EVERBLISS

Everolimus Tablets and Everolimus Tablets for Oral Suspension are kinase inhibitors.

The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.0 4,9 ]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone.

The molecular formula is

C 53 H 83 NO and the molecular weight is 958.2 g/mol.

The structural formula is

Everolimus tablets for oral administration contain 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus and the following inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, and magnesium stearate.

Everolimus tablets for oral suspension for oral administration contains 2 mg, 3 mg, or 5 mg of everolimus and the following inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, anhydrous lactose, magnesium stearate, mannitol, and microcrystalline cellulose.

It's used in case of kidney transplants with cyclospore and crustacean steroids.

It's used in case of liver transplants with tacrolymes and crustacean steroids.

Do not eat grape-graft or drink grapefruit juice during treatment; avoid exposure to direct sunlight; avoid pregnancy during treatment.

PHARMACOLOGY 12.1 Mechanism of Action Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway.

The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC).

Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity.

Everolimus reduced the activity of

S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis.

S6K1 is a substrate of mTORC1 and phosphorylates the activation domain of the estrogen receptor which results in ligand-independent activation of the receptor.

In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF).

Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

Constitutive activation of the

PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer.

In vitro studies show that estrogen-dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combination treatment with everolimus and Akt, HER2, or aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner.

Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes and 2 ( TSC1, TSC2 ).

Loss or inactivation of either

TSC1 or TSC2 leads to activation of downstream signaling.

In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body as well as seizures and epileptogenesis.

Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function.

Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death. 12.2 Pharmacodynamics Exposure-Response Relationship In patients with TSC-associated subependymal giant cell astrocytoma (SEGA), the magnitude of the reduction in SEGA volume was correlated with the everolimus trough concentration.

In patients with

TSC-associated partial-onset seizures, the magnitude of the reduction in absolute seizure frequency was correlated with the everolimus trough concentration.

In a randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered a single oral dose of everolimus tablets (20 mg and 50 mg) and placebo.

Everolimus tablets at single doses up to 50 mg did not prolong the QT/QTc interval. 12.3 Pharmacokinetics Absorption After administration of everolimus tablets in patients with advanced solid tumors, peak everolimus concentrations are reached to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, C max is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in C max is less than dose-proportional; however, AUC shows dose-proportionality over the 5 mg to 70 mg dose range.

Steady-state was achieved within 2 weeks following once-daily dosing.

In patients with TSC-associated

SEGA, everolimus C min was approximately dose-proportional within the dose range from 1.35 mg/m to 14.4 mg/m 2.

In healthy subjects, a high-fat meal (containing approximately 1000 calories and 55 grams of fat) reduced systemic exposure to everolimus tablets 10 mg (as measured by AUC) by 22% and the peak blood concentration C max by 54%.

Light-fat meals (containing approximately 500 calories and 20 grams of fat) reduced AUC by 32% and C max by 42%.

In healthy subjects who received 9 mg of everolimus tablets for oral suspension, high-fat meals (containing approximately 1000 calories and 55 grams of fat) reduced everolimus AUC by 12% and C max by 60% and low-fat meals (containing approximately 500 calories and 20 grams of fat) reduced everolimus AUC by 30% and C max by 50%.

The AUC inf of everolimus was equivalent between everolimus tablets for oral suspension and everolimus tablets; the C max of everolimus in the everolimus tablets for oral suspension dosage form was 20% to 36% lower than that of everolimus tablets.

The predicted trough concentrations at steady-state were similar after daily administration.

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of to 5000 ng/mL, is 17% to 73%.

The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given everolimus tablets 10 mg orally once daily.

Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.

The mean elimination half-life of everolimus is approximately 30 hours.

Everolimus is a substrate of CYP3A4.

Following oral administration, everolimus is the main circulating component in human blood.

Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus.

These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.

No specific elimination studies have been undertaken in cancer patients.

Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine.

The parent substance was not detected in urine or feces.

No relationship was apparent between oral clearance and age or sex in patients with cancer.

No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus.

Compared to normal subjects, there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively.

In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function.

In patients with TSC-associated SEGA or TSC-associated partial-onset seizures, the mean C min values normalized to mg/m 2 dose in pediatric patients (< 18 years of age) were lower than those observed in adults, suggesting that everolimus clearance adjusted to BSA was higher in pediatric patients as compared to adults.

Based on a cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose.

Oral clearance (CL/F) is on average 20% higher in Black patients than in White patients.

Drug Interaction Studies Effect of

CYP3A4 and P-glycoprotein (P-gp) Inhibitors on Everolimus: Everolimus exposure increased when everolimus tablets were coadministered with: ketoconazole (a P-gp and strong CYP3A4 inhibitor).

• C max and AUC increased by 3.9.

• and 15.

• fold, respectively. erythromycin (a P-gp and moderate CYP3A4 inhibitor).

• C max and AUC increased by 2.

• and 4.4.

• fold, respectively. verapamil (a P-gp and moderate CYP3A4 inhibitor).

• C max and AUC increased by 2.3.

• and 3.5.

• fold, respectively.

Effect of

CYP3A4 and P-gp Inducers on Everolimus: The coadministration of everolimus tablets with rifampin, a P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and C max by 58% compared to everolimus tablets alone.

Effect of Everolimus on

CYP3A4 Substrates: No clinically significant pharmacokinetic interactions were observed between everolimus tablets and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate).

The coadministration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus tablets resulted in a 25% increase in midazolam C max and a 30% increase in midazolam AUC 0-inf.

The coadministration of everolimus tablets with exemestane increased exemestane C min by 45% and C 2h by 64%; however, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms.

No increase in adverse reactions related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.

The coadministration of everolimus tablets with long-acting octreotide increased octreotide C min by approximately 50%.

Drugs (AEDs): Everolimus increased pre-dose concentrations of the carbamazepine, clobazam, oxcarbazepine, and clobazam's metabolite N-desmethylclobazam by about 10%.

Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin.

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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.

Most common adverse reaction (incidence ≥ 30%) is stomatitis.

Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection.

To report SUSPECTED ADVERSE

REACTIONS, contact Breckenridge Pharmaceutical, Inc.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.

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 3-4 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.

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.

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 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0.

Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration. 67 8 No Grade 4 adverse reactions were reported. 11 0.8 Diarrhea 33 2 18 0.8 Nausea 29 0.4 28 1 Vomiting 17 1 12 0.8 Constipation 14 0.4 13 0.4 Dry mouth 11 0 7 0 General Fatigue 36 4 27 1 Edema peripheral 19 1 6 0.4 Pyrexia 15 0.2 7 0.4 Asthenia 13 2 4 0.

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 0.4 Hyperglycemia 14 5 2 0.4 Musculoskeletal and connective tissue Arthralgia 20 0.8 17 0 Back pain 14 0.2 10 0.8 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 6 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 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0.

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 0.4 Lymphopenia 54 12 37 6 Neutropenia 31 2 11 2 Chemistry Hypercholesterolemia 70 1 38 2 Hyperglycemia 69 9 44 1 Increased AST 69 4 45 3 Increased ALT 51 4 29 5 Hypertriglyceridemia 50 0.8 26 0 Hypoalbuminemia 33 0.8 16 0.8 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/5 mL 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 to 4 stomatitis within 8 weeks.

The incidence of

Grade to 4 stomatitis within 8 weeks was 2%, which was lower than the 33% reported in the BOLERO-2 trial.

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.

Tumors (PNET) In a randomized, controlled trial (RADIANT-3) of everolimus tablets (n = 204) vs. placebo (n = 203) in patients with advanced PNET the median age of patients was 58 years (20 to 87 years), 79% were White, and 55% were male.

Patients on the placebo arm could cross over to open-label everolimus tablets upon disease progression.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache.

Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea.

The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST.

Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, anemia, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased AST, hypokalemia, and thrombocytopenia.

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.

In female patients aged to 55 years, irregular menstruation occurred in of 46 (11%) everolimus tablets-treated females.

Table 8: Adverse Reactions Reported in ≥ 10% of Patients With PNET in RADIANT-3 Everolimus Tablets N = 204 Placebo N = 203 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0.

Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. 70 7 No Grade 4 adverse reactions were reported. 20 0 Diarrhea Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. 50 6 25 3 Abdominal pain 36 4 32 7 Nausea 32 2 33 2 Vomiting 29 1 21 2 Constipation 14 0 13 0.5 Dry mouth 11 0 4 0 General Fatigue/malaise 45 4 27 3 Edema (general and peripheral) 39 2 12 1 Fever 31 1 13 0.5 Asthenia 19 3 20 3.

Infections Nasopharyngitis/rhinitis/URI 25 0 13 0 Urinary tract infection 16 0 6 0.5.

Investigations Weight loss 28 0.5 11 0 Metabolism and nutrition Decreased appetite 30 1 18 1 Diabetes mellitus 10 2 0.5 0 Musculoskeletal and connective tissue Arthralgia 15 1 7 0.5 Back pain 15 1 11 1 Pain in extremity 14 0.5 6 1 Muscle spasms 10 0 4 0 Nervous system Headache/migraine 30 0.5 15 1 Dysgeusia 19 0 5 0 Dizziness 12 0.5 7 0 Psychiatric Insomnia 14 0 8 0 Respiratory, thoracic and mediastinal Cough/productive cough 25 0.5 13 0 Epistaxis 22 0 1 0 Dyspnea/dyspnea exertional 20 3 7 0.5 Pneumonitis Includes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease. 17 4 0 0 Oropharyngeal pain 11 0 6 0 Skin and subcutaneous Rash 59 0.5 19 0 Nail disorders 22 0.5 2 0 Pruritus/pruritus generalized 21 0 13 0 Dry skin/xeroderma 13 0 6 0 Vascular Hypertension 13 1 6 1 Table 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients With PNET in RADIANT-3 Laboratory parameter Everolimus Tablets N = 204 Placebo N = 203 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Grading according to NCI CTCAE Version 3.0.

Anemia 86 15 63 1 Lymphopenia 45 16 22 4 Thrombocytopenia 45 3 11 0 Leukopenia 43 2 13 0 Neutropenia 30 4 17 2 Chemistry Hyperglycemia (fasting) 75 17 53 6 Increased alkaline phosphatase 74 8 66 8 Hypercholesterolemia 66 0.5 22 0 Bicarbonate decreased 56 0 40 0 Increased AST 56 4 41 4 Increased ALT 48 2 35 2 Hypophosphatemia 40 10 14 3 Hypertriglyceridemia 39 0 10 0 Hypocalcem.

Everolimus tablets/everolimus tablets for oral suspension 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.

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.

Cancer: 10 mg orally once daily.

NET: 10 mg orally once daily.

RCC: 10 mg orally once daily.

Angiomyolipoma: 10 mg orally once daily.

SEGA: 4.5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL.

Seizures: 5 mg/ m 2 orally once daily; adjust dose to attain trough concentrations of 5-­15 ng/mL. 2.1 Important Dosage Information Everolimus tablets and everolimus tablets for oral suspension are two different dosage forms.

Select the recommended dosage form based on the indication.

Do not combine everolimus tablets and everolimus tablets for oral suspension to achieve the total dose.

Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4. 2.2 Recommended Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for Neuroendocrine Tumors (NET) The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.4 Recommended Dosage for Renal Cell Carcinoma (RCC) The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.5 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.6 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of everolimus tablets/everolimus tablets for oral suspension is 4.5 mg/m 2 orally once daily until disease progression or unacceptable toxicity. 2.7 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures The recommended starting dosage of everolimus tablets for oral suspension is 5 mg/m2 orally once daily until disease progression or unacceptable toxicity. 2.8 Therapeutic Drug Monitoring (TDM) and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) and TSC-Associated Partial-Onset Seizures 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 Event When to Assess Trough Concentrations After Event Abbreviation: P-gp, P-glycoprotein.

Initiation of everolimus tablets/everolimus tablets for oral suspension to 2 weeks Modification of everolimus tablets/everolimus tablets for oral suspension dose to 2 weeks Switch between everolimus tablets/everolimus tablets for oral suspension to 2 weeks Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor 2 weeks Initiation or discontinuation of P-gp and strong CYP3A4 inducer 2 weeks Change in hepatic function 2 weeks Stable dose with changing body surface area (BSA) Every to 6 months Stable dose with stable BSA Every to 12 months 2.9 Dosage Modifications for Adverse Reactions 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 Adverse Reactions Adverse Reaction Severity Dosage Modification Non-infectious pneumonitis Grade 2 Withhold until improvement to Grade 0 or 1.

Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.

Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks.

Grade 3 Withhold until improvement to Grade 0 or 1.

If toxicity recurs at

Grade 3, permanently discontinue.

Grade 4 Permanently discontinue.

Grade 2 Withhold until improvement to Grade 0 or 1.

Resume at same dose.

If recurs at

Grade 2, withhold until improvement to Grade 0 or 1.

Metabolic events (e.g., hyperglycemia, dyslipidemia) Grade 3 Withhold until improvement to Grade 0, 1, or 2.

Other non-hematologic toxicities

Grade 2 If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1.

Consider resuming at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.

Grade 3 OR Grade 4 Withhold until improvement to Grade 0 or 1.

Grade 3 Withhold until improvement to Grade 0, 1, or 2.

Grade 4 Withhold until improvement to Grade 0, 1, or 2.

Febrile neutropenia

Grade 3 Withhold until improvement to Grade 0, 1, or 2, and no fever.

Grade 4 Permanently discontinue. 2.10 Dosage Modifications 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 Dosage Modifications for Patients With Hepatic Impairment Indication Dose Modification for Everolimus Tablets/Everolimus Tablets for Oral Suspension Abbreviations: NET, Neuroendocrine Tumors; RCC, Renal Cell Carcinoma; SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex.

• Associated Renal Angiomyolipoma Mild hepatic impairment (Child-Pugh class A) – 7.5 mg orally once daily; decrease the dose to 5 mg orally once daily if a dose of 7.5 mg once daily is not tolerated.

Moderate hepatic impairment (Child-Pugh class B) – 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if a dose of 5 mg once daily is not tolerated.

Severe hepatic impairment (Child-Pugh class C) – 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed a dose of 2.5 mg once daily.

TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures

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.

May increase dose to 5 mg once daily if tolerated.

Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days.

Reduce the daily dose by 50%.

Change to every other day dosing if the reduced dose is lower than the lowest available strength.

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.

If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less.

Multiple increments may be required.

Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days.

Double the daily dose using increments of 5 mg or less.

Addition of another strong

CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification.

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.

SUPPLIED/STORAGE AND HANDLING Everolimus Tablets 2.5 mg tablets White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '2.5' on the other side; available in: Bottles of 30 tablets NDC 51991-821-33 Blisters of 28 tablets NDC 51991-821-28 Each carton contains 4 blister cards of 7 tablets each 5 mg tablets White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '5' on the other side; available in: Bottles of 30 tablets NDC 51991-822-33 Blisters of 28 tablets NDC 51991-822-28 Each carton contains 4 blister cards of 7 tablets each 7.5 mg tablets White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '7.5' on the other side; available in: Bottles of 30 tablets NDC 51991-823-33 Blisters of 28 tablets NDC 51991-823-28 Each carton contains 4 blister cards of 7 tablets each 10 mg tablets White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and 'NAT' on the other side; available in: Bottles of 30 tablets NDC 51991-824-33 Blisters of 28 tablets NDC 51991-824-28 Each carton contains 4 blister cards of 7 tablets each Everolimus Tablets for Oral Suspension 2 mg tablets for oral suspension: White to off white colored, round, flat tablets, debossed with "2" on one side and "E" on other side; available in: Blisters of 28 tablets NDC 51991-990-28 Bottles of 28 tablets NDC 51991-990-77 Each carton contains 4 blister cards of 7 tablets each 3 mg tablets for oral suspension: White to off white colored, round, flat tablets, debossed with "3" on one side and "E" on other side; available in: Blisters of 28 tablets NDC 51991-991-28 Bottles of 28 tablets NDC 51991-991-77 Each carton contains 4 blister cards of 7 tablets each 5 mg tablets for oral suspension: White to off white colored, round, flat tablets, debossed with "5" on one side and "E" on other side; available in: Blisters of 28 tablets NDC 51991-992-28 Bottles of 28 tablets NDC 51991-992-77 Each carton contains 4 blister cards of 7 tablets each Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Store in the original container, protect from light and moisture.

Follow special handling and disposal procedures for anti-cancer pharmaceuticals.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Store in the original container, protect from light and moisture.

Follow special handling and disposal procedures for anti-cancer pharmaceuticals.

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.

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.

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.

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.

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.

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.

Use of 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-3) with additional pharmacokinetic data in pediatric patients.

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.

Seventy-seven percent of 70 everolimus tablets for oral suspension-treated patients < 6 years had at least one infection, compared to 53% of 177 everolimus tablets for oral suspension-treated patients ≥ 6 years.

Sixteen percent of 70 everolimus tablets for oral suspension-treated patients < 6 years of age had at least 1 serious infection, compared to 4% of 177 everolimus tablets for oral suspension-treated patients ≥ 6 years of age.

Two fatal cases due to infections were reported in pediatric patients.

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.

In BOLERO-2, 40% of patients with breast cancer treated with everolimus tablets were ≥ 65 years of age, while 15% were ≥ 75 years of age.

No overall differences in effectiveness were observed between elderly and younger patients.

The incidence of deaths due to any cause within 28 days of the last everolimus tablets dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age.

Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age.

In RECORD-1, 41% of patients with renal cell carcinoma treated with everolimus tablets were ≥ 65 years of age, while 7% were ≥ 75 years of age.

In RADIANT-3, 30% of patients with PNET treated with everolimus tablets were ≥ 65 years of age, while 7% were ≥ 75 years of age.

No overall differences in safety or effectiveness were observed between elderly and younger patients.