g-afi-1070510_g 2013 afi breast adv bc aim - hcp brochure
TRANSCRIPT
Advise. Identify. Manage.Take AIM through a targeted treatment strategy
A program designed to optimize treatment experience by establishing the benefits of AFINITOR with an emphasis on early identification, monitoring, and effective management of key adverse events (AEs).
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
References: 1. AFINITOR [summary of product characteristics]. Novartis Pharma AG; 2013. 2. Rugo HS, Gnant M, Geberth M, et al. Everolimus-related adverse events: safety insights from BOLERO-2. Poster presented at: St. Gallen International Breast Cancer Conference; March 2013; St. Gallen, Switzerland. 3. Data on file. Novartis Pharma AG. 4. Grünwald V, Weikert S, Pavel ME, et al. Practical management of everolimus-related toxicities in patients with advanced solid tumors. Onkologie. 2013;36:295-302. 5. Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, Mita M. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Targ Oncol. 2009;4:135-142. 6. Piccart M, Baselga J, Noguchi S, et al. Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer. Poster presented at: San Antonio Breast Cancer Symposium; December, 2012; San Antonio, TX. 7. Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer. 2010;116:210-215. 8. Rugo HS, Gnant M, Geberth M, et al. Everolimus-related adverse events: safety insights from BOLERO-2. Abstract presented at: St. Gallen International Breast Cancer Conference; March 2013; St. Gallen, Switzerland. 9. National Cancer Institute. Common terminology criteria for adverse events (CTCAE) v3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications /docs/ctcaev3.pdf. Published May 09, 2006. Accessed June 12, 2013.
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
Novartis Pharma AGCH-4002 Basel Switzerland © Novartis 2013 9/13 G-AFI-1070510
safety and efficacy of AFINITOR in patients with carcinoid tumours have not been established. ♦ Hepatic Impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk. ♦ Vaccination: Avoid use of live vaccines and close contact with people who have received live vaccines. ♦ Lactose: Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. ♦ Wound healing complications: Impaired wound healing is a class effect of Rapamycin derivatives, including AFINITOR. Caution should be exercised with use of AFINITOR in peri-surgical period. ♦ Pregnancy: AFINITOR should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus. Male patients taking AFINITOR should not be prohibited from attempting to father children. ♦ Women of childbearing potential: Use highly 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: Male and female fertility may be compromised by treatment with AFINITOR. Menstrual irregularities, secondary amenorrhea, and associated luteinizing hormone (LH) / follicle stimulating hormone (FSH) imbalance have been observed in female patients receiving AFINITOR.Interactions: Avoid concurrent treatment with strong CYP3A4 inhibitors or PgP inhibitors (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, telithromycin). ♦ Caution with moderate CYP3A4 inhibitors or PgP inhibitors (e.g. erythromycin, verapamil, diltiazem, fluconazole, ciclosporin, amprenavir, fosamprenavir, aprepitant). Consider a dose decrease of AFINITOR when co-administered with moderate inhibitors. ♦ Avoid concurrent treatment with strong CYP3A4 inducers or PgP inducers (e.g. rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine, dexamethasone, prednisone, prednisolone, St. John’s Wort (Hypericum perforatum)). Consider a dose increase of AFINITOR when co-administered with strong inducers. ♦ Avoid grapefruit juice, grapefruit, star fruit, Seville oranges and other foods affecting CYP3A4 or PgP. ♦ Caution when used in combination with orally administered CYP3A4 substrates with a narrow therapeutic index.Adverse drug reactions: ♦ Very common (≥10%): Infections, anemia, thrombocytopenia, hyperglycaemia, hypercholesterolemia, hypertriglyceridaemia, anorexia, dysgeusia, headache, pneumonitis, dyspnoea, epistaxis, cough, stomatitis, diarrhoea, mucosal inflammation, vomiting, nausea, rash, dry skin, pruritus, nail disorder, fatigue, asthenia, peripheral oedema, pyrexia, weight decreased ♦ Common (≥1 to <10%): leukopenia, lymphopenia, neutropenia, diabetes mellitus, hypophosphatemia, hypokalemia, hyperlipidaemia, hypocalcemia, dehydration, insomnia, conjunctivitis, eyelid oedema, hypertension, haemorrhage, pulmonary embolism, haemoptysis, dry mouth, abdominal pain, oral pain, dysphagia, dyspepsia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, palmar-plantar erythrodysaesthesia syndrome, erythema, skin exfoliation, acneiform dermatitis, oncychoclasis, skin lesion, mild alopecia, arthralgia, creatinine increased, renal failure (including acute renal failure), proteinuria, chest pain ♦ Uncommon (<1%): pure red cell aplasia, ageusia, congestive cardiac failure, flushing, deep vein thrombosis, acute respiratory distress syndrome, angioedema, impaired wound healing ♦ Not known: hypersensitivity. ♦ Laboratory abnormalities: abnormalities were observed in some hematology and clinical chemistry laboratory tests ♦ In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infections is an expected event during periods of immunosuppression. In clinical trials and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome), proteinuria, and cases of amenorrhea (secondary amenorrhea and other menstrual irregularities).Packs and prices: Country specific. Legal classification: Country specific.
IN THE BOLERO-2 STUDY:• The majority of AEs were mild to moderate in severity (grade 1/2), generally manageable, and
typically resolved over time2,3
• The most common grade 3/4 AEs (incidence <10%) were stomatitis (8%), infections (7%), hyperglycemia (6%), fatigue (5%), pneumonitis (3%), diarrhea (3%), and rash (1%) 2,6
• Serious AEs have been observed during AFINITOR therapy, including noninfectious pneumonitis, infections, and acute renal failure; on rare occasions, fatal outcomes were observed1
Key Adverse EventsSTOMATITIS• mTOR inhibitor–associated stomatitis (mIAS) is
distinct from conventional chemotherapy-induced mucositis in both its pathophysiology and clinical presentation7
• In BOLERO-2, the median time to onset was approximately 2 weeks8
Grade 1 = Minimal symptoms, normal diet9
Grade 2 = Symptomatic but can eat and swallow modified diet9
Grade 3 = Symptomatic and unable to adequately aliment or hydrate orally9
Grade 4 = Symptoms associated with life-threatening consequences9
Proactive planning for optimal treatment—partner with your patients to identify AEs early
IDENTIFY
Incidence of Stomatitis6
in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 4
59% 8% 0%
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
* AFINITOR is currently also approved for the treatment of unresectable or metastatic, well or moderately differentiated neuroendocrine tumors of pancreatic origin in adults with progressive disease and advanced renal cell carcinoma that has progressed on or after treatment with VEGF-targeted therapy.1
An established safety profile1,3
• More than 100,000 patients have been treated worldwide since the first oncology approval of AFINITOR in 20093 *
A safety profile consistent with the known AEs of mTOR inhibitors1,3 • mTOR inhibitors have a distinct safety profile—key AEs include stomatitis,
noninfectious pneumonitis, hematologic and nonhematologic toxicities, and metabolic events2,4,5
Advise. Identify. Manage. 94
ADVISE
IDENTIFY
MANAGE
ADVISE
>2x median
PFS
• Postmenopausal women with HR+/HER2-negative advanced breast cancer in the BOLERO-2 trial were initiated at the 10-mg dose of AFINITOR, and in combination with exemestane, demonstrated more than double the median PFS without deterioration of QoL vs placebo plus exemestane1
• Both investigator (7.8 months vs 3.2 months) and independent (11.0 months vs 4.1 months) reviews confirmed the magnitude of benefit of AFINITOR plus exemestane vs placebo plus exemestane1
• All preplanned subgroups in BOLERO-2 derived significant PFS benefit1
• AFINITOR offers once-daily oral administration1
– Median dose intensity of AFINITOR in BOLERO-2 was 8.6 mg/day2
• Early identification, careful monitoring, and timely management of AEs in the oncology setting are important to help patients optimize treatment2
• Encourage patients to proactively communicate at the earliest sign of an AE
10mg
10mg
once daily
Optimize AFINITOR’s magnitude of benefit through patient education
ADVISE
2 3
ADVISE
IDENTIFY
MANAGE
ADVISE
>2x median
PFS
• Postmenopausal women with HR+/HER2-negative advanced breast cancer in the BOLERO-2 trial were initiated at the 10-mg dose of AFINITOR, and in combination with exemestane, demonstrated more than double the median PFS without deterioration of QoL vs placebo plus exemestane1
• Both investigator (7.8 months vs 3.2 months) and independent (11.0 months vs 4.1 months) reviews confirmed the magnitude of benefit of AFINITOR plus exemestane vs placebo plus exemestane1
• All preplanned subgroups in BOLERO-2 derived significant PFS benefit1
• AFINITOR offers once-daily oral administration1
– Median dose intensity of AFINITOR in BOLERO-2 was 8.6 mg/day2
• Early identification, careful monitoring, and timely management of AEs in the oncology setting are important to help patients optimize treatment2
• Encourage patients to proactively communicate at the earliest sign of an AE
10mg
10mg
once daily
Optimize AFINITOR’s magnitude of benefit through patient education
ADVISE
2 3
Advise. Identify. Manage.Take AIM through a targeted treatment strategy
A program designed to optimize treatment experience by establishing the benefits of AFINITOR with an emphasis on early identification, monitoring, and effective management of key adverse events (AEs).
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
References: 1. AFINITOR [summary of product characteristics]. Novartis Pharma AG; 2013. 2. Rugo HS, Gnant M, Geberth M, et al. Everolimus-related adverse events: safety insights from BOLERO-2. Poster presented at: St. Gallen International Breast Cancer Conference; March 2013; St. Gallen, Switzerland. 3. Data on file. Novartis Pharma AG. 4. Grünwald V, Weikert S, Pavel ME, et al. Practical management of everolimus-related toxicities in patients with advanced solid tumors. Onkologie. 2013;36:295-302. 5. Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, Mita M. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Targ Oncol. 2009;4:135-142. 6. Piccart M, Baselga J, Noguchi S, et al. Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer. Poster presented at: San Antonio Breast Cancer Symposium; December, 2012; San Antonio, TX. 7. Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer. 2010;116:210-215. 8. Rugo HS, Gnant M, Geberth M, et al. Everolimus-related adverse events: safety insights from BOLERO-2. Abstract presented at: St. Gallen International Breast Cancer Conference; March 2013; St. Gallen, Switzerland. 9. National Cancer Institute. Common terminology criteria for adverse events (CTCAE) v3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications /docs/ctcaev3.pdf. Published May 09, 2006. Accessed June 12, 2013.
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
Novartis Pharma AGCH-4002 Basel Switzerland © Novartis 2013 9/13 G-AFI-1070510
safety and efficacy of AFINITOR in patients with carcinoid tumours have not been established. ♦ Hepatic Impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk. ♦ Vaccination: Avoid use of live vaccines and close contact with people who have received live vaccines. ♦ Lactose: Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. ♦ Wound healing complications: Impaired wound healing is a class effect of Rapamycin derivatives, including AFINITOR. Caution should be exercised with use of AFINITOR in peri-surgical period. ♦ Pregnancy: AFINITOR should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus. Male patients taking AFINITOR should not be prohibited from attempting to father children. ♦ Women of childbearing potential: Use highly 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: Male and female fertility may be compromised by treatment with AFINITOR. Menstrual irregularities, secondary amenorrhea, and associated luteinizing hormone (LH) / follicle stimulating hormone (FSH) imbalance have been observed in female patients receiving AFINITOR.Interactions: Avoid concurrent treatment with strong CYP3A4 inhibitors or PgP inhibitors (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, telithromycin). ♦ Caution with moderate CYP3A4 inhibitors or PgP inhibitors (e.g. erythromycin, verapamil, diltiazem, fluconazole, ciclosporin, amprenavir, fosamprenavir, aprepitant). Consider a dose decrease of AFINITOR when co-administered with moderate inhibitors. ♦ Avoid concurrent treatment with strong CYP3A4 inducers or PgP inducers (e.g. rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine, dexamethasone, prednisone, prednisolone, St. John’s Wort (Hypericum perforatum)). Consider a dose increase of AFINITOR when co-administered with strong inducers. ♦ Avoid grapefruit juice, grapefruit, star fruit, Seville oranges and other foods affecting CYP3A4 or PgP. ♦ Caution when used in combination with orally administered CYP3A4 substrates with a narrow therapeutic index.Adverse drug reactions: ♦ Very common (≥10%): Infections, anemia, thrombocytopenia, hyperglycaemia, hypercholesterolemia, hypertriglyceridaemia, anorexia, dysgeusia, headache, pneumonitis, dyspnoea, epistaxis, cough, stomatitis, diarrhoea, mucosal inflammation, vomiting, nausea, rash, dry skin, pruritus, nail disorder, fatigue, asthenia, peripheral oedema, pyrexia, weight decreased ♦ Common (≥1 to <10%): leukopenia, lymphopenia, neutropenia, diabetes mellitus, hypophosphatemia, hypokalemia, hyperlipidaemia, hypocalcemia, dehydration, insomnia, conjunctivitis, eyelid oedema, hypertension, haemorrhage, pulmonary embolism, haemoptysis, dry mouth, abdominal pain, oral pain, dysphagia, dyspepsia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, palmar-plantar erythrodysaesthesia syndrome, erythema, skin exfoliation, acneiform dermatitis, oncychoclasis, skin lesion, mild alopecia, arthralgia, creatinine increased, renal failure (including acute renal failure), proteinuria, chest pain ♦ Uncommon (<1%): pure red cell aplasia, ageusia, congestive cardiac failure, flushing, deep vein thrombosis, acute respiratory distress syndrome, angioedema, impaired wound healing ♦ Not known: hypersensitivity. ♦ Laboratory abnormalities: abnormalities were observed in some hematology and clinical chemistry laboratory tests ♦ In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infections is an expected event during periods of immunosuppression. In clinical trials and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome), proteinuria, and cases of amenorrhea (secondary amenorrhea and other menstrual irregularities).Packs and prices: Country specific. Legal classification: Country specific.
IN THE BOLERO-2 STUDY:• The majority of AEs were mild to moderate in severity (grade 1/2), generally manageable, and
typically resolved over time2,3
• The most common grade 3/4 AEs (incidence <10%) were stomatitis (8%), infections (7%), hyperglycemia (6%), fatigue (5%), pneumonitis (3%), diarrhea (3%), and rash (1%) 2,6
• Serious AEs have been observed during AFINITOR therapy, including noninfectious pneumonitis, infections, and acute renal failure; on rare occasions, fatal outcomes were observed1
Key Adverse EventsSTOMATITIS• mTOR inhibitor–associated stomatitis (mIAS) is
distinct from conventional chemotherapy-induced mucositis in both its pathophysiology and clinical presentation7
• In BOLERO-2, the median time to onset was approximately 2 weeks8
Grade 1 = Minimal symptoms, normal diet9
Grade 2 = Symptomatic but can eat and swallow modified diet9
Grade 3 = Symptomatic and unable to adequately aliment or hydrate orally9
Grade 4 = Symptoms associated with life-threatening consequences9
Proactive planning for optimal treatment—partner with your patients to identify AEs early
IDENTIFY
Incidence of Stomatitis6
in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 4
59% 8% 0%
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
* AFINITOR is currently also approved for the treatment of unresectable or metastatic, well or moderately differentiated neuroendocrine tumors of pancreatic origin in adults with progressive disease and advanced renal cell carcinoma that has progressed on or after treatment with VEGF-targeted therapy.1
An established safety profile1,3
• More than 100,000 patients have been treated worldwide since the first oncology approval of AFINITOR in 20093 *
A safety profile consistent with the known AEs of mTOR inhibitors1,3 • mTOR inhibitors have a distinct safety profile—key AEs include stomatitis,
noninfectious pneumonitis, hematologic and nonhematologic toxicities, and metabolic events2,4,5
Advise. Identify. Manage. 94
NONINFECTIOUS PNEUMONITIS• Noninfectious pneumonitis should be investigated
in patients with nonspecific respiratory signs2
– Pulmonary function tests,radiographic imaging, bronchoscopy,and bronchoalveolar lavage can be used to evaluate2
• In BOLERO-2, the median time to onset was 16 weeks8
Grade 1 = Asymptomatic, radiographic findings only9
Grade 2 = Symptomatic,* not interfering with ADL9
Grade 3 = Symptomatic,* interfering with ADL; O2 indicated9
Grade 4 = Life-threatening, ventilatory support indicated9
Incidence of Noninfectious Pneumonitis6
in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 416% 3% 0%
RASH†
• Presents as rash and pain on palms of hands or soles of feet (hand-foot syndrome), skin exfoliation, erythema, pimples, acne, or skin lesions1
Incidence of Rash6 in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 439% 1% 0%
Incidence of Hematologic Toxicities3 in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 4Thrombocytopenia (platelet count decreased): 54% 3% <1%
Neutropenia (neutrophils decreased): 30% 2% <1%
Incidence of Metabolic Events3 in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 4Hyperglycemia: 67% 7% <1%
Hypercholesterolemia: 66% <1% <1%
Hypertriglyceridemia: 44% <1% 0%
IDENTIFY
* Benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol.
† Triamcinolone oral paste.
Tips to optimize AFINITOR treatment
In the 18-month median follow-up analysis of the BOLERO-2 study, the majority of patients did not require a dose reduction2
STOMATITISGrade 1:• Recommend management with nonalcoholic or saltwater (0.9%) mouthwash several
times a day3
Grade 2/3: • Recommend management with topical analgesic mouth treatments* with or without
topical corticosteroids3†
Advise patients to:
• Look out for mouth ulcers, pain, discomfort, or open sores1
• Avoid products containing alcohol, hydrogen peroxide, iodine, or thyme derivatives1
NONINFECTIOUS PNEUMONITIS
Grade 2/3:• Rule out infection and consider treatment with corticosteroids until symptoms
improve to grade ≤11,3
Advise patients to: • Promptly report any new or worsening respiratory symptoms, such as:
– Cough, chest pain, sudden onset of shortness of breath, coughing up blood1
Patients should communicate with their healthcare team if they experience any of these AEs as they may need additional treatments1
Of the dose-modification events that resolved with re-initiation of the full 10-mg dose, 76% resolved within 2 weeks2
61%required ≥1 dose
reduction2
39%did not require a dose reduction2
MAN
AGE
HEMATOLOGIC TOXICITIES†
METABOLIC EVENTS†
• Monitor fasting blood glucose and lipid levels at the start of therapy and periodically thereafter1
† See enclosed flashcards for guidance on distinguishing grades of key AEs.
5
ADL = activities of daily living.*Nonspecific respiratory signs and symptoms include hypoxia, pleural effusion, cough, or dyspnoea.1
MANAGEManage therapy with established strategies2,3
Management of adverse events may require dose reduction and/or temporary interruption of AFINITOR therapy1
Advise. Identify. Manage.
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
* If toxicity is tolerable, no dose adjustment required. † Until recovery to grade ≤ 1. ‡ Until recovery to grade ≤ 1. Discontinue if failure to recover within 4 weeks. § Until recovery to grade ≤ 2 (≥1x109/L). || Noninfectious pneumonitis and nonhematologic toxicities: if event recurs at grade 3, consider discontinuation.
If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily.1
The medical judgment of the treating physicians should guide all treatment decisions.
GRADE 1
GRADE 2
No Dose Adjustment
FIRST OCCURRENCE UPON RECURRENCEADVERSE EVENT
GRADE 4Interrupt
AFINITOR†§ 15 mg
Reinitiate 2 Per Physician DiscretionThrombocytopenia†
and Neutropenia§
GRADE 3
Interrupt AFINITOR† 1
5 mg
Reinitiate 2All Other Adverse
Events||
DiscontinueAll Other Adverse Events
Per Physician Discretion
Interrupt AFINITOR§ 1
10 mg
Reinitiate 2Neutropenia
No Dose Adjustment Per Physician DiscretionMetabolic Events (eg, hyperglycemia, dyslipidemia)
Neutropenia
Interrupt AFINITOR† 1
10 mg
Reinitiate 2Stomatitis
Nonhematologic Toxicities*
4Reinitiate
5 mg 3 Interrupt
AFINITOR†
10 mg
Reinitiate 2
Interrupt AFINITOR† 1Thrombocytopenia Per Physician Discretion
5 mg
Reinitiate 2
Interrupt AFINITOR‡ 1Noninfectious
Pneumonitis Per Physician Discretion
6 7
NONINFECTIOUS PNEUMONITIS• Noninfectious pneumonitis should be investigated
in patients with nonspecific respiratory signs2
– Pulmonary function tests,radiographic imaging, bronchoscopy,and bronchoalveolar lavage can be used to evaluate2
• In BOLERO-2, the median time to onset was 16 weeks8
Grade 1 = Asymptomatic, radiographic findings only9
Grade 2 = Symptomatic,* not interfering with ADL9
Grade 3 = Symptomatic,* interfering with ADL; O2 indicated9
Grade 4 = Life-threatening, ventilatory support indicated9
Incidence of Noninfectious Pneumonitis6
in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 416% 3% 0%
RASH†
• Presents as rash and pain on palms of hands or soles of feet (hand-foot syndrome), skin exfoliation, erythema, pimples, acne, or skin lesions1
Incidence of Rash6 in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 439% 1% 0%
Incidence of Hematologic Toxicities3 in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 4Thrombocytopenia (platelet count decreased): 54% 3% <1%
Neutropenia (neutrophils decreased): 30% 2% <1%
Incidence of Metabolic Events3 in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 4Hyperglycemia: 67% 7% <1%
Hypercholesterolemia: 66% <1% <1%
Hypertriglyceridemia: 44% <1% 0%
IDENTIFY
* Benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol.
† Triamcinolone oral paste.
Tips to optimize AFINITOR treatment
In the 18-month median follow-up analysis of the BOLERO-2 study, the majority of patients did not require a dose reduction2
STOMATITISGrade 1:• Recommend management with nonalcoholic or saltwater (0.9%) mouthwash several
times a day3
Grade 2/3: • Recommend management with topical analgesic mouth treatments* with or without
topical corticosteroids3†
Advise patients to:
• Look out for mouth ulcers, pain, discomfort, or open sores1
• Avoid products containing alcohol, hydrogen peroxide, iodine, or thyme derivatives1
NONINFECTIOUS PNEUMONITIS
Grade 2/3:• Rule out infection and consider treatment with corticosteroids until symptoms
improve to grade ≤11,3
Advise patients to: • Promptly report any new or worsening respiratory symptoms, such as:
– Cough, chest pain, sudden onset of shortness of breath, coughing up blood1
Patients should communicate with their healthcare team if they experience any of these AEs as they may need additional treatments1
Of the dose-modification events that resolved with re-initiation of the full 10-mg dose, 76% resolved within 2 weeks2
61%required ≥1 dose
reduction2
39%did not require a dose reduction2
MAN
AGE
HEMATOLOGIC TOXICITIES†
METABOLIC EVENTS†
• Monitor fasting blood glucose and lipid levels at the start of therapy and periodically thereafter1
† See enclosed flashcards for guidance on distinguishing grades of key AEs.
5
ADL = activities of daily living.*Nonspecific respiratory signs and symptoms include hypoxia, pleural effusion, cough, or dyspnoea.1
MANAGEManage therapy with established strategies2,3
Management of adverse events may require dose reduction and/or temporary interruption of AFINITOR therapy1
Advise. Identify. Manage.
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
* If toxicity is tolerable, no dose adjustment required. † Until recovery to grade ≤ 1. ‡ Until recovery to grade ≤ 1. Discontinue if failure to recover within 4 weeks. § Until recovery to grade ≤ 2 (≥1x109/L). || Noninfectious pneumonitis and nonhematologic toxicities: if event recurs at grade 3, consider discontinuation.
If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily.1
The medical judgment of the treating physicians should guide all treatment decisions.
GRADE 1
GRADE 2
No Dose Adjustment
FIRST OCCURRENCE UPON RECURRENCEADVERSE EVENT
GRADE 4Interrupt
AFINITOR†§ 15 mg
Reinitiate 2 Per Physician DiscretionThrombocytopenia†
and Neutropenia§
GRADE 3
Interrupt AFINITOR† 1
5 mg
Reinitiate 2All Other Adverse
Events||
DiscontinueAll Other Adverse Events
Per Physician Discretion
Interrupt AFINITOR§ 1
10 mg
Reinitiate 2Neutropenia
No Dose Adjustment Per Physician DiscretionMetabolic Events (eg, hyperglycemia, dyslipidemia)
Neutropenia
Interrupt AFINITOR† 1
10 mg
Reinitiate 2Stomatitis
Nonhematologic Toxicities*
4Reinitiate
5 mg 3 Interrupt
AFINITOR†
10 mg
Reinitiate 2
Interrupt AFINITOR† 1Thrombocytopenia Per Physician Discretion
5 mg
Reinitiate 2
Interrupt AFINITOR‡ 1Noninfectious
Pneumonitis Per Physician Discretion
6 7
Advise. Identify. Manage.Take AIM through a targeted treatment strategy
A program designed to optimize treatment experience by establishing the benefits of AFINITOR with an emphasis on early identification, monitoring, and effective management of key adverse events (AEs).
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
References: 1. AFINITOR [summary of product characteristics]. Novartis Pharma AG; 2013. 2. Rugo HS, Gnant M, Geberth M, et al. Everolimus-related adverse events: safety insights from BOLERO-2. Poster presented at: St. Gallen International Breast Cancer Conference; March 2013; St. Gallen, Switzerland. 3. Data on file. Novartis Pharma AG. 4. Grünwald V, Weikert S, Pavel ME, et al. Practical management of everolimus-related toxicities in patients with advanced solid tumors. Onkologie. 2013;36:295-302. 5. Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, Mita M. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Targ Oncol. 2009;4:135-142. 6. Piccart M, Baselga J, Noguchi S, et al. Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer. Poster presented at: San Antonio Breast Cancer Symposium; December, 2012; San Antonio, TX. 7. Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer. 2010;116:210-215. 8. Rugo HS, Gnant M, Geberth M, et al. Everolimus-related adverse events: safety insights from BOLERO-2. Abstract presented at: St. Gallen International Breast Cancer Conference; March 2013; St. Gallen, Switzerland. 9. National Cancer Institute. Common terminology criteria for adverse events (CTCAE) v3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications /docs/ctcaev3.pdf. Published May 09, 2006. Accessed June 12, 2013.
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
Novartis Pharma AGCH-4002 Basel Switzerland © Novartis 2013 9/13 G-AFI-1070510
safety and efficacy of AFINITOR in patients with carcinoid tumours have not been established. ♦ Hepatic Impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk. ♦ Vaccination: Avoid use of live vaccines and close contact with people who have received live vaccines. ♦ Lactose: Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. ♦ Wound healing complications: Impaired wound healing is a class effect of Rapamycin derivatives, including AFINITOR. Caution should be exercised with use of AFINITOR in peri-surgical period. ♦ Pregnancy: AFINITOR should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus. Male patients taking AFINITOR should not be prohibited from attempting to father children. ♦ Women of childbearing potential: Use highly 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: Male and female fertility may be compromised by treatment with AFINITOR. Menstrual irregularities, secondary amenorrhea, and associated luteinizing hormone (LH) / follicle stimulating hormone (FSH) imbalance have been observed in female patients receiving AFINITOR.Interactions: Avoid concurrent treatment with strong CYP3A4 inhibitors or PgP inhibitors (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, telithromycin). ♦ Caution with moderate CYP3A4 inhibitors or PgP inhibitors (e.g. erythromycin, verapamil, diltiazem, fluconazole, ciclosporin, amprenavir, fosamprenavir, aprepitant). Consider a dose decrease of AFINITOR when co-administered with moderate inhibitors. ♦ Avoid concurrent treatment with strong CYP3A4 inducers or PgP inducers (e.g. rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine, dexamethasone, prednisone, prednisolone, St. John’s Wort (Hypericum perforatum)). Consider a dose increase of AFINITOR when co-administered with strong inducers. ♦ Avoid grapefruit juice, grapefruit, star fruit, Seville oranges and other foods affecting CYP3A4 or PgP. ♦ Caution when used in combination with orally administered CYP3A4 substrates with a narrow therapeutic index.Adverse drug reactions: ♦ Very common (≥10%): Infections, anemia, thrombocytopenia, hyperglycaemia, hypercholesterolemia, hypertriglyceridaemia, anorexia, dysgeusia, headache, pneumonitis, dyspnoea, epistaxis, cough, stomatitis, diarrhoea, mucosal inflammation, vomiting, nausea, rash, dry skin, pruritus, nail disorder, fatigue, asthenia, peripheral oedema, pyrexia, weight decreased ♦ Common (≥1 to <10%): leukopenia, lymphopenia, neutropenia, diabetes mellitus, hypophosphatemia, hypokalemia, hyperlipidaemia, hypocalcemia, dehydration, insomnia, conjunctivitis, eyelid oedema, hypertension, haemorrhage, pulmonary embolism, haemoptysis, dry mouth, abdominal pain, oral pain, dysphagia, dyspepsia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, palmar-plantar erythrodysaesthesia syndrome, erythema, skin exfoliation, acneiform dermatitis, oncychoclasis, skin lesion, mild alopecia, arthralgia, creatinine increased, renal failure (including acute renal failure), proteinuria, chest pain ♦ Uncommon (<1%): pure red cell aplasia, ageusia, congestive cardiac failure, flushing, deep vein thrombosis, acute respiratory distress syndrome, angioedema, impaired wound healing ♦ Not known: hypersensitivity. ♦ Laboratory abnormalities: abnormalities were observed in some hematology and clinical chemistry laboratory tests ♦ In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infections is an expected event during periods of immunosuppression. In clinical trials and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome), proteinuria, and cases of amenorrhea (secondary amenorrhea and other menstrual irregularities).Packs and prices: Country specific. Legal classification: Country specific.
IN THE BOLERO-2 STUDY:• The majority of AEs were mild to moderate in severity (grade 1/2), generally manageable, and
typically resolved over time2,3
• The most common grade 3/4 AEs (incidence <10%) were stomatitis (8%), infections (7%), hyperglycemia (6%), fatigue (5%), pneumonitis (3%), diarrhea (3%), and rash (1%) 2,6
• Serious AEs have been observed during AFINITOR therapy, including noninfectious pneumonitis, infections, and acute renal failure; on rare occasions, fatal outcomes were observed1
Key Adverse EventsSTOMATITIS• mTOR inhibitor–associated stomatitis (mIAS) is
distinct from conventional chemotherapy-induced mucositis in both its pathophysiology and clinical presentation7
• In BOLERO-2, the median time to onset was approximately 2 weeks8
Grade 1 = Minimal symptoms, normal diet9
Grade 2 = Symptomatic but can eat and swallow modified diet9
Grade 3 = Symptomatic and unable to adequately aliment or hydrate orally9
Grade 4 = Symptoms associated with life-threatening consequences9
Proactive planning for optimal treatment—partner with your patients to identify AEs early
IDENTIFY
Incidence of Stomatitis6
in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 4
59% 8% 0%
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
* AFINITOR is currently also approved for the treatment of unresectable or metastatic, well or moderately differentiated neuroendocrine tumors of pancreatic origin in adults with progressive disease and advanced renal cell carcinoma that has progressed on or after treatment with VEGF-targeted therapy.1
An established safety profile1,3
• More than 100,000 patients have been treated worldwide since the first oncology approval of AFINITOR in 20093 *
A safety profile consistent with the known AEs of mTOR inhibitors1,3 • mTOR inhibitors have a distinct safety profile—key AEs include stomatitis,
noninfectious pneumonitis, hematologic and nonhematologic toxicities, and metabolic events2,4,5
Advise. Identify. Manage. 94
Basic Succinct Statement
AFINITOR®
Important note: Before prescribing, consult full prescribing information. AFINITOR®
Presentation: Tablets containing 2.5 mg, 5 mg or 10 mg of everolimus.Indication: AFINITOR is indicated for the treatment of hormone 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 nonsteroidal aromatase inhibitor.Dosage: one 10 mg AFINITOR Tablet once daily. ♦ The daily dose should be taken orally at the same time every day, either consistently with or consistently without food. ♦ Dose adjustment: Dose adjustment may be required due to adverse drug reactions (ADRs), use of moderate CYP3A4/PgP inhibitors or strong CYP3A4 inducers, or hepatic status (Child-Pugh). ♦ Children: not recommended for use in children or adolescents. ♦ Patients with hepatic impairment: 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), unless benefit outweighs the risk. In the latter case, a dose of 2.5 mg daily must not be exceeded. Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment.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 hypoxia, pleural effusion, cough or dyspnoea, and in whom infectious, neoplastic, and other non-medicinal causes have been excluded. In some cases, management of pneumonitis may require interruption or discontinuation of treatment. The use of corticosteroids may be indicated. AFINITOR may be reinitiated at a lower dose. ♦ Infections: AFINITOR is immunosuppressive. Localized and systemic bacterial, fungal, viral, or protozoal infections (e.g. pneumonia, aspergillosis, candidiasis, and hepatitis B reactivation) have been described in patients taking AFINITOR; some of these have been severe and occasionally fatal. Pre-existing infections should be resolved prior to starting treatment with AFINITOR. Be vigilant for symptoms or signs of infection during treatment with AFINITOR. In case of emergent infections, 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: reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema have been observed with everolimus. ♦ Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis have been seen in patients treated with AFINITOR. Management of these adverse reactions may require dose temporary interruption, dose reduction or discontinuation. Topical treatments are recommended, but alcohol-, hydrogen peroxide, iodine-, or thyme containing mouthwashes should be avoided. AFINITOR may be reinitiated at the same dose or at a lower dose. ♦ Renal failure: Cases of renal failure (including acute renal failure), some fatal, have been observed in patients treated with AFINITOR. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair their renal function. ♦ Laboratory tests and monitoring: Renal function, blood glucose, blood lipids, and complete blood counts are recommended prior to initiation of and periodically during treatment. ♦ Carcinoid tumours: The
Please see accompanying Summary of Product Characteristics.8
Advise. Identify. Manage.Take AIM through a targeted treatment strategy
A program designed to optimize treatment experience by establishing the benefits of AFINITOR with an emphasis on early identification, monitoring, and effective management of key adverse events (AEs).
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
References: 1. AFINITOR [summary of product characteristics]. Novartis Pharma AG; 2013. 2. Rugo HS, Gnant M, Geberth M, et al. Everolimus-related adverse events: safety insights from BOLERO-2. Poster presented at: St. Gallen International Breast Cancer Conference; March 2013; St. Gallen, Switzerland. 3. Data on file. Novartis Pharma AG. 4. Grünwald V, Weikert S, Pavel ME, et al. Practical management of everolimus-related toxicities in patients with advanced solid tumors. Onkologie. 2013;36:295-302. 5. Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, Mita M. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Targ Oncol. 2009;4:135-142. 6. Piccart M, Baselga J, Noguchi S, et al. Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer. Poster presented at: San Antonio Breast Cancer Symposium; December, 2012; San Antonio, TX. 7. Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer. 2010;116:210-215. 8. Rugo HS, Gnant M, Geberth M, et al. Everolimus-related adverse events: safety insights from BOLERO-2. Abstract presented at: St. Gallen International Breast Cancer Conference; March 2013; St. Gallen, Switzerland. 9. National Cancer Institute. Common terminology criteria for adverse events (CTCAE) v3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications /docs/ctcaev3.pdf. Published May 09, 2006. Accessed June 12, 2013.
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
Novartis Pharma AGCH-4002 Basel Switzerland © Novartis 2013 9/13 G-AFI-1070510
safety and efficacy of AFINITOR in patients with carcinoid tumours have not been established. ♦ Hepatic Impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk. ♦ Vaccination: Avoid use of live vaccines and close contact with people who have received live vaccines. ♦ Lactose: Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. ♦ Wound healing complications: Impaired wound healing is a class effect of Rapamycin derivatives, including AFINITOR. Caution should be exercised with use of AFINITOR in peri-surgical period. ♦ Pregnancy: AFINITOR should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus. Male patients taking AFINITOR should not be prohibited from attempting to father children. ♦ Women of childbearing potential: Use highly 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: Male and female fertility may be compromised by treatment with AFINITOR. Menstrual irregularities, secondary amenorrhea, and associated luteinizing hormone (LH) / follicle stimulating hormone (FSH) imbalance have been observed in female patients receiving AFINITOR.Interactions: Avoid concurrent treatment with strong CYP3A4 inhibitors or PgP inhibitors (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, telithromycin). ♦ Caution with moderate CYP3A4 inhibitors or PgP inhibitors (e.g. erythromycin, verapamil, diltiazem, fluconazole, ciclosporin, amprenavir, fosamprenavir, aprepitant). Consider a dose decrease of AFINITOR when co-administered with moderate inhibitors. ♦ Avoid concurrent treatment with strong CYP3A4 inducers or PgP inducers (e.g. rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine, dexamethasone, prednisone, prednisolone, St. John’s Wort (Hypericum perforatum)). Consider a dose increase of AFINITOR when co-administered with strong inducers. ♦ Avoid grapefruit juice, grapefruit, star fruit, Seville oranges and other foods affecting CYP3A4 or PgP. ♦ Caution when used in combination with orally administered CYP3A4 substrates with a narrow therapeutic index.Adverse drug reactions: ♦ Very common (≥10%): Infections, anemia, thrombocytopenia, hyperglycaemia, hypercholesterolemia, hypertriglyceridaemia, anorexia, dysgeusia, headache, pneumonitis, dyspnoea, epistaxis, cough, stomatitis, diarrhoea, mucosal inflammation, vomiting, nausea, rash, dry skin, pruritus, nail disorder, fatigue, asthenia, peripheral oedema, pyrexia, weight decreased ♦ Common (≥1 to <10%): leukopenia, lymphopenia, neutropenia, diabetes mellitus, hypophosphatemia, hypokalemia, hyperlipidaemia, hypocalcemia, dehydration, insomnia, conjunctivitis, eyelid oedema, hypertension, haemorrhage, pulmonary embolism, haemoptysis, dry mouth, abdominal pain, oral pain, dysphagia, dyspepsia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, palmar-plantar erythrodysaesthesia syndrome, erythema, skin exfoliation, acneiform dermatitis, oncychoclasis, skin lesion, mild alopecia, arthralgia, creatinine increased, renal failure (including acute renal failure), proteinuria, chest pain ♦ Uncommon (<1%): pure red cell aplasia, ageusia, congestive cardiac failure, flushing, deep vein thrombosis, acute respiratory distress syndrome, angioedema, impaired wound healing ♦ Not known: hypersensitivity. ♦ Laboratory abnormalities: abnormalities were observed in some hematology and clinical chemistry laboratory tests ♦ In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infections is an expected event during periods of immunosuppression. In clinical trials and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome), proteinuria, and cases of amenorrhea (secondary amenorrhea and other menstrual irregularities).Packs and prices: Country specific. Legal classification: Country specific.
IN THE BOLERO-2 STUDY:• The majority of AEs were mild to moderate in severity (grade 1/2), generally manageable, and
typically resolved over time2,3
• The most common grade 3/4 AEs (incidence <10%) were stomatitis (8%), infections (7%), hyperglycemia (6%), fatigue (5%), pneumonitis (3%), diarrhea (3%), and rash (1%) 2,6
• Serious AEs have been observed during AFINITOR therapy, including noninfectious pneumonitis, infections, and acute renal failure; on rare occasions, fatal outcomes were observed1
Key Adverse EventsSTOMATITIS• mTOR inhibitor–associated stomatitis (mIAS) is
distinct from conventional chemotherapy-induced mucositis in both its pathophysiology and clinical presentation7
• In BOLERO-2, the median time to onset was approximately 2 weeks8
Grade 1 = Minimal symptoms, normal diet9
Grade 2 = Symptomatic but can eat and swallow modified diet9
Grade 3 = Symptomatic and unable to adequately aliment or hydrate orally9
Grade 4 = Symptoms associated with life-threatening consequences9
Proactive planning for optimal treatment—partner with your patients to identify AEs early
IDENTIFY
Incidence of Stomatitis6
in BOLERO-2 (AFINITOR + exemestane arm)
All Grades Grade 3 Grade 4
59% 8% 0%
Please see Basic Succinct Statement on pages 8-9.Please see accompanying Summary of Product Characteristics.
* AFINITOR is currently also approved for the treatment of unresectable or metastatic, well or moderately differentiated neuroendocrine tumors of pancreatic origin in adults with progressive disease and advanced renal cell carcinoma that has progressed on or after treatment with VEGF-targeted therapy.1
An established safety profile1,3
• More than 100,000 patients have been treated worldwide since the first oncology approval of AFINITOR in 20093 *
A safety profile consistent with the known AEs of mTOR inhibitors1,3 • mTOR inhibitors have a distinct safety profile—key AEs include stomatitis,
noninfectious pneumonitis, hematologic and nonhematologic toxicities, and metabolic events2,4,5
Advise. Identify. Manage. 94
IDENTIFY
ADL = activities of daily living.In the BOLERO-2 trial, the CTCAE Version 3.0 was used.ADL = activities of daily living.
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.09
Adverse Event GRADE 1 GRADE 2 GRADE 3 GRADE 4
Stomatitis
Clinic
al Ex
amErythema of the mucosa Patchy ulcerations or
pseudomembranes
Confl uent ulcerations or pseudomembranes, bleeding with minor trauma
Tissue necrosis, signifi cant spontaneous bleeding, life-threatening consequences
Func
tiona
l/Sy
mptom
atic
Minimal symptoms,normal diet
Symptomatic but can eat and swallow modifi ed diet
Symptomatic and unable to adequately aliment or hydrate orally
Symptoms associated with life-threatening consequences
Nonhematologic Toxicities: Rash
Macular or papular eruption or erythema without associated symptoms
Macular or papular eruption or erythema with pruritus or other associated symptoms; localized desquamation or other lesions covering <50% of body surface area (BSA)
Severe, generalized erythroderma or macular, papular, or vesicular eruption; desquamation covering ≥50% BSA
Generalized exfoliative, ulcerative, or bullous dermatitis
Noninfectious Pneumonitis
Asymptomatic, radiographic fi ndings only
Symptomatic, not interfering with ADL
Symptomatic, interfering with ADL; oxygen indicated
Life-threatening, ventilatory support indicated
IDENTIFYCommon Terminology Criteria for Adverse Events (CTCAE), Version 3.0 (cont)9
Adverse Event GRADE 1 GRADE 2 GRADE 3 GRADE 4
Metabolic Events
- Hyperglycemia >ULN-8.9 mmol/L >8.9-13.9 mmol/L >13.9-27.8 mmol/L >27.8 mmol/L
- Hypercholesterolemia >ULN-7.75 mmol/L >7.75-10.34 mmol/L >10.34-12.92 mmol/L >12.92 mmol/L
- Hypertriglyceridemia >ULN-2.5 x ULN >2.5-5.0 x ULN >5.0-10 x ULN >10 x ULN
Hematologic Toxicities
- Thrombocytopenia <LLN-75.0 x 109/L <75.0-50.0 x 109/L <50.0-25.0 x 109/L <25.0 x 109/L
- Neutropenia <LLN-1.5 x 109/L <1.5-1.0 x 109/L <1.0-0.5 x 109/L <0.5 x 109/L
LLN = lower limit of normal; ULN = upper limit of normal.In the BOLERO-2 trial, the CTCAE Version 3.0 was used.
Febrile NeutropeniaGrade 3: Absolute neutrophil count (ANC) <1.0 x 109/L with a temperature of ≥38.5°C.Grade 4: Life-threatening consequences (eg, septic shock, hypotension, acidosis, necrosis).