1 INDICATIONS AND USAGE Everolimus tablets for oral suspension are 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 is 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 is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

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 Biocon Pharma Inc., at 1-866-924-6266 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.

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.

AFINITOR N = 78 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade 3-4 % 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 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.

a No Grade 4 laboratory abnormalities were reported.

AFINITOR N = 78 Placebo N = 39 All Grades % Grade 3-4 % All Grades % Grade 3-4 % 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 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 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 3b 64 4b 9 0 Diarrhea 17 0 22 0 5 0 Vomiting 12 0 10 2b 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 19: 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 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