everolimus 10 MG Oral Tablet

Generic Name: EVEROLIMUS
Brand Name: Afinitor
  • Substance Name(s):
  • EVEROLIMUS

DRUG INTERACTIONS

7 P-gp and strong CYP3A4 inhibitors: Avoid concomitant use.

(2.11, 7.1) P-gp and moderate CYP3A4 inhibitors: Reduce the dose as recommended.

(2.11, 7.1) P-gp and strong CYP3A4 inducers: Increase the dose as recommended.

(2.12, 7.1) 7.1 Effect of Other Drugs on AFINITOR/AFINITOR DISPERZ Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].

Reduce the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and moderate CYP3A4 inhibitor as recommended [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].

Inducers Increase the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and strong CYP3A4 inducer as recommended [see Dosage and Administration (2.12), Clinical Pharmacology (12.3)].

7.2 Effects of Combination Use of Angiotensin Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema.

Avoid the concomitant use of ACE inhibitors with AFINITOR/AFINITOR DISPERZ [see Warnings and Precautions (5.4)].

DESCRIPTION

11 AFINITOR (everolimus) and AFINITOR DISPERZ (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[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone.

The molecular formula is C53H83NO14 and the molecular weight is 958.2.

The structural formula is: AFINITOR for oral administration contains 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus and the following inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate.

AFINITOR DISPERZ 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, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose.

everolimus structural formula

CLINICAL STUDIES

14 Figure 1: Kaplan-Meier Progression-free Survival Curves (Investigator Radiological Review) Figure 2: Kaplan-Meier Investigator-Determined Progression-free Survival Curves Figure 4: Kaplan-Meier Progression-free Survival Curves Figure 3: Kaplan-Meier Progression-free Survival Curves 14.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer A randomized, double-blind, multicenter study (BOLERO-2, NCT00863655) of AFINITOR in combination with exemestane vs.

placebo in combination with exemestane was conducted in 724 postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole.

Randomization was stratified by documented sensitivity to prior hormonal therapy (yes vs.

no) and by the presence of visceral metastasis (yes vs.

no).

Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence.

Patients were permitted to have received 0-1 prior lines of chemotherapy for advanced disease.

The major efficacy outcome measure was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on investigator (local radiology) assessment.

Other outcome measures included overall survival (OS) and objective response rate (ORR).

Patients were randomized 2:1 to AFINITOR 10 mg orally once daily in combination with exemestane 25 mg once daily (n = 485) or to placebo in combination with exemestane 25 mg orally once daily (n = 239).

The two treatment groups were generally balanced with respect to baseline demographics and disease characteristics.

Patients were not permitted to cross over to AFINITOR at the time of disease progression.

The trial demonstrated a statistically significant improvement in PFS by investigator assessment (Table 20 and Figure 1).

The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment.

PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy.

ORR was higher in the AFINITOR in combination with exemestane arm vs.

the placebo in combination with exemestane arm (Table 20).

There were 3 complete responses (0.6%) and 58 partial responses (12%) in the AFINITOR arm.

There were no complete responses and 4 partial responses (1.7%) in the placebo in combination with exemestane arm.

After a median follow-up of 39.3 months, there was no statistically significant difference in OS between the AFINITOR in combination with exemestane arm and the placebo in combination with exemestane arm [HR 0.89 (95% CI: 0.73, 1.10)].

Table 20: Efficacy Results in Hormone-Receptor Positive, HER-2 Negative Breast Cancer in BOLERO-2 aHazard ratio is obtained from the stratified Cox proportional-hazards model by sensitivity to prior hormonal therapy and presence of visceral metastasis bp-value is obtained from the one-sided log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis cObjective response rate = proportion of patients with CR or PR dNot applicable Analysis AFINITOR with Exemestane N = 485 Placebo with Exemestane N = 239 Hazard ratio p-value Median progression-free survival (months, 95% CI) Investigator radiological review 7.8 (6.9, 8.5) 3.2 (2.8, 4.1) 0.45a (0.38, 0.54) < 0.0001b Independent radiological review 11.0 (9.7, 15.0) 4.1 (2.9, 5.6) 0.38a (0.3, 0.5) < 0.0001b Best overall response (%, 95% CI) Objective response rate (ORR)c 12.6% (9.8, 15.9) 1.7% (0.5, 4.2) n/ad Figure 1: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in Hormone Receptor-Positive, HER-2 Negative Breast Cancer in BOLERO-2 14.2 Neuroendocrine Tumors (NET) Pancreatic Neuroendocrine Tumors (PNET) A randomized, double-blind, multi-center trial (RADIANT-3, NCT00510068) of AFINITOR in combination with best supportive care (BSC) compared to placebo in combination with BSC was conducted in patients with locally advanced or metastatic advanced PNET and disease progression within the prior 12 months.

Patients were stratified by prior cytotoxic chemotherapy (yes vs.

no) and WHO performance status (0 vs.

1 and 2).

Treatment with somatostatin analogs was allowed as part of BSC.

The major efficacy outcome was PFS evaluated by RECIST.

After documented radiological progression, patients randomized to placebo could receive open-label AFINITOR.

Other outcome measures included ORR, response duration, and OS.

Patients were randomized 1:1 to receive either AFINITOR 10 mg once daily (n = 207) or placebo (n = 203).

Demographics were well balanced (median age 58 years, 55% male, 79% White).

Of the 203 patients randomized to BSC, 172 patients (85%) received AFINITOR following documented radiologic progression.

The trial demonstrated a statistically significant improvement in PFS (Table 21 and Figure 2).

PFS improvement was observed across all patient subgroups, irrespective of prior somatostatin analog use.

The PFS results by investigator radiological review, central radiological review and adjudicated radiological review are shown below in Table 21.

Table 21: Progression-Free Survival Results in PNET in RADIANT-3 aIncludes adjudication for discrepant assessments between investigator radiological review and central radiological review Analysis N AFINITOR N = 207 Placebo N = 203 Hazard Ratio (95% CI) p-value 410 Median progression-free survival (months) (95% CI) Investigator radiological review 11.0 (8.4, 13.9) 4.6 (3.1, 5.4) 0.35 (0.27, 0.45) < 0.001 Central radiological review 13.7 (11.2, 18.8) 5.7 (5.4, 8.3) 0.38 (0.28, 0.51) < 0.001 Adjudicated radiological reviewa 11.4 (10.8, 14.8) 5.4 (4.3, 5.6) 0.34 (0.26, 0.44) < 0.001 Figure 2: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in PNET in RADIANT-3 Investigator-determined response rate was 4.8% in the AFINITOR arm and there were no complete responses.

OS was not statistically significantly different between arms [HR = 0.94 (95% CI 0.73, 1.20); p = 0.30].

NET of Gastrointestinal (GI) or Lung Origin A randomized, double-blind, multicenter study (RADIANT-4, NCT01524783) of AFINITOR in combination with BSC compared to placebo in combination with BSC was conducted in patients with unresectable, locally advanced or metastatic, well differentiated, non-functional NET of GI (excluding pancreatic) or lung origin.

The study required that patients had well-differentiated (low or intermediate grade) histology, no prior or current history of carcinoid symptoms, and evidence of disease progression within 6 months prior to randomization.

Patients were randomized 2:1 to receive either AFINITOR 10 mg once daily or placebo, and stratified by prior somatostatin analog use (yes vs.

no), tumor origin and WHO performance status (0 vs.

1).

The major efficacy outcome measure was PFS based on independent radiological assessment evaluated by RECIST.

Additional efficacy outcome measures were OS and ORR.

A total of 302 patients were randomized, 205 to the AFINITOR arm and 97 to the placebo arm.

The median age was 63 years (22 to 86 years); 47% were male; 76% were White; 74% had WHO performance status of 0 and 26% had WHO performance status of 1.

The most common primary sites of tumor were lung (30%), ileum (24%), and rectum (13%).

The study demonstrated a statistically significant improvement in PFS per independent radiological review (Table 22 and Figure 3).

There was no statistically significant difference in OS at the planned interim analysis.

Table 22: Progression-Free Survival in NET of GI or Lung Origin in RADIANT-4 a Hazard ratio is obtained from the stratified Cox model.

b p-value is obtained from the stratified log-rank test.

AFINITOR N = 205 Placebo N = 97 Progression-Free Survival Number of Events 113 (55%) 65 (67%) Progressive Disease 104 (51%) 60 (62%) Death 9 (4%) 5 (5%) Median PFS in months (95% CI) 11.0 (9.2, 13.3) 3.9 (3.6, 7.4) Hazard Ratio (95% CI)a 0.48 (0.35, 0.67) p-valueb < 0.001 Overall Response Rate 2% 1% Figure 3: Kaplan-Meier Curves for Progression-Free Survival in NET of GI or Lung Origin in RADIANT-4 Lack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid Tumors The safety and effectiveness of AFINITOR in patients with locally advanced or metastatic functional carcinoid tumors have not been demonstrated.

In a randomized (1:1), double-blind, multi-center trial (RADIANT-2, NCT00412061) in 429 patients with carcinoid tumors, AFINITOR in combination with long-acting octreotide (Sandostatin LAR®) was compared to placebo in combination with long-acting octreotide.

After documented radiological progression, patients on the placebo arm could receive AFINITOR; of those randomized to placebo, 67% received open-label AFINITOR in combination with long-acting octreotide.

The study did not meet its major efficacy outcome measure of a statistically significant improvement in PFS and the final analysis of OS favored the placebo in combination with long-acting octreotide arm.

14.3 Renal Cell Carcinoma (RCC) An international, multi-center, randomized, double-blind trial (RECORD-1, NCT00410124) comparing AFINITOR 10 mg once daily and placebo, both in conjunction with BSC, was conducted in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially.

Prior therapy with bevacizumab, interleukin 2, or interferon-α was also permitted.

Randomization was stratified according to prognostic score and prior anticancer therapy.

The major efficacy outcome measure for the trial was PFS evaluated by RECIST, based on a blinded, independent, central radiologic review.

After documented radiological progression, patients randomized to placebo could receive open-label AFINITOR.

Other outcome measures included OS.

In total, 416 patients were randomized 2:1 to receive AFINITOR (n = 277) or placebo (n = 139).

Demographics were well balanced between the arms (median age 61 years; 77% male, 88% White, 74% received prior sunitinib or sorafenib, and 26% received both sequentially).

AFINITOR was superior to placebo for PFS (Table 23 and Figure 4).

The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib.

Final OS results yield a hazard ratio of 0.90 (95% CI: 0.71, 1.14), with no statistically significant difference between the arms.

Planned cross-over from placebo due to disease progression to open-label AFINITOR occurred in 80% of the 139 patients and may have confounded the OS benefit.

Table 23: Progression-Free Survival and Objective Response Rate by Central Radiologic Review in RCC in RECORD-1 aLog-rank test stratified by prognostic score.

bNot applicable.

AFINITOR N = 277 Placebo N = 139 Hazard R atio (95% CI) p-valuea Median P rogression- free S urvival (95% CI) 4.9 months (4.0, 5.5) 1.9 months (1.8, 1.9) 0.33 (0.25, 0.43) < 0.0001 Objective R esponse R ate 2% 0% n/ab n/ab Figure 4: Kaplan-Meier Curves for Progression-Free Survival in RCC in RECORD-1 14.4 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma A randomized (2:1), double-blind, placebo-controlled trial (EXIST-2, NCT00790400) of AFINITOR was conducted in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5).

The key eligibility requirements for this trial were at least one angiomyolipoma of ≥ 3 cm in longest diameter on CT/MRI based on local radiology assessment, no immediate indication for surgery, and age ≥ 18 years.

Patients received AFINITOR 10 mg or matching placebo orally once daily until disease progression or unacceptable toxicity.

CT or MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks and annually thereafter.

Clinical and photographic assessment of skin lesions were conducted at baseline and every 12 weeks thereafter until treatment discontinuation.

The major efficacy outcome measure was angiomyolipoma response rate based on independent central radiology review, which was defined as a ≥ 50% reduction in angiomyolipoma volume, absence of new angiomyolipoma lesion ≥ 1 cm, absence of kidney volume increase ≥ 20%, and no angiomyolipoma related bleeding of ≥ Grade 2.

Key supportive efficacy outcome measures were time to angiomyolipoma progression and skin lesion response rate.

The primary analyses of efficacy outcome measures were limited to the blinded treatment period and conducted 6 months after the last patient was randomized.

The comparative angiomyolipoma response rate analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs.

no).

Of the 118 patients enrolled, 79 were randomized to AFINITOR and 39 to placebo.

The median age was 31 years (18 to 61 years), 34% were male, and 89% were White.

At baseline, 17% of patients were receiving EIAEDs.

On central radiology review at baseline, 92% of patients had at least 1 angiomyolipoma of ≥ 3 cm in longest diameter, 29% had angiomyolipomas ≥ 8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions.

The median values for the sum of all target renal angiomyolipoma lesions at baseline were 85 cm3 (9 to 1612 cm3) and 120 cm3 (3 to 4520 cm3) in the AFINITOR and placebo arms, respectively.

Forty-six (39%) patients had prior renal embolization or nephrectomy.

The median duration of follow-up was 8.3 months (0.7 to 24.8 months) at the time of the primary analysis.

The renal angiomyolipoma response rate was statistically significantly higher in AFINITOR-treated patients (Table 24).

The median response duration was 5.3+ months (2.3+ to 19.6+ months).

There were 3 patients in the AFINITOR arm and 8 patients in the placebo arm with documented angiomyolipoma progression by central radiologic review (defined as a ≥ 25% increase from nadir in the sum of angiomyolipoma target lesion volumes to a value greater than baseline, appearance of a new angiomyolipoma ≥ 1 cm in longest diameter, an increase in renal volume ≥ 20% from nadir for either kidney and to a value greater than baseline, or Grade ≥ 2 angiomyolipoma-related bleeding).

The time to angiomyolipoma progression was statistically significantly longer in the AFINITOR arm (HR 0.08 [95% CI: 0.02, 0.37]; p < 0.0001).

Table 24: Angiomyolipoma Response Rate in TSC-Associated Renal Angiomyolipoma in EXIST-2 aPer independent central radiology review AFINITOR Placebo p-value N = 79 N = 39 Primary analysis Angiomyolipoma response ratea – % 41.8 0 < 0.0001 95% CI (30.8, 53.4) (0.0, 9.0) Skin lesion response rates were assessed by local investigators for 77 patients in the AFINITOR arm and 37 patients in the placebo arm who presented with skin lesions at study entry.

The skin lesion response rate was statistically significantly higher in the AFINITOR arm (26% vs.

0, p = 0.0011); all skin lesion responses were partial responses, defined as visual improvement in 50% to 99% of all skin lesions durable for at least 8 weeks (Physician’s Global Assessment of Clinical Condition).

Patients randomized to placebo were permitted to receive AFINITOR at the time of angiomyolipoma progression or after the time of the primary analysis.

After the primary analysis, patients treated with AFINITOR underwent additional follow-up CT or 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 112 patients (79 randomized to AFINITOR and 33 randomized to placebo) received at least one dose of AFINITOR.

The median duration of AFINITOR treatment was 3.9 years (0.5 months to 5.3 years) and the median duration of follow-up was 3.9 years (0.9 months to 5.4 years).

During the follow-up period after the primary analysis, 32 patients (in addition to the 33 patients identified at the time of the primary analysis) had an angiomyolipoma response based upon independent central radiology review.

Among the 65 responders out of 112 patients, the median time to angiomyolipoma response was 2.9 months (2.6 to 33.8 months).

Fourteen percent of the 112 patients treated with AFINITOR had angiomyolipoma progression by the end of the follow-up period.

No patient underwent a nephrectomy for angiomyolipoma progression and one patient underwent renal embolization while treated with AFINITOR.

14.5 Tuberous 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/m2 daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 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 cm3 (0.18 to 25.15 cm3) and 1.30 cm3 (0.32 to 9.75 cm3) 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 25).

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 25: Subependymal Giant Cell Astrocytoma Response Rate in TSC-Associated SEGA in EXIST-1 aPer independent central radiology review AFINITOR Placebo p-value N = 78 N = 39 Primary analysis SEGA response ratea – (%) 35 0 < 0.0001 95% CI 24, 46 0, 9 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 treatment and follow-up was 3.9 years (0.2 to 4.9 years).

By four years after the last patient was enrolled, 58% of the 111 patients treated with AFINITOR had a ≥ 50% reduction in SEGA volume relative to baseline, including 27 patients identified at the time of the primary analysis and 37 patients with a SEGA response after the primary analysis.

The median time to SEGA response was 5.3 months (2.5 to 33.1 months).

Twelve percent of the 111 patients treated with AFINITOR had documented disease progression by the end of the follow-up period and no patient required surgical intervention for SEGA during the study.

Study 2485 Study 2485 (NCT00411619) was an open-label, single-arm trial conducted to evaluate the antitumor activity of AFINITOR 3 mg/m2/orally once daily in patients with SEGA and TSC.

Serial radiological evidence of SEGA growth was required for entry.

Tumor assessments were performed every 6 months for 60 months after the last patient was enrolled or disease progression, whichever occurred earlier.

The major efficacy outcome measure was the reduction in volume of the largest SEGA lesion with 6 months of treatment, as assessed via independent central radiology review.

Progression was defined as an increase in volume of the largest SEGA lesion over baseline that was ≥ 25% over the nadir observed on study.

A total of 28 patients received AFINITOR for a median duration of 5.7 years (5 months to 6.9 years); 82% of the 28 patients remained on AFINITOR for at least 5 years.

The median age was 11 years (3 to 34 years), 61% male, 86% White.

At the primary analysis, 32% of the 28 patients (95% CI: 16%, 52%) had an objective response at 6 months, defined as at least a 50% decrease in volume of the largest SEGA lesion.

At the completion of the study, the median duration of durable response was 12 months (3 months to 6.3 years).

By 60 months after the last patient was enrolled, 11% of the 28 patients had documented disease progression.

No patient developed a new SEGA lesion while on AFINITOR.

Nine additional patients were identified as having a > 50% volumetric reduction in their largest SEGA lesion between 1 to 4 years after initiating AFINITOR including 3 patients who had surgical resection with subsequent regrowth prior to receiving AFINITOR.

14.6 Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures The efficacy of AFINITOR DISPERZ as an adjunctive anti-epileptic drug (AED) was evaluated in a randomized, double-blind, multicenter, placebo-controlled study conducted in patients with TSC-associated partial-onset seizures (EXIST-3, NCT01713946).

Patients with a history of inadequate control of partial-onset seizures despite treatment with ≥ 2 sequential AED regimens were randomized to receive placebo or AFINITOR DISPERZ once daily at a dose to achieve a low trough (LT) level (3-7 ng/mL) or a high trough (HT) level (9-15 ng/mL).

Randomization was stratified by age group (1 to < 6, 6 to < 12, 12 to < 18, ≥ 18 years).

The study consisted of 3 phases: an 8-week Baseline observation phase; an 18-week double-blind, placebo-controlled Core phase (6-week titration period and a 12-week maintenance period), and an Extension phase of ≥ 48 weeks.

Patients were required to have a diagnosis of TSC per the modified Gomez criteria, and ≥ 16 partial-onset seizures during the Baseline phase while receiving a stable dose of 1 to 3 concomitant AEDs.

The starting doses for AFINITOR DISPERZ in the Core phase ranged from 3 to 6 mg/m2 orally once daily, depending on age, in patients not receiving concomitant CYP3A4/P-gp inducers and from 5 to 9 mg/m2 orally once daily, depending on age, in patients receiving concomitant CYP3A4/P-gp inducers.

During the 6-week titration period, everolimus trough levels were assessed every 2 weeks and up to 3 dose adjustments were allowed to attempt to reach the targeted everolimus trough concentration range.

The major efficacy outcome measure was the percentage reduction in seizure frequency from the Baseline phase, during the maintenance period of the Core phase.

Additional efficacy outcome measures included response rate, defined as at least a 50% reduction in seizure frequency from the Baseline phase during the maintenance period of the Core phase, and seizure freedom rate during the maintenance period of the Core phase.

A total of 366 patients were randomized to AFINITOR DISPERZ LT (n = 117), AFINITOR DISPERZ HT (n = 130) or placebo (n = 119).

Median age was 10.1 years (2.2 to 56 years); 28% of patients were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years).

The majority were White (65%) and male (52%).

The most common major features of TSC were cortical tubers (92%), hypomelanotic macules (84%), and subependymal nodules (83%).

While 17% of the patients had SEGA, 42% had renal angiomyolipoma, and 9% had both SEGA and renal angiomyolipoma; no patients were receiving treatment with AFINITOR or AFINITOR DISPERZ for these manifestations of TSC.

During the Baseline phase, 65% of patients had complex partial seizures, 52% had secondarily generalized seizures, 19% had simple partial seizures, and 2% had generalized onset seizures.

The median seizure frequency per week during the Baseline phase was 9.4 for all patients and 47% of patients were receiving 3 AEDs during the Baseline phase.

The efficacy results are summarized in Table 26.

Table 26: Percentage Reduction in Seizure Frequency and Response Rate in TSC-Associated Partial-Onset Seizures in EXIST-3 aIf patient discontinued before starting the Maintenance period, then the Titration period is used b95% CI of the median based on bootstrap percentiles cp-values were for superiority vs.

placebo, and obtained from rank ANCOVA with Baseline seizure frequency as covariate, stratified by age subgroup dExact 95% CI obtained using Clopper-Pearson method AFINITOR DISPERZ Placebo Target of 3-7 ng/mL N = 117 Target of 9-15 ng/mL N = 130 N = 119 Seizures per week Median at Baseline (Min, Max) 8.6 (1.4, 192.9) 9.5 (0.3, 218.4) 10.5 (1.3, 231.7) Median at Core phasea (Min, Max) 6.8 (0.0, 193.5) 4.9 (0.0, 133.7) 8.5 (0.0, 217.7) Percentage reduction from Baseline to Core phase (Maintenance a) Median 29.3 39.6 14.9 95% CIb 18.8, 41.9 35.0, 48.7 0.1, 21.7 p-valuec 0.003 < 0.001 Response rate Responders, n (%) 28.2 40 15.1 95% CId 20.3, 37.3 31.5, 49.0 9.2, 22.8

HOW SUPPLIED

16 /STORAGE AND HANDLING AFINITOR 2.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “LCL” on one side and “NVR” on the other; available in: Blisters of 28 tablets………………………………………………………………………………NDC 0078-0594-51 Each carton contains 4 blister cards of 7 tablets each 5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “5” on one side and “NVR” on the other; available in: Blisters of 28 tablets………………………………………………………………………………NDC 0078-0566-51 Each carton contains 4 blister cards of 7 tablets each 7.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “7P5” on one side and “NVR” on the other; available in: Blisters of 28 tablets………………………………………………………………………………NDC 0078-0620-51 Each carton contains 4 blister cards of 7 tablets each 10 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “UHE” on one side and “NVR” on the other; available in: Blisters of 28 tablets………………………………………………………………………………NDC 0078-0567-51 Each carton contains 4 blister cards of 7 tablets each AFINITOR DISPERZ 2 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D2” on one side and “NVR” on the other; available in: Blisters of 28 tablets………………………………………………………………………………NDC 0078-0626-51 Each carton contains 4 blister cards of 7 tablets each 3 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D3” on one side and “NVR” on the other; available in: Blisters of 28 tablets………………………………………………………………………………NDC 0078-0627-51 Each carton contains 4 blister cards of 7 tablets each 5 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D5” on one side and “NVR” on the other; available in: Blisters of 28 tablets………………………………………………………………………………NDC 0078-0628-51 Each carton contains 4 blister cards of 7 tablets each Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

See USP Controlled Room Temperature.

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

Follow special handling and disposal procedures for anticancer pharmaceuticals.1

RECENT MAJOR CHANGES

Indications and Usage (1.6) 4/2018 Dosage and Administration (2.7, 2.8) 4/2018 Warnings and Precautions (5.2, 5.3, 5.9, 5.10) 4/2018

GERIATRIC USE

8.5 Geriatric Use In BOLERO-2, 40% of patients with breast cancer treated with AFINITOR 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 AFINITOR 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 AFINITOR were ≥ 65 years of age, while 7% were ≥ 75 years of age.

In RADIANT-3, 30% of patients with PNET treated with AFINITOR 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.

DOSAGE FORMS AND STRENGTHS

3 AFINITOR Tablets, white to slightly yellow and elongated with a bevelled edge: 2.5 mg: engraved with “LCL” on one side and “NVR” on the other.

5 mg: engraved with “5” on one side and “NVR” on the other.

7.5 mg: engraved with “7P5” on one side and “NVR” on the other.

10 mg: engraved with “UHE” on one side and “NVR” on the other.

AFINITOR DISPERZ Tablets for oral suspension, white to slightly yellowish, round, and flat with a bevelled edge: 2 mg: engraved with “D2” on one side and “NVR” on the other.

3 mg: engraved with “D3” on one side and “NVR” on the other.

5 mg: engraved with “D5” on one side and “NVR” on the other.

AFINITOR: 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets (3) AFINITOR DISPERZ: 2 mg, 3 mg, and 5 mg tablets (3)

MECHANISM OF ACTION

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 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.

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 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.

INDICATIONS AND USAGE

1 AFINITOR is a kinase inhibitor 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.

(1.1) Adults with progressive neuroendocrine tumors of pancreatic origin (PNET) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic.

Limitation of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors.

(1.2) Adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.

(1.3) Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

(1.4) AFINITOR and AFINITOR DISPERZ are kinase inhibitors indicated for the treatment of 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.

(1.5) AFINITOR DISPERZ is a kinase inhibitor indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

(1.6) 1.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer AFINITOR® is 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.

1.2 Neuroendocrine Tumors (NET) AFINITOR is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.

AFINITOR is indicated for the treatment of adult patients with progressive, well-differentiated, non-functional NET of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.

Limitation of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2)].

1.3 Renal Cell Carcinoma (RCC) AFINITOR is indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib.

1.4 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma AFINITOR is indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery.

1.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) AFINITOR and AFINITOR DISPERZ® are indicated in adult and pediatric patients aged 1 year and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected.

1.6 Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures AFINITOR DISPERZ is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

PEDIATRIC USE

8.4 Pediatric Use TSC-Associated SEGA The safety and effectiveness of AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ 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 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.5)].

The safety and effectiveness of AFINITOR/AFINITOR DISPERZ 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 AFINITOR-treated patients < 6 years had at least one infection compared to 67% of 55 AFINITOR-treated patients ≥ 6 years.

Thirty-five percent of 23 AFINITOR-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 AFINITOR-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, AFINITOR did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with AFINITOR for a median duration of 4.1 years.

TSC-Associated Partial-Onset Seizures The safety and effectiveness of AFINITOR DISPERZ has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

Use of AFINITOR DISPERZ 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 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6)].

The safety and effectiveness of AFINITOR DISPERZ and AFINITOR 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 AFINITOR DISPERZ-treated patients < 6 years had at least one infection, compared to 53% of 177 AFINITOR DISPERZ-treated patients ≥ 6 years.

Sixteen percent of 70 AFINITOR DISPERZ-treated patients < 6 years of age had at least 1 serious infection, compared to 4% of 177 AFINITOR DISPERZ-treated patients ≥ 6 years of age.

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

Other Indications The safety and effectiveness of AFINITOR/AFINITOR DISPERZ 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

PREGNANCY

8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman.

There are limited case reports of AFINITOR 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 AFINITOR 10 mg orally once daily (see Data).

Advise pregnant women of the potential risk to the fetus.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.

Data Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development.

These effects occurred in the absence of maternal toxicities.

Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the human exposure at the recommended dose of AFINITOR 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/m2), approximately 1.6 times the recommended dose of AFINITOR 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 body surface area.

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/m2), 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Non-Infectious Pneumonitis: Monitor for clinical symptoms or radiological changes.

Withhold or permanently discontinue based on severity.

(2.9, 5.1) Infections: Monitor for signs and symptoms of infection.

Withhold or permanently discontinue based on severity.

(2.9, 5.2) Severe Hypersensitivity Reactions: Permanently discontinue for clinically significant hypersensitivity.

(5.3) Angioedema: Patients taking concomitant ACE inhibitors may be at increased risk for angioedema.

Permanently discontinue for angioedema.

(5.4, 7.2) Stomatitis: Initiate dexamethasone alcohol-free mouthwash when starting treatment.

(5.5, 6.1) Renal Failure: Monitor renal function prior to treatment and periodically thereafter.

(5.6) Impaired Wound Healing: Exercise caution in the peri-surgical period.

(5.7) Geriatric Patients: Monitor and adjust dose for adverse reactions.

(5.8) Metabolic Disorders: Monitor serum glucose and lipids prior to treatment and periodically thereafter.

Withhold or permanently discontinue based on severity (2.9, 5.9) Myelosuppression: Monitor hematologic parameters prior to treatment and periodically thereafter.

Withhold or permanently discontinue based on severity.

(2.9, 5.10) Risk of Infection or Reduced Immune Response with Vaccination: Avoid live vaccines and close contact with those who have received live vaccines.

Complete recommended childhood vaccinations prior to starting treatment.

(5.11) Embryo-Fetal Toxicity: Can cause fetal harm.

Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception.

(5.12, 8.1, 8.3) 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives.

Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR/AFINITOR DISPERZ in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event.

The incidence of Grade 3 and 4 non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions (6.1)].

Fatal outcomes have been observed.

Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms.

Consider opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis.

Advise patients to report promptly any new or worsening respiratory symptoms.

Continue AFINITOR/AFINITOR DISPERZ without dose alteration in patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms.

Imaging appears to overestimate the incidence of clinical pneumonitis.

For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity [see Dosage and Administration (2.9)].

Corticosteroids may be indicated until clinical symptoms resolve.

Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.

The development of pneumonitis has been reported even at a reduced dose.

5.2 Infections AFINITOR/AFINITOR DISPERZ has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)].

Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP) and viral infections (e.g., reactivation of hepatitis B virus) have occurred.

Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal.

The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively.

The incidence of serious infections was reported at a higher frequency in patients < 6 years of age [see Use in Specific Populations (8.4)].

Complete treatment of preexisting invasive fungal infections prior to starting treatment.

Monitor for signs and symptoms of infection.

Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity of infection [see Dosage and Administration (2.9)].

Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.

5.3 Severe Hypersensitivity Reactions Hypersensitivity reactions to AFINITOR/AFINITOR DISPERZ have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Contraindications (4)].

The incidence of Grade 3 hypersensitivity reactions was up to 1%.

Permanently discontinue AFINITOR/AFINITOR DISPERZ for the development of clinically significant hypersensitivity.

5.4 Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment).

In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking AFINITOR with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor.

Permanently discontinue AFINITOR/AFINITOR DISPERZ for angioedema.

5.5 Stomatitis Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR/AFINITOR DISPERZ at an incidence ranging from 44% to 78% across clinical trials.

Grades 3-4 stomatitis was reported in 4% to 9% of patients [see Adverse Reactions (6.1)].

Stomatitis most often occurs within the first 8 weeks of treatment.

When starting AFINITOR/AFINITOR DISPERZ, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis [see Adverse Reactions (6.1)].

If stomatitis does occur, mouthwashes and/or other topical treatments are recommended.

Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme- containing products, as they may exacerbate the condition.

Do not administer antifungal agents, unless fungal infection has been diagnosed.

5.6 Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR.

Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR/AFINITOR DISPERZ [see Adverse Reactions (6.1)].

The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively.

The incidence of Grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively.

Monitor renal function prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter.

Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

5.7 Impaired Wound Healing AFINITOR/AFINITOR DISPERZ delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma.

These wound-related complications may require surgical intervention.

Exercise caution with the use of AFINITOR/AFINITOR DISPERZ in the peri-surgical period.

5.8 Geriatric Patients In the randomized hormone receptor-positive, HER2-negative breast cancer study (BOLERO-2), the incidence of deaths due to any cause within 28 days of the last AFINITOR 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.

Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.9), Use in Specific Populations (8.5)].

5.9 Metabolic Disorders Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR/AFINITOR DISPERZ at an incidence up to 75%, 86%, and 73%, respectively.

The incidence of these Grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively [see Adverse Reactions (6.1)].

In non-diabetic patients, monitor fasting serum glucose prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter.

In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated.

Monitor lipid profile prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter.

When possible, achieve optimal glucose and lipid control prior to starting AFINITOR/AFINITOR DISPERZ.

For Grade 3 to 4 metabolic events, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity [see Dosage and Administration (2.9)].

5.10 Myelosuppression Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR/AFINITOR DISPERZ.

The incidence of these Grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively [see Adverse Reactions (6.1)].

Monitor complete blood count prior to starting AFINITOR/AFINITOR DISPERZ every 6 months for the first year of treatment and annually thereafter.

Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity [see Dosage and Administration (2.9)].

5.11 Risk of Infection or Reduced Immune Response with Vaccination The safety of immunization with live vaccines during AFINITOR/AFINITOR DISPERZ therapy has not been studied.

Due to the potential increased risk of infection, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with AFINITOR/AFINITOR DISPERZ.

Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy.

An accelerated vaccination schedule may be appropriate.

5.12 Embryo-Fetal Toxicity Based on animal studies and the mechanism of action, AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman.

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 clinical dose of 10 mg once daily.

Advise pregnant women of the potential risk to a fetus.

Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 4 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Non-infectious Pneumonitis Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions (5.1)].

Infections Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infections to their healthcare provider [see Warnings and Precautions (5.2)].

Hypersensitivity Reactions Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications (4), Warnings and Precautions (5.3)].

Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors Advise patients to avoid angiotensin-converting enzyme (ACE) inhibitors and to promptly contact their healthcare provider or seek emergency care for signs or symptoms of angioedema [see Warnings and Precautions (5.4)].

Stomatitis Advise patients of the risk of stomatitis and to use alcohol-free mouthwashes during treatment [see Warnings and Precautions (5.5)].

Renal Impairment Advise patients of the risk of developing kidney failure and the need to monitor their kidney function periodically during treatment [see Warnings and Precautions (5.6)].

Impaired Wound Healing Advise patients of the risk of impaired wound healing or dehiscence during treatment [see Warnings and Precautions (5.7)].

Geriatric Patients Inform patients that in a study conducted in patients with breast cancer, the incidence of deaths and adverse reactions leading to permanent discontinuation was higher in patients ≥ 65 years compared to patients < 65 years [see Warnings and Precautions (5.8), Use in Specific Populations (8.5)].

Metabolic Disorders Advise patients of the risk of metabolic disorders and the need to monitor glucose and lipids periodically during therapy [see Warnings and Precautions (5.9)].

Myelosuppression Advise patients of the risk of myelosuppression and the need to monitor complete blood counts periodically during therapy [see Warnings and Precautions (5.10)].

Risk of Infection or Reduced Immune Response with Vaccination Advise patients to avoid the use of live vaccines and close contact with those who have received live vaccines [see Warnings and Precautions (5.11)].

Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment and for 8 weeks after the last dose.

Advise patients to inform their healthcare provider of a known or suspected pregnancy.

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 weeks after the last dose [see Warnings and Precautions (5.12) and Use in Specific Populations (8.1, 8.3)].

Lactation Advise women not to breastfeed during treatment with AFINITOR/AFINITOR DISPERZ and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

Infertility Advise males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)].

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 T2018-50

DOSAGE AND ADMINISTRATION

2 Do not combine AFINITOR and AFINITOR DISPERZ to achieve the total daily dose.

(2.1) Modify the dose for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4.

(2.1) Breast Cancer: 10 mg orally once daily.

(2.2) NET: 10 mg orally once daily.

(2.3) RCC: 10 mg orally once daily.

(2.4) TSC-Associated Renal Angiomyolipoma: 10 mg orally once daily.

(2.5) TSC-Associated SEGA: 4.5 mg/m2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL.

(2.6, 2.8) TSC-Associated Partial-Onset Seizures: 5 mg/m2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL.

(2.7, 2.8) 2.1 Important Dosage Information AFINITOR and AFINITOR DISPERZ are two different dosage forms.

Select the recommended dosage form based on the indication [see Indications and Usage (1)].

Do not combine AFINITOR and AFINITOR DISPERZ 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 [see Dosage and Administration (2.10, 2.11, 2.12)].

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

2.3 Recommended Dosage for Neuroendocrine Tumors (NET) The recommended dosage of AFINITOR 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 AFINITOR 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 AFINITOR 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 AFINITOR/AFINITOR DISPERZ is 4.5 mg/m2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8)].

2.7 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures The recommended starting dosage of AFINITOR DISPERZ is 5 mg/m2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8)].

2.8 Therapeutic Drug Monitoring 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* = current dose x (target concentration divided by current concentration) *The maximum dose increment at any titration must not exceed 5 mg.

Multiple dose titrations may be required to attain the target trough concentration.

When possible, use the same assay and laboratory for therapeutic drug monitoring throughout treatment.

Table 1: Recommended Timing of Therapeutic Drug Monitoring Event When to Assess Trough Concentrations After Event Initiation of AFINITOR/AFINITOR DISPERZ 1 to 2 weeks Modification of AFINITOR/AFINITOR DISPERZ dose 1 to 2 weeks Switch between AFINITOR and AFINITOR DISPERZ 1 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 Every 3 to 6 months Stable dose with stable body surface area Every 6 to 12 months 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of AFINITOR/AFINITOR DISPERZ for the management of adverse reactions.

Table 2: Recommended Dosage Modifications for AFINITOR/AFINITOR DISPERZ for Adverse Reactions Adverse Reaction Severity Dosage Modification Non-infectious pneumonitis [see Warnings and Precautions (5.1)] 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.

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

If toxicity recurs at Grade 3, permanently discontinue.

Grade 4 Permanently discontinue.

Stomatitis [see Warnings and Precautions (5.5)] 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.

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

Grade 3 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.

Grade 4 Permanently discontinue.

Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions (5.9)] Grade 3 Withhold until improvement to Grade 0, 1, or 2.

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

Grade 4 Permanently discontinue.

Other non-hematologic toxicities Grade 2 If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1.

Resume at same dose.

If toxicity recurs at 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.

Grade 3 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.

If recurs at Grade 3, permanently discontinue.

Grade 4 Permanently discontinue.

Thrombocytopenia [see Warnings and Precautions (5.10)] Grade 2 Withhold until improvement to Grade 0 or 1.

Resume at same dose.

Grade 3 OR Grade 4 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.

Neutropenia [see Warnings and Precautions (5.10)] Grade 3 Withhold until improvement to Grade 0, 1 or 2.

Resume at same dose.

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

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

Febrile neutropenia [see Warnings and Precautions (5.10)] Grade 3 Withhold until improvement to Grade 0, 1 or 2 and no fever.

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

Grade 4 Permanently discontinue.

2.10 Dosage Modifications for Hepatic Impairment The recommended dosages of AFINITOR/AFINITOR DISPERZ for patients with hepatic impairment are described in Table 3 [see Use in Specific Populations (8.6)]: Table 3: Recommended Dosage Modifications for Patients with Hepatic Impairment Indication Dose Modification for AFINITOR/AFINITOR DISPERZ Breast Cancer, NET, RCC, and TSC-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/m2 orally once daily.

Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8)].

2.11 Dosage Modifications for P-gp and CYP3A4 Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.1)].

Avoid ingesting grapefruit and grapefruit juice.

Reduce the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Table 4: Recommended Dosage Modifications for Concurrent Use of AFINITOR/AFINITOR DISPERZ with a P-gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for AFINITOR/AFINITOR DISPERZ 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.

TSC-Associated SEGA and TSC- Associated Partial-Onset Seizures Reduce the daily dose by 50%.

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

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

Assess trough concentrations when initiating and discontinuing the inhibitor [see Dosage and Administration (2.8)].

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 AFINITOR/AFINITOR DISPERZ with a P-gp and strong CYP3A4 inducer as recommended in Table 5 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Table 5: Recommended Dosage Modifications for Concurrent Use of AFINITOR/AFINITOR DISPERZ with P-gp and Strong CYP3A4 Inducers Indication Dose Modification for AFINITOR/AFINITOR DISPERZ 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.

TSC-Associated SEGA and TSC- Associated Partial-Onset Seizures Double the daily dose using increments of 5 mg or less.

Multiple increments may be required.

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 [see Dosage and Administration (2.8)].

Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days.

2.13 Administration and Preparation Administer AFINITOR/AFINITOR DISPERZ at the same time each day.

Administer AFINITOR/AFINITOR DISPERZ consistently either with or without food [see Clinical Pharmacology (12.3)].

If a dose of AFINITOR/AFINITOR DISPERZ 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, AFINITOR/AFINITOR DISPERZ should be administered at its usual time.

Double doses should not be administered to make up for the dose that was missed.

AFINITOR AFINITOR should be swallowed whole with a glass of water.

Do not break or crush tablets.

AFINITOR DISPERZ Wear gloves to avoid possible contact with everolimus when preparing suspensions of AFINITOR DISPERZ 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.

Do not break or crush tablets.

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.

After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into the same syringe, and swirl the contents to suspend remaining particles.

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.

Do not exceed a total of 10 mg per glass.

If higher doses are required, prepare an additional glass.

Do not break or crush tablets.

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.