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
`
`----------------------------INDICATIONS AND USAGE---------------------------
`AFINITOR is a kinase inhibitor indicated for the treatment of patients with
`advanced renal cell carcinoma after failure of treatment with sunitinib or
`sorafenib. (1)
`
`
`------------------------DOSAGE AND ADMINISTRATION---------------------
`
`• 10 mg once daily with or without food. (2.1)
`
`
`
`• Treatment interruption 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 of 20 mg once daily. (2.2)
`
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`5 mg and 10 mg tablets with no score. (3)
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`Hypersensitivity to everolimus, to other rapamycin derivatives, 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)
`
`• 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
`
`woman. Apprise women of potential harm to the fetus. (5.8, 8.1)
`
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common adverse reactions (incidence ≥30%) are stomatitis, infections,
`asthenia, fatigue, cough, and diarrhea. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch
`
`
`
`------------------------------DRUG INTERACTIONS-------------------------------
`
`• 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 POPULATIONS------------------------
`
`• Nursing mothers: Discontinue drug or nursing, taking into consideration
`the importance 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 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
`
`
`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 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 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
`
`
`
`Revised: 07/2009
`
`
`
`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 failure 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
`without food [see Clinical Pharmacology (12.3)]. AFINITOR tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed.
`
`
`Continue treatment as long as clinical 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 Specific
`Populations (8.7)].
`Strong CYP3A4 Inducers: Avoid the use of concomitant strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital).
`
`
`If patients require co-administration of a 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 observed without inducers. However, there are no
`
`clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the 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 mg tablet
`
`
`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 “UHE” on one side and “NVR” on the other.
`
`
`4 CONTRAINDICATIONS
`
`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 interrupting 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 AFINITOR 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 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 candidiasis, have
`occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory failure) or fatal. Physicians and patients should be aware
`of the increased risk of infection with AFINITOR, be vigilant for signs and symptoms of infection and institute appropriate treatment 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 1 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 profile 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,
`clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir, voriconazole, aprepitant,
`erythromycin, fluconazole, grapefruit juice, verapamil or diltiazem) 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 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 been 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 Specific Populations (8.7)].
`5.7 Vaccinations
`The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines
`
`are: intranasal 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
`
`recommended dose of 10 mg daily. 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 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 Use in Specific 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=137) 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 61 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 abnormalities
`(incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4
`
`
`laboratory abnormalities (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 arm but none on the placebo arm. The rates of treatment-emergent
`
`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 during AFINITOR treatment were for
`
`
`infections, anemia, and stomatitis.
`Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% 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 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm
`
`AFINITOR 10 mg/day
`Placebo
`N=274
`N=137
`Grade 3
`Grade 3
`%
`%
`52
`23
`
`Grade 4
`%
`13
`
`All grades
`%
`93
`
`Grade 4
`%
`5
`
`
`
`All grades
`%
`97
`
`
`
`Any Adverse Reaction
`
`Gastrointestinal Disorders
`
`Stomatitis a
`
`44
`
`30
`Diarrhea
`
`26
`Nausea
`
`20
`Vomiting
`
`37
`Infections and Infestations b
`
`General Disorders and Administration Site Conditions
`
`Asthenia
`33
`
`Fatigue
`31
`
`Edema peripheral
`25
`
`Pyrexia
`20
`
`Mucosal inflammation
`19
`
`
`4
`1
`1
`2
`7
`
`3
`5
`<1
`<1
`1
`
`<1
`0
`0
`0
`3
`
`<1
`0
`0
`0
`0
`
`8
`7
`19
`12
`18
`
`23
`27
`8
`9
`1
`
`0
`0
`0
`0
`1
`
`4
`3
`<1
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`<1
`0
`0
`0
`
`

`

`
`
`AFINITOR 10 mg/day
`N=274
`Grade 3
`%
`
`Grade 4
`%
`
`All grades
`%
`
`Placebo
`N=137
`Grade 3
`%
`
`Grade 4
`%
`
`29
`14
`13
`
`25
`
`0
`3
`0
`0
`
`0
`0
`0
`
`<1
`
`<1
`0
`
`0
`60
`
`0
`0
`0
`0
`
`0
`0
`0
`
`0
`
`0
`0
`
`0
`
`All grades
`
`%
`
`Respiratory, Thoracic and Mediastinal Disorders
`
`
`Cough
`30
`
`Dyspnea
`24
`
`Epistaxis
`18
`Pneumonitis c
`
`
`14
`Skin and Subcutaneous Tissue Disorders
`
`
`Rash
`
`Pruritus
`
`Dry skin
`
`Metabolism and Nutrition Disorders
`
`
`
`Anorexia
`
`Nervous System Disorders
`
`19
`Headache
`
`10
`Dysgeusia
`
`Musculoskeletal and Connective Tissue Disorders
`
`
`
`Pain in extremity
`10
`Median Duration of Treatment (d)
`
`CTCAE Version 3.0
`
`a 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 (<1%), candidiasis (<1%), and sepsis (<1%).
`
`
`c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.
`
`
`
`<1
`6
`0
`4
`
`1
`<1
`<1
`
`1
`
`<1
`0
`
`1
`141
`
`0
`1
`0
`0
`
`0
`0
`0
`
`0
`
`<1
`0
`
`0
`
`16
`15
`0
`0
`
`7
`7
`5
`
`14
`
`9
`2
`
`7
`
`
`Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% 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%), chills (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 (<1%)
`
`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
`AFINITOR 10 mg/day
`Placebo
`N=274
`N=137
`All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
`%
`%
`%
`%
`%
`%
`
`
`
`
`
`
`92
`12
`1
`79
`5
`<1
`51
`16
`2
`28
`5
`0
`23
`1
`0
`2
`0
`<1
`14
`0
`<1
`4
`0
`0
`
`
`
`
`
`
`
`Hematologya
`
`
`Hemoglobin decreased
`
`Lymphocytes decreased
`Platelets decreased
`
`
`Neutrophils decreased
`
`Clinical Chemistry
`
`

`

`77
`73
`57
`50
`37
`25
`21
`3
`
`4
`<1
`15
`1
`6
`<1
`1
`<1
`
`0
`0
`<1
`0
`0
`<1
`0
`<1
`
`35
`34
`25
`34
`8
`7
`4
`2
`
`0
`0
`1
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`
`erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively.
`
`
`
`Cholesterol increased
`
`Triglycerides increased
`
`Glucose increased
`
`
`Creatinine increased
`
`Phosphate decreased
`
`Aspartate transaminase (AST) increased
`
`Alanine transaminase (ALT) increased
`
`Bilirubin increased
`
`CTCAE Version 3.0
`a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia.
`
`7 DRUG INTERACTIONS
`
`Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of
`
`CYP3A4 and a mixed inhibitor of CYP2D6.
`7.1 Agents that may Increase Everolimus 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 coadministered with:
`
`
`ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-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 or moderate inhibitors of CYP3A4 and PgP inhibitors should not be used [see Warnings and Precautions (5.5)].
`
`
`7.2 Agents that may Decrease Everolimus Blood Concentrations
`
`CYP3A4 Inducers: In healthy subjects, co-administration 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 or PgP if
`alternative treatment cannot be administered [see Dosage and Administration (2.2) and Warnings and Precautions (5.5)].
`7.3 Agents whose Plasma Concentrations may be Altered by Everolimus
`Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic 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 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
`
`recommended dose of 10 mg daily. 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 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 of live 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 (AUC0-24h) 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.
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`In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose
`
`
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`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 ≥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
`
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`natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2).
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`8.3 Nursing Mothers
`
`
`It is not known 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
`
`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
`everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
`8.4 Pediatric Use
`
`The safety and effectiveness in pediatric patients have not been established.
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`8.5 Geriatric Use
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`
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`In the randomized study, 41% of AFINITOR-treated patients were ≥ 65 years in age, while 7% percent were 75 and over. No overall differences in safety or
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`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)].
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`
`No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3)].
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`

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`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)].
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`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/kg (limit test).
`
`Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg
`
`dose was consistent with that for the 10 mg dose.
`
`11 DESCRIPTION
`AFINITOR (everolimus), an inhibitor of mTOR, is an antineoplastic agent.
`
`
`The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2­
`hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta­
`16,24,26,28-tetraene-2,3,10,14,20-pentaone.
`
`The molecular formula is C53H83NO14 and the molecular weight is 958.2. The structural formula is
`
`
`AFINITOR is supplied as tablets for oral administration containing 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
`
`Everolimus is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is
`
`
`
`dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation and inhibition of mTOR
`
`kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP), downstream
`
`
`effectors of mTOR, involved in protein synthesis. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression
`of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in
`vitro and/or in vivo studies.
`
`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 of a 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, Cmax is dose-proportional between 5 mg and 10 mg. At doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however
`
`AUC 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: In healthy subjects, high fat meals reduced systemic exposure to Afinitor 10 mg tablet (as measured by AUC) by 22% and the peak plasma concentration
`
`Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the post absorption phase concentration-time profile..
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`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 of CYP3A4 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
`
`everolimus itself.
`
`In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. The mean steady-state
`
`Cmax following an oral dose of 10 mg daily is more than 12-fold below the Ki-values of the in vitro inhibition. Therefore, an effect of everolimus on the metabolism of
`
`
` CYP3A4 and CYP2D6 substrates is unlikely.
`
`Excretion
`No specific excretion studies have been undertaken in cancer patients. Following the admini