EVEROLIMUS

5 WARNINGS AND PRECAUTIONS Non-Infectious Pneumonitis : Monitor for clinical symptoms or radiological changes. Withhold or permanently discontinue based on severity. ( 2.9 , 5.1 ) Infections: Monitor for signs and symptoms of infection. Withhold or permanently discontinue based on severity. ( 2.9 , 5.2 ) Severe Hypersensitivity Reactions : Permanently discontinue for clinically significant hypersensitivity. ( 5.3 ) Angioedema : Patients taking concomitant angiotensin-converting-enzyme (ACE) inhibitors may be at increased risk for angioedema. Permanently discontinue for angioedema. ( 5.4 , 7.2 ) Stomatitis : Initiate dexamethasone alcohol-free mouthwash when starting treatment. ( 5.5 ) Renal Failure : Monitor renal function prior to treatment and periodically thereafter. ( 5.6 ) Risk of Impaired Wound Healing : Withhold for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment after resolution of wound healing complications has not been established. ( 5.7 ) Metabolic Disorders : Monitor serum glucose and lipids prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. ( 2.9 , 5.9 ) Myelosuppression : Monitor hematologic parameters prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. ( 2.9 , 5.10 ) Risk of Infection or Reduced Immune Response with Vaccination : Avoid live vaccines and close contact with those who have received live vaccines. Complete recommended childhood vaccinations prior to starting treatment. ( 5.11 ) Radiation Sensitization and Radiation Recall : Severe radiation reactions may occur. ( 5.12 , 6.2 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.13 , 8.1 , 8.3 ) 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to 19% of patients treated with everolimus tablets for oral suspension in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Grade 3 and 4 non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions (6.1) ] . Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms. Consider opportunistic infections, such as pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms. Continue everolimus tablets for oral suspension without dose alteration in patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis. For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue everolimus tablets for oral suspension based on severity [see Dosage and Administration (2.9) ] . Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose. 5.2 Infections Everolimus tablets for oral suspension have immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1) ] . Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP) and viral infections (e.g., reactivation of hepatitis B virus) have occurred. Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal. The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively. The incidence of serious infections was reported at a higher frequency in patients < 6 years of age [see Use in Specific Populations (8.4) ] . Complete treatment of pre-existing invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue everolimus tablets for oral suspension based on severity of infection [see Dosage and Administration (2.9) ] . Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. 5.3 Severe Hypersensitivity Reactions Hypersensitivity reactions to everolimus tablets for oral suspension have been observed and include anaphylaxis, dyspnea, flushing, chest pain and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Contraindications (4) ] . The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue everolimus tablets for oral suspension for the development of clinically significant hypersensitivity. 5.4 Angioedema With Concomitant 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 (e.g., swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking AFINITOR with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue everolimus tablets for oral suspension for angioedema. 5.5 Stomatitis Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with everolimus tablets for oral suspension at an incidence ranging from 44% to 78% across clinical trials. Grades 3 to 4 stomatitis was reported in 4% to 9% of patients. Stomatitis most often occurs within the first 8 weeks of treatment. When starting everolimus tablets for oral suspension, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis. If stomatitis does occur, mouthwashes and/or other topical treatments are recommended. Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme-containing products, as they may exacerbate the condition. Do not administer antifungal agents, unless fungal infection has been diagnosed. 5.6 Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking everolimus tablets for oral suspension [see Adverse Reactions (6.1) ] . The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of Grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting everolimus tablets for oral suspension and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure. 5.7 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, everolimus tablets for oral suspension have the potential to adversely affect wound healing. Withhold everolimus tablets for oral suspension for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment upon resolution of wound healing complications has not been established. 5.9 Metabolic Disorders Hyperglycemia, hypercholesterolemia and hypertriglyceridemia have been reported in patients taking everolimus tablets for oral suspension at an incidence up to 75%, 86% and 73%, respectively. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively [see Adverse Reactions (6.1) ] . In non-diabetic patients, monitor fasting serum glucose prior to starting everolimus tablets for oral suspension and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting everolimus tablets for oral suspension and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting everolimus tablets for oral suspension. For Grade 3 to 4 metabolic events, withhold or permanently discontinue everolimus tablets for oral suspension based on severity [see Dosage and Administration (2.9) ] . 5.10 Myelosuppression Anemia, lymphopenia, neutropenia and thrombocytopenia have been reported in patients taking everolimus tablets for oral suspension. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively [see Adverse Reactions (6.1) ] . Monitor complete blood count (CBC) prior to starting everolimus tablets for oral suspension every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue everolimus tablets for oral suspension based on severity [see Dosage and Administration (2.9) ] . 5.11 Risk of Infection or Reduced Immune Response With Vaccination The safety of immunization with live vaccines during everolimus tablets for oral suspension therapy has not been studied. Due to the potential increased risk of infection, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with everolimus tablets for oral suspension. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. 5.12 Radiation Sensitization and Radiation Recall Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) have been reported in patients treated with radiation prior to, during, or subsequent to everolimus tablets for oral suspension treatment [see Adverse Reactions (6.2) ] . Monitor patients closely when everolimus tablets for oral suspension are administered during or sequentially with radiation treatment. 5.13 Embryo-Fetal Toxicity Based on animal studies and the mechanism of action, everolimus tablets for oral suspension can cause fetal harm when administered to a pregnant woman. 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 clinical dose of 10 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with everolimus tablets for oral suspension and for 8 weeks after the last dose. 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 [see Use in Specific Populations (8.1 , 8.3) ] .

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 Amneal Pharmaceuticals LLC at 1-877-835-5472 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 to 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 to 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 17. Laboratory abnormalities are presented in Table 18. Table 17: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1 AFINITOR N = 78 Placebo N = 39 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Gastrointestinal Stomatitis a 62 9 f 26 3 f Vomiting 22 1 f 13 0 Diarrhea 17 0 5 0 Constipation 10 0 3 0 Infections Respiratory tract infection b 31 3 23 0 Gastroenteritis c 10 5 3 0 Pharyngitis streptococcal 10 0 3 0 General Pyrexia 23 6 f 18 3 f Fatigue 14 0 3 0 Psychiatric Anxiety, aggression or other behavioral disturbance d 21 5 f 3 0 Skin and subcutaneous tissue Rash e 21 0 8 0 Acne 10 0 5 0 Grading according to NCI CTCAE Version 3.0. a Includes mouth ulceration, stomatitis, and lip ulceration. b Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral. c Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection. d Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder. e Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria. f No Grade 4 adverse reactions were reported. 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 18: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1 AFINITOR N = 78 Placebo N = 39 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Hematology Elevated partial thromboplastin time 72 3 a 44 5 a Neutropenia 46 9 a 41 3 a 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 a 3 0 Grading according to NCI CTCAE Version 3.0. a No Grade 4 laboratory abnormalities were reported. 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 19. Laboratory abnormalities are presented in Table 20. Table 19: Adverse Reactions Reported in ≥ 10% of Everolimus Tablets for Oral Suspension-Treated Patients With 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 All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 % Gastrointestinal Stomatitis a 55 3 b 64 4 b 9 0 Diarrhea 17 0 22 0 5 0 Vomiting 12 0 10 2 b 9 0 Infections Nasopharyngitis 14 0 16 0 16 0 Upper respiratory tract infection 13 0 15 0 13 0.8 b General Pyrexia 20 0 14 0.8 b 5 0 Respiratory, thoracic and mediastinal Cough 11 0 10 0 3 0 Skin and subcutaneous tissue Rash 6 0 10 0 3 0 Grading according to NCI CTCAE Version 4.03. a Includes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain. b No Grade 4 adverse reactions were reported. 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 20: Selected Laboratory Abnormalities Reported in ≥ 10% Everolimus Tablets for Oral Suspension -Treated Patients With TSC-Associated Partial-Onset Seizures 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 a 37 6 23 7 a Anemia 27 0.9 a 30 0 21 0.8 a Thrombocytopenia 12 0 15 0 6 0 Chemistry Hypercholesterolemia 86 0 85 0.8 a 58 0 Hypertriglyceridemia 43 2 a 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 a 16 2 3 0 Grading according to NCI CTCAE version 4.03. a No Grade 4 laboratory abnormalities were reported. 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 Post-marketing Experience The following adverse reactions have been identified during post-approval 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

<table width="100%" cellspacing="0" cellpadding="0" border="1"><col width="17px"/><col width="17px"/><col width="17px"/><col/><col/><tbody><tr><td rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">AFINITOR</content></paragraph><paragraph><content styleCode="bold">N = 78</content></paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N = 39</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Grade 3 to 4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Grade 3 to 4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Stomatitis^a</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>62</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9^f</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>26</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3^f</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vomiting</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>22</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1^f</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diarrhea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Constipation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Infections</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Respiratory tract infection^b</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>31</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>23</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Gastroenteritis^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pharyngitis streptococcal</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">General</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pyrexia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>23</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6^f</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3^f</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anxiety, aggression or other behavioral disturbance^d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>21</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5^f</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Skin and subcutaneous tissue</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rash^e</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>21</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Acne</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Grading according to NCI CTCAE Version 3.0.</paragraph><paragraph>^aIncludes mouth ulceration, stomatitis, and lip ulceration.</paragraph><paragraph>^bIncludes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral.</paragraph><paragraph>^cIncludes gastroenteritis, gastroenteritis viral, and gastrointestinal infection.</paragraph><paragraph>^dIncludes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder.</paragraph><paragraph>^eIncludes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria.</paragraph><paragraph>^fNo Grade 4 adverse reactions were reported.</paragraph></td></tr></tbody></table>

<table width="100%" cellspacing="0" cellpadding="0" border="1"><col width="17px"/><col width="17px"/><col width="17px"/><col/><col/><tbody><tr><td rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">AFINITOR</content></paragraph><paragraph><content styleCode="bold">N = 78</content></paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N = 39</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Grade 3 to 4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Grade 3 to 4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Hematology</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Elevated partial thromboplastin time</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>72</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3^a</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5^a</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Neutropenia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>46</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9^a</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3^a</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anemia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>21</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Chemistry</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hypercholesterolemia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>81</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>39</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Elevated AST</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hypertriglyceridemia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>27</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Elevated ALT</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hypophosphatemia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1^a</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Grading according to NCI CTCAE Version 3.0.</paragraph><paragraph>^aNo Grade 4 laboratory abnormalities were reported.</paragraph></td></tr></tbody></table>

<table width="100%" cellspacing="0" cellpadding="0" border="1"><col width="17px"/><col width="1pt1pt1ptmedium"/><col width="1pt1pt1ptmedium"/><col/><col/><col/><col/><tbody><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="4"><paragraph><content styleCode="bold">Everolimus Tablets for Oral Suspension</content></paragraph></td><td colspan="2"><paragraph><content styleCode="bold">Placebo</content></paragraph></td></tr><tr><td colspan="2"><paragraph><content styleCode="bold">Target of 3-7 ng/mL</content></paragraph><paragraph><content styleCode="bold">N = 117</content></paragraph></td><td colspan="2"><paragraph><content styleCode="bold">Target of 9-15 ng/mL</content></paragraph><paragraph><content styleCode="bold">N = 130</content></paragraph></td><td colspan="2"><paragraph><content styleCode="bold">N = 119</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td><paragraph><content styleCode="bold">Grade 3-4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td><paragraph><content styleCode="bold">Grade 3-4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td><paragraph><content styleCode="bold">Grade 3-4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="7"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td></tr><tr><td><paragraph>Stomatitis^a</paragraph></td><td><paragraph>55</paragraph></td><td><paragraph>3^b</paragraph></td><td><paragraph>64</paragraph></td><td><paragraph>4^b</paragraph></td><td><paragraph>9</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td><paragraph>17</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>22</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>5</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>12</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>10</paragraph></td><td><paragraph>2^b</paragraph></td><td><paragraph>9</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td colspan="7"><paragraph><content styleCode="bold">Infections</content></paragraph></td></tr><tr><td><paragraph>Nasopharyngitis</paragraph></td><td><paragraph>14</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>16</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>16</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Upper respiratory tract infection</paragraph></td><td><paragraph>13</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>15</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>13</paragraph></td><td><paragraph>0.8^b</paragraph></td></tr><tr><td colspan="7"><paragraph><content styleCode="bold">General</content></paragraph></td></tr><tr><td><paragraph>Pyrexia</paragraph></td><td><paragraph>20</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>14</paragraph></td><td><paragraph>0.8^b</paragraph></td><td><paragraph>5</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td colspan="7"><paragraph><content styleCode="bold">Respiratory, thoracic and mediastinal</content></paragraph></td></tr><tr><td><paragraph>Cough</paragraph></td><td><paragraph>11</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>10</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>3</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td colspan="7"><paragraph><content styleCode="bold">Skin and subcutaneous tissue</content></paragraph></td></tr><tr><td><paragraph>Rash</paragraph></td><td><paragraph>6</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>10</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>3</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td colspan="7"><paragraph>Grading according to NCI CTCAE Version 4.03.</paragraph><paragraph>^aIncludes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain.</paragraph><paragraph>^bNo Grade 4 adverse reactions were reported.</paragraph></td></tr></tbody></table>