. Serial radiological evidence of SEGA growth was required for entry. Tumor assessments were performed every 6 months for 60 months after the last patient was enrolled or disease progression, whichever occurred earlier. The major efficacy outcome measure was the reduction in volume of the largest SEGA lesion with 6 months of treatment, as assessed via independent central radiology review. Progression was defined as an increase in volume of the largest SEGA lesion over baseline that was ≥ 25% over the nadir observed on study. A total of 28 patients received AFINITOR for a median duration of 5.7 years (5 months to 6.9 years); 82% of the 28 patients remained on AFINITOR for at least 5 years. The median age was 11 years (3 to 34 years), 61% male, 86% white. At the primary analysis, 32% of the 28 patients (95% CI: 16%, 52%) had an objective response at 6 months, defined as at least a 50% decrease in volume of the largest SEGA lesion. At the completion of the study, the median duration of durable response was 12 months (3 months to 6.3 years). By 60 months after the last patient was enrolled, 11% of the 28 patients had documented disease progression. No patient developed a new SEGA lesion while on AFINITOR. Nine additional patients were identified as having a ≥ 50% volumetric reduction in their largest SEGA lesion between 1 to 4 years after initiating AFINITOR, including 3 patients who had surgical resection with subsequent regrowth prior to receiving AFINITOR. 14.6 Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures The efficacy of everolimus tablets for oral suspension as an adjunctive anti-epileptic drug (AED) was evaluated in a randomized, double-blind, multicenter, placebo-controlled study conducted in patients with TSC-associated partial-onset seizures (EXIST-3, NCT01713946). Patients with a history of inadequate control of partial-onset seizures despite treatment with ≥ 2 sequential AED regimens were randomized to receive placebo or everolimus tablets for oral suspension once daily at a dose to achieve a low trough (LT) level (3-7 ng/mL) or a high trough (HT) level (9-15 ng/mL). Randomization was stratified by age group (1 to < 6, 6 to < 12, 12 to < 18, ≥ 18 years). The study consisted of 3 phases: an 8-week Baseline observation phase; an 18-week double-blind, placebo-controlled Core phase (6-week titration period and a 12-week maintenance period), and an Extension phase of ≥ 48 weeks. Patients were required to have a diagnosis of TSC per the modified Gomez criteria, and ≥ 16 partial-onset seizures during the Baseline phase while receiving a stable dose of 1 to 3 concomitant AEDs. The starting doses for everolimus tablets for oral suspension in the Core phase ranged from 3 to 6 mg/m 2 orally once daily, depending on age, in patients not receiving concomitant CYP3A4/P-gp inducers and from 5 to 9 mg/m 2 orally once daily, depending on age, in patients receiving concomitant CYP3A4/P-gp inducers. During the 6-week titration period, everolimus trough levels were assessed every 2 weeks and up to 3 dose adjustments were allowed to attempt to reach the targeted everolimus trough concentration range. The major efficacy outcome measure was the percentage reduction in seizure frequency from the Baseline phase, during the maintenance period of the Core phase. Additional efficacy outcome measures included response rate, defined as at least a 50% reduction in seizure frequency from the Baseline phase during the maintenance period of the Core phase, and seizure freedom rate during the maintenance period of the Core phase. A total of 366 patients were randomized to everolimus tablets for oral suspension LT (n = 117), everolimus tablets for oral suspension HT (n = 130) or placebo (n = 119). Median age was 10.1 years (2.2 to 56 years); 28% of patients were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years). The majority were white (65%) and male (52%). The most common major features of TSC were cortical tubers (92%), hypomelanotic macules (84%), and subependymal nodules (83%). While 17% of the patients had SEGA, 42% had renal angiomyolipoma, and 9% had both SEGA and renal angiomyolipoma; no patients were receiving treatment with AFINITOR or everolimus tablets for oral suspension for these manifestations of TSC. During the Baseline phase, 65% of patients had complex partial seizures, 52% had secondarily generalized seizures, 19% had simple partial seizures, and 2% had generalized onset seizures. The median seizure frequency per week during the Baseline phase was 9.4 for all patients and 47% of patients were receiving 3 AEDs during the Baseline phase. The efficacy results are summarized in Table 26. Table 26: Percentage Reduction in Seizure Frequency and Response Rate in TSC-Associated Partial-Onset Seizures in EXIST-3 Everolimus Tablets for Oral Suspension Placebo Target of 3-7 ng/mL N = 117 Target of 9-15 ng/mL N = 130 N = 119 Seizures per week Median at Baseline (Min, Max) 8.6 (1.4, 192.9) 9.5 (0.3, 218.4) 10.5 (1.3, 231.7) Median at Core phase If patient discontinued before starting the Maintenance period, then the Titration period is used. (Min, Max) 6.8 (0.0, 193.5) 4.9 (0.0, 133.7) 8.5 (0.0, 217.7) Percentage reduction from Baseline to Core phase (Maintenance ) Median 29.3 39.6 14.9 95% CI 95% CI of the median based on bootstrap percentiles. 18.8, 41.9 35.0, 48.7 0.1, 21.7 p-value p-values were for superiority vs. placebo, and obtained from rank ANCOVA with Baseline seizure frequency as covariate, stratified by age subgroup. 0.003 < 0.001 Response rate Responders, n (%) 28.2 40 15.1 95% CI Exact 95% CI obtained using Clopper-Pearson method. 20.3, 37.3 31.5, 49.0 9.2, 22.8

15 REFERENCES 1. OSHA Hazardous Drugs. OSHA . http://www.osha.gov/SLTC/hazardousdrugs/index.html.

8.4 Pediatric Use TSC-Associated SEGA The safety and effectiveness of everolimus tablets for oral suspension have been established in pediatric patients age 1 year and older with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected. Use of everolimus tablets for oral suspension for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-1); an open-label, single-arm trial in adult and pediatric patients (Study 2485); and additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.5) ] . The safety and effectiveness of everolimus tablets for oral suspension have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA. In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age. Ninety-six percent of 23 AFINITOR-treated patients < 6 years had at least one infection compared to 67% of 55 AFINITOR-treated patients ≥ 6 years. Thirty-five percent of 23 AFINITOR-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 AFINITOR-treated patients ≥ 6 years. Although a conclusive determination cannot be made due to the limited number of patients and lack of a comparator arm in the open label follow-up periods of EXIST-1 and Study 2485, AFINITOR did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with AFINITOR for a median duration of 4.1 years. TSC-Associated Partial-Onset Seizures The safety and effectiveness of everolimus tablets for oral suspension has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. Use of everolimus tablets for oral suspension for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-3) with additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.6) ]. The safety and effectiveness of everolimus tablets for oral suspension and AFINITOR have not been established for the adjunctive treatment of pediatric patients less than 2 years of age with TSC-associated partial-onset seizures. The incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age compared to patients ≥ 6 years old. Seventy-seven percent of 70 everolimus tablets for oral suspension-treated patients < 6 years had at least one infection, compared to 53% of 177 everolimus tablets for oral suspension-treated patients ≥ 6 years. Sixteen percent of 70 everolimus tablets for oral suspension-treated patients < 6 years of age had at least 1 serious infection, compared to 4% of 177 everolimus tablets for oral suspension-treated patients ≥ 6 years of age. Two fatal cases due to infections were reported in pediatric patients.

8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ] , everolimus tablets for oral suspension can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR 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 AFINITOR 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 AFINITOR 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 AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), and 1.3 times the median dose administered to patients with TSC-associated partial-onset seizures based on BSA. 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.

8 USE IN SPECIFIC POPULATIONS • For patients with TSC-associated SEGA or TSC-associated partial-onset seizures and severe hepatic impairment, reduce the starting dose and adjust dose to attain target trough concentrations. ( 2.8 , 2.10 , 8.6 ) 8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ] , everolimus tablets for oral suspension can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR 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 AFINITOR 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 AFINITOR 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 AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), and 1.3 times the median dose administered to patients with TSC-associated partial-onset seizures based on BSA. 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. 8.2 Lactation Risk Summary There are no data on the presence of everolimus or its metabolites in human milk, the effects of everolimus on the breastfed infant or on milk production. Everolimus and its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because of the potential for serious adverse reactions in breastfed infants from everolimus, advise women not to breastfeed during treatment with everolimus tablets for oral suspension and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to starting everolimus tablets for oral suspension [see Use in Specific Populations (8.1) ] . Contraception Everolimus tablets for oral suspension can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Females Advise female patients of reproductive potential to use effective contraception during treatment with everolimus tablets for oral suspension and for 8 weeks after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with everolimus tablets for oral suspension and for 4 weeks after the last dose. Infertility Females Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking everolimus tablets for oral suspension. Based on these findings, everolimus tablets for oral suspension may impair fertility in female patients [see Adverse Reactions (6.1) , Nonclinical Toxicology (13.1) ] . Males Cases of reversible azoospermia have been reported in male patients taking AFINITOR. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of AFINITOR 10 mg orally once daily. Based on these findings, everolimus tablets for oral suspension may impair fertility in male patients [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use TSC-Associated SEGA The safety and effectiveness of everolimus tablets for oral suspension have been established in pediatric patients age 1 year and older with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected. Use of everolimus tablets for oral suspension for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-1); an open-label, single-arm trial in adult and pediatric patients (Study 2485); and additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.5) ] . The safety and effectiveness of everolimus tablets for oral suspension have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA. In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age. Ninety-six percent of 23 AFINITOR-treated patients < 6 years had at least one infection compared to 67% of 55 AFINITOR-treated patients ≥ 6 years. Thirty-five percent of 23 AFINITOR-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 AFINITOR-treated patients ≥ 6 years. Although a conclusive determination cannot be made due to the limited number of patients and lack of a comparator arm in the open label follow-up periods of EXIST-1 and Study 2485, AFINITOR did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with AFINITOR for a median duration of 4.1 years. TSC-Associated Partial-Onset Seizures The safety and effectiveness of everolimus tablets for oral suspension has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. Use of everolimus tablets for oral suspension for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-3) with additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.6) ]. The safety and effectiveness of everolimus tablets for oral suspension and AFINITOR have not been established for the adjunctive treatment of pediatric patients less than 2 years of age with TSC-associated partial-onset seizures. The incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age compared to patients ≥ 6 years old. Seventy-seven percent of 70 everolimus tablets for oral suspension-treated patients < 6 years had at least one infection, compared to 53% of 177 everolimus tablets for oral suspension-treated patients ≥ 6 years. Sixteen percent of 70 everolimus tablets for oral suspension-treated patients < 6 years of age had at least 1 serious infection, compared to 4% of 177 everolimus tablets for oral suspension-treated patients ≥ 6 years of age. Two fatal cases due to infections were reported in pediatric patients. 8.6 Hepatic Impairment Everolimus exposure may increase in patients with hepatic impairment [see Clinical Pharmacology (12.3) ] . For patients with TSC-associated SEGA and TSC-associated partial-onset seizures who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of everolimus tablets for oral suspension as recommended and adjust the dose based on everolimus trough concentrations [see Dosage and Administration (2.8 , 2.10) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Everolimus Tablets for Oral Suspension are available containing 2 mg, 3 mg, or 5 mg of everolimus. The 2 mg tablets are white to slightly yellow, round, unscored tablets debossed with M on one side of the tablet and EVD over 2 on the other side. They are available as follows: NDC 0378-0005-85 cartons of 28 tablets The 3 mg tablets are white to slightly yellow, round, unscored tablets debossed with M on one side of the tablet and EVD over 3 on the other side. They are available as follows: NDC 0378-0006-85 cartons of 28 tablets The 5 mg tablets are white to slightly yellow, round, unscored tablets debossed with M on one side of the tablet and EVD over 5 on the other side. They are available as follows: NDC 0378-0007-85 cartons of 28 tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture. Follow special handling and disposal procedures for anti-cancer pharmaceuticals. 1