HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`AFINITOR safely and effectively. See full prescribing information for
`AFINITOR.
`
`AFINITOR (everolimus) tablets for oral administration
`Initial U.S. Approval: 2009
`
`------RECENT MAJOR CHANGES
`
`. Dosage and Administration (2.2) 6/2010
`
`. Warnings and Precautions: Infections (5.2) 6/2010
`-----INDICATIONS AND USAGE---­
`
`patients with
`AFINITOR is a kinase inibitor indicated for the treatment of
`advanced renal cell carcinoma after failure of treatment with sunitinib or
`sorafenib. (\)
`
`
`----DOSAGE AND ADMINISTRATION--­
`
`. 10 mg once daily with or without food. (2.1)
`
`
`. Treatment interrption and/or dose reduction to 5 mg once daily may be
`
`neeed to manage adverse drug reactions. (2.2)
`. For patients with Child-Pugh class B hepatic impairent, reduce dose to 5
`
`mg once daily. (2.2)
`. If moderate inhbitors ofCYP3A4 or P-glycoprotein (PgP) are required,
`tolerated, consider
`reduce the dose of AFINITOR to 2.5 mg once daily; if
`increasing to 5 mg once daily. (2.2)
`. If strong inducers of CYP3A4 are required, increase AFINITOR dose in
`5 mg increments to a maximum of20 mg once daily. (2.2)
`AND STRENGTHS---­
`---DOSAGE FORMS
`
`2.5 mg, 5 mg and 10 mg tablets with no score. (3)
`-----CONTRANDICATIONS
`Hypersensitivity to everolimus, to other rapamycin dervatives, or to any of
`the excipients. (4)
`
`
`----WARNINGS AND PRECAUTIONS--­
`
`. Non-infectious pneumonitis: Monitor for clinical symptoms or radiological
`
`changes; fatal cases have occurred. Manage by dose reduction or
`
`discontinuation until symptoms resolve, and consider use of
`
`corticosteroids. (5.1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dose
`2.2 Dose Modifications
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Non-infectious Pueumonitis
`5.2 Infections
`5.3 Oral Ulceration
`5.4 Laboratory Tests and Monitoring
`5.5 Drg-drug Interactions
`5.6 Hepatic Impairment
`5.7 Vaccinations
`5.8 Use in Pregnancy
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`
`7 DRUG INTERACTIONS
`
`7.1 Agents that may Increase Everolimus Blood Concentrations
`7.2 Agents that may Decrease Everolimus Blood Concentrations
`7.3 Agents whose Plasma Concentrations may be altered by
`Everolimus
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`. Infections: Increased risk of infections, some fataL. Monitor for signs and
`
`symptoms, and treat promptly. (5.2)
`. Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis are common.
`Management includes mouthwashes (without alcohol or peroxide) and
`topical treatments. (5.3)
`. Laboratory test alterations: Elevations of serum creatinine, blood glucose,
`
`and lipids may occur. Decreases in hemoglobin, neutrophils, and platelets
`may also occur. Monitor renal function, blood glucose, lipids, and
`hematologic parameters prior to treatment and periodically thereafter. (5.4)
`. Vaccinations: Avoid live vaccines and close contact with those who have
`
`received live vaccines. (5.7) .
`
`
`. Use in pregnancy: Fetal harm can occur when administered to a pregnant
`potential har to the fetus. (5.8, 8.1)
`
`woman. Apprise women of
`
`------ADVERSE REACTIONS----­
`
`Most common advere reactions (incidence 2:30%) are stomatitis, infections,
`asthenia, fatigue, cough, and diarhea. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at
`1-800-FDA-I088 or www.fda.gov/medwatch
`-----DRUG INTERACTIONS-----­
`. Strong CYP3A4 or PgP inibitors: Avoid concomitant use. (2.2,5.5,7.1)
`. Moderte CYP3A4 or PgP inhibitors: If combination is required, use
`caution and reduce dose of AFINITOR. (2.2,5.5,7.1)
`. Strong CYP3A4 inducers: Avoid concomitant use. If combination canot
`be avoided, increase dose of AFINITOR. (2.2, 5.5,7.2)
`
`----USE IN SPECIFIC POPULATIONS
`
`. Nuring mother: Discontinue drug or nursing, taing into considertion
`the importnce of drug to the mother. (8.3)
`. Hepatic impairent: AFINITOR should not be used in patients with Child-
`Pugh class C hepatic impairment. For patients with Child-Pugh class B
`hepatic impairment, reduce dose to 5 mg daily. (2.2, 5.6, 8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling
`
`Revised: 06/2010
`
`
`8.6 Renal Impairent
`8.7 Hepatic Impairent
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARACOLOGY
`12.1 Mechanism of Action
`12.2 Pharacodynamics
`
`i 2.3 Pharmacokinetics
`
`13 NON CLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Non-infectious Pneumonitis
`17.2 Infections
`
`17.3 Oral Ulceration
`17.4 Laboratory Tests and Monitorig
`17.5 Drg-drug Interactions
`17.6 Hepatic Impairent
`17.7 Vaccinations
`17.8 Pregnancy
`17.9 Dosing Instructions
`
`* Sections or subsections omitted from the full prescribing information are
`not listed
`
`

`

`FULL PRESCRIBING INFORMATION
`I INDICATIONS AND USAGE
`
`AFINITOR'" is indicated for the treatment of
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose
`
`patients with advanced renal cell carcinoma after failure of
`
`treatment with sunitinib or sorafenib.
`
`The recommended dose of AFINITOR for treatment of advanced renal cell carcinoma is io mg, to be taken once daily at the same time every day, either with or
`water. The tablets should not be chewed or crushed.
`without food (see Clinical Pharmacology (12.3)l AFINITOR tablets should be swallowed whole with a glass of
`
`
`Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.
`2.2 Dose Modifications
`
`Management of severe and/or intolerble advere reactions may require temporary dose reduction and/or interption of AFINITOR therpy. If dose reduction is
`required, the suggested dose is 5 mg daily (see Warnings and Precautions (5.1)l
`
`Hepatic Impairment: For patients with moderte hepatic impairment (Child-Pugh class B), reduce the dose to 5 mg daily. AFINITOR has not been evaluated in patients
`with severe hepatic impairment (Child-Pugh class C) and should not be used in this patient population (see Warnings and Precautions (5.6) and Use in Specifc
`Populations (8.7)l
`
`CYP3A4 or PgP inhibitors: Use caution when admiistered in combination with moderte CYP3A4 inhibitors (e.g., amprenavir, fosamprenavir, aprepitant,
`erhromycin, fluconazole, verapamil, diltiazem) or moderate P-glycoprotein (PgP) inhibitors. Ifpatients require co-administration ofa moderate CYP3A4 or PgP
`inhibitor, reduce the AFINITOR dose to 2.5 mg daily. The reduced dose of AFINITOR is predicted to adjust the area under the curve (AUC) to the range obsered
`the moderte inibitor is discontinued, a
`without inibitors. An AFINITOR dose increae from 2.5 mg to 5 mg may be considered based on patient tolerance. If
`the moderte inibitor is discontinued, the AFINITOR dose
`
`washout period of
`
`approximately 2 to 3 days should be allowed before the AFINITOR dose is increased. if
`the moderte CYP3A4 or PgP inhibitor.
`
`should be retued to the dose used prior to initiation of
`
`Avoid the use of strong inbitors ofCYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ataanavir, nefazodone, saquinavir, telithomycin, ritonavir, indinavir,
`juice, sta frit, Sevile oranges and other foods that are known to affect cytochrome P450 and PgP activity
`nelfinavir, voriconazole) or PgP. Grapefrit, grpefruit
`should also be avoided durng treatment (see Warnings and Precautions (5.5) and Drug Interactions (7.1)).
`
`Strong CYP 3A 4 Inducers: Avoid the use of concomitant strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
`phenobarbital).fpatients require co-admiistration ofa strong CYP3A4 inducer, consider increasing the AFINITOR dose from 10 mg daily up to 20 mg daily (based
`
`on pharmacokinetic data), using 5 mg increments. This dose of AFINITOR is predicted to adjust the AUC to the range obsered without inducers. However, there are
`the strong inducer is discontinued, the AFINITOR dose should be returned
`no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If
`to the dose used prior to initiation of the strong CYP3A4 inducer (see Warnings and Precautions (5.5) and Drug Interactions (7.2)l
`3 DOSAGE FORMS AND STRENGTHS
`
`2.5 mg tablet
`
`White to slightly yellow, elongated tablets with a bevelled edge and no score, engrved with "LCL" on one side and "NVR" on the other.
`
`
`5 mgtablet
`
`White to. slightly yellow, elongated tablets with a bevelled edge and no score, engrved with "5" on one side and "NVR" on the other.
`
`
`10 mg tablet
`
`White to slightly yellow, elongated tablets with a bevelled edge and no score, engrved with "UHE" on one side and "NVR" on the other.
`
`4 CONTRAINDICATIONS
`
`the excipients. Hyperensitivity reactions manifested by symptoms including, but
`Hypersensitivity to the active substace, to other rapamycin dervatives, or to any of
`not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been
`observed with everolimus and other rapamycin dervatives.
`5 WARNINGS AND PRECAUTIONS
`5.1 Non-infectious Pneumonitis
`
`Non-infectious pneumonitis is a class effect ofrapamycin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonitis was reported in 14%
`of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grde 3 and 4 non-infectious pneumonitis was 4% and 0%, respectively (see
`Adverse Reactions (6.1)). Fatal outcomes have been obsered.
`
`Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effsion, cough, or
`dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new
`or worsening respiratory symptoms.
`
`non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose
`Patients who develop radiological changes suggestive of
`alteration. If symptoms are moderate, consider interrpting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be
`reintroduced at 5 mg daily.
`
`For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical
`symptoms resolve. Therapy with AFlNlTOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.
`5.2 Infections
`
`AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoan infections, including infections with opportnistic
`pathogens (see Adverse Reactions (6.1)). Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as
`aspergilosis or candidiasis, and viral infections including reactivation of hepatitis B virs have occurred in patients takig AFINITOR. Some of these infections have
`been severe (e.g., leading to respiratory or hepatic failure) or fataL. Physicians and patients should be aware of the increased risk of infection with AFINITOR.
`Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms
`of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interption or discontiuation of AFINITOR. If a diagnosis
`of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.
`
`

`

`5.3 Oral Ulceration
`
`Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. Tn the randomized study, approximately 44% of AFINITOR-treated
`patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 (see Adverse Reactions (6.1)). In such cases, topical treatments
`are recommended, but alcohol- or peroxide-containig mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used
`unless fungal infection has been diagnosed (see Diug Interactions (7.1))
`5.4 Laboratory Tests and Monitoring
`
`Renal Function
`
`Elevations of serum creatinine, usually mild, have been reported in clinical trials (see Adverse Reactions (6.1)J. Monitorig of renal function, including measurement of
`blood urea nitrogen (BUN) or serum creatinine, is recommended prior to thestart of AFINITOR therpy and periodically thereafter.
`
`Blood Glucose and Lipids
`
`Hyperglycema, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trals (see Adverse Reactions (6.1)) Monitorig offasting serm glucose and
`lipid profie is recommended prior to the sta of AFINITOR therapy and perodically thereafter. When possible, optimal glucose and lipid control should be achieved
`before starting a patient on AFINITOR.
`
`Hematological Parameters
`
`Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials (see Adverse Reactions (6.1)) Monitorig of complete blood count
`is recommended prior to the start of AFINITOR therapy and periodically thereafter.
`5.5 Drug-drug Interactions
`
`Due to significant increases in exposure of everolimus, co-admiistration with strong inibitors ofCYP3A4 (e.g'., ketoconazole, itraconazole, clarthromycin,
`juice
`atazanavir, nefazodone, saquinavir, telithomycin, ritonavir, indinavir, nelfinavir , voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefrit, grapefrit
`
`and other foods that are known to affect cytochrome P450 and PgP activity should also be avoided during treatment (see Dosage and Administration (2.2) and Drug
`Interactions (7.1)f.
`
`A reduction of the AFINITOR dose is recommended when co-administered with a moderte CYP3A4 inibitor (e.g., amprenavir, fosamprenavir, aprepitant,
`
`erhromycin, fluconazole, verpamil, diItiazem) or PgP inhibitor (see Dosage and Administration (2.2) and Drug Interactions (7.I)f.
`
`An increase in the AFINITOR dose is recommended when co-administered with a strongCYP3A4 inducer (e.g., St. John's Wort (Hypericum peroratum),
`
`dexamethasone, prednisone, prednisolone, phenytoin, carbainazepine, rifampin, rifabutin, rifapentine, phenobarbital) (see Dosage and Administration (2.2) and Drug
`Interactions (7.2)).
`5.6 Hepatic Impairment
`
`The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight subjects
`with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended.
`
`AFINITOR has not bee studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population (see Dosage and
`Administration (2.2) and Use in Specifc Populations (8.7)f.
`5.7 Vaccinations
`
`The use of live vaccines and close contact with those who have received live vaccines should be avoided durig treatment with AFINITOR Examples of live vaccines
`are: intrasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
`
`5.8 Use in Pregnancy
`
`Pregnancy Category D
`
`There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when
`administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the
`the
`the patient becomes pregnant while takg the drug, the patient should be apprised of
`ths drug is used during pregnancy or if
`recommended dose of 10 mg daily. If
`potential hazard to the fetus. Women of childbearig potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8
`weeks after ending treatment (see Use in Specifc Populations (8. I)j
`6 ADVERSE REACTIONS
`
`The following serous adverse reactions are discussed in greater detail in another section of
`
`
`the label:
`
`. Non-infectious pneumonitis (see Warnings and Precautions (5.1))
`
`
`. Infections (see Warnings and Precautions (5.2)f.
`
`6.1 Clinical Studies Experience
`
`Because clinical trials are conducted under widely varying conditions, the advere reaction rates obsered cannot be directly compared to rates in other trials and may
`not reflect the rates observed in clinical practice.
`
`The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled tral in patients with metastatic renal cell carcinoma
`patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The
`who received prior treatment with sunitinib and/or sorafenib. The median age of
`median duration of blinded study treatment was 141 days (range i 9-45 I) for patients receiving AFINITOR and 60 days (range 21-295) for those receiving placebo.
`
`common grde 3/4 advere reactions
`The most common adverse reactions (incidence ~30%) were stomatitis, infections, asthenia, fatigue, cough, and diarhea. The most
`(incidence ô%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities
`(incidence ~50%) were anemia, hypercholesterolemia, hyperriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most cominon grade 3/4
`laboratory abnormalities (incidence ~3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respirtory
`treatment-emergent
`failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of
`
`adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The
`most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis
`were the most common reasons for treatment delay or dose reduction. The most common medical interventions required durig AFINITOR treatment were for
`infections, anemia, and stomatitis.
`
`

`

`Table I compares the incidence of treatment-emergent adverse reactions reported with an incidence of2:1 0% for patients receiving AFINITOR 10 mg daily versus
`placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.
`Table I Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm
`Placebo
`AFINITOR 10 mglday
`N=137
`N=274
`
`Any Adverse Reaction
`Gastrointestinal Disorders
`Stomatitis'
`Diarrhea
`Nausea
`Vomiting
`
`Infections and Infestatitins b
`
`All grades
`0/0
`
`97
`
`44
`30
`26
`20
`37
`
`31
`25
`20
`19
`
`Grade
`
`3
`
`Grade
`
`4
`
`%
`
`52
`
`4
`
`1
`
`1
`
`2
`7
`
`3
`
`5
`.:1
`.:1
`
`%
`
`13
`
`.:1
`
`0
`
`0
`0
`
`3
`
`.:1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`All grades
`0/0
`
`93
`
`8
`
`7
`
`19
`
`12
`
`18
`
`23
`27
`
`8
`
`9
`
`1
`
`16
`
`Grade
`
`3
`
`Grade
`
`4
`
`%
`
`23
`
`0
`
`0
`
`0
`0
`
`1
`
`4
`
`3
`
`.:1
`
`0
`
`0
`
`0
`
`3
`
`%
`
`5
`
`0
`
`0
`
`0
`
`0
`0
`
`0
`
`.:1
`
`0
`0
`
`0
`
`0
`
`0
`
`General Disorders and Administration Site Conditions
`Asthenia
`33
`Fatigue
`Edema perpheral
`Pyrexia
`Mucosal inflammation
`Respiratory, Thoracic and Mediastinal Disorders
`30
`Cough
`24
`
`Dyspnea
`Epistaxis
`
`Pneumonitis 0
`
`Skin and Subcutaneous Tissue Disorders
`Rash
`Pruritus
`Dr skin
`Metabolism and Nutrition Disorders
`Anorexia
`Nervous System Disorders
`Headache
`
`18
`
`14
`
`29
`14
`
`13
`
`25
`
`19
`
`Dysgeusia
`
`Musculoskeletal and Connective
`
`Pain in extremity
`
`10
`Tissue Disorders
`
`10
`
`Median Duration of
`
`Treatment (d)
`
`.:1
`6
`
`0
`4
`
`.:1
`.:1
`
`.:1
`0
`
`1
`
`141
`
`1
`
`0
`
`0
`
`0
`0
`
`0
`
`0
`
`.:1
`
`0
`
`0
`
`15
`
`0
`
`0
`
`7
`
`7
`
`5
`
`14
`
`9
`2
`
`7
`
`0
`
`0
`
`0
`
`0
`
`0
`
`.:1
`
`.:1
`
`0
`
`0
`
`60
`
`0
`0
`
`0
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`CTCAE Version 3.0
`. Stomatitis (including aphthous stomatitis), and mouth and tongue ulcertion.
`b Includes all prefered ters within the 'infections and infestations' system organ class, the most common being nasopharygitis (6%), pneumonia (6%),
`
`uriary trct infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergilosis (':1 %), candidiasis (':1 %), and sepsis (.:1 %).
`o Includes pneumonitis, intertitiallung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.
`
`Other notable adverse reactions occurrng more frequently with AFINITOR than with placebo, but with an incidence of.:lO% include:
`
`Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)
`
`Generl disorder and administration site conditions: Weight decreased (9%), chest pain (5%), chils (4%), impaired wound healing (.: 1 %)
`
`Respiratory, thoracic and mediastinal disorder: Pleural effsion (7%), pharyngolarygeal pain (4%), rhinorrhea (3%)
`
`
`Ski and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erhrodysesthesia syndrome) (5%), nail disorder (5%), erhema (4%),
`
`onychoclasis (4%), skiillesion (4%), acneiform deratitis (3%)
`
`
`Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes melItus (2%), new onset of diabetes melItus (.: 1 %)
`
`Psychiatric disorders: Insomnia (9%)
`
`Nervous system disorders: Dizziness (7%), paresthesia (5%)
`
`Eye disorders: Eyelid edema (4%), conjunctivitis (2%)
`
`Vascular disorder: Hypertension (4%)
`
`
`Renal and uriary disorders: Renal failure (3%)
`
`

`

`Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1 %)
`
`Musculoskeletal and connective tissue disorders: Jaw pain (3%)
`
`Hematologic disorders: Hemorrhage (3%)
`
`Key treatment-emergent laboratory abnormalities are presented in Table 2.
`
`Table
`
`2
`
`Key Laboratory Abnormalities Reported at a
`
`Laboratory Parameter
`
`Higher rate in the AFINITOR Arm than the Placebo Arm
`Placebo
`N=137
`
`4
`
`All grades
`0/0
`
`Grade
`
`3
`
`Grade
`
`4
`
`0/0
`
`0/0
`
`AFINITOR 10 mglday
`N=274
`All grades Grade
`%
`%
`
`3
`
`Grade
`%
`
`Hematology"
`Hemoglobin decreased
`Lymphocytes decreased
`Platelets decreased
`Neutrophils decreased
`Clinical Chemistry
`Cholesterol increased
`Triglycerdes increaed
`Glucose increased
`Creatinine increased
`Phosphate decreased
`Aspartate trasaminase (AST) increased
`
`Alanine trsaminase (ALT) increased
`
`Bilrubin increased
`
`92
`
`51
`23
`
`14
`
`77
`73
`57
`50
`37
`25
`
`21
`
`3
`
`12
`
`16
`
`1
`
`0
`
`4
`
`.:1
`
`15
`
`1
`
`6
`
`.:1
`
`.:1
`
`1
`
`2
`
`0
`
`.:1
`
`0
`
`0
`.:1
`
`0
`
`0
`.:1
`
`0
`.:1
`
`79
`28
`
`2
`4
`
`35
`34
`25
`34
`
`8
`
`7
`4
`2
`
`5
`
`5
`
`0
`
`0
`
`0
`
`0
`
`1
`
`0
`
`0
`0
`
`0
`
`0
`
`.:1
`0
`.:1
`
`0
`
`0
`
`0
`0
`0
`0
`0
`0
`0
`
`CTCAE Verion 3.0
`a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia.
`
`Informatìon from further clinical trials
`
`In clinical trals, everolimus has been associated with serious cases of
`
`hepatitis B reactivation, including fatal outcomes.
`
`7 DRUG INTERACTIONS
`
`Everolimus is a substrte of CYP3A4, and also a substrate and moderate inibitor of the multidrug effux pump PgP. In vitro, everolimus is a competitive inibitor of
`CYP3A4 and a mixed inhibitor of CYP2D6.
`7.1 Agents that may Increase Everolimiis Blood Concentrations
`
`CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when
`AFINITOR was coadmistered with:
`
`
`. ketoconazole (a strong CYP3A4 inibitor and a PgP inbitor) - Cma and AUC increased by 3.9- and l5.0-fold, respectively.
`
`
`. eryhromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cm", and AUC increased by 2.0- and 4.4-fold, respectively.
`
`. verpamil (a moderte CYP3A4 inibitor and a PgP inibitor) - Cirx and AUC increased by 2.3-and 3.5-fold, respectively.
`
`Concomitat strong inibitors ofCYP3A4 and PgP should not be used (see Warnings and Precautions (5.5)).
`Use caution when AFINITOR is used in combination with moderte CYP3A4 or PgP inhbitors. Ifa1ternative treatment can not be admiistered reduce the AFINITOR
`dose. (See Dosage and Administration (2.2))
`7.2 Agents that may Decrease Everolimus Blood Concentrations
`
`CYP3A4 Inducers: In healthy subjects, co-admiistration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and
`58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 (e.g.
`dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP if alterative treatment cannot be admiistered. St. John's Wort may decrease
`
`everolimus exposure unpredictably and should be avoided (see Dosage and Administration (2.2))
`7.3 Agents whose Plasma Concentrations may be Altered by Everolimus
`
`Studies in healthy subjects indicate that there are no clinically significant phanacokinetic interactions between AFINITOR and the HMG-CoA reductase inibitors
`atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence ofsimvastatin (a
`CYP3A4 substrate) on the clearance of AFINITOR.
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`
`Pregnancy Category D (see Warnings and Precautions (5.8))
`
`
`There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechaiism of action, AFINITOR may cause fetal harm when
`administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the
`the patient becomes pregnant while taking the drug, the patient should be appiised ofthe
`recommended dose of io mg daily. ifthis drug is used durig pregnancy or if
`
`

`

`potential hazard to the fetus. Women of childbearig 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 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., steral cleft) and retarded skeletal
`development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUCo-24h) in patients
`
`receiving the recomrnended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorplions occurred at an oral dose approximately 1.6 times the
`recommended human dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.
`
`the recommended human dose
`In a pre- and post-natal development study in rats, animals were dosed from implantation though lactation. At approximately 10% of
`
`based on body surface area, there were no advere effects on delivery and lactation and there were no sigos of materal toxicity. However, there was reduced body
`weight (up to 9% reduction from the control) and slight reduction in survival in offspring (-5% died or missing). There were no drug-related effects on the
`developmental parameter (morphological development, motor activity, learning, or ferility assessment) in the offspring.
`
`Doses that resulted in embryo-fetal toxicities in rats and rabbits were ~0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post­
`natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/g (0.6 mg/m2).
`8.3 Nursing Mothers
`
`It is not knoo/ whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times
`the potential for serous advere reactions in nursing infants from
`higher than iÌ materal serum. Because many drgs are excreted in human milk and because of
`
`everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importce of the drug to the mother.
`8.4 Pediatric Use
`
`The safety and effectiveness in pediatrc patients have not been established.
`8.5 Geriatric Use
`
`In the radomized study, 41 % of AFINITOR-treated patients were ~ 65 years in age, while 7% percent were 75 and over. No overall differences in safety or
`effectiveness were obsered between these subjects and younger subjects, and other reported clincal experience has not identified differences in responses between the
`elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see Clinical Pharmacology (12.3))
`
`No dosage adjustment is required in elderly patients (see Clinical Pharmacology (12.3))
`8.6 Renal Impairment
`
`No clinical studies were conducted with AFINITOR in patients with decreased renal fuction. Renal impairent is not expected to influence drug exposure and no
`dosage adjustment of everolimus is recommended in patients with renal impairent (see Clinical Pharmacology (/2.3))
`
`8.7 Hepatic Impairment
`
`For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily (see Dosage and Administration (2.2), Warnings and
`Precautions (5.6) and Clinical Pharmacology (12.3))
`
`The impact of severe hepatic impairent (Child-Pugh class C) has not been assessed and use in this patient population is not recommended (see Warnings and
`Precautions (5.6))
`10 OVERDOSAGE
`
`In animal studies, everolimus showed a low acute toxic potentiaL. No lethality or severe toxicity were obsered in either mice or rats given single oral doses of
`2000 mg/g (limit test).
`
`Reported experence with overdose in humans is ver limited. Single doses of
`dose was consistent with that for the 10 mg dose.
`11 DESCRIPTION
`
`AFINITOR (everolimus), an inibitor ofmTOR, is an antineoplastic agent.
`
`up to 70 mg have been admiistered. The acute toxicity profie obsered with the 70 mg
`
`The chemical name of everolimus is (\ R,9S,12S,15R,16E,18R,19R,2l R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-HlR)-2-((IS,3R,4R)-4-(2­
`hydroxyethoxy)-3-methoxycyclohexylj-1-methylethyl) -19,30-dimethoxy-15, 17,21,23 ,29,35-hexamethyl-ll ,36-dioxa-4-aza-tricyclo(30.3.1.04.9jhexatriaconta­
`l6,24,26,28-tetrene-2,3, 1 0, 14,20-pentaone.
`
`
`The molecular formula is CsiHsJNOl4 and the molecular weight is 958.2. The structural formula is
`
`H¡C,
`
`;:
`
`f''''l
`'t~o
`
`0",
`
`

`

`AFINITOR is supplied as tablets for oral administration containing 2.5 mg, 5 mg and 10 mg of everolimus together with butylated hydroxytoluene, magnesium stearate,
`lactose monohydrate, hypromellose, crospovidone and lactose anhydrous as inactive ingredients.
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`the PI3K/AKT pathway. The mTORpathway is
`Everolimus is an inibitor ofmTOR (mammalian target ofrapamycin), a serine-threonine kiase, downstream of
`
`dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation and inhibition ofmTOR
`kinase activity. Everolimus reduced the activity of S6 ribosomal protein kiase (S6KI) and eukarotic elongation factor 4E-binding protein (4E-BP), downstream
`effectors of mTOR, involved in protein synthesis. In addition, everolimus inibited the expression of hypoxia-inducible factor (e.g., HIF-l) and reduced the expression
`of vascular endothelial growth factor (VEGF). Inibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in
`vitro and/or in vivo studies.
`12.2 Pharmacodynamics
`
`QT/QTc Prolongation Potential
`
`In a randomized, placebo-controlled, crossover study, 59 healthy subjects were adminstered a single oral dose of AFINITOR (20 mg and 50 mg) and placebo. There is
`
`no indication ofa QT/QTc prolonging effect of AFINITOR in single doses up to 50 mg.
`
`
`Exposure Response Relationships
`
`
`Markers of protein synthesis show that inibition ofmTOR is complete after a 10 mg daily dose.
`
`12.3 Pharmacokinetics
`
`Absorptìon
`
`In patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to