Everolimus 3 mg Tablet, For Suspension — NDC 60219-2280-2 (Billing 60219-2280-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 1 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. Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 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.

12.2Pharmacodynamics 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. Cardiac Electrophysiology In a randomized, placebo-controlled, cross-over study, 59 healthy subjects received a single oral dose of AFINITOR (20 mg and 50 mg) and placebo.

AFINITOR at single doses up to 50 mg did not prolong the QT/QTc interval.

12.3Pharmacokinetics Absorption In patients with TSC-associated SEGA, everolimus C min was approximately dose-proportional within the dose range from 1.35 mg/m 2 to 14.4 mg/m 2 . Effect of Food: In healthy subjects who received 9 mg of everolimus tablets for oral suspension, high-fat meals (containing approximately 1,000 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%.

Relative Bioavailability: The AUC inf of everolimus was equivalent between everolimus tablets for oral suspension and AFINITOR; the C max of everolimus in the everolimus tablets for oral suspension dosage form was 20% to 36% lower than that of AFINITOR. The predicted trough concentrations at steady state were similar after daily administration. Distribution The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 ng/mL to 5,000 ng/mL, is 17% to 73%.

The amount of everolimus confined to plasma is approximately 20% at blood concentrations observed in cancer patients given AFINITOR 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. Elimination The mean elimination half-life of everolimus is approximately 30 hou… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 1 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. Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 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.

12.3Pharmacokinetics Absorption In patients with TSC-associated SEGA, everolimus C min was approximately dose-proportional within the dose range from 1.35 mg/m 2 to 14.4 mg/m 2 . Effect of Food: In healthy subjects who received 9 mg of everolimus tablets for oral suspension, high-fat meals (containing approximately 1,000 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%.

Relative Bioavailability: The AUC inf of everolimus was equivalent between everolimus tablets for oral suspension and AFINITOR; the C max of everolimus in the everolimus tablets for oral suspension dosage form was 20% to 36% lower than that of AFINITOR. The predicted trough concentrations at steady state were similar after daily administration. Distribution The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 ng/mL to 5,000 ng/mL, is 17% to 73%.

The amount of everolimus confined to plasma is approximately 20% at blood concentrations observed in cancer patients given AFINITOR 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. Elimination The mean elimination half-life of everolimus is approximately 30 hours.

Metabolism: 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. Excretion: No specific elimination studies have been undertaken in 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. Specific Populations No relationship was apparent between oral clearance and age or sex in patients. Patients with Renal Impairment: No significant influence of creatinine clearance (25 mL/min to 178 mL/min) was detected on oral clearance (CL/F) of everolimus.

Patients with Hepatic Impairment: 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 [see Dosage and Administration (2.10) , Use in Specific Populations (8.6) ] . Pediatric Patients: 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.

Race or Ethnicity: 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 Strong or Moderate CYP3A Inhibitor and P-gp Inhibitor: Everolimus exposure increased when AFINITOR was co-administered with: ketoconazole (strong CYP3A inhibitor and P-gp inhibitor) - C max and AUC increased 3.9- and 15-fold, respectively. erythromycin (moderate CYP3A inhibitor and P-gp inhibitor) - C max and AUC increased 2- and 4.4-fold, respectively. verapamil (moderate… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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. Cardiac Electrophysiology In a randomized, placebo-controlled, cross-over study, 59 healthy subjects received a single oral dose of AFINITOR (20 mg and 50 mg) and placebo.

AFINITOR at single doses up to 50 mg did not prolong the QT/QTc interval.

14 CLINICAL STUDIES

14.5Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) EXIST-1 A randomized (2:1), double-blind, placebo-controlled trial (EXIST-1, NCT00789828) of AFINITOR was conducted in 117 pediatric and adult patients with SEGA and TSC. Eligible patients had at least one SEGA lesion ≥ 1 cm in longest diameter on MRI based on local radiology assessment and one or more of the following: serial radiological evidence of SEGA growth, a new SEGA lesion ≥ 1 cm in longest diameter, or new or worsening hydrocephalus.

Patients randomized to the treatment arm received AFINITOR at a starting dose of 4.5 mg/m 2 daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 ng/mL to 15 ng/mL as tolerated. AFINITOR or matched placebo continued until disease progression or unacceptable toxicity. MRI scans for disease assessment were obtained at baseline, 12, 24 and 48 weeks and annually thereafter.

The main efficacy outcome measure was SEGA response rate based on independent central radiology review. SEGA response was defined as a ≥ 50% reduction in the sum of SEGA volume relative to baseline, in the absence of unequivocal worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm and new or worsening hydrocephalus. The primary analysis of SEGA response rate was limited to the blinded treatment period and conducted 6 months after the last patient was randomized.

The analysis of SEGA response rate was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no). Of the 117 patients enrolled, 78 were randomized to AFINITOR and 39 to placebo. The median age was 9.5 years (0.8 to 26 years); a total of 20 patients were < 3 years, 54 patients were 3 to < 12 years, 27 patients were 12 to < 18 years and 16 patients were ≥ 18 years; 57% were male and 93% were white.

At baseline, 18% of patients were receiving EIAEDs. Based on central radiology review at baseline, 98% of patients had at least one SEGA lesion ≥ 1.0 cm in longest diameter, 79% had bilateral SEGAs, 43% had ≥ 2 target SEGA lesions, 26% had growth in or into the inferior surface of the ventricle, 9% had evidence of growth beyond the subependymal tissue adjacent to the ventricle and 7% had radiographic evidence of hydrocephalus. The median values for the sum of all target SEGA lesions at baseline were 1.63 cm 3 (0.18 cm 3 to 25.15 cm 3 ) and 1.30 cm 3 (0.32 cm 3 to 9.75 cm 3 ) in the AFINITOR and placebo arms, respectively.

Eight (7%) patients had prior SEGA-related surgery. The median duration of follow-up was 8.4 months (4.6 to 17.2 months) at the time of primary analysis. The SEGA response rate was statistically significantly higher in AFINITOR-treated patients (Table 26).

At the time of the primary analysis, all SEGA responses were ongoing and the median duration of response was 5.3 months (2.1 to 8.4 months). With a median follow-up of 8.4 months, SEGA progression was detected in 15.4% of the 39 patients randomized to receive placebo and none of the 78 patients randomized to receive AFINITOR. No patient in either treatment arm required surgical intervention.

Table 26: Subependymal Giant Cell Astrocytoma Response Rate in TSC-Associated SEGA in EXIST-1 AFINITOR N = 78 Placebo N = 39 p-value Primary analysis SEGA response rate a - (%) 35 0 < 0.0001 95% CI 24, 46 0, 9 a Per independent central radiology review. Patients randomized to placebo were permitted to receive AFINITOR at the time of SEGA progression or after the primary analysis, whichever occurred first. After the primary analysis, patients treated with AFINITOR underwent additional follow-up MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized.

A total of 111 patients (78 patients randomized to AFINITOR and 33 patients randomized to placebo) received at least one dose of AFINITOR. Median duration of AFINITOR t… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Administration of everolimus tablets for oral suspension for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding, respectively to 3.9 and 0.2 times the estimated human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily. Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells and chromosome aberration assay in V79 Chinese hamster cells).

Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1,500 mg/m 2 /day, approximately 255-fold the recommended dose of AFINITOR 10 mg orally once daily and approximately 200-fold the median dose administered to patients with TSC-associated SEGA and TSC-associated partial-onset seizures, based on the BSA), administered as 2 doses, 24 hours apart. Based on non-clinical findings, everolimus tablets for oral suspension may impair male fertility. In a 13-week male fertility study in rats, testicular morphology was affected at doses of 0.5 mg/kg and above.

Sperm motility, sperm count and plasma testosterone levels were diminished in rats treated with 5 mg/kg. The exposures at these doses (52 ng•hr/mL and 414 ng•hr/mL, respectively) were within the range of human exposure at the recommended dose of AFINITOR 10 mg orally once daily (560 ng•hr/mL) and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at AUC 0-24h values 10% to 81% lower than human exposure at the recommended dose of AFINITOR 10 mg orally once daily.

After a 10 to 13 week non-treatment period, the fertility index increased from zero (infertility) to 60%. Oral doses of everolimus in female rats at doses ≥ 0.1 mg/kg (approximately 4% the human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility.

13.2Animal Toxicology and/or Pharmacology In juvenile rat toxicity studies, dose-related delayed attainment of developmental landmarks, including delayed eye-opening, delayed reproductive development in males and females and increased latency time during the learning and memory phases were observed at doses as low as 0.15 mg/kg/day.