Torpenz Drug Information

Hormone Receptor-Positive, HER2-Negative Breast Cancer

TORPENZ tablets are indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. 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.

Recommended Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer The recommended dosage of TORPENZ tablets is 10 mg orally once daily until disease progression or unacceptable toxicity.

Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The recommended dosage of TORPENZ tablets is 10 mg orally once daily until disease progression or unacceptable toxicity.

Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of TORPENZ tablets is 4.5 mg/m 2 orally once daily until disease progression or unacceptable toxicity.

Therapeutic Drug Monitoring (TDM) and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) 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 The maximum dose increment at any titration must not exceed 5 mg.

Multiple dose titrations may be required to attain the target trough concentration. = current dose × (target concentration divided by current concentration) When possible, use the same assay and laboratory for TDM throughout treatment. Table 1: Recommended Timing of Therapeutic Drug Monitoring s Table 2 summarizes recommendations for dosage modifications of TORPENZ tablets for the management of adverse reactions. Table 2: Recommended Dosage Modifications for TORPENZ for Metabolic events (e.g., hyperglycemia, dyslipidemia)

Dosage Modifications for Hepatic Impairment

The recommended dosages of TORPENZ tablets for patients with hepatic impairment are described in Table 3: Table 3: Recommended Dosage Modifications for Patients with Hepatic Impairment Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m 2 orally once daily. Adjust dose based on everolimus trough concentrations as recommended.

Dosage Modifications for P-gp and CYP3A4 Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors. Avoid ingesting grapefruit and grapefruit juice. Reduce the dose for patients taking TORPENZ tablets with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4.

Table 4: Recommended Dosage Modifications for Concurrent Use of TORPENZ with a P-gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for TORPENZ Breast Cancer and TSC-Associated Renal Angiomyolipoma Reduce dose to 2.5 mg once daily. TSC-Associated SEGA Reduce the daily dose by 50%. Assess trough concentrations when initiating and discontinuing the inhibitor.

Dosage Modifications for P-gp and CYP3A4 Inducers

Avoid concomitant use of St. John's Wort (Hypericum perforatum). Increase the dose for patients taking TORPENZ tablets with a P-gp and strong CYP3A4 inducer as recommended in Table 5.

Table 5: Recommended Dosage Modifications for Concurrent Use of TORPENZ with P-gp and Strong CYP3A4 Inducers Indication Dose Modification for TORPENZ Breast Cancer and TSC-Associated Renal Angiomyolipoma Avoid coadministration where alternatives exist. Multiple increments may be required. TSC-Associated SEGA Double the daily dose using increments of 5 mg or less.

Assess trough concentrations when initiating and discontinuing the inducer. Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days.

Administration and Preparation Administer

TORPENZ tablets at the same time each day. Administer TORPENZ tablets consistently either with or without food. If a dose of TORPENZ tablets 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, TORPENZ tablets should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed.

TORPENZ tablets should be swallowed whole with a glass of water. Do not break or crush tablets.

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 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. 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 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. 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 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 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 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. Laboratory abnormalities are presented in Table 15. Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%).

Table 15: Selected Laboratory Abnormalities Reported in Everolimus Tablets-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2 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 ( %). 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 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.

There were no adverse reactions resulting in permanent discontinuation. 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.

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 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. 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

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