Because Endocrine Monotherapy Can Only Take you So Far

1

Go Beyond Conventional Endocrine Treatment

2

AFINITOR® (everolimus) Tablets is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information.•AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of

the excipients

•There have been reports of noninfectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR, some with fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared with patients <65 years of age

•Oral ulceration is the most frequently occurring adverse event and occurred in 44% to 86% of AFINITOR-treated patients across the clinical trial experience. Most of these events were grade 1/2. Grade 3/4 stomatitis was reported in 4% to 9% of patients

•Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have also been reported; monitoring of laboratory tests is recommended

•The use of live vaccines and close contact with those who have received live vaccines should be avoided

•AFINITOR can cause fetal harm when administered to a pregnant woman

Please see Brief Summary of Prescribing Information on adjacent pages.

In postmenopausal women with advanced HR+, HER2-negative breast cancer after failure of treatment with letrozole or anastrozole

AFINITOR® (everolimus) Tablets is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information.•AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of

the excipients

•There have been reports of noninfectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR, some with fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared with patients <65 years of age

•Oral ulceration is the most frequently occurring adverse event and occurred in 44% to 86% of AFINITOR-treated patients across the clinical trial experience. Most of these events were grade 1/2. Grade 3/4 stomatitis was reported in 4% to 9% of patients

•Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have also been reported; monitoring of laboratory tests is recommended

•The use of live vaccines and close contact with those who have received live vaccines should be avoided

•AFINITOR can cause fetal harm when administered to a pregnant woman

In postmenopausal women with advanced HR+, HER2-negative breast cancer after failure of treatment with letrozole or anastrozole

Go Beyond Conventional Endocrine Treatment

3

Please see Brief Summary of Prescribing Information on adjacent pages.

Change the Treatment Paradigm With AFINITOR Plus ExemestaneAFINITOR Plus Exemestane More Than Doubles Median Progression-Free Survival (PFS) Over Exemestane Monotherapy1-4

In postmenopausal women with advanced HR+, HER2-negative breast cancer after failure of treatment with letrozole or anastrozole

• Median PFS was 7.8 months with AFINITOR® (everolimus) Tablets plus exemestane [95% CI, 6.9-8.5] vs 3.2 months [95% CI, 2.8-4.1] with placebo plus exemestane (P<0.0001)1

PFS curves for the 2 treatment arms began to diverge at 6 weeks (the first tumor assessment)1,2

An independent central review confirmed a significant PFS improvement with AFINITOR® plus exemestane treatment vs placebo plus exemestane1,2

• Median PFS was 11.0 months with AFINITOR plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6] (HR=0.38 [95% CI, 0.3-0.5]; P<0.00011

AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information.

• AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients

Noninfectious Pneumonitis:• Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria

(CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed

• If symptoms are moderate, patients should be managed with dose interruption until symptoms improve

• The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve

• For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1

• AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR

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

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

Median PFS in BOLERO-2 (Investigator Radiological Review)1

Median PFS: 7.8 months

PFS

Prob

abili

ty (%

)

AFINITOR plus exemestane (n/N=310/485)

Placebo plus exemestane (n/N=200/239)

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Time (months)

55%reduction in risk of progression

or death2

AFINITOR plusexemestane:

Placebo plusexemestane:

HR=0.45 [95% CI, 0.38-0.54]Log rank P value: <0.0001

7.8 months3.2 months

Median PFS: 3.2 months

References: 1. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2012. 2. Data on file. Novartis Pharmaceuticals Corp. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)®. Breast Cancer. V 1.2012. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#breast. Accessed May 23, 2012. 4. Fedele P, Calvani N, Marino A, et al. Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: where are we now and where are we going? [published online ahead of print April 9, 2012]. Crit Rev Oncol Hematol. doi:10.1016/j.critrevonc. 2012.03.004.

BOLERO-2=Breast Cancer Trials of Oral Everolimus-2

Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936-1080 ©2012 Novartis 9/12 AFB-1043056

Important Safety Information.Infections: • AFINITOR® (everolimus) Tablets has immunosuppressive properties

and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred

• Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal

• Physicians and patients should be aware of the increased risk of infection with AFINITOR

• Treatment of preexisting invasive fungal infections should be completed prior to starting treatment

• Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered

• Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment

Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in

patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients

• In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided

• Antifungal agents should not be used unless fungal infection has been diagnosed

Renal Failure: • Cases of renal failure (including acute renal failure), some

with a fatal outcome, have been observed in patients treated with AFINITOR

Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-

negative breast cancer study, 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 discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age

• Careful monitoring and appropriate dose adjustments for adverse reactions are recommended

Laboratory Tests and Monitoring: • Elevations of serum creatinine, proteinuria, glucose, lipids,

and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported

• Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter

• When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR

Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4 inhibitors (eg,

ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole)

• Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem)

• Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments

Hepatic Impairment: • Exposure of everolimus was increased in patients with hepatic

impairment• For patients with severe hepatic impairment (Child-Pugh class C),

AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended

Vaccinations: • The use of live vaccines and close contact with those who

have received live vaccines should be avoided during treatment with AFINITOR

Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant

woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment

Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were

stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%)

• The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%)

Laboratory Abnormalities:• The most common laboratory abnormalities (incidence ≥50%)

were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%)

• The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%)

Please see Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

AFINITOR (everolimus) tablets for oral administrationInitial U.S. Approval: 2009

Brief Summary of Prescribing Information. See full prescribing information forcomplete product information. 1 INDICATIONS AND USAGE

AFINITOR® is indicated for the treatment of postmenopausal women withadvanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole oranastrozole.

4 CONTRAINDICATIONSHypersensitivity to the active substance, to other rapamycin derivatives, or to anyof the excipients. Hypersensitivity reactions manifested by symptoms including,but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g.,swelling of the airways or tongue, with or without respiratory impairment) havebeen observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONSNon-infectious PneumonitisNon-infectious pneumonitis is a class effect of rapamycin derivatives, includingAFINITOR. Non-infectious pneumonitis was reported in up to 19% of patientstreated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full pre-scribing information]. Fatal outcomes have been observed.Consider a diagnosis of non-infectious pneumonitis in patients presenting withnon-specific respiratory signs and symptoms such as hypoxia, pleural effusion,cough, or dyspnea, and in whom infectious, neoplastic, and other causes havebeen excluded by means of appropriate investigations. Advise patients to reportpromptly any new or worsening respiratory symptoms.Patients who develop radiological changes suggestive of non-infectious pneumoni-tis and have few or no symptoms may continue AFINITOR therapy without dosealteration. Imaging appears to overestimate the incidence of clinical pneumonitis.If symptoms are moderate, consider interrupting therapy until symptoms improve.The use of corticosteroids may be indicated. AFINITOR may be reintroduced at adaily dose approximately 50% lower than the dose previously administered [seeTable 1 in Dosage and Administration (2.2) in the full prescribing information].For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Cortico -steroids may be indicated until clinical symptoms resolve. For cases of grade 3non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equalto grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lowerthan the dose previously administered depending on the individual clinical circum-stances [see Table 1 in Dosage and Administration (2.2) in the full prescribinginformation]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR.The development of pneumonitis has been reported even at a reduced dose.InfectionsAFINITOR has immunosuppressive properties and may predispose patients to bac-terial, fungal, viral, or protozoal infections, including infections with opportunisticpathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribinginformation]. Localized and systemic infections, including pneumonia, mycobac -terial infections, other bacterial infections, invasive fungal infections, such asaspergillosis or candidiasis, and viral infections including reactivation of hepatitis Bvirus have occurred in patients taking AFINITOR. Some of these infections havebeen severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians andpatients should be aware of the increased risk of infection with AFINITOR. Com-plete treatment of pre-existing invasive fungal infections prior to starting treatmentwith AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms ofinfection; if a diagnosis of an infection is made, institute appropriate treatmentpromptly and consider interruption or discontinuation of AFINITOR. If a diagnosisof invasive systemic fungal infection is made, discontinue AFINITOR and treat withappropriate antifungal therapy.Oral UlcerationMouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience.Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse Reactions(6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topicaltreatments are recommended, but alcohol- or peroxide-containing mouthwashesshould be avoided as they may exacerbate the condition. Antifungal agents shouldnot be used unless fungal infection has been diagnosed [see Drug Interactions].Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome,have been observed in patients treated with AFINITOR [see Laboratory Tests andMonitoring].Geriatric PatientsIn the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the lastAFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuationoccurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65years of age. Careful monitoring and appropriate dose adjustments for adversereactions are recommended [see Dosage and Administration (2.2) in the full pre-scribing information, Use in Specific Populations].

Laboratory Tests and MonitoringRenal FunctionElevations of serum creatinine and proteinuria have been reported in clinical trials[see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information].Monitoring of renal function, including measurement of blood urea nitrogen (BUN),urinary protein, or serum creatinine, is recommended prior to the start of AFINITORtherapy and periodically thereafter.Blood Glucose and LipidsHyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported inclinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribinginformation]. Monitoring of fasting serum glucose and lipid profile is recommendedprior to the start of AFINITOR therapy and periodically thereafter. When possible,optimal glucose and lipid control should be achieved before starting a patient onAFINITOR.Hematologic ParametersDecreased hemoglobin, lymphocytes, neutrophils, and platelets have been reportedin clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescrib-ing information]. Monitoring of complete blood count is recommended prior to thestart of AFINITOR therapy and periodically thereafter.Drug-drug InteractionsDue to significant increases in exposure of everolimus, co-administration withstrong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2,2.4) in the full prescribing information and Drug Interactions].A reduction of the AFINITOR dose is recommended when co-administered with amoderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4)in the full prescribing information and Drug Interactions].An increase in the AFINITOR dose is recommended when co-administered with astrong CYP3A4 inducer [see Dosage and Administration (2.2, 2.4) in the full pre-scribing information and Drug Interactions].Hepatic ImpairmentExposure to everolimus was increased in patients with hepatic impairment [seeClinical Pharmacology (12.3) in the full prescribing information].For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipomawith TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITORmay be used at a reduced dose if the desired benefit outweighs the risk. For patientswith mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impair-ment, a dose reduction is recommended [see Dosage and Administration (2.2) andClinical Pharmacology (12.3) in the full prescribing information].For SEGA patients with severe hepatic impairment, AFINITOR is not recommended.For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B)hepatic impairment, adjustment to the starting dose may not be needed; howeversubsequent dosing should be individualized based on therapeutic drug monitoring[see Dosage and Administration (2.4, 2.5) in the full prescribing information].VaccinationsThe use of live vaccines and close contact with those who have received live vac-cines should be avoided during treatment with AFINITOR. Examples of live vaccinesare: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever,varicella, and TY21a typhoid vaccines.The timing of routine vaccinations in pediatric patients with SEGA should be con-sidered prior to the start of everolimus therapy.Embryo-fetal ToxicityThere are no adequate and well-controlled studies of AFINITOR in pregnantwomen; however, based on the mechanism of action, AFINITOR can cause fetalharm. Everolimus caused embryo-fetal toxicities in animals at maternal exposuresthat were lower than human exposures. If this drug is used during pregnancy or ifthe patient becomes pregnant while taking this drug, the patient should be apprisedof the potential hazard to a fetus. Women of childbearing potential should beadvised to use an effective method of contraception while using AFINITOR and forup to 8 weeks after ending treatment [see Use in Specific Populations].

6 ADVERSE REACTIONSThe efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day)(n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in arandomized, controlled trial in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on amedian follow-up of approximately 13 months.The most common adverse reactions (incidence ≥ 30%) were stomatitis, infec-tions, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia,fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnor-malities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increasedAST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, andhypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (inci-dence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium,increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred more frequently in patients who received AFINITORplus exemestane (2%) compared to patients on the placebo plus exemestane arm(0.4%). The rates of treatment-emergent adverse events resulting in permanentdiscontinuation were 24% and 5% for the AFINITOR plus exemestane and placeboplus exemestane treatment groups, respectively. Dose adjustments (interruptionsor reductions) were more frequent among patients in the AFINITOR plus exemes-tane arm than in the placebo plus exemestane arm (63% versus 14%).Table 3 compares the incidence of treatment-emergent adverse reactions reportedwith an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versusplacebo.

Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC*AFINITOR (10 mg/day) Placebo

+ exemestanea + exemestanea

N=482 N=238All All

grades Grade 3 Grade 4 grades Grade 3 Grade 4% % % % % %

Any adverse reaction 100 41 9 90 22 5Gastrointestinal disorders

Stomatitisb 67 8 0 11 0.8 0Diarrhea 33 2 0.2 18 0.8 0Nausea 29 0.2 0.2 28 1 0Vomiting 17 0.8 0.2 12 0.8 0Constipation 14 0.4 0 13 0.4 0Dry mouth 11 0 0 7 0 0

General disorders and administration site conditionsFatigue 36 4 0.4 27 1 0Edema peripheral 19 1 0 6 0.4 0Pyrexia 15 0.2 0 7 0.4 0Asthenia 13 2 0.2 4 0 0

Infections and infestationsInfectionsc 50 4 1 25 2 0

InvestigationsWeight decreased 25 1 0 6 0 0

Metabolism and nutrition disordersDecreased appetite 30 1 0 12 0.4 0Hyperglycemia 14 5 0.4 2 0.4 0

Musculoskeletal and connective tissue disordersArthralgia 20 0.8 0 17 0 0Back pain 14 0.2 0 10 0.8 0Pain in extremity 9 0.4 0 11 2 0

Nervous system disordersDysgeusia 22 0.2 0 6 0 0Headache 21 0.4 0 14 0 0

Psychiatric disordersInsomnia 13 0.2 0 8 0 0

Respiratory, thoracic and mediastinal disordersCough 24 0.6 0 12 0 0Dyspnea 21 4 0.2 11 0.8 0.4Epistaxis 17 0 0 1 0 0Pneumonitisd 19 4 0.2 0.4 0 0

Skin and subcutaneous tissue disordersRash 39 1 0 6 0 0Pruritus 13 0.2 0 5 0 0Alopecia 10 0 0 5 0 0

Vascular disordersHot flush 6 0 0 14 0 0Median Duration of Treatmente 23.9 weeks 13.4 weeks

CTCAE Version 3.0*160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks)a Exemestane (25 mg/day)b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival

pain, glossitis and lip ulcerationc Includes all preferred terms within the ‘infections and infestations’ system organ

class, the most common being nasopharyngitis (10%), urinary tract infection (10%),upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis(3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), andhepatitis C (<1%).

d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosise Exposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 4. Table 4: Key Laboratory Abnormalities Reported in ≥ 10% of

Patients with Advanced HR+ BCLaboratory parameter AFINITOR (10 mg/day) Placebo

+ exemestanea + exemestanea

N=482 N=238All All

grades Grade 3 Grade 4 grades Grade 3 Grade 4% % % % % %

Hematologyb

Hemoglobin decreased 68 6 0.6 40 0.8 0.4WBC decreased 58 1 0 28 5 0.8Platelets decreased 54 3 0.2 5 0 0.4Lymphocytes decreased 54 11 0.6 37 5 0.8Neutrophils decreased 31 2 0 11 0.8 0.8Clinical ChemistryGlucose increased 69 9 0.4 44 0.8 0.4Cholesterol increased 70 0.6 0.2 38 0.8 0.8Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4

Alanine transaminase (ALT) increased 51 4 0.2 29 5 0Triglycerides increased 50 0.8 0 26 0 0Albumin decreased 33 0.8 0 16 0.8 0Potassium decreased 29 4 0.2 7 1 0Creatinine increased 24 2 0.2 13 0 0CTCAE Version 3.0a Exemestane (25 mg/day)b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lympho -

penia, neutropenia, and thrombocytopenia (collectively as pancytopenia), whichoccurred at lower frequency.

7 DRUG INTERACTIONSEverolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor ofthe multi drug efflux pump PgP. In vitro, everolimus is a competitive inhibitor ofCYP3A4 and a mixed inhibitor of CYP2D6.Agents that may Increase Everolimus Blood ConcentrationsCYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significantincreases in everolimus exposure when AFINITOR was coadministered with:• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC

increased by 3.9- and 15.0-fold, respectively.• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC

increased by 2.0- and 4.4-fold, respectively.• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC

increased by 2.3- and 3.5-fold, respectively.Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage andAdministration (2.2, 2.4) in the full prescribing information and Warnings and Precautions].Use caution when AFINITOR is used in combination with moderate CYP3A4 and/orPgP inhibitors. If alternative treatment cannot be administered reduce the AFINITORdose [see Dosage and Administration (2.2, 2.4) in the full prescribing informationand Warnings and Precautions].Agents that may Decrease Everolimus Blood ConcentrationsCYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducerof CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, com-pared to everolimus treatment alone. Consider a dose increase of AFINITOR whenco-administered with strong CYP3A4 inducers if alternative treatment cannot beadministered. St. John’s Wort may decrease everolimus exposure unpredictablyand should be avoided [see Dosage and Administration (2.2, 2.4) in the full pre-scribing information].Agents whose Plasma Concentrations may be Altered by EverolimusStudies in healthy subjects indicate that there are no clinically significant pharmaco-kinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) andpopulation pharmaco kinetic analyses also detected no influence of simvastatin (aCYP3A4 substrate) on the clearance of AFINITOR.A study in healthy subjects demonstrated that co-administration of an oral dose of mid azolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25%increase in mid azolam Cmax and a 30% increase in midazolam AUC(0-inf).Coadministration of everolimus and exemestane increased exemestane Cmin by45% and C2h by 64%. However, the corresponding estradiol levels at steady state(4 weeks) were not different between the two treatment arms. No increase in adverseevents related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin byapproximately 50%.

8 USE IN SPECIFIC POPULATIONSPregnancy Pregnancy Category D [see Warnings and Precautions].There are no adequate and well-controlled studies of AFINITOR in pregnantwomen; however, based on the mechanism of action, AFINITOR can cause fetalharm when administered to a pregnant woman. Everolimus caused embryo-fetaltoxicities in animals at maternal exposures that were lower than human exposures.If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to a fetus.Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.In animal reproductive studies, oral administration of everolimus to female ratsbefore mating and through organogenesis induced embryo-fetal toxicities, includ-ing increased resorption, pre-implantation and post-implantation loss, decreasednumbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletaldevelopment. 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 resultingexposures of approximately 4% of the exposure (AUC0-24h) achieved in patientsreceiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident asan increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2),approximately 1.6 times either the 10 mg daily dose or the median dose adminis-tered to SEGA patients on a body surface area basis. The effect in rabbits occurredin the presence of maternal toxicities.In a pre- and post-natal development study in rats, animals were dosed fromimplantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there wereno 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 insurvival of offspring (~5% died or missing). There were no drug-related effects onthe developmental parameters (morphological development, motor activity, learn-ing, or fertility assessment) in the offspring.Nursing MothersIt is not known whether everolimus is excreted in human milk. Everolimus and/orits metabolites passed into the milk of lactating rats at a concentration 3.5 timeshigher than in maternal serum. Because many drugs are excreted in human milkand because of the potential for serious adverse reactions in nursing infants fromeverolimus, a decision should be made whether to discontinue nursing or to dis-continue the drug, taking into account the importance of the drug to the mother.Pediatric UseAFINITOR is recommended for use only in patients with SEGA who are aged ≥ 3 years.A prospective, open-label, single-arm trial was conducted to evaluate the safetyand efficacy of AFINITOR in patients with SEGA associated with TSC. In total, 28patients received treatment with AFINITOR; median age was 11 years (range 3-34).AFINITOR has not been studied in patients with SEGA < 3 years of age.Geriatric UseIn the randomized advanced hormone receptor positive, HER2-negative breast can-cer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15%were 75 and over. No overall differences in effectiveness were observed betweenelderly and younger subjects. The incidence of deaths due to any cause within 28days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to2% in patients < 65 years of age. Adverse reactions leading to permanent treat-ment discontinuation occurred in 33% of patients ≥ 65 years of age compared to17% in patients < 65 years of age [see Warnings and Precautions].In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety oreffectiveness were observed between elderly and younger subjects. In the random-ized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years ofage, while 7% were 75 and over. In the randomized advanced PNET study, 30% ofAFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 and over.

Other reported clinical experience has not identified differences in responsebetween the elderly and younger patients, but greater sensitivity of some olderindividuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full pre-scribing information].No dosage adjustment in initial dosing is required in elderly patients, but closemonitoring and appropriate dose adjustments for adverse reactions is recom-mended. [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) inthe full prescribing information].Renal ImpairmentNo clinical studies were conducted with AFINITOR in patients with decreased renalfunction. Renal impairment is not expected to influence drug exposure and nodosage adjustment of everolimus is recommended in patients with renal impair-ment [see Clinical Pharmacology (12.3) in the full prescribing information].Hepatic ImpairmentThe safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34subject single oral dose study of everolimus in subjects with impaired hepaticfunction relative to subjects with normal hepatic function. Exposure was increasedin patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), andsevere (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3)in the full prescribing information].For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipomawith TSC patients with severe hepatic impairment, AFINITOR may be used at areduced dose if the desired benefit outweighs the risk. For patients with mild(Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dosereduction is recommended [see Dosage and Administration (2.2) in the full pre-scribing information].For SEGA patients with severe hepatic impairment (Child-Pugh class C), AFINITORis not recommended. For SEGA patients with mild (Child-Pugh class A) or moder-ate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose maynot be needed; however, subsequent dosing should be individualized based ontherapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the fullprescribing information].

10 OVERDOSAGEIn animal studies, everolimus showed a low acute toxic potential. No lethality orsevere toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).Reported experience with overdose in humans is very limited. Single doses of up to70 mg have been administered. The acute toxicity profile observed with the 70 mgdose was consistent with that for the 10 mg dose.

Manufactured by:Novartis Pharma Stein AGStein, SwitzerlandDistributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936© NovartisT2012-132July 2012