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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.

ADVISE

ADVISE
Optimize AFINITORs magnitude of benefit through patient education

>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 conrmed the magnitude of benet of AFINITOR plus exemestane vs placebo plus exemestane1 All preplanned subgroups in BOLERO-2 derived signicant PFS benet1 AFINITOR offers once-daily oral administration1 Median dose intensity of AFINITOR in BOLERO-2 was 8.6 mg/day 2

ADVISE IDENTIFY MANAGE


10 once daily
mg

10

Early identication, careful monitoring, and timely management of AEs in the oncology setting are 2 important mg to help patients optimize treatment

Encourage patients to proactively communicate at the earliest sign of an AE

IDENTIFY
Proactive planning for optimal treatmentpartner with your patients to identify AEs early
An established safety profile1,3 More than 100,000 patients have been treated worldwide since the first oncology approval of AFINITOR in 2009 3 * A safety profile consistent with the known AEs of mTOR inhibitors1,3 mTOR inhibitors have a distinct safety profilekey AEs include stomatitis, noninfectious pneumonitis, hematologic and nonhematologic toxicities, and metabolic events2,4,5 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 Events

STOMATITIS mTOR inhibitorassociated 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 weeks 8 Grade 1 = Minimal symptoms, normal diet 9

Incidence of Stomatitis 6
All Grades 59%

in BOLERO-2 (AFINITOR + exemestane arm)

Grade 3 8%

Grade 4 0%

Grade 2 = Symptomatic but can eat and swallow modified diet 9 Grade 3 = Symptomatic and unable to adequately aliment or hydrate orally 9 Grade 4 = Symptoms associated with life-threatening consequences 9
*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

NONINFECTIOUS PNEUMONITIS Noninfectious pneumonitis should be investigated safety and efcacy of AFINITOR in patients with carcinoid tumours Incidence of have not been established. Hepatic Noninfectious Pneumonitis6(Child-Pugh C) unless the in patients with respiratory signs2with severe Impairment: Notnonspecific recommended in patients hepatic impairment in BOLERO-2 (AFINITOR + exemestane arm) potential benet outweighs Pulmonary function tests, the risk. Vaccination: Avoid use of live vaccines and close contact with All Grades Grade 3 Grade 4 of galactose people who have received live vaccines. Lactose: Patients with rare hereditary problems radiographic imaging, bronchoscopy, intolerance, Lapp lactase deciency or glucose-galactose malabsorption should not 0% take this medicinal 16% 3% and bronchoalveolar lavage can be product. Wound 2healing complications: Impaired wound healing is a class effect of Rapamycin used to evaluate derivatives, including AFINITOR. Caution should be exercised with use of AFINITOR in peri-surgical period. Pregnancy: AFINITOR In BOLERO-2, the medianshould time tonot be given to pregnant women unless the potential benet outweighs 8 the potential risk to the fetus. Male patients taking AFINITOR should not be prohibited from attempting onset was 16 weeks to father children. Women of childbearing potential: Use highly effective contraception methods Grade 1 = Asymptomatic, radiographic findings only9 while receiving AFINITOR and for up to 8 weeks after ending treatment. Breast-feeding: Women taking Grade 2 = Symptomatic,* not interfering with ADL9 AFINITOR should not breast-feed. Fertility: Male and female fertility may be compromised by treatment with AFINITOR. Menstrual irregularities, secondary Grade 3 = Symptomatic,* interfering with ADL; O2 amenorrhea, indicated9 and associated luteinizing hormone (LH) / follicle stimulating hormone (FSH) imbalance have been observed in female patients receiving AFINITOR. 9 Grade 4 = Life-threatening, ventilatory support indicated Interactions: Avoid concurrent treatment with strong CYP3A4 inhibitors or PgP inhibitors (e.g. ketoconazole, ADL = activities of daily living. 1 itraconazole, ritonavir, clarithromycin, telithromycin). Caution with moderate CYP3A4 inhibitors or PgP *Nonspecific respiratory signs and symptoms include hypoxia, pleural effusion, cough, or dyspnoea. inhibitors (e.g. erythromycin, verapamil, diltiazem, uconazole, ciclosporin, amprenavir, fosamprenavir, RASH 6 aprepitant). Consider a dose decrease of AFINITOR when co-administered with moderate inhibitors. Avoid Incidence of Rash concurrent treatment with inducers or + PgP inducers (e.g. rifampicin, rifabutin, carbamazepine, Presents as rash and painstrong on CYP3A4 in BOLERO-2 (AFINITOR exemestane arm) phenobarbital, phenytoin, efavirenz, nevirapine, prednisolone, St. Johns Wort palms of hands or soles of All Grades dexamethasone, Grade 3 prednisone, Grade 4 (Hypericum perforatum )). Consider a dose increase of AFINITOR when co-administered with strong inducers. feet (hand-foot syndrome), 39% 1% 0% skin Avoid grapefruiterythema, juice, grapefruit, star fruit, Seville oranges and other foods affecting CYP3A4 or PgP. exfoliation, 1 pimples, Caution when used in combination acne, or skin lesions with orally administered CYP3A4 substrates with a narrow therapeutic index. Adverse drug reactions: Very common (10%): Infections, anemia, thrombocytopenia, hyperglycaemia, METABOLIC EVENTS Incidence of anorexia, Metabolic dysgeusia, Events3 hypercholesterolemia, hypertriglyceridaemia, headache, pneumonitis, dyspnoea, Monitor fasting blood in BOLERO-2 (AFINITOR + exemestane arm) epistaxis, cough, stomatitis, diarrhoea, mucosal inammation, vomiting, nausea, rash, dry skin, pruritus, glucose and lipid levels at All Grades 3 decreased Grade 4 Common (1 to <10%): nail disorder, fatigue, asthenia, peripheral oedema, pyrexia, Grade weight the start of therapy leukopenia, lymphopenia, neutropenia, diabetes mellitus, hypophosphatemia, hypokalemia, hyperlipidaemia, Hyperglycemia: 67% 7% <1% and periodically thereafter1insomnia, conjunctivitis, eyelid oedema, hypertension, haemorrhage, pulmonary hypocalcemia, dehydration, Hypercholesterolemia: 66% <1% <1% embolism, haemoptysis, dry mouth, abdominal pain, oral pain, dysphagia, dyspepsia, alanine aminotransferase Hypertriglyceridemia: 44% <1% (ALT) increased, aspartate aminotransferase (AST) increased, palmar-plantar 0% erythrodysaesthesia syndrome, erythema, skin exfoliation, acneiform dermatitis, oncychoclasis, skin lesion, mild alopecia, arthralgia, creatinine HEMATOLOGIC 3 pain increased, renalTOXICITIES failure (including acute renalof failure), proteinuria, chest Uncommon (<1%): pure red Incidence Hematologic Toxicities cell aplasia, ageusia, congestive cardiac failure, ushing, deep arm) vein thrombosis, acute respiratory distress in BOLERO-2 (AFINITOR + exemestane syndrome, angioedema, impaired wound healing Not known: hypersensitivity. All Grades Grade 3 Laboratory Grade 4 abnormalities: abnormalities were observed in some hematology and clinical chemistry laboratory tests In clinical trials, Thrombocytopenia (platelet 3% <1% fatal outcome. everolimus has been associated with serious cases of hepatitis B reactivation, including count decreased): 54% Reactivation of infections is an expected event during periods of immunosuppression. In clinical trials and Neutropenia (neutrophils decreased): 30% 2%failure <1% post-marketing spontaneous reports, everolimus has been associated with renal events (including fatal outcome), proteinuria, and cases of amenorrhea (secondary amenorrhea and other menstrual irregularities). Packs and prices: Country specic. Legal classication: Country specic.

IDENTIFY

Please see Basic Succinct Statement on pages 8-9. Please see accompanying Summary of Product Characteristics. 4
Advise. Identify. Manage.

See enclosed ashcards for guidance on distinguishing grades of key AEs.


5

MANAGE

Manage therapy with established strategies2,3


Management of adverse events may require dose reduction and/or temporary interruption of AFINITOR therapy1

MANAGE
FIRST OCCURRENCE

Tips to optimize AFINITOR treatment


STOMATITIS Grade 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:

Interrupt AFINITOR
Reinitiate
5 mg

ADVERSE EVENT GRADE 1 GRADE 2


Stomatitis Nonhematologic Toxicities* Thrombocytopenia Noninfectious Pneumonitis Metabolic Events
(eg, hyperglycemia, dyslipidemia)

UPON RECURRENCE
No Dose Adjustment

Look out for mouth ulcers, pain, discomfort, or open sores1 Avoid products containing alcohol, hydrogen peroxide, iodine, or thyme derivatives1

1 1 1

Interrupt AFINITOR Interrupt AFINITOR Interrupt AFINITOR

2 2 2

Reinitiate
10 mg

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

Reinitiate
10 mg

Per Physician Discretion Per Physician Discretion Per Physician Discretion

Reinitiate
5 mg

Neutropenia

No Dose Adjustment
Reinitiate
10 mg

GRADE 3
Neutropenia All Other Adverse Events||

1 1

Interrupt AFINITOR Interrupt AFINITOR

2 2

Reinitiate
5 mg

Per Physician Discretion

GRADE 4
Thrombocytopenia and Neutropenia All Other Adverse Events

Interrupt AFINITOR

Reinitiate
5 mg

Per Physician Discretion

Discontinue

In the 18-month median follow-up analysis of the BOLERO-2 study, the majority of patients did not require a dose reduction2

*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.

did not require a dose reduction2

61%

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.
Please see Basic Succinct Statement on pages 8-9. Please see accompanying Summary of Product Characteristics. 6
Advise. Identify. Manage.

required 1 dose reduction2

39%

Of the dose-modification events that resolved with re-initiation of the full 10-mg dose, 76% resolved within 2 weeks2

*Benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol. Triamcinolone oral paste.

Basic Succinct Statement

AFINITOR Important note: Before prescribing, consult full prescribing information. AFINITOR Proactive planning for treatmentpartner Presentation: Tablets containing 2.5 mg, 5 mg oroptimal 10 mg of everolimus. Indication: AFINITOR is indicated for the treatment of hormone receptor-positive, with your patients to identify AEs early HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease An established safety profile1,3 aromatase inhibitor. after recurrence or progression following a nonsteroidal More than 100,000 patients have been treated since the first Dosage: one 10 mg AFINITOR Tablet once daily. The daily dose worldwide should be taken orally atoncology the same time * approval of AFINITOR in 2009 3without every day, either consistently with or consistently food. Dose adjustment: Dose adjustment may 1,3 or strong CYP3A4 be required due toA adverse drug reactions (ADRs), use of moderate CYP3A4/PgP inhibitors safety profile consistent with the known AEs of mTOR inhibitors inducers, or hepatic status (Child-Pugh). Children: not recommended for use in children or adolescents. mTOR inhibitors have a distinct safety profilekey AEs include stomatitis, Patients with hepatic impairment: recommended dose is 7.5 mg daily in patients with mild hepatic noninfectious pneumonitis, hematologic and nonhematologic toxicities, and impairment (Child-Pugh A); 5 mg daily in patients with moderate hepatic impairment (Child-Pugh B); not metabolic events2,4,5 recommended in patients with severe hepatic impairment (Child-Pugh C), unless benet 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 IN THE BOLERO-2 STUDY: patients hepatic (Child-Pugh) status changes treatment. The majority of AEs were mild during to moderate in severity (grade 1/2), generally manageable, and typically resolved over Contraindications: Hypersensitivity totime the 2,3 active substance, to other rapamycin derivatives or to any of the excipients. The most common grade 3/4 AEs (incidence <10%) were stomatitis (8%), infections (7%), 2,6 hyperglycemia (6%), fatigue (5%), pneumonitis (3%), diarrhea and rash (1%)in Warnings/Precautions: Non-infectious pneumonitis: Cases have (3%), been described patients Serious taking AFINITOR, some AEs of these been severe and on rare occasions, a fatal noninfectious outcome was observed. have have been observed during AFINITOR therapy, including A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specic pneumonitis, infections, and acute renal failure; on rare occasions, fatal outcomes 1 respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea, and in whom were observed infectious, neoplastic, and other non-medicinal causes have been excluded. In some cases, management Key Adverse Events of pneumonitis may require interruption or discontinuation of treatment. The use of corticosteroids may be STOMATITIS indicated. AFINITOR may be reinitiated at a lower dose. Infections: AFINITOR is immunosuppressive. 6 mTOR inhibitorassociated is infections Incidence of Stomatitisaspergillosis, Localized and systemic bacterial, fungal, stomatitis viral, or (mIAS) protozoal (e.g. pneumonia, in BOLERO-2 + exemestane from conventional chemotherapy-induced candidiasis, anddistinct hepatitis B reactivation) have been described in patients taking (AFINITOR AFINITOR; some ofarm) these mucositis in both its pathophysiology and clinical have been severe and occasionally fatal. Pre-existing infections should be resolved prior to starting treatment All Grades Grade 3 Grade 4 7 with AFINITOR. presentation Be vigilant for symptoms or signs of infection during treatment with AFINITOR. In case of 59% 8% 0% of emergent infections, institutethe appropriate treatment promptly or discontinuation In BOLERO-2, median time to onset was and consider interruption 8 AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with approximately 2 weeks appropriate antifungal therapy. Hypersensitivity reactions: reactions manifested by symptoms including, Grade 1 = Minimal symptoms, normal diet 9pain or angioedema have been observed with but not limited to, anaphylaxis, dyspnoea, ushing, chest 9 everolimus. Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis been seen in patients Grade 2 = Symptomatic but can eat and swallow modified diethave treated with AFINITOR. Management of these adverse reactions may require dose temporary interruption, Grade 3 = Symptomatic and unable to adequately aliment or hydrate orally 9 dose reduction or discontinuation. Topical treatments are recommended, but alcohol-, hydrogen peroxide, 9 4 = Symptoms associated with consequences iodine-, or thymeGrade containing mouthwashes should be life-threatening avoided. AFINITOR may be reinitiated at the same dose or at a lower dose. Renal failure: Cases of renal failure (including acute renal failure), fatal, *AFINITOR is currently also approved for the treatment of unresectable or metastatic, well or moderately some differentiated have been observed in patients treated with AFINITOR. Renal function ofand patients should be monitored neuroendocrine tumors of pancreatic origin in adults with progressive disease advanced renal cell carcinoma that 1 has progressed on have or after additional treatment with VEGF-targeted particularly where patients risk factors therapy. 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 Basic Succinct Statement on pages 8-9.
8

IDENTIFY

safety and efcacy 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 benet 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 deciency 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 benet 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, uconazole, 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. Johns 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 inammation, 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, ushing, 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 specic. Legal classication: Country specic.

Please see accompanying Summary of Product Characteristics. PleaseAdvise. see accompanying Identify. Manage. Summary of Product Characteristics. 4

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 le. Novartis Pharma AG. 4. Grnwald 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 prole 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 AG CH-4002 Basel Switzerland

Novartis 2013

9/13

G-AFI-1070510

IDENTIFY
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 9

Adverse Event
Functional/ Symptomatic Clinical Exam

GRADE 1
Erythema of the mucosa

GRADE 2
Patchy ulcerations or pseudomembranes

GRADE 3
Conuent ulcerations or pseudomembranes, bleeding with minor trauma

GRADE 4
Tissue necrosis, signicant spontaneous bleeding, life-threatening consequences

Stomatitis

Minimal symptoms, normal diet

Symptomatic but can eat and swallow modied diet

Symptomatic and unable to adequately aliment or hydrate orally

Symptoms associated with life-threatening consequences

Nonhematologic Toxicities: Rash Noninfectious Pneumonitis


ADL = activities of daily living.

Macular or papular eruption or erythema without associated symptoms

Macular or papular eruption or erythema with pruritus or other Severe, generalized erythroderma or associated symptoms; localized macular, papular, or vesicular eruption; desquamation or other lesions desquamation covering 50% BSA covering <50% of body surface area (BSA) Symptomatic, not interfering with ADL Symptomatic, interfering with ADL; oxygen indicated

Generalized exfoliative, ulcerative, or bullous dermatitis

Asymptomatic, radiographic ndings only

Life-threatening, ventilatory support indicated

In the BOLERO-2 trial, the CTCAE Version 3.0 was used.

IDENTIFY
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 (cont)9

Adverse Event
Metabolic Events - Hyperglycemia - Hypercholesterolemia - Hypertriglyceridemia Hematologic Toxicities - Thrombocytopenia - Neutropenia

GRADE 1

GRADE 2

GRADE 3

GRADE 4

>ULN-8.9 mmol/L

>8.9-13.9 mmol/L

>13.9-27.8 mmol/L

>27.8 mmol/L

>ULN-7.75 mmol/L

>7.75-10.34 mmol/L

>10.34-12.92 mmol/L

>12.92 mmol/L

>ULN-2.5 x ULN

>2.5-5.0 x ULN

>5.0-10 x ULN

>10 x ULN

<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

<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 Neutropenia Grade 3: Absolute neutrophil count (ANC) <1.0 x 109/L with a temperature of 38.5C. Grade 4: Life-threatening consequences (eg, septic shock, hypotension, acidosis, necrosis).