Everolimus Drug Information

2. DOSAGE AND ADMINISTRATION Do not combine everolimus tablets and everolimus tablets for oral suspension to achieve the total daily dose. Modify the dose for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4.

Breast Cancer: 10 mg orally once daily. NET: 10 mg orally once daily. RCC: 10 mg orally once daily.

TSC-Associated Renal Angiomyolipoma: 10 mg orally once daily. TSC-Associated SEGA: 4.5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. Select the recommended dosage form based on the indication.

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 everolimus tablets/everolimus tablets for oral suspension for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus Tablets/Everolimus Tablets for Oral Suspension for Metabolic events (e.g., hyperglycemia, dyslipidemia) s for Hepatic Impairment The recommended dosages of everolimus tablets/everolimus tablets for oral suspension for patients with hepatic impairment are described in Table 3: Table 3: Recommended Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m 2 orally once daily. Adjust dose based on everolimus trough concentrations as recommended. 2.11 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 everolimus tablets/everolimus tablets for oral suspension with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4. Table 4: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets/Everolimus Tablets for Oral Suspension With a P-gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for Everolimus Tablets/Everolimus Tablets for Oral Suspension Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Reduce dose to 2.5 mg once daily.

TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures Reduce the daily dose by 50%. Assess trough concentrations when initiating and discontinuing the inhibitor. 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/everolimus tablets for oral suspension with a P-gp and strong CYP3A4 inducer as recommended in Table 5. Table 5: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets/Everolimus Tablets for Oral Suspension With P-gp and Strong CYP3A4 Inducers Indication Dose Modification for Everolimus Tablets/Everolimus Tablets for Oral Suspension Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Avoid coadministration where alternatives exist. Multiple increments may be required.

TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures 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. 2.13 Administration and Preparation Administer everolimus tablets/everolimus tablets for oral suspension at the same time each day.

Administer everolimus tablets/everolimus tablets for oral suspension consistently either with or without food. If a dose of everolimus tablets/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/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 Everolimus Tablets should be swallowed whole with a glass of water.

Do not break or crush tablets. 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.

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.

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. If higher doses are required, prepare an additional glass.

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.

6. ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Non-Infectious Pneumonitis Infections Severe Hypersensitivity Reactions Angioedema with Concomitant Use of ACE inhibitors Stomatitis Renal Failure Impaired Wound Healing Metabolic Disorders Myelosuppression Radiation Sensitization and Radiation Recall Breast cancer, NET, RCC: Most common adverse reactions (incidence ≥ 30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, and decreased appetite. TSC-Associated Renal Angiomyolipoma: Most common adverse reaction (incidence ≥ 30%) is stomatitis.

TSC-Associated SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. TSC-Associated Partial-Onset Seizures: Most common adverse reaction (incidence ≥ 30%) is stomatitis. To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 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.

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 Grade 3-4 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 3-4 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 vs. 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 tablets/everolimus tablets for oral suspension and dexamethasone alcohol-free oral solution has not been studied in pediatric patients. Patients on the placebo arm could cross over to open-label everolimus tablets upon disease progression.

The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST. Deaths during double-blind treatment where an adverse reaction was the primary cause occurred in seven patients on everolimus tablets. Causes of death on the everolimus tablets arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis.

After cross-over to open-label everolimus tablets, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rate of adverse reactions resulting in permanent discontinuation was 20% for the everolimus tablets group. Dose delay or reduction was necessary in 61% of everolimus tablets patients.

Grade 3-4 renal failure occurred in six patients in the everolimus tablets arm. Thrombotic events included five patients with pulmonary embolus in the everolimus tablets arm as well as three patients with thrombosis in the everolimus tablets arm. Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets vs. placebo.

Laboratory abnormalities are summarized in Table 9. The median duration of treatment in patients who received everolimus tablets was 37 weeks. Everolimus tablets was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of everolimus tablets-treated patients.

Serious adverse reactions occurred in 42% of everolimus tablets-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). Laboratory abnormalities are presented in Table 11. Table 10: Adverse Reactions in ≥ 10% of Everolimus Tablets-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4: Selected Laboratory Abnormalities in ≥ 10% of Everolimus Tablets-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4 0 8 0 Renal Cell Carcinoma (RCC) The data described below reflect exposure to everolimus tablets (n = 274) and placebo (n = 137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib.

The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving everolimus tablets. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia.

Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the everolimus tablets arm. The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction.

The most common medical interventions required during everolimus tablets treatment were for infections, anemia, and stomatitis. Laboratory abnormalities are presented in Table 13. 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 3-4 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 ( %).

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 3-4 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. 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 = % were male. Patients received between one and three concomitant antiepileptic drugs. 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. 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 19: Selected Laboratory Abnormalities Reported in ≥ 10% Everolimus Tablets For Oral Suspension -Treated Patients With TSC-Associated Partial-Onset Seizures 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/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

7. DRUG INTERACTIONS P-gp and strong CYP3A4 inhibitors: Avoid concomitant use. P-gp and moderate CYP3A4 inhibitors: Reduce the dose as recommended.

P-gp and strong CYP3A4 inducers: Increase the dose as recommended. 7.1 Effect of Other Drugs on Everolimus Tablets/Everolimus Tablets for Oral Suspension Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors. Inducers Increase the dose for patients taking everolimus tablets/everolimus tablets for oral suspension with a P-gp and strong CYP3A4 inducer as recommended. 7.2 Effects of Combination Use of Angiotensin Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitors with everolimus tablets/everolimus tablets for oral suspension may be at increased risk for angioedema.

Pregnancy Risk Summary Based on animal studies and the mechanism of action, everolimus tablets/everolimus tablets for oral suspension can cause fetal harm when administered to a pregnant woman. There are limited case reports of everolimus tablets 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), 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.

Pediatric Use TSC-Associated SEGA The safety and effectiveness of everolimus tablets/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/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. The safety and effectiveness of everolimus tablets/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. 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. 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.

The safety and effectiveness of everolimus tablets for oral suspension and everolimus tablets 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. Two fatal cases due to infections were reported in pediatric patients.

Other Indications The safety and effectiveness of everolimus tablets/everolimus tablets for oral suspension in pediatric patients have not been established in: Hormone receptor-positive, HER2-negative breast cancer Neuroendocrine tumors (NET) Renal cell carcinoma (RCC) TSC-associated renal angiomyolipoma

4. CONTRAINDICATIONS Everolimus tablets/everolimus tablets for oral suspension are contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.