Torpenz Drug Information

Post marketing Experience

The following adverse reactions have been identified during post approval use of everolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: Blood and Lymphatic Disorders: Thrombotic microangiopathy Cardiac: Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event Gastrointestinal: Acute pancreatitis Hepatobiliary: Cholecystitis and cholelithiasis Infections: Sepsis and septic shock Nervous System: Reflex sympathetic dystrophy Vascular: Arterial thrombotic events, lymphedema Injury, Poisoning and Procedural Complications: Radiation sensitization and radiation recall

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Hormone Receptor-Positive, HER2-Negative Breast Cancer The safety of everolimus tablets (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (28 to 93 years), and 75% were white.

The median follow-up was approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3 to 4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea.

The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3 to 4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypokalemia, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred in 2% of patients who received everolimus tablets.

The rate of adverse reactions resulting in permanent discontinuation was 24% for the everolimus tablets arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the everolimus tablets arm. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets versus placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with everolimus tablets was 23.9 weeks; 33% were exposed to everolimus tablets for a period of ≥ 32 weeks.

Table 6: Adverse Reactions Reported in ≥ 10% of Patients With Hormone Receptor-Positive Breast Cancer in BOLERO-2 Everolimus Tablets with Exemestane N = 482 Placebo with Exemestane N = 238 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Grading according to NCI CTCAE Version 3.0. Gastrointestinal Stomatitis Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration. 67 8 No Grade 4 adverse reactions were reported. 11

Diarrhea 33 2 18 0.8 Nausea 29 0.4 28 1 Vomiting 17

1 12

Constipation 14 0.4 13 0.4 Dry mouth 11 0 7 0 General

Fatigue 36 4 27 1 Edema peripheral 19 1 6

Pyrexia 15 0.2 7 0.4 Asthenia 13 2 4 0 Infections Infections

Includes all reported infections including but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections. 50 6 25 2 Investigations Weight loss 25 1 6 0 Metabolism and Nutrition Decreased appetite 30 1 12

Hyperglycemia 14 5 2 0.4 Musculoskeletal and connective tissue Arthralgia 20 0.8

17 0 Back pain 14 0.2 10

Pain in extremity 9 0.4 11 2 Nervous system Dysgeusia 22 0.2

6 0 Headache 21 0.4 14 0 Psychiatric Insomnia 13 0.2 8 0 Respiratory, thoracic and mediastinal Cough 24 0.6 12 0 Dyspnea 21 4 11 1 Epistaxis 17 0 1 0 Pneumonitis Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis. 19 4 0.4 0 Skin and subcutaneous tissue Rash 39 1 8 0 Pruritus 13 0.2 5 0 Alopecia 10 0 5 0 Vascular Hot Flush 6 0 14 0 Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2 Laboratory Parameter Everolimus Tablets with Exemestane N = 482 Placebo with Exemestane N = 238 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Grading according to NCI CTCAE Version 3.0. Hematology Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. Anemia 68 6 40 1 Leukopenia 58 2 No Grade 4 laboratory abnormalities were reported. 28 6 Thrombocytopenia 54 3 5

Lymphopenia 54 12 37 6 Neutropenia 31 2 11 2 Chemistry Hypercholesterolemia

70 1 38 2 Hyperglycemia 69 9 44 1 Increased aspartate transaminase (AST) 69 4 45 3 Increased alanine transaminase (ALT) 51 4 29 5 Hypertriglyceridemia 50 0.8 26 0 Hypoalbuminemia 33 0.8 16

Hypokalemia 29 4 7 1 Increased creatinine 24 2 13 0 Topical

Prophylaxis for Stomatitis In a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning everolimus tablets (10 mg orally once daily) in combination with exemestane (25 mg orally once daily), patients started dexamethasone 0.5 mg/5mL alcohol-free mouthwash (10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks) concurrently with everolimus tablets and exemestane. No food or drink was to be consumed for at least 1 hour after swishing and spitting the dexamethasone mouthwash. The primary objective of this study was to assess the incidence of Grade 2 to 4 stomatitis within 8 weeks.

The incidence of Grade 2 to 4 stomatitis within 8 weeks was 2%, which was lower than the 33% reported in the BOLERO-2 trial. The incidence of Grade 1 stomatitis was 19%. No cases of Grade 3 or 4 stomatitis were reported. Oral candidiasis was reported in 2% of patients in this study compared to 0.2% in the BOLERO-2 trial.

Coadministration of everolimus and dexamethasone alcohol-free oral solution has not been studied in pediatric patients. Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of everolimus tablets in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The median age of patients was 31 years (18 to 61 years), 89% were white, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving everolimus tablets.

The most common adverse reaction reported for everolimus tablets (incidence ≥ 30%) was stomatitis. The most common Grade 3 to 4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia.

The most common Grade 3 to 4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia. The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the everolimus tablets-treated patients. Adverse reactions leading to permanent discontinuation in the Everolimus tablets arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia.

Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of everolimus tablets-treated patients. The most common adverse reaction leading to everolimus tablets dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets and occurring more frequently with everolimus tablets than with placebo are presented in Table 14. Laboratory abnormalities are presented in Table 15. Table 14: Adverse Reactions Reported in ≥ 10% of Everolimus Tablets-Treated Patients with TSC Associated Renal Angiomyolipoma in EXIST-2 Everolimus Tablets N = 79 Placebo N = 39 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Grading according to NCI CTCAE Version 3.0. Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.

No Grade 4 adverse reactions were reported. Gastrointestinal Stomatitis a 78 6 b 23 0 Vomiting 15 0 5 0 Diarrhea 14 0 5 0 General Peripheral Edema 13 0 8 0 Infections Upper Respiratory tract infection 11 0 5 0 Musculoskeletal and connective tissue Arthralgia 13 0 5 0 Respiratory, thoracic and mediastinal Cough 20 0 13 0 Skin and subcutaneous tissue Acne 22 0 5 0 Amenorrhea occurred in 15% of everolimus tablets -treated females (8 of 52). Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%). The following additional adverse reactions occurred in less than 10% of everolimus tablets -treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), ovarian cyst (3%), pneumonitis (1%), and angioedema (1%). Table 15: Selected Laboratory Abnormalities Reported in Everolimus Tablets-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus Tablets N = 79 Placebo N = 39 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Grading according to NCI CTCAE Version 3.0. Hematology Anemia 61 0 49 0 Leukopenia 37 0 21 0 Neutropenia 25 1 26 0 Lymphopenia 20 1 No Grade 4 laboratory abnormalities were reported. 8 0 Thrombocytopenia 19 0 3 0 Chemistry Hypercholesterolemia 85 1 46 0 Hypertriglyceridemia 52 0 10 0 Hypophosphatemia 49 5 15 0 Increased alkaline phosphatase 32 1 10 0 Increased AST 23 1 8 0 Increased ALT 20 1 15 0 Hyperglycemia (fasting) 14 0 8 0 Updated safety information from 112 patients treated with everolimus tablets for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), urinary tract infection (31%), proteinuria (18%), abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%). 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 everolimus tablets 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 everolimus tablets.

The most common adverse reactions reported for everolimus tablets (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 everolimus tablets-treated patients.

The most common adverse reaction leading to everolimus tablets dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets and occurring more frequently with everolimus tablets than with placebo are reported in Table 16. Laboratory abnormalities are presented in Table 17. Table 16: Adverse Reactions Reported in ≥ 10% of Everolimus Tablets-Treated Patients with TSC Associated SEGA in EXIST-1 Everolimus Tablets N = 78 Placebo N = 39 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Grading according to NCI CTCAE Version 3.0. 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 everolimus tablets-treated females aged 10 to 55 years (3 of 18). For this same group of everolimus tablets-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 everolimus tablets-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 Everolimus Tablets-Treated Patients With TSC-Associated SEGA in EXIST-1 Everolimus Tablets N = 78 Placebo N = 39 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Grading according to NCI CTCAE Version 3.0. 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 everolimus tablets 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%).

Effect of Other Drugs on

TORPENZ Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors . Reduce the dose for patients taking TORPENZ with a P-gp and moderate CYP3A4 inhibitor as recommended . Inducers Increase the dose for patients taking TORPENZ with a P-gp and strong CYP3A4 inducer as recommended .

Effects of Combination Use of Angiotensin-Converting Enzyme (ACE) Inhibitors Patients taking concomitant

ACE inhibitors with TORPENZ may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with TORPENZ .

Pregnancy Risk Summary Based on animal studies and the mechanism of action , everolimus can cause fetal harm when administered to a pregnant woman. There are limited case reports of everolimus use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of everolimus tablets 10 mg orally once daily (see Data ). Advise pregnant women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Data Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities.

Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m 2 ) with resulting exposures of approximately 4% of the human exposure at the recommended dose of everolimus tablets 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m 2 ), approximately 1.6 times the recommended dose of everolimus tablets 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA). The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m 2 ), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Pediatric Use TSC-Associated SEGA The safety and effectiveness of everolimus 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 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 . The safety and effectiveness of everolimus 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 everolimus tablets-treated patients < 6 years had at least one infection compared to 67% of 55 everolimus tablets-treated patients ≥ 6 years.

Thirty-five percent of 23 everolimus tablets-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 everolimus tablets-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, everolimus tablets did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with everolimus tablets for a median duration of 4.1 years. Other Indications The safety and effectiveness of everolimus in pediatric patients have not been established in: Hormone receptor-positive, HER2-negative breast cancer TSC-associated renal angiomyolipoma

tablets are contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives . Clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.