CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`APPLICATION NUMBER:
`22-334
`22-334
`
`LABELING
`LABELING
`
`

`

`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
`
`----------------------- INICA TI 0 NS AND USA GE----------------------
`AFINITOR is a kinase inhibitor indicated for the treatment of patients with
`advanced renal cell carcinoma after failure of treatment with sunitinib or
`sorafenib. (I)
`
`---------------------DOSAGE AND ADMINISTRA TION-----------------
`. 10 mg once daily with or without food. (2.1)
`. Treatment interrption and/or dose reduction to 5 mg once daily may be
`needed to manage adverse drug reactions. (2.2)
`. For patients with Child-Pugh class B hepatic impairment, reduce dose 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)
`
`------------------DOSAGE FORMS AND STRENGTHS--------------------
`5 mg and 10 mg tablets with no score. (3)
`
`----------------------------CONTRAIND I CA TI 0 NS--------------------------
`Hypersensitivity to everolimus, to other rapamycin derivatives, or to any of
`the excipients. (4)
`
`-------------------- WARNINGS AND PRECA UTIONS--------------------
`. 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)
`. Infections: Increased risk of infections, some fataL. Monitor for signs and
`symptoms, and treat promptly. (5.2)
`
`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
`INICATIONS
`4 CONTRA
`5 WARNINGS AND PRECAUTIONS
`5.1 Non-infectious Pneumonitis
`5.2 Infections
`5.3 Oral Ulceration
`5.4 Laboratory Tests and Monitoring
`5.5 Drug-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 IncreaseEverolimus 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
`
`. 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 contactwith those who have
`received live vaccines. (5.7)
`. Use in pregnancy: Fetal harm can occur when administered to a pregnant
`potential harm to the fetus. (5.8, 8.1)
`
`woman. Apprise women of
`
`---------------------------ADVERSE REA CTI 0 NS---------------------------
`Most common adverse reactions (incidence ~30%) are stomatitis, infections,
`asthenia, fatigue, cough, and diarrhea. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporatiou at 1-888-669-6682 or FDA at
`1-800-FDA-I088 or ww.fda.gov/medwatch
`
`----------------------------- DRUG INTERA CTI ONS---------------------------
`. Strong and moderate CYP3A4 or PgP inhibitors: Avoid concomitant use.
`(5.5,7.1)
`. Strong CYP3A4 inducers: Avoid concomitant use. If combination cannot
`be avoided, increase dose of AFINITOR. (2.2, 7.2)
`
`--------------------USE IN SPECIFIC POPULA TIONS--------------------
`. Nursing mothers: Discontinue drug or nursing, taking into consideration
`the importnce of drug to the mother. (8.3)
`. Hepatic impairment: AFINITOR should not be used in patients with Child-
`Pugh class C hepatic impairment. For patients with Child-Pugh dass 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: 03/2009
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL 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 Monitoring
`17.5 Drug-drug Interactions
`17.6 Hepatic Impairment
`17.7 Vaccinations
`17.8 Pregnancy
`17.9 FDA-approved Patient Labeling
`· Sections or subsections omitted from the full prescribing information are
`not listed
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`AFINITOR~ is indicated for the treatment of patients with advanced renal cell carcinoma after fail ure of treatment with sunitinib or sorafenib.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dose
`
`The recommended dose of AFINITOR for treatment of advanced renal cell carcinoma is 10 mg, to be taken once daily at the same time every day, either with or
`water. The tablets should not be chewed or
`without food (see Clinical Pharmacology (J 2.3)) AFINITOR tablets should be swallowed whole with a glass of
`crushed.
`
`Continue treatment as long as clinic.al benefit is observed or until unacceptable toxicity occurs.
`
`2.2 Dose Modifications
`
`Management of severe and/or intolerable adverse reactions may require temporary dose reduction and/or interruption of AFINITOR therapy. If dose reduction is
`required, the suggested dose is 5 mg daily (see Warnings and Precautions (5.1))
`
`Hepatic impairment: For patients with moderate 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))
`
`Strong CYP 3A4 inducers: A void the use of concomitant strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,
`phenobarbital). If patients require co-administration of a strong CYl3A4 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 AVC to the range observed without inducers.
`However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. Ifthe strong inducer is discontinued, the AFINITOR
`dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer (see Drug Interactions (7.2)).
`
`3 DOSAGE FORMS AND STRENGTHS
`
`5 mgtablet
`White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved 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, engraved with "VHE" on one side and "NVR" on the other.
`
`4 CONTRA
`
`INDICATIONS
`
`Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of 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) have
`been observed with everolimus and other rapamycin derivatives.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Non-infectious Pneumonitis
`
`Non-infectious pneumonitis is a class effect of rapamycin 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) grade 3 and 4 non-infectious pneumonitis was 4% and 0%,
`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 such as hypoxia, pleural effusion,
`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.
`
`Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without
`dose 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
`reduced dose of 5 mg daily depending on the individual clinical circumstances.
`symptoms resolve. Therapy with AFINITOR may be re-initiated at a
`
`5.2 Infections
`
`AFINITOR has immunosuppressive properties and may predispose patients to infections, especially infections with opportunistic pathogens (see Adverse
`Reactions (6.1)) Localized and systemic infections, including pneumonia, other bacterial infections and invasive fungal infections, such as aspergillosis or
`these infections have been severe (e.g., leading to respiratory failure) or fataL. Physicians and
`candidiasis, have occurred in patients taking AFINITOR. Some of
`infection and institute appropriate treatment
`patients should be aware of the increased risk of infection with AFINITOR, be vigilant for signs and symptoms of
`promptly. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with 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. In the randomized study, approximately 44% of AFINITOR-
`treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade i and 2 (see Adverse Reactions (6.1)) In such cases, topical
`treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should
`not be used unless fungal infection has been diagnosed (see Drug 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)). Monitoring of renal function, including
`measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.
`
`Blood Glucose and Lipids
`
`Hyperglycemia, hyperlipidemia,. and hypertriglyceridemia have been reported in clinical trials (see Adverse Reactions (6.1)) Monitoring of fasting serum glucose
`and lipid profie is recommended prior to the start of AFINITOR therapy and periodically 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)). Monitoring 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-administration with strong or moderate inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole,
`c1arithromycin, ataznavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir, voriconazole,
`aprepitant, eryhromycin, fluconazole, grapefruit juice, verapamil or diltazem) or P-glycoprotein (PgP) should be avoided (see Drug Interactions (7.1))
`
`An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer (e.g., dexamethasone, phenytoin, carbamazepine,
`rifampin, rifabutin, phenobarbital) (see Dosage and Administration (2.2) and Drug Interactions (7.2))
`
`5.6 Hepatic Impairment
`
`The safety and phannacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight
`subjects with nonnal hepatic function. Exposure was increased in patients with moderate hepatic impainnent, therefore a dose reduction is recommended.
`
`AFINITOR has not been studied in patients with severe hepatic impainnent (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))
`
`5.7 Vaccinations
`
`The use oflive vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples oflive
`vaccines are: intranasal influenz, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY2 i a 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 har
`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 apprised
`recommended dose of 10 mg daily. Ifthis drug is used during pregnancy or if
`of the potential hazrd to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and
`for up to 8 weeks after ending treatment (see Us.e in Specifc Populations (8.1))
`
`6 ADVERSE REACTIONS
`
`The following serious 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)).
`
`6.1 Clinical Studies Experience
`
`Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and
`may not reflect the rates observed in clinical practice.
`
`The data described below reflect exposure to AFINITOR (n=274) and placebo (n=1 37) in a randomized, controlled trial in patients with metastatic renal cell
`carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 6 I years (range 27-85), 88% were Caucasian, and 78%
`were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those
`receiving placebo.
`
`The most common adverse reactions (incidence ::30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse
`reactions (incidence ::3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory
`abnonnalities (incidence ::50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most
`common grade 3/4 laboratory abnonnalities (incidence ::3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths
`due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the AFINITOR ann but none on the placebo ann. The
`rates of treatment-emergent adverse events (irrespective of causality) resulting in pennanent discontinuation were i 4% 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
`during AFINITOR treatment were for infections, anemia, and stomatitis.
`
`Table i compares the incidence of treatment-emergent adverse reactions reported with an incidence of::l0% 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.
`Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm
`
`Table 1 Adverse Reactions Reported in at least 10% of
`
`AFINITOR 10 mg/day
`N=274
`
`All grades
`%
`
`97
`
`Grade
`
`3
`
`Grade
`
`4
`
`%
`
`52
`
`%
`
`13
`
`All grades
`%
`
`93
`
`Placebo
`N=137
`
`Grade
`
`3
`
`%
`
`23
`
`Grade
`
`4
`
`%
`
`5
`
`Any Adverse Reaction
`
`

`

`All grades
`%
`
`AFINITOR 10 mg/day
`N=274
`
`Grade
`
`3
`
`Grade
`
`4
`
`%
`
`4
`
`I
`
`I
`
`2
`
`7
`
`3
`
`5
`~i
`~I
`
`~I
`6
`
`%
`
`~i
`0
`0
`0
`
`3
`
`~i
`0
`
`0
`0
`0
`
`0
`
`I
`
`All grades
`%
`
`8
`
`7
`
`19
`
`12
`
`18
`
`23
`27
`
`8
`9
`
`I
`
`16
`
`15
`
`Placebo
`N=137
`
`Grade
`
`3
`
`%
`
`0
`0
`0
`0
`
`I
`
`4
`
`3
`~i
`0
`0
`
`0
`
`3
`
`Grade
`
`4
`
`%
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`~i
`0
`0
`
`0
`
`0
`
`Gastrointestinal Disorders
`Stomatitis 0
`Diarrhea
`Nausea
`Vomiting
`Infections and Infestations b
`General Disorders and Administration Site Conditions
`Asthenia
`33
`Fatigue
`Edema peripheral
`
`44
`30
`26
`20
`37
`
`31
`
`25
`20
`Pyrexia
`Mucosal inflammation
`19
`Respiratory, Tboracic and Mediastinal Disorders
`Cough
`30
`24
`
`18
`
`14
`
`29
`14
`
`13
`
`Dyspnea
`Epistaxis
`Pneumonitis'
`Skin and Snbcutaneous Tissue Disorders
`Rash
`Pruritus
`Dry skin
`Metabolism and Nutrition Disorders
`Anorexia
`Nervous System Disorders
`Headache
`Dysgeusia
`10
`Musculoskeletal and Connective Tissue Disorders
`Pain in extremity
`
`25
`
`19
`
`10
`
`0
`4
`
`~I
`~I
`
`~I
`0
`
`I
`
`141
`
`0
`
`0
`
`0
`0
`0
`
`0
`
`~I
`0
`
`0
`
`0
`
`0
`
`7
`
`7
`
`5
`
`14
`
`9
`2
`
`7
`
`0
`0
`
`0
`0
`0
`
`~i
`
`~I
`0
`
`0
`60
`
`0
`
`0
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`0
`
`0
`
`Median Duration of Treatment (d)
`
`CTCAE Version 3.0
`o Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration.
`b Includes all preferred terms within the 'infections and infestations' system organ class, the most common being nasopharyngitis (6%), pneumonia (6%),
`
`urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (~i %), candidiasis (~L %), and sepsis (~I %).
`, Includes pneumonitis, interstitial lung disease, lung infitration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.
`
`Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of ~I 0% include:
`
`Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)
`
`General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chils (4%)
`
`Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%)
`
`Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema
`(4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%)
`
`Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (~I %)
`
`Nervous system disorders: Insomnia (9%), dizziness (7%), paresthesia (5%)
`
`Eye disorders: Eyelid edema (4%), conjunctivitis (2%)
`
`Vascular disorders: Hypertension (4%)
`
`Renal and urinary 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 Higher rate in the AFINITOR Arm than the Placebo Arm
`
`Laboratory Parameter
`
`Hematology'
`Hemoglobin decreased
`Lymphocytes decreased
`Platelets decreased
`Neutrophils decreased
`Clinical Chemistry
`
`Cholesterol increased
`Triglycerides increased
`Glucose increased
`Creatinine increased
`
`Phosphate decreased
`
`Aspartte transaminase (AST) increased
`
`Alanine transaminase (AL T) increased
`Bilirubin increased
`
`AFINITOR 10 mglday
`N=274
`
`Placebo
`N=137
`
`All grades
`%
`
`3
`
`Grade
`%
`
`Grade
`%
`
`4 All grades
`%
`
`3
`
`Grade
`%
`
`4
`
`Grade
`%
`
`92
`51
`
`23
`
`14
`
`77
`73
`57
`50
`37
`25
`
`21
`
`3
`
`12
`
`16
`
`I
`
`0
`
`4
`
`-:1
`
`15
`
`I
`
`6
`
`-:1
`
`-:1
`
`I
`
`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
`
`I
`
`0
`0
`0
`0
`0
`
`-:1
`
`0
`
`-:1
`
`0
`
`0
`0
`0
`
`0
`
`0
`0
`0
`
`0
`
`CTCAE Version 3.0
`. Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia.
`
`7 DRUG INTERACTIONS
`
`Everolimus is a substrate ofCYP3A4, and also a substrate and moderate inhibitor ofthe multi
`of CYP3A4 and a mixed inhibitor of CYP2D6.
`
`7.1 Agents that may Increase Everolimus Blood Concentrations
`
`drug effux pump PgP. In vitro, everolimus is a competitive inhibitor
`
`CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone there were significant increases 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) - Cm.. and AVC increased by 2.0- and 4.4-fold, respectively.
`
`verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cm.. and AVC increased by 2.3-and 3.5-fold, respectively_
`
`Concomitant strong or moderate inhibitors ofCYP3A4 and PgP inhibitors should not be used (see Warnings and Precautions (5.5)l
`
`7.2 Agents that may Decrease Everolimus Blood Concentrations
`
`CYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer ofCYP3A4, decreased everolimus AVC and Cm.. by 64%
`and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 or
`PgP if alternative treatment cannot be administered (see Dosage and Administration (2.2) and Warnings and Precautions (5.5)l
`
`7.3 Agents whose Plasma Concentrations may be Altered by Everolimus
`
`Studies in healthy subjects indicate that there are no clinically significant pharacokinetic interactions between AFINITOR and the HMG-CoA reductase
`inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of
`simvastatin (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 mechani1;m 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
`recommended dose of I 0 mg daily. If this drug is used during pregnancy or ifthe patient becomes pregnant while taking the drug, the patient should be apprised
`of the potential hazard to the 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 rats before mating and through organogenesis induced embryo-fetal toxicities,
`including increased resorption, pre-implantation and post-implantation loss, decreased numbers oflive fetuses, malformation (e.g., sternal cleft) and retarded
`skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AVCO_24h)
`in patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions 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
`In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of
`dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal 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 parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.
`
`Doses that resulted in embryo-fetal toxicities in rats and rabbits were ~O. I 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 O. I mg/g (0.6 mg/m2).
`
`8.3 Nursing Mothers
`
`It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk oflactating rats at a concentration 3.5 times
`higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from
`to discontinue the drug, taking into account the importnce of the drug to the mother.
`everolimus, a decision should be made whether to discontinue nursing or
`
`8.4 Pediatric Use
`
`The safety and effectiveness in pediatric patients have not been established.
`
`8.5 Geriatric Use
`
`In the randomized study, 4 I % of AFINITOR-treated patients were ~ 65 years in age, while 7% percent were 75 and over. No overall differences in safety or
`effectiveness were observed between these subjects and younger subjects, and other reported clinical 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 function. Renal impairment is not expected to influence drug exposure and no
`dosage adjustment of everolimus is recommended in patients with renal impairment (see Clinical Pharmacology (12.3))
`
`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 impairment (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 observed in either mice or rats given single oral doses of
`2000 mg/g (limit test).
`
`Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profie observed with the
`70 mg dose was consistent with that for the 10 mg dose.
`
`11 DESCRITION
`
`AFINITOR (everolimus), an inhibitor ofmTOR, is an antineoplastic agent.
`
`The chemical name of everolimus is (I R,9S, 1 2S, 1 5R,1 6E, 1 8R,1 9R,21 R,23S,24E,26E,28E,30S,32S,35R)- 1,18- dihydroxy- 12-( (I R)-2-((I S,3R,4R)-4-(2-
`ethyl )- 1 9,30-dimethoxy-15, 1 7,2 1 ,23,29,35-hexamethyl- 1 1 ,36-dioxa-4-aza-tricyclo(30.3. 1 .04.9Jhexatriaconta-
`hydroxyethoxy)-3-methoxycyclohexyIJ- 1 -methyl
`16,24, 26,28-tetraene-2,3, 10,1 4,20-pentaone.
`
`The molecular formula is CS3H8JNOI4 and the molecular weight is 958.2. The structural formula is
`
`l.
`
`LC
`
`H3
`
`H3C,
`
`o
`
`H.C
`
`CH:
`
`

`

`AFINITOR is supplied as tablets for oral administration containing 5 mg and 10 mg of everolimus together with butylated hydroxy
`lactose monohydrate, hypromellose, crospovidone and lactose anhydrous as inactive ingredients.
`
`toluene, magnesium stearate,
`
`12 CLINICAL PHARMCOLOGY
`
`12.1 Mechanism of Action
`
`the Pl3K1AKT pathway. The mTOR pathway is
`Everolimus is an inhibitor ofmTOR (mammalian target ofrapamycin), a serine-threonine kinase, downstream of
`dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP- 1 2, resulting in an inhibitory complex formation and inhibition of
`mTOR kinase activity. Everolimus reduced the activity ofS6 ribosomal protein kinase (S6KI) and eukaryotic elongation factor 4E-binding protein (4E-BP),
`hypoxia-inducible factor (e.g., HIF-l) and
`downstream effectors ofmTOR, involved in protein synthesis. In addition, everolimus inhibited the expression of
`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.
`
`12.2 Pharmacodynamics
`
`QT/QTc Prolongation Potential
`
`In a randomized, placebo-controlled, crossover study, 59 healthy subjects were administered 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 inhibition of mTOR is complete after a 10 mg daily dose.
`
`12.3 Pharmacokinetics
`
`Absorption
`
`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 70 mg.
`Following single doses, Cmox is dose-proportional between 5 mg and 10 mg. At doses of20 mg and higher, the increase in Cm" is less than dose-proportional,
`however AVC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within two weeks following once-daily dosing.
`
`Food effect: Based on data in healthy subjects taking I mg everolimus tablets, a high-fat meal reduced Cm"and AVC by 60% and 16%, respectively. No data are
`available with AFINITOR 5 mg and 10 mg tablets.
`
`Distribution
`
`The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus
`confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given AFINITOR 10 mg/day. Plasma protein binding is
`approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.
`
`Metabolism
`
`Everolimus is a substrate ofCYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main
`metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a
`phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-
`times less activity than everol imus itself.
`
`In vitro, everolimus competitively inhibited the metabol ism of CYP3A4 and was a mixed inhibitor of the CYl2D6 substrate dextromethorphan. The mean steady-
`state Cmox following an oral dose of 10 mg daily is more than 12-fold below the Ki-values ofthe in vitro inhibition. Therefore, an effect of everolimus on the
`metabolism ofCYl3A4 and CYP2D6 substrates is unlikely.
`
`Excretion
`
`No specific excretion studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabelled everolimus in patients
`who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not
`detected in urine or feces. The mean elimination half-life of everolimus is approximately 30 hours.
`
`Patients with Renal Impairment
`
`total radioactivity was excreted in the urine following a 3 mg dose of (I4CJ-Iabeled everolimus. In a population phai:acokinetic analysis
`Approximately 5% of
`which included 170 patients with advanced cancer, no significant influence of creatinine clearance (25 - 178 mL/min) was detected on oral clearance (CL/F) of
`everolimus (see Use in Specifc Populations (8.6)).
`
`Patients with Hepatic Impairment
`
`The average AVC of everolimus in eight subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in eight subjects with normal
`prothrombin time and negatively correlated with
`hepatic function. AVC was positively correlated with serum bilirubin concentration and with prolongation of
`serum albumin concentration. A dose