FULL PRESCRIBING INt'ORMA TION
`
`I 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
`
`?.1 Recommended Dooe
`The recommended dose or AFINITOR for treatment of advanced renal cell carcinoma is 10 mg, to be C!ken once daily at ihe same time every day, either with or
`without food {see Clinical Pharmacology (I 1.3)). 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 ModlOcatlons
`
`Management of severe and/or intolerable adverse reactions may require temporary dose reduction and/or interruption of AFlNITOR therapy. If dose reduction is
`required, the suggested dose is S mg daily {see Warnings nnd Precautions (5.1 )/.
`
`'
`Hepatic impairment: For patients with moderate hepatic impairment (Child-Pugh class B}, reduce the dose to.S mg daily. AFINITOR has not been evaluated in
`patients with severe hepatic impairment (Child-Pugh class C) and shouldcnot be used in !his patient population [!ee Warnings and Precautinns (5.6) and Use in
`Specific Populations (8. 7)].
`
`Srrong CYPJA.4 inducers: Avoid the use of concomitant strong CYP3A4 inducers (e.g., dcxamelhasone, phenytoin, carbamazepine, rifampin, rifabutin,
`phenobarbital). If patients require co-administration of a strong CYP3A4 inducer, consider increasing the AFINJTOR dose from 10 mg daily up to 20 mg daily
`(based on pharmacokinetic data), using S mg increments. This dose of AFINITOR is predicted tO adjust !he AUC to the range observed without inducers.
`However, there arc no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued, lhe AFINITOR
`dose should be rewmed to the dose used prior to initiation of the strong CYP3A4 inducer [see Drug /nteractinns (7.2)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`S mg tablet
`White to slightly yellow. elongated tablelS with a bevelled edge and no score, 'engraved with "S" on one side and "NVR" on the other.
`
`10 mg tablet
`.
`White to slightly.yellow, elongated tablcl~ with a hevelled edge and no score. engraved .with."UHE" on one side: and "NVR" on the other.
`
`4 CONTRAINDICATIONS
`
`Hypersensitivity to the active substance, to other rnpamycin derivatives, or to any of the cxcipients. Hypersensitivit}- reactions manifested by symptoms including,
`but not limited to, anaphylaxis, dyspnea. flushing, chest pain, or angioederna (e.g., swelling of the airways or tongue, with or without respiratory impairment) have
`been observed with eve1olimus and other rapamycin derivatives.
`
`5 WARNlNGS AND PRECAUflONS
`
`5.1 Non-fnrect1ou1 Pneumonltls
`
`Non-infectious pneumonitis is a class effect of rapam»cin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonilis was reported in
`14% of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonilis was 4% and 0%,
`·
`respectively [see Adverse Reactions (6. /)}. Fatal outcomes have been observed.
`
`Consider a diagnosis of non-infectious pneumonitis.in palients presenting with non-specific respiratory signs and sym·ptoms such as hypoxia, pleural effusion,
`cough, or dyspnea, and in whom infectious, neoplastic, and oilier causes have been excluded by means of appropriate investigations. Advise patients to report
`promptly any new or worsening respiratory symptoms.
`
`Patients who develop radiological c!ianges suggestive ofnon-in_fectious 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 S mg daily.
`
`For cases where symptoms of non-infectious pneumonitis nre 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.
`
`S.2 Jnfecdon1
`
`AF!NITOR has immunosuppressive properties and may predispose patienlS to infections, especially infec1ions with opponunistic pathogens {see Adverse
`Reacti(JllJ (6.1 )]. Localized an1hystemic infections, including pneumonia, other bacterial infections and invasive fungal infections, such. as aspergillosis or
`C11ndidiasis, have occurred in patiems taking AflNITOR. 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 instilllte appropriate trealmcnt
`promptly. Complete lreatment of pre-existing invasive fungal infections prior to stllrting treatment with AFINITOR. lf a diagnosis of invasive systemic fungal
`infection is made, dimintinue AFINITOR and treat with appropriate antifwigal therapy.
`
`5.3 Oral Ulceration
`
`Mouth ulcers, stomalitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized study, approximately 44% of AFINITOR(cid:173)
`treated patients deveh~ped mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade I and 2 [see Adverse Reaclio11s (6. I JI. In such-cases, 1opical
`treatments are recommended, but akohol- 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 ln1erac1ions (7. I)].
`
`5.4 Labt>ratory Tests and Moailorlng
`
`Renal Funcrion
`
`
`
`

`
`Elevations of serum creatinine, usually mild, have been reponed in clinical !rials [see Adverse Reactions (6.1 )] . Monitoring of renal function, including
`measurement of blood unca nitrogen (DUN) or scrum crcatininc, is recommended prior to the start of AFINITOR therapy and periodically thereafter.
`
`Blood Glucose and lipids
`
`Hyperglycemia. hyperlipidcmia, and hypenriglyceridemia have been reported in clinical trials [see Atlwrse Reactions (6. /)]. Monitoring of fasting scrum glucose
`and lipid profile is recommended prior to the start of AFINITOR therapy nnd periodirolly thereafter. When possible, optimal glucose and lipid control sllould be
`achieved before staning a patient on AFINITOR.
`
`Hematological Ptlrameten
`
`Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been rcpor1Cd in clinical trials {ue· Adverse Reactions (6.1 )]. Monitoring of complete blood
`coum is reco.mmended prior to the s!Brt of AFINITOR therapy and periodically thereafter.
`
`S.5 Drug-drug lnaractlons
`
`Due to significant inaeases in exposure of everolimus, co-administration with strong or moderate inhibitors of CYP3A4 (e.g., ketoconazole, itraconaz.ole,
`clarithromycin, atazanavir: nefazodone, saquinavir, telithromycin, ritonavir, arnprcnavir, indinavir, nelflnavir, dclavirdinc, fosamprenavir, voriconazolc,
`aprcpimnt, crythromycin, fluconazole, grapefruitjuice, verapamil or diltazem) or P-glycoprotein (PgP) should be avoided {see Drug Interactions (7. /jj.
`
`An increase in the AFINITOR dose is recommended when c~administered with a strong CYP3A4 inducer (e.g., dcxamethasonc, phcnytoin, carbamazepine,
`rifnmpin, rifubutin, phenobarbital) [see Dosage and Adminisrration (2.2) and Drug lntl!rattions (7.2jj.
`
`S.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
`subjcclS with nonnal hepatic fonction. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended.
`
`AFINITOR has not been.studied in palients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population [see. Dosage nnd
`·
`Administration (2.2) and Use in Specific Popu/alions (8. 7)].
`
`5.7 Vai:dnatlon1
`
`The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatrncnl with AFINITOR. Examples oflive
`vaccines are: intranasal innuenza. measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY2la typhoid vaccines.
`
`5.8 Use In Prqoancy
`
`Pregnancy Categoiy D
`
`There are no adequate and well-<:entrolled studies of AFINJTOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm
`when administered to.a.pregnant woman. Everolimus causal embryo-fellll 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 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 Ill use an effective method of contraceptfon while using AFINITOR and
`for up to 8 weeks after ending treatment [see Use in Specific Populations (8. l)j.
`'
`
`6 ADVERSE REACTIONS
`
`The following serious adverse reactions are discussed in greater detail in another section of the label:
`
`Non-infectious pncumonitis {see Warnings and Prec.aulions (5.l)j.
`
`Infections {see Warnings and Precaution.< (5.1)].
`
`6.1 Clinical Studies Experience
`
`Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared Ill 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=l 37) in a randomized, controlled trial in patients with metastatic renal cell
`carcinoma who received prior treatment with suni1inib and/or sorafenib. The m.,,;i'lll 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 19-45 I) for patients receiving AFINITOR and 60 days (range 21-295) for those
`receiving placebo.
`
`The most common advcn<: reaLiions (incidence ~/o) were stornatitis, infections, aslhenia, fatigue, cough, and.diarrhea. The most common grade 3/4 adverse
`~ons (incidence ~3%) were infections, dyspnea, fatigue, s!{)rnatitis .. dehydralion, pncumonitis, abdominal pain, and asthenia . .The most.common laboratory
`abnormalities (incidence 2:50%) were anemia, hypercholesterolemia, hypertriglyccridemia, hyperglycemia, lymphopenia, and increased creatinine. The most
`common grade 3/4 laboratory abnonnalitics (incidence ~3%) were lymphopenia, hyperglycemia, anemia, llypophosphatemia. and hypereholesterolemia. 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 anm. The
`rates of treatment-emergent adverse events (irrespective of causality) resulting in pcnnanent 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 pncumonitis and dyspnea.
`lnfec1ions, stomatitis, and pneumonitis were the most common reasons· for treatment delay or dose reduction. The most common medical interventions required
`during AFJNITOR treatment wen:: for infectiom, anemia, and stornatitis.
`Table I compares the incidence of 1reatmcnt-emergent adverse reactions rcponed with an incidence of~I 0% for patients receiving AFINITOR to mg daily ~us
`placebo. Within each MedDRA system organ class. the adverse reactions are presented in order of decreasing frequency.
`Table I
`Advene Reactiont Reported la at lust 10% 'of PatleolJ and •ta Hlgbrr R•te In the AFINITOR Arm than In the Placebo .Arm
`
`AFINITOR 10 mgfd•y
`N•274
`Grade)
`.,,.
`
`52
`
`All grades
`.,,.
`97
`
`Grade4
`
`AU grades
`
`%
`
`13
`
`%
`
`93
`
`Placebo
`N-137
`Grade3
`
`%
`
`23
`
`Grade4
`.,,.
`
`Any Adverse Reaction
`
`
`
`

`
`AFINITOR 10 ma/day
`Nn274
`Grade 3
`
`All grades
`
`Grade4
`
`All grades
`
`Placebo·
`N~137
`Gradel
`
`Grade4
`
`Gastrointestinal Dlsorden
`Stomatitis •
`Diarrhea
`Nausea
`Vomiting
`Infections and Infestations•
`
`%
`
`44
`30
`26
`20
`37
`
`General Disorders and Administration Site Conditions
`Aslhenia
`33
`31
`Fatigue
`Edema peripheral
`25
`Pyrexia
`20
`Mucosa! inflammation·
`19
`
`Respiratory, Thoracic and Medlastlnal Disorders
`Cough
`30
`24
`Dyspnea
`Epistaxis
`18
`Pneumonitis <
`14
`Skin· and Subcutaneous Tissue Dlsorden
`Rash
`Pruritus
`Dry skin
`
`29
`14
`13
`
`25
`
`MetaboUsm and Nutrition Disorders
`Anorexia
`Nervo111 System Disorders
`19
`Headache
`IO
`Dysgeusia
`Musculoskeletal and Connective Tissue Disorders
`Pain in extremily
`10
`Median Duration of Treatment (d)
`
`%
`
`4
`l
`
`<l
`<!
`
`<l
`6
`0
`
`<I
`<I
`
`<I
`
`141
`
`%
`
`<l
`0
`0
`0
`
`<l
`0
`0
`0
`0
`
`0
`
`0
`0
`
`0
`0
`0
`
`0
`
`<I
`0
`
`0
`
`%
`
`19
`12
`18
`
`23
`27
`8
`
`16
`IS
`0
`
`14
`
`"lo
`
`0
`0
`0
`0
`0
`
`0
`<I
`0
`0
`0
`
`0
`
`0
`0
`0
`
`0
`
`0
`0
`
`0
`
`0
`0
`0
`0
`
`<I
`0
`0
`
`0
`
`0
`0
`
`0
`0
`0
`
`<I
`
`<I
`0
`
`0
`60
`
`CTCAE Version 3.0
`• Stomatilis (including aphthous stomatitis), and mouth and tongue ulceration.
`•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%).
`• Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage. pulmonary toxicity, and alveolitis.
`
`Other notable adverse reactions occurring mere frequently.with .AFINITOR than with placebo, but with an incidence of <10"/o i:tclude:
`
`Gastrointestinal di,,.;rders: 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: Ple.ural effusion (7%), pharyngobuyngeal pain (4%). rhinorrhea (3%)
`
`Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmer-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erylherna
`(4%), onychoclasis (4%), skin lesion (4%), a1<neiforrn dermatitis (3%)
`
`Metabolism and nutrition disorders: Exacerbation of pre-existing .diabetes mellitus (2%), new onset of diabetes mellitus (<1 %)
`
`NerYous system disorders: Insomnia (9%), dizziness (7%), paresthesia (5%)
`
`Eye disorders: Eyelid edema (4%), conjunctivitis (2%)
`
`Vascutardisordtts: Hypertension (4%)
`
`Renal and urinary disorders: Renal failure (3%)
`
`Cardiac disorders: Tachycardia(3%), congcstiYc cardiac failure (I%)
`
`MuseuloskclC!al and connectiYc liSsue disorders: Jaw pain (3%)
`
`HemalOlogic disorders: Hemorrhage (3%)
`
`Key treatment-emergent laboratory abnormalities me presented in Table 2.
`
`
`
`

`
`Table 1
`
`Key Laboratory Abnormalllles Reported at a Higher rate In the AFINITOR Arm than the Placebo Arm
`
`Laboratory Parameter
`
`Hematology'
`Hemoglobin decreased
`L ymphocyteS decreased
`Platelets decreased
`Neutroph ils decreased
`
`Clinical Chemistry
`Cholesterol increased
`Triglycerides increased
`Glucose increased
`Creatinine increased
`Phosphate decreased
`Aspartate transaminase (AST) increased
`Alanine transaminase {ALT) increased
`Bilirubin increased
`
`Placebo
`AFINITOR JO mg/day
`N-137
`N°274
`All grades Grade3 Grade4 All grades Gradel Grade 4
`%
`%
`%
`%
`
`"o
`
`"·
`
`91
`51
`23
`14
`
`77
`73
`51
`50
`37
`15
`21
`3
`
`12
`16
`l
`
`<l
`15
`I
`6
`<!
`
`<l
`
`2
`0
`<I
`
`0
`0
`<I
`0
`0
`<l
`0
`<1
`
`79
`28
`
`35
`34
`25
`34
`
`4
`2
`
`5
`0
`0
`
`0
`0
`
`0
`0
`0
`0
`0
`
`<I
`0
`<I
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`
`CTCAE Version 3.0
`' Includes reports of anemia, leukopenia, lymphopenia, ncutropenia. pancylDpenia, thrombocytopenia.
`
`7 DRUG ll'ITERACTIONS
`
`Evcrolimus is a substrate ofCYP3A4, and also a substrate and modcralc inhibilDr of the multidrug cffiux pump PgP. /11 vitro, cverolimus is a competitive inhibitor
`of CYP3A4 and a mixed inhibitor of CYP2D6.
`
`7.1.Agents that may Increase Everollmus Blood Concentratloo1
`
`CYP3A4 /11/iibitors and PgP Inhibitors: ln healthy subjecu, compared to AFINITOR treatment alone there -re significant increases in evcrolimus exposure
`
`when AFINITOR was coadministercd with:
`
`·
`
`ketoconazole (a stcong 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) - c_, and AUC increased by 2.0- and 4.4-fold, respectively.
`verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor)~ C_, and AUC 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)}.
`
`7.1 Agents that may Decrease Everollmus Blood Concentrations
`CYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer orCYP3A4, decreased everolimus AUC and c_ by 64%
`und 58% respectively, compared lD evcrolimus treatment alone. Consider a dose increase or AFINITOR when co-administered with stcong inducers ofCYP3A4 or
`·
`·
`PgP if alternative treatment cannot be administered /see Dosage and Administration (2.2) and Warnings and PrecaUJions (5.5)}.
`
`7.3 Agenll whose Plasma Concentrations may be Altered by EveroUmus
`
`Studies in healthy subjects indicate that there arc no clinically significantpharmacokinetic interactions between AFINITOR and the HMG-CoA reductase
`inhibitors atorvasllltin (a CYP3A4 substrnte) and pravastatin {a non-CYPJA4 substrate) and population pharmacokinctic analyses also detected no influence of
`simvastatin {a CYP3A4 substrate) on the clearance of AFINJTOR.
`
`8 USE.IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy Category D [see Warnings and Precautions (5.8)) •
`
`There are no adequate and wcll..:ontrolled 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 !hat were lower than human exposures at the
`recommended dose of I 0 mg dili!y. tr 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 or childbearing.potential should be advised to use an elTcctive method of coniraception while receiving AFINITOR
`and for up to 8 weeks after ending treatment.
`
`In animal reproductive studies, oral adminisUlltion of everolimus to female rats before mating and through organogenesis induced embiyo-fetal toxicitie.,
`including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live retuscs, malformation (e.g., sternal cleft) and retarded
`skeletal development. These: elTects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC..m)
`in patients receiving the recommended dose of I 0 mg daily. In rabbits, cmbryotoxicity evident as an increase in rcsorpti~ns occurred at an oral dose approxi~ly
`1.6 times the recommended human dose on a body surface area basis. The clTect in rabbiu occurred in the presence of maternal toxicities.
`
`ln. a pre· ond post-naml development s1udy in rats, animals were dosed from imp!aniation through l.actation. At approximately IO"IG of the recommended human
`dose based on body surface area, there were no adverse elTccts on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced
`
`
`
`

`
`body weight (up to 9% reduction from !he control) and slight reduction in sutVival in olfspring (-5% died or missing). There "'-ere no drug-related elfccts on !he
`developmental parameters (morphological development, motor activity, learning, or fenility assessment) in the olfspring.
`
`Doses !hat resulted in embryo-fetal toxicities in rats and rabbits were~. I mg/kg (0.6 mgfm') and 0.8 mg/kg (9.6 mglm2
`), respectively. The dose in the pre- and
`post-natal development study in rats that caused reduction in body weights and survival of o!Tspring was 0.1 mg/kg (0.6 mg/m1
`).
`
`8.J Nu rsin11 Mothers
`
`It is not known whether evetolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk oflactating rats at a concentration 3.S times
`higher than in maternal serum. Because many drugs are excrell!d in human milk and because of the potential for serious adverse reactions in nursing infants from
`evcrolimus, a decision should be made whether to discontinue nursing or to discontinue lhe 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.
`
`8.5 Geriatric Use
`
`In the randomized srudy, 41% of AFINITOR-trea!ild patients were~ 6S 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 cxpcrierice hll! not identified dilferences 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 (11.3)].
`
`8.6 Renal Impairment
`
`No clinical studies were conducled 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 [ue Clinical Pliannacology (11.3)/.
`
`8. 7 Hepatic Impairment
`
`For patients with moderate hepatic impairment (Child-Pugh class B), the dose snould be reduced to S mg daily [see Dosage and Adminis1ration (2.2). Warnings
`and Precautions (J.6) and Clinical Pltannacology (12.3)].
`
`The impact of severe hepatic impairment (Cnild-Pugh class C) has not been assessed·and use in thiS patient population is not recommended [.•ee Warnings and
`Precautions (J.6)/.
`
`IO OVERDOSAGE
`
`In animal srudies, evetolimus sho\\-ed 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 vel)' limiled. Single doses of up to 70 mg have been administen:d. 1be acute toxicity profile observed with the
`70 mg do5e was eorisistent with that for the I 0 mg dose.
`
`11 DESCRIPTION
`
`AFINJTOR (everolimus), an inhibitor of mTOR, is an antineoplastic agent.
`
`The encmical name of evcrolimus is (IR,9S,12S,15R,16E,18R,19R.21R.23S,24E,26E,28E,30S,32S,35R}-l,18- dihydroxy-12·({1 R)-2-[(.IS,3R.4R)-4-{2-
`hydroxyethoxy)-3-methoxycyclobexyl]-l-methylcthyl}-l9,30-dimethoxy-1 S;l7,21,23,29,JS-heumethyl-l I ,36-dioxa-4-aza-tricyclo[30.3. I .O'·']iiexatriaconta-
`16,24, 26,28-tetr.>ene-2,3, I0, 14,20-pentaone.
`
`The molecular formula is C,,H,,NO,. and the molecular weight is 958.2. The structural formula is
`
`
`
`

`
`AFlNITOR is supplied as tablets for oral administration containing S mg and 10 mg of evcrolimus together with butylated hydroxytolucne. magnesiwn stearate.
`lactose monohydrate. hyprornellose. crospovidonc and lactose anhydrous as inactive ingredients.
`
`(
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Ai:tlon
`
`Everolimus is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the P!3KJAKT pathway. The mTOR path"11y is
`dysregulaled in several human cancers. Evcrolimus binds to an in1racellular protein, FKBP· 12, resulling_ in an inhibitory complex formation_ and inhibition of
`mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6KI) and eukaryotic elongation factor 4E-binding protein (4E-BP),
`downstream effectors of mTOR, involved in protein synthesis. In addition, e¥erolimus inhibited the expression of hypoxia-inducible facoor (e.g.; HIF-1) Md
`reduced the expression of vascular endothelial growth factor (VEGF). Inhibition ofmTOR by e\·erolimus has been shown to reduce cell proliferation,
`angiogcnesis, and glucose uptake in in vitro and/or in vivo studies.
`
`12.2 Pbarmacodynamla
`
`QTIQTc Prolonga1icn Potential
`
`In a randomized, placebo-controlled, crossover s1udy, 59 healthy subjects were administered a single oral dose of AFINITOR (20 mg and SO mg) and placebo.
`There is no indication of a QTIQTc prolonging effect of AFINITOR in single doses up to SO mg.
`
`£xpo1ure Re1po1ue Relationship•
`
`Markers of protein synthesis show that inhibition of mTOR is complete after a 10 mg daily dose.
`
`12.3 Pbarmacokinetlcs
`
`Abwrption
`
`In palients with advanced solid tumors, peak everolimus concentrations are reached I to 2 hours after administra1ion of orol doses ranging from S mg to 70 mg.
`Following single doses, C..., is dose-proportional between S mg and 10 mg. Al doses of20 mg and higher, the increase in C..... is less than dose-proportional,
`however AUC shows dose-proponionality over the S mg to 70 mg dose range. Slelldy-statc was achieved within two weeks following once-daily dosing.
`
`Food effect: Based on data in ncalthy subjects taking I mg cverolimus tablets, a high-fat meal reduced C .... and AUC by 60% and 16%, respectively. No data are
`available with AFINITOR S mg and JO mg tablets.
`
`Dutribution
`
`The blood-to-plasma ratio of everolimus, which is concentration-depcndi:nt over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of evcrolimus
`confined to the plasma is approximately 20'Yo at blood concentrations observed in cancer patients given AFINlTOR I 0 mg/day. Plasma protein binding is
`approximately 74% both in healthy ·Subjects and in patients witli rnodcra!e hepatic impairment
`
`Metabolum
`
`Everolimus is a substrate ofCYP3A4 and PgP. Following oral administration, everolimus is the main circulaling component in human blood. Six main
`melaboliles of evcrolimus have been detected in human blood, including three rnonohydroxylated metabolites, lwo hydrolytic ring-opened products, and a
`phospllatidylcholinc 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 melllbolism of CYP3A4 and was a mixed inhibitor of !he CYP2D6 substrate dcxtromcthorpban: The mean steady(cid:173)
`statc C~. follo~ing an 01111 dose of JO mg daify is more than 12-fold below the Ki-values of the in vitro inhibition. Therefore, an effect of everolimus on the
`metabolism ofCYP3A4 and CYP2D6 substrates is wilikely.
`
`Excretion
`
`No specific excretion studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabclled everolimus in patients
`who were receiving cyclosporine, 80"/o of the rodioactivity 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 e~erolimus is approximately 30 hours.
`Pa1ien1s with Renal Impairment
`
`Approximately 5% of total radioactivity was excreted in the urine following a 3 mg dose of c••c)-lnbeled everolimus. In a populaiion pharrnacokinetic analysis
`which included 170 palients with advanced cancer, no sfgnificant influence of creatinine clearance (25 - 178 ml/min) was detected on oral clearance (CL/F) of
`everolimus [Jee Use in Specific Populations (8.6)}.
`
`Patients with Hepatic Impairment
`
`The average AUC of everolimus in eight subjects with moderate hepalic impainnent (Child-Pugh class B) was twice that found in eight subjects with normal
`hepatic function. AUC was positively correlated with serum bilirubin concentration and with prolongation of prothrombin time and negatively correlated with
`serum albumin concentration. A dose reduction for patients with Child-Pugh class B hepatic impairment is recommended. AFINITOR should not be used in
`patients with severe (Child-Pugh class C) hepatic impairment as the impact of severe hepatic impairment on everolimus exposure has not been assessed [see
`Dosage and Administration (1.1). Warning• and Precautions (5.6).and U.e in Specific Populatiou j8. 7)}.
`
`Effec1s of Age ond Gender
`
`In a population pharmacolcinetic evaluation in cancer patients. no relationship was apparent between oral clearance and patient age or gender.
`
`Eilrnicity
`
`Based on a cross-study comparison. Japanese patients (n = 6) had on average exposures that were higher than non-Japanese patients receiving the same dose.
`
`Based on analysis of population pharmacokinctics, oral.clearance (CL/F) is on average 20% higher in Black.patients than in Caucasians.
`
`The significance of these differences on lhe safety and efficacy of everolimus in Japanese or Black patients has not been established.
`
`
`
`

`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Cmrclnogenesls, Mutageoesis, Impairment ofFertWty
`
`Administration of everolimus for up to 2 years did not indicate Oll(;()genic potential in mia: and rats up to the highest doses tested (0. 9 mg/kg) cor1esponding
`respectively to 4.3 and 0.2 times the estimated clinical exposure (AlJC.,.,.J at the recommended human dose of 10 mg daily.
`
`Everofirnus was not genotoxic in a banery of in \lilro assays (Ames mutation le5t in Sa/mMella. mutation test in LSl71!Y mouse lymphoma cells. and chromosome
`aberration assay in V79 Chinese hamster cells). Everolirnus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up w 500 mg/lg/day
`( 1500 mg/m1/day. approximately 255-fold the recommended human dose. based on the body surface area). administered as two doses. 24 hours apan
`
`Based on non-clinical findings, male fertility may be compromised by treatment with AFINITOR. In a 13".weelc. male fenility study in rats, testicular morphology
`•••as affected at 0.5 mg/leg and above, and spenn motility, spenn count. and plasma testosterone levels were diminished at S mg/kg, which resulted in infertility at
`5 mg/kg. Effects on male fertility occurred at the AUC,., .. values below that of therapeutic exposure (approximarely 1 Oo/o-81% of the AUC.,.,.,. in patients
`receiving the recommended dose of I 0 mg daily). Atler a 10-ll week. non-tteacrnent period, the fertility index increased from zero (infertility) to 60% (12120
`mated females were pregnant).
`
`Oral doses of everolimus in female rats at<! 0.1 mg/kg (approximately 4% the AUC.,.1.,. in patients receiving the recommended dose of IO mg daily) resulted in
`increases in pre-implantation loss, suggesting that the drug may reduce female fertility. Everolimus crossed the placenta and was toxic to the conceptus {see Ure
`·
`in Specific Populatioru (8.1)].
`
`14 CLINICAL STUDlES
`
`An international, multicenter, randomized; double-blind trial comparing AFINITOR IO mg dail)I and placeho, both in conjunction with best supponive care, was
`conducted in. patients with metastatic renal cell carcinoma whose disease had progressed despite prior treatment with sunitinib. sorafenib, or both sequentially.
`Prior therapy with bevacizurnab, interleukin 2, or interferon-a was also pennitted. Randomiz.ation was stratified according to prognostic.score' and prior
`anticarn:er therapy.
`
`Progression-free su1Vivnl (PFS), documented using RECIST (Response Evaluation Criteria in Solid Tumors) was assessed via a blinded, independent, ceniral
`radiologic review. After documented radiological progression, patients could be unblinded by the investiga!Or: those randomized to placebo were then able to
`receive open-label A.FINITOR 10 mg daily.
`
`In total,.416 patients were randomized 2: I to receive AFINITOR (n=277) or placebo (n=l 39). Demographics were well balanced between the two arms (medim
`·
`age 61 )'ears; 77% male, 88% Caucasian, 74% received prior sunitinib or somfenib, and 26% received both sequentially).
`
`AFINITOR was superior to placebo for progression-free su1Vival (see Table 3 and Figure I). The treatment effect was similar across prognostic scores and prior
`sorafenib and/or sunitinib. The overall SUTVival (OS) results were not mature and 32% of patients had died by the time of cut-off.
`
`Table 3
`
`Efficacy Res11lts by Central Radlolo!!lc Review
`Hazard Ratio
`AFINITOR
`Placebo
`N°277
`. N•l39
`(95%CJ)
`4.9 months
`1.9 months
`0.33
`(4.010 5.5)
`(l.8 to 1.9)
`(0.25 to 0.43)
`n/a •
`2%
`
`p-value'
`
`<0.000!
`
`n/a •
`
`Median Progreaslon-free Survival
`(95"/o Cl)
`Objective Response Rate
`' Log-rank test stratified by prognostic score.
`· 'Not applicable.
`
`