האגודה למלחמה בסרטן - ביטאון לעובדי בריאות בנושא מחלת הסרטן והשלכותיה - גיליון 20 אוקטובר 2014

AFINITOR ® - Important Safety Information AFINIT ® - I rt t ti

AFINITOR ® 2.5, 5 & 10 mg tablets National Succinct Statement Israel AFINITOR ® 2.5, 5 & 10 mg tablets National Succinct Statement Israel

monitoring: Renal function, fasting serum glucose and lipid profile and complete blood counts are recommended prior to initiation and periodically during treatment ♦• Hepatic Impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh class C) unless the potentialbenefitoutweighstherisk ♦ • Vaccination: Avoiduseof livevaccinesandclosecontact with those who have received live vaccines should be avoided during treatment with Afinitor. The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy.♦• Pregnancy: should not be given to pregnant women unless the potential benefit outweighs the potential risk to the foetus ♦• Women of childbearing potential: Use effective contraception methods while receiving AFINITOR, and for up to 8 weeks after ending treatment ♦• Breast-feeding: Women taking AFINITOR should not breast feed ♦• Fertility: The potential for everolimus to cause infertility in male and female patients is unknown. However, amenorrhea (including secondary amenorrhea) has been observed. Based on non-clinical findings, male fertility may be compromised by treatment with Afinitor Female fertility was not affected (see section 14 Non-clinical safety data). Interactions: •Avoid concurrent treatment with strong CYP3A4 or PgP inhibitors (e.g. ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, telithromycin) •Caution with moderate inhibitors of CYP3A4 or PgP inhibitors (e.g. erythromycin, verapamil, diltiazem, fluconazole, ciclosporin, amprenavir, fosamprenavir, aprepitant). Concurrent treatment with moderate inhibitors of CYP3A4 or PgP require dose reduction •Avoid concurrent treatment with strong inducers of CYP3A4 or PgP (e.g. rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine, dexamethasone, prednisone, prednisolone, St. John’s Wort (Hypericum perforatum)) •Avoid grapefruit juice, grapefruit, star fruit, Seville oranges and other foods affecting CYP3A4 and PgP. •Exercise caution when used in combination with orally administered CYP 3A4 substrates with a narrow therapeutic index. Adverse reactions: BC, NET, RCC: •Very common ( ≥ 10%): Infections, decreased appetite, dysgeusia, headache, cough, pneumonitis, epistaxis, dyspnea, stomatitis, diarrhea, nausea, vomiting, rash, dry skin, pruritus, nail disorder, fatigue, asthenia, mucosal inflammation, peripheral edema, pyrexia, weight decreased, creatinine increased, alanine aminotransferase increased, aspartate aminotransferase increased, lymphocytes decreased, haemoglobin decreased, platelets decreased, neutrophils decreased, glucose increased, cholesterol increased, triglycerides increased, phosphate decreased, •Common ( ≥ 1 to <10%): Diabetes mellitus, exacerbation pre-existing of diabetes mellitus, dehydration, insomnia, hypertension, hemorrhages, pulmonary embolism, haemoptysis, dry mouth, dyspepsia, dysphagia, oral pain, abdominal pain, acne, Palmar-plantar erythrodysaesthesia syndrome, erythema, arthralgia, proteinuria, renal failure including acute renal failure, skin exfoliation, acneiform dermatitis, onychoclasis, haemoptysis, bilirubin increased, conjuctiviti, edema, increased daytime urination, chest pain •Uncommon (<1%): pure red cell aplasia, new onset diabetes mellitus, ageusia, congestive cardiac failure, deep vein thrombosis, acute respiratory distress syndrome, impaired wound healing, angioedema . Not Known: Hypersensitivity, hemorrhage, TSC with SEGA: Phase III study M2301 (78 patients treated with AFINITOR for a median duration of 9.6 months): •Very common ( ≥ 10%): Stomatitis •Common ( ≥ 1 to <10%): Upper respiratory tract infection, pneumonia, otitis media, gastroenteritis viral, neutropenia, anemia, hypercholesterolemia, aggression, insomnia, convulsion, cough, epistaxis, pneumonitis, oral pain, rash, amenorrhea, menstruation irregular, fatigue, irritability, pyrexia, gait disturbance, blood cholesterol increased, low density lipoprotein increased, neutrophil count decreased, blood triglycerides increased. Additional adverse reactions observed in Phase II study C2485 (28 Patients treated with AFINITOR for a median duration of 34.2 months): •Very common ( ≥ 10%): Sinusitis, cellulitis, gastroenteritis, pharyngitis, otitis externa, skin infection, body tinea, gastric infection, urinary tract infection, furuncle, nasopharyngitis, conjunctivitis, hypertriglyceridemia, diarrhea, dermatitis acneiform, acne •Common ( ≥ 1 to <10%): Infection, abscess limb, bronchitis viral, agitation, pharyngeal inflammation, gastritis, vomiting, proteinuria, blood immunoglobulin G decreased. The following clinically relevant ADRs were reported in a higher frequency category in the phase II study C2485 than in the phase III study M2301 (increase from common to very common): upper respiratory tract infection, otitis media, pneumonia, cough, pyrexia, blood cholesterol increased, blood triglycerides increased, and neutrophil count decreased . •Laboratory abnormalities: abnormalities were observed in some hematology and clinical chemistry laboratory tests. Pack: 30 tablets. Legal classification: Prescription only. AFI NSS MAR 2013 Based on IL PI AFI API FEB13 CL V3 References: 1. Yardley da, noguchi s, pritchard ki, et al. everolimus plus exemestane in postmenopausal patients with hr+ breast cancer: bolero-2 final progression-free survival analysis. adv ther. 2013;30(10):870-884. 2. NHB committee recommendation -2014 update . monitoring: Renal function, fasting serum glucose and lipid profile and complete blood counts are recommended prior to initiation and periodically during treatment ♦• Hepatic Impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh class C) unless the potential benefit outweighs the risk ♦ • Vaccination: Avoid use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Afinitor. The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy.♦• Pregnancy: should not be given to pregnant women unless the potential benefit outweighs the potential risk to the foetus ♦• Women of childbearing potential: Use effective contraception methods while receiving AFINITOR, and for up to 8 weeks after ending treatment ♦• Breast-feeding: Women taking AFINITOR should not breast feed ♦• Fertility: The potential for everolimus to cause infertility in male and female patients is unknown. However, amenorrhea (including secondary amenorrhea) has been observed. Based on non-clinical findings, male fertility may be compromised by treatment with Afinitor Female fertility was not affected (see section 14 Non-clinical safety data). In eracti ns: •Avoid concurrent treatment with strong CYP3A4 or PgP inhibitors (e.g. ke oconazole, traconazole, voriconazole, ritonavir, clarithromycin, telithro ycin) •Caution with mod rate inhibitors of CYP3A4 or PgP inhibitors (e.g. erythromycin, verap il, diltiazem, flucon zole, cicl p rin, amprenavir, fosamprenavir, aprepitant). Con urrent treatment with moderate inhibito of CYP3A4 or gP require dose red ction •Avoid concurr t trea ment with s ro g inducers of CYP3A4 or PgP ( .g. rifampicin, r fabutin, carbamaz pine, p enobarbital, phenytoin, efavirenz, nevirapine, dexame hasone, prednisone, prednisolone, St. John’s Wort (Hypericum perforatum)) • void grapefruit juic , grapefruit, star fruit, Seville ora ges and ther foods aff cting CYP3A4 and PgP. •Exercise caution whe used in combination with orally administered CYP 3A4 substrates with a arrow therapeutic index. Adverse reactions: BC, NET, RCC: •Very common ( ≥ 10%): Infections, decreased appetite, dysgeusia, headache, cough, pneumonitis, epistaxis, dyspnea, stomatitis, diarrhea, nausea, vomiting, rash, dry skin, pruritus, nail disorder, fatigue, asthenia, mucosal inflammation, peripheral edema, pyrexia, weight decreased, creatinine increased, alanine aminotransferase increased, aspartate aminotransferase increased, lymphocytes decreased, haemoglobin decreased, platelets decreased, neutrophils decreased, glucose increased, cholesterol increased, triglycerides increased, phosphate decreased, •Common ( ≥ 1 to <10%): Diabetes mellitus, exacerbation pre-existing of diabetes mellitus, dehydration, insomnia, hypertension, hemorrhages, pulmonary embolism, haemoptysis, dry mouth, dyspepsia, dysphagia, oral pain, abdominal pain, acne, Palmar-plantar erythrodysaesthesia syndrome, erythema, arthralgia, proteinuria, renal failure including acute renal failure, skin exfoliation, acneiform dermatitis, onychoclasis, haemoptysis, bilirubin increased, conjuctiviti, edema, increased daytime urination, chest pain •Uncommon (<1%): pure red cell aplasia, new onset diabetes mellitus, ageusia, congestive cardiac failure, deep vein thrombosis, acute respiratory distress syndrome, impaired wound healing, angioedema . Not Known: Hypersensitivity, hemorrhage, TSC with SEGA: Phase III study M2301 (78 patients treated with AFINITOR for a median duration of 9.6 months): •Very common ( ≥ 10%): Stomatitis •Common ( ≥ 1 to <10%): Upper respiratory tract infection, pneumonia, otitis media, gastroenteritis viral, neutropenia, anemia, hypercholesterolemia, aggression, insomnia, convulsion, cough, epistaxis, pneumonitis, oral pain, rash, amenorrhea, menstruation irregular, fatigue, irritability, pyrexia, gait disturbance, blood cholesterol increased, low density lipoprotein increased, neutrophil count decreased, blood triglycerides increased. Additional adverse reactions observed i Phase II study C2485 (28 Patients treated with AFINITOR for a median duration of 34.2 m ths): •Very common ( ≥ 10%): Sinusitis, cellulitis, gastroenteritis, pharyngitis, otitis ex erna, skin infection, ody tinea, gastric infection, urinary tract i fection, furuncle, nasopha yngitis, conjunctivitis, hypertriglyceridemia, diarrh a, dermatitis acne form, ac e •Commo ( ≥ 1 to <10%): Infectio , bscess limb, bron hitis viral, agitation, pharyngeal inflammation, gastritis, vomiting, proteinuria, blood immunoglobuli G dec eased. The following clinic lly relevant ADRs were r ported in a h gher frequency category in th phas II study C2485 than in the phase III stu y M2301 (increase f om common to ve common): upper respi atory tract infection, otitis media, pneumoni , cough, pyrexia, blood cholesterol increased, blood triglycerides increased, and neutrophil count decreased . •Laboratory abnormalities: abnormalities were observed in some hematology and clinical chemistry laboratory tests. Pack: 30 tablets. Legal classification: Prescription only. AFI NSS MAR 2013 Based on IL PI AFI API FEB13 CL V3 References: 1. Yardley da, noguchi s, pritchard ki, et al. everolimus plus exemestane in postmenopausal patients with hr+ breast cancer: bolero-2 final progression-free survival analysis. adv ther. 2013;30(10):870-884. 2. NHB committee recommendation -2014 update . רופא/ה נכבד/ה, למידע נוסף, יש לעיין בעלון לרופא כפי שאושר ע"י משרד הבריאות הישראלי.

Important note: Before prescribing, consult full prescribing information. Presentation: Tablets containing 2.5 mg, 5 mg or 10 mg of everolimus. Indications: Important note: Before prescribing, consult full prescribing information. Presentation: Tablets containing 2.5 mg, 5 mg or 10 mg of everolimus. Indications:

AFINITOR ® 2.5, 5 & 10mg are indicated for the: Treatment of patients with SEGA associated with tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for curative surgical resection. The effectiveness of AFINITOR ® is based on an analysis of change in SEGA volume. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been demonstrated. Treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of AFINITOR ® in the treatment of patients with carcinoid tumorshavenotbeenestablished.AFINITOR ® isindicatedforthetreatmentofhormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. AFINITOR ® 5 and 10 mg only are indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Dosage: BC, NET, RCC: Tablets: one 10 mg dose once daily. TSC with SEGA: recommended starting daily dose is 4.5 mg/m2 according to Body Surface Area (BSA) rounded to the nearest strength of AFINITOR Tablets. Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after the initial dose, any change in dose, initiation of or change in co-administration of CYP3A4 inducers or inhibitors,. or after any change in hepatic status (Child-Pugh). Therapeutic drug monitoring is required and dosing should be titrated to attain everolimus trough concentrations of 3 to 15 ng/mL. • •The daily dose should be taken at the same time every day, either consistently with or consistently without food. • Dose adjustment: Dose adjustment may be required due to side-effects (e.g. non-infectious pneumonitis, stomatitis, non-hematologic toxicities), use of moderate CYP3A4 or PgP inhibitors or strong CYP3A4 inducers, hepatic status (Child-Pugh). Avoid the use of strong CYP3A4 inhibitors or inducers . Grapefruit, grapefruit juice and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment. St. John’s Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided. • Children: BC, NET, RCC: not recommended for use in pediatric patients. TSC with SEGA: can be used in children and adolescents with normal hepatic function. • Patients with hepatic impairment: BC, NET, RCC: recommended dose is 7.5 mg daily in patients with mild hepatic impairment (Child-Pugh A); 5 mg daily in patients with moderate hepatic impairment (Child-Pugh B); not recommended in patients with severe hepatic impairment (Child-Pugh C),.. TSC with SEGA: patients <18 years of age: not recommended; patients ≥ 18 years of age: recommended dose is 75% of the dose calculated based on BSA in patients with mild hepatic impairment (Child-Pugh A); 25% of the dose calculated based on BSA in patients with moderate hepatic impairment (Child-Pugh B); not recommended in patients with severe hepatic impairment (Child-Pugh C). Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after commencing treatment, after any change in dose, or after an initiation or change in co-administration of CYP3A4 inducers or inhibitors, or after any change in hepatic status (Child-Pugh). Contraindications: Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients. Warnings/Precautions: • Non-infectious pneumonitis: Cases have been described in patients taking AFINITOR, some of these have been severe and on rare occasions, a fatal outcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as pyrexia, pleural effusion, cough or dyspnea, and in whom infectious, neoplastic, and other non-medicinal causes have been excluded. In some cases, management of pneumonitis may require dose reduction, dose interruption or discontinuation. The use of corticosteroids may be indicated.♦• Infections: AFINITOR is immunosuppressive. Localised and systemic bacterial, fungal, viral or protozoan infections (e.g. pneumonia, aspergillosis or candidiasis, hepatitis B reactivation) have been described in patients taking AFINITOR, some of these have been severe and occasionally fatal. Pre-existing infections should be treated prior to starting treatment with AFINITOR.. Institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy • Hypersensitivity reactions have been observed with everolimus ♦• Oral ulceration: Mouth ulcers, stomatitis and oral mucositis have been seen in patients treated with Afinitor. Management of stomatitis reactions may require dose reduction, dose interruption or discontinuation. Topical treatments are recommended, but alcohol- or peroxide- containing mouthwashes should be avoided. • Renal failure: Cases of renal failure, some fatal, have been observed in patients treated with AFINITOR. ♦• Laboratory tests and AFINITOR ® 2.5, 5 & 10mg are indicated for the: Treatment of patients with SEGA associated with tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for curative surgical resection. The effectiveness of AFINITOR ® is based on an analysis of change in SEGA volume. Clinical benefit such as improvement in disease-related symptoms or increase in ov rall survival has not been demonstrated. Tr atment of progressive neuroendocrine tu ors of pancr tic origin (PNET) i patients with unresectable, locally advanced or metastatic disease. The safety nd effectiveness of AFINITOR ® in the treatm nt f pati nts with carcin id tumorshavenotbe nestablished.AFINITOR ® isindicatedforth treatmentofh rmone receptor-positive, HER2/neu neg tive advanced breast cancer, in ombination with exemesta e, in postm nopausal omen without sympt tic visceral disease after recurrence or progress on following a non-steroidal romatase inhibitor. AFINITOR ® 5 and 10 mg only are indicated for the treatmen of patients w th advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Do ge: BC, NET, RCC: Tablets: one 10 mg dose once daily. TSC with SEGA: recommended starting daily dose is 4.5 mg/m2 according to Body Surface Area (BSA) rounded to the nearest trength of AFINITOR Tabl ts. Ev rolimus whole blood trough concentrations should be assessed approximately 2 weeks after the initial dose, any change in dose, initiation of or change in co-administration of CYP3A4 inducers or inhibitors,. or after any change in hepatic status (Child-Pugh). Therapeutic drug monitoring is required and dosing should be titrated to attain everolimus trough concentrations of 3 to 15 ng/mL. • •The daily dose should be taken at the same time every day, either consistently with or consistently without food. • Dose adjustment: Dose adjustment may be required due to side-effects (e.g. non-infectious pneumonitis, stomatitis, non-hematologic toxicities), use of moderate CYP3A4 or PgP inhibitors or strong CYP3A4 inducers, hepatic status (Child-Pugh). Avoid the use of strong CYP3A4 inhibitors or inducers . Grapefruit, grapefruit juice and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment. St. John’s Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided. • Children: BC, NET, RCC: not recommended for use in pediatric patients. TSC with SEGA: can be used in children and adolescents with normal hepatic function. • Patients with hepatic impairment: BC, NET, RCC: recommended dose is 7.5 mg daily in patients with mild hepatic impairment (Child-Pugh A); 5 mg daily in patients with moderate hepatic impairment (Child-Pugh B); not recommended in patients with severe hepatic impairment (Child-Pugh C),.. TSC with SEGA: patients <18 years of age: not recommended; patients ≥ 18 years of age: recommended dose is 75% of the dose calculated based on BSA in patients with mild hepatic impairment (Child-Pugh A); 25% of the dose calculated based on BSA in patients with moderate hepatic impairment (Child-Pugh B); not recommended in patients with severe h p tic impairment (Child-Pugh C). Everolimus whole blood tro gh concentrations should be assessed approximately 2 weeks after commencing treatment, after any change in dose, or after initiation or change in co- dministration f CYP3A4 inducers or inhibitors, or after any change in hepatic status (Child-Pugh). Contraindications: Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients. Warnings/Precautions: • Non-infectious pneumonitis: Case ave en described in taking AFINITOR, som o th e have been severe and on rare occasions a fat outcome was obse ved. A di gnosis of non-infectious neumonitis should be considered in patients pr s nting with n n-specific respiratory signs and sympto s such as pyrexia, pleural effusion, cough or dyspnea, and in whom infecti us, ne plastic, and other non-medici al auses have been excluded. In some cas s, management of pneumoni is may require dose reducti n, dose interruption or discontinuation. The u e of corticosteroids may be indi ated.♦• Infections: AFINITOR is immunosuppressive. Localised and systemic bact rial, fungal, viral or protozo n infections (e.g. pneumonia, aspergillosis or candidiasis, hepatitis B reactivation) have been described in patients taking AFINITOR, some of these have been severe and occasionally fatal. Pre-existing infections should be treated prior to starting treatment with AFINITOR.. Institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy • Hypersensitivity reactions have been observed with everolimus ♦• Oral ulceration: Mouth ulcers, stomatitis and oral mucositis have been seen in patients treated with Afinitor. Management of stomatitis reactions may require dose reduction, dose interruption or discontinuation. Topical treatments are recommended, but alcohol- or peroxide- containing mouthwashes should be avoided. • Renal failure: Cases of renal failure, some fatal, have been observed in patients treated with AFINITOR. ♦• Laboratory tests and

רופא/ה נכבד/ה, למידע נוסף, יש לעיין בעלון לרופא כפי שאושר ע"י משרד הבריאות הישראלי.

נוברטיס פארמה סרויסס איי ג'יי, רח' שחם 63, פתח-תקוה, טל. 1011029-30, פקס. 3843229-30 נוברטיס פארמה סרויסס איי ג'יי, רח' שחם 63, פתח-תקוה, טל. 1011029-30, פקס. 3843229-30