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Oncology

Oncology
Therapies to target specific alterations that drive the growth and progression of cancer and specific tumors types.

Oncology Medications

Please select a product from the list to view its approved indications as well as the link to its full prescribing information. The list is not an all-inclusive list of Pfizer medications in a therapeutic area and inclusion of a product within this list should not suggest it is approved for a broad therapeutic area. Please refer to each medication’s individual prescribing information for specific details.

AROMASIN® (exemestane)

These highlights do not include all the information needed to use AROMASIN safety and effectively. See full prescribing information for AROMASIN.

4 CONTRAINDICATIONS

AROMASIN is contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients.

5 WARNINGS AND PRECAUTIONS

5.1 Reductions in Bone Mineral Density (BMD)

Reductions in bone mineral density (BMD) over time are seen with exemestane use. Table 1 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027). Concomitant use of bisphosphonates, vitamin D supplementation, and calcium was not allowed.

Table 1. Percent Change in BMD from Baseline to 24 months, Exemestane vs. Control1
IES 027
BMD Exemestane
  N=29
Tamoxifen1
  N=38
Exemestane
  N=59
Placebo1
  N=65
Lumbar spine (%) -3.14 -0.18 -3.51 -2.35
Femoral neck (%) -4.15 -0.33 -4.57 -2.59

During adjuvant treatment with exemestane, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment. Monitor patients for bone mineral density loss and treat as appropriate.

5.2 Vitamin D Assessment

Routine assessment of 25-hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be performed, due to the high prevalence of vitamin D deficiency in women with early breast cancer (EBC). Women with vitamin D deficiency should receive supplementation with vitamin D.

5.3 Administration with Estrogen-Containing Agents

AROMASIN should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action.

5.4 Laboratory Abnormalities

In patients with early breast cancer, the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade ≥1 was lower in the exemestane treatment group, compared with tamoxifen. Incidence of CTC grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment groups. Approximately 20% of patients receiving exemestane in clinical studies in advanced breast cancer experienced CTC grade 3 or 4 lymphocytopenia. Of these patients, 89% had a pre-existing lower grade lymphopenia. Forty percent of patients either recovered or improved to a lesser severity while on treatment. Patients did not have a significant increase in viral infections, and no opportunistic infections were observed. Elevations of serum levels of AST, ALT, alkaline phosphatase, and gamma glutamyl transferase >5 times the upper value of the normal range (i.e., ≥ CTC grade 3) have been rarely reported in patients treated for advanced breast cancer but appear mostly attributable to the underlying presence of liver and/or bone metastases. In the comparative study in advanced breast cancer patients, CTC grade 3 or 4 elevation of gamma glutamyl transferase without documented evidence of liver metastasis was reported in 2.7% of patients treated with AROMASIN and in 1.8% of patients treated with megestrol acetate.

In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving exemestane than either tamoxifen or placebo. Treatment-emergent bilirubin elevations (any CTC grade) occurred in 5.3% of exemestane patients and 0.8% of tamoxifen patients on the Intergroup Exemestane Study (IES), and in 6.9% of exemestane treated patients vs. 0% of placebo treated patients in the 027 study. CTC grade 3–4 increases in bilirubin occurred in 0.9% of exemestane treated patients compared to 0.1% of tamoxifen treated patients. Alkaline phosphatase elevations of any CTC grade occurred in 15.0% of exemestane treated patients on the IES compared to 2.6% of tamoxifen treated patients, and in 13.7% of exemestane treated patients compared to 6.9% of placebo treated patients in study 027. Creatinine elevations occurred in 5.8% of exemestane treated patients and 4.3% of tamoxifen treated patients on the IES and in 5.5% of exemestane treated patients and 0% of placebo treated patients in study 027.

5.5 Use in Premenopausal Women

AROMASIN is not indicated for the treatment of breast cancer in premenopausal women.

5.6 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, AROMASIN can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of exemestane to pregnant rats and rabbits caused increased incidence of abortions and embryo-fetal toxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with AROMASIN and for 1 month after the last dose [see Use in Specific Populations (8.1), (8.3) and Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

In the adjuvant treatment of early breast cancer, the most common adverse reactions occurring in ≥10% of patients in any treatment group (AROMASIN vs. tamoxifen) were mild to moderate hot flushes (21.2% vs. 19.9%), fatigue (16.1% vs. 14.7%), arthralgia (14.6% vs. 8.6%), headache (13.1% vs. 10.8%), insomnia (12.4% vs. 8.9%), and increased sweating (11.8% vs. 10.4%). Discontinuation rates due to AEs were similar between AROMASIN and tamoxifen (6.3% vs. 5.1%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were AROMASIN 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: AROMASIN 0.4%, tamoxifen 0.3%.

In the treatment of advanced breast cancer, the most common adverse reactions were mild to moderate and included hot flushes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for AROMASIN and megestrol acetate, respectively.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adjuvant Therapy

The data described below reflect exposure to AROMASIN in 2325 postmenopausal women with early breast cancer. AROMASIN tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study (14.1) and the 027 study (a randomized, placebo-controlled, double-blind, parallel group study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids, and coagulation factors over 2 years of treatment).

The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients receiving AROMASIN or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving AROMASIN or placebo within the 027 study. Median duration of observation after randomization for AROMASIN was 34.5 months and for tamoxifen was 34.6 months. Median duration of observation was 30 months for both groups in the 027 study.

Certain adverse reactions, which were expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checklist. Signs and symptoms were graded for severity using CTC in both studies. Within the IES study, the presence of some illnesses/conditions was monitored through a positive checklist without assessment of severity. These included myocardial infarction, other cardiovascular disorders, gynecological disorders, osteoporosis, osteoporotic fractures, other primary cancer, and hospitalizations.

Within the IES study, discontinuations due to adverse reactions occurred in 6.3% and 5.1% of patients receiving AROMASIN and tamoxifen, respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo respectively within study 027.

Deaths due to any cause were reported for 1.3% of the exemestane treated patients and 1.4% of the tamoxifen treated patients within the IES study. There were 6 deaths due to stroke on the exemestane arm compared to 2 on tamoxifen. There were 5 deaths due to cardiac failure on the exemestane arm compared to 2 on tamoxifen.

The incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) was 1.6% in exemestane treated patients and 0.6% in tamoxifen treated patients in the IES study. Cardiac failure was observed in 0.4% of exemestane treated patients and 0.3% of tamoxifen treated patients.

Treatment-emergent adverse reactions and illnesses including all causalities and occurring with an incidence of ≥5% in either treatment group of the IES study during or within one month of the end of treatment are shown in Table 2.

Table 2. Incidence (%) of Adverse Reactions of all Grades* and Illnesses Occurring in (≥5%) of Patients in Any Treatment Group in Study IES in Postmenopausal Women with Early Breast Cancer
% of patients
Body system and Adverse Reaction by MedDRA dictionary AROMASIN
25 mg daily
(N=2252)
Tamoxifen
20 mg daily
(N=2280)
*
Graded according to Common Toxicity Criteria;
75 patients received tamoxifen 30 mg daily;
Event actively sought.
Eye
  Visual disturbances 5.0 3.8
Gastrointestinal
  Nausea 8.5 8.7
General Disorders
  Fatigue 16.1 14.7
Musculoskeletal
  Arthralgia 14.6 8.6
  Pain in limb 9.0 6.4
  Back pain 8.6 7.2
  Osteoarthritis 5.9 4.5
Nervous System
  Headache 13.1 10.8
  Dizziness 9.7 8.4
Psychiatric
  Insomnia 12.4 8.9
  Depression 6.2 5.6
Skin & Subcutaneous Tissue
  Increased sweating 11.8 10.4
Vascular
  Hot flushes 21.2 19.9
  Hypertension 9.8 8.4

In the IES study, as compared to tamoxifen, AROMASIN was associated with a higher incidence of events in musculoskeletal disorders and in nervous system disorders, including the following events occurring with frequency lower than 5% (osteoporosis [4.6% vs. 2.8%], osteochondrosis and trigger finger [0.3% vs. 0 for both events], paresthesia [2.6% vs. 0.9%], carpal tunnel syndrome [2.4% vs. 0.2%], and neuropathy [0.6% vs. 0.1%]). Diarrhea was also more frequent in the exemestane group (4.2% vs. 2.2%). Clinical fractures were reported in 94 patients receiving exemestane (4.2%) and 71 patients receiving tamoxifen (3.1%). After a median duration of therapy of about 30 months and a median follow-up of about 52 months, gastric ulcer was observed at a slightly higher frequency in the AROMASIN group compared to tamoxifen (0.7% vs. <0.1%). The majority of patients on AROMASIN with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.

Tamoxifen was associated with a higher incidence of muscle cramps [3.1% vs. 1.5%], thromboembolism [2.0% vs. 0.9%], endometrial hyperplasia [1.7% vs. 0.6%], and uterine polyps [2.4% vs. 0.4%].

Common adverse reactions occurring in study 027 are described in Table 3.

Table 3. Incidence of Selected Treatment-Emergent Adverse Reactions of all CTC Grades* Occurring in ≥ 5% of Patients in Either Arm in Study 027
Adverse Reaction Exemestane
N=73
(% incidence)
Placebo
N=73
(% incidence)
*
Most events were CTC grade 1–2
Hot flushes 32.9 24.7
Arthralgia 28.8 28.8
Increased sweating 17.8 20.6
Alopecia 15.1 4.1
Hypertension 15.1 6.9
Insomnia 13.7 15.1
Nausea 12.3 16.4
Fatigue 11.0 19.2
Abdominal pain 11.0 13.7
Depression 9.6 6.9
Diarrhea 9.6 1.4
Dizziness 9.6 9.6
Dermatitis 8.2 1.4
Headache 6.9 4.1
Myalgia 5.5 4.1
Edema 5.5 6.9

Treatment of Advanced Breast Cancer

A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. Only one death was considered possibly related to treatment with exemestane; an 80-year-old woman with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. In the clinical trials program, only 3% of the patients discontinued treatment with exemestane because of adverse reactions, mainly within the first 10 weeks of treatment; late discontinuations because of adverse reactions were uncommon (0.3%).

In the comparative study, adverse reactions were assessed for 358 patients treated with AROMASIN and 400 patients treated with megestrol acetate. Fewer patients receiving AROMASIN discontinued treatment because of adverse reactions than those treated with megestrol acetate (2% vs. 5%). Adverse reactions that were considered drug related or of indeterminate cause included hot flashes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for AROMASIN and megestrol acetate, respectively. The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with AROMASIN (17% vs. 8%). Table 4 shows the adverse reactions of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with AROMASIN or megestrol acetate.

Table 4. Incidence (%) of Adverse Reactions of all Grades* and Causes Occurring in ≥5% of Advanced Breast Cancer Patients In Each Treatment Arm in the Comparative Study
Body system and Adverse Reaction by WHO ART dictionary AROMASIN
25 mg
once daily
(N=358)
Megestrol Acetate
40 mg QID (N=400)
*
Graded according to Common Toxicity Criteria
Autonomic Nervous
  Increased sweating 6 9
Body as a Whole
  Fatigue 22 29
  Hot flashes 13 6
  Pain 13 13
  Influenza-like symptoms 6 5
  Edema (includes edema, peripheral edema, leg edema) 7 6
Cardiovascular
  Hypertension 5 6
Nervous
  Depression 13 9
  Insomnia 11 9
  Anxiety 10 11
  Dizziness 8 6
  Headache 8 7
Gastrointestinal
  Nausea 18 12
  Vomiting 7 4
  Abdominal pain 6 11
  Anorexia 6 5
  Constipation 5 8
  Diarrhea 4 5
  Increased appetite 3 6
Respiratory
  Dyspnea 10 15
  Coughing 6 7

Less frequent adverse reactions of any cause (from 2% to 5%) reported in the comparative study for patients receiving AROMASIN 25 mg once daily were fever, generalized weakness, paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary tract infection, and lymphedema.

Additional adverse reactions of any cause observed in the overall clinical trials program (N = 1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), asthenia (6%), and fever (5%). Adverse reactions of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the overall clinical trials program but not in the comparative study included chest pain, hypoesthesia, confusion, dyspepsia, arthralgia, back pain, skeletal pain, infection, upper respiratory tract infection, pharyngitis, rhinitis, and alopecia.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of AROMASIN. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders- hypersensitivity

Hepatobiliary disorders- hepatitis including cholestatic hepatitis

Nervous system disorders- paresthesia

Skin and subcutaneous tissue disorders- acute generalized exanthematous pustulosis, urticaria, pruritus

1 INDICATIONS AND USAGE

1.1 Adjuvant Treatment of Postmenopausal Women

AROMASIN is indicated for adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to AROMASIN for completion of a total of five consecutive years of adjuvant hormonal therapy [see Clinical Studies (14.1)].

1.2 Advanced Breast Cancer in Postmenopausal Women

AROMASIN is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy [see Clinical Studies (14.2)].

BOSULIF® (bosutinib)

These highlights do not include all the information needed to use BOSULIF safety and effectively. See full prescribing information for BOSULIF.

4 CONTRAINDICATIONS

BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included anaphylaxis. In the BOSULIF clinical trials, anaphylactic shock occurred in less than 0.2% of treated patients.

5 WARNINGS AND PRECAUTIONS

5.1 Gastrointestinal Toxicity

Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement. Among 546 patients in a single-arm Phase 1/2 clinical trial, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1–268). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)].

5.2 Myelosuppression

Thrombocytopenia, anemia and neutropenia occur with BOSULIF treatment. Perform complete blood counts weekly for the first month of therapy and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.4) and Adverse Reactions (6)].

5.3 Hepatic Toxicity

One case consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×ULN) occurred in a trial of BOSULIF in combination with letrozole. The patient recovered fully following discontinuation of BOSULIF. This case represented 1 out of 1209 patients in BOSULIF clinical trials.

Among the 546 patients in a single-arm Phase 1/2 clinical trial the incidence of ALT elevation was 18% and AST elevation was 15%. Twenty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations occurred early in treatment; of patients who experienced transaminase elevations of any grade, more than 80% experienced their first event within the first 3 months. The median time to onset of increased ALT and AST was 35 and 33 days, respectively, and the median duration for each was 21 days.

Perform hepatic enzyme tests monthly for the first three months of BOSULIF treatment and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)].

5.4 Fluid Retention

Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema.

Among 546 patients in a single-arm Phase 1/2 clinical trial, Grade 3 or 4 fluid retention was reported in 26 patients (5%). Some patients experienced more than one fluid retention event. Specifically, 21 patients experienced Grade 3 or 4 pleural effusions, 7 patients experienced Grade 3 or Grade 4 pericardial effusions, and 6 patients experienced Grade 3 edema.

Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)].

5.5 Renal Toxicity

An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with BOSULIF. Table 2 identifies the shift from baseline to lowest observed estimated glomerular filtration rate (eGFR) during BOSULIF therapy for patients in the global Ph+ Leukemia studies. The median duration of therapy with BOSULIF was approximately 17 months (range, 0.03 to 95) for patients in these studies.

Table 2: Shift from Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies (n=818)*
Baseline Follow-Up
Renal Function Status n Normal
n (%)
Mild
n (%)
Mild to Moderate
n (%)
Moderate to Severe
n (%)
Severe
n (%)
Kidney Failure
n (%)
Notes: Grading is based on Modification in Diet in Renal Disease method (MDRD).
KDIGO Classification by eGFR: Normal: greater than or equal to 90, Mild: 60 to less than 90, Mild to Moderate: 45 to less than 60, Moderate to Severe: 30 to less than 45, Severe: 15 to less than 30, Kidney Failure: less than 15 ml/min/1.73 m2.
*
Among the 818 patients, eGFR was missing in 5 patients at baseline or on-therapy. There were no patients with kidney failure at baseline.
Normal 274 53 (19) 174 (64) 30 (11) 14 (5) 1 (<1) 1 (<1)
Mild 438 10 (2) 170 (39) 177 (40) 63 (14) 14 (3) 2 (1)
Mild to Moderate 79 0 4 (5) 28 (35) 37 (47) 10 (13) 0
Moderate to Severe 24 0 1 (4) 1 (4) 6 (25) 15 (63) 1 (4)
Severe 1 0 0 0 0 0 1 (100)
Total 816 63 (8) 349 (43) 236 (29) 120 (15) 40 (5) 5 (1)

Monitor renal function at baseline and during therapy with BOSULIF, with particular attention to those patients who have preexisting renal impairment or risk factors for renal dysfunction. Consider dose adjustment in patients with baseline and treatment emergent renal impairment [see Dosage and Administration (2.7)].

5.6 Embryofetal Toxicity

BOSULIF can cause fetal harm when administered to a pregnant woman. Bosutinib caused embryofetal toxicities in rabbits at maternal exposures that were greater than the clinical exposure at the recommended bosutinib dose of 500 mg/day. There are no adequate and well controlled studies of BOSULIF in pregnant women. Advise females of reproductive potential to use effective contraceptive measures to prevent pregnancy while being treated with BOSULIF and for at least 30 days after the final dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Serious adverse reactions reported include anaphylactic shock [see Contraindications (4)], myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash.

Adverse reactions of any toxicity grade reported for greater than 20% of patients in Phase 1/2 trial (n=546) were diarrhea (82%), nausea (47%), thrombocytopenia (42%), rash (41%), vomiting (39%), abdominal pain (39%), respiratory tract infection (39%), anemia (30%), pyrexia (27%), liver test abnormalities (24%), fatigue (25%), cough (22%), and headache (20%) [see Clinical Studies (14)].

Adverse Reactions in Patients with Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CML

The single-arm Phase 1/2 clinical trial (Study 1) enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) and with resistance or intolerance to prior therapy [see Clinical Studies (14)]. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients:

  • 284 patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 26 months, and a median dose intensity of 442 mg/day.
  • 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of BOSULIF treatment of 9 months and a median dose intensity of 442 mg/day.
  • 143 patients with advanced phase CML including 79 patients with AP CML and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of BOSULIF treatment was 10 months and 3 months, respectively. The median dose intensity was 425 mg/day, and 456 mg/day, in the AP CML and BP CML cohorts, respectively.

Table 3 identifies adverse reactions greater than or equal to 10% for all grades and grades 3 or 4 for the Phase 1/2 CML safety population based on long-term follow-up.

Table 3: Adverse Reactions (10% or Greater) in Patients with CML in Study 1*
Chronic Phase CML
N=403
Advanced Phase CML
N=143
All Grades
(%)
Grade 3/4
(%)
All Grades
(%)
Grade 3/4
(%)
Advanced Phase CML includes patients with Accelerated Phase and Blast Phase CML
*
Based on a Minimum of 48 Months of Follow-up
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain
Thrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia
§
Respiratory tract infection includes the following preferred terms: Acute sinusitis, Acute tonsillitis, Atypical pneumonia, Bronchitis, Bronchitis bacterial, Bronchitis pneumococcal, Bronchopneumonia, Chronic tonsillitis, H1N1 influenza, Influenza, Laryngitis, Lobar pneumonia, Lower respiratory tract infection, Lung infection, Nasopharyngitis, Pertussis, Pharyngitis, Pharyngotonsillitis, Pneumonia, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia pneumococcal, Pneumonia streptococcal, Pulmonary mycosis, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Sinusitis, Tonsillitis, Tonsillitis bacterial, Tracheitis, Upper respiratory tract infection, Viral upper respiratory tract infection
Rash includes the following preferred terms: Acne, Dermatitis, Dermatitis acneiform, Dermatitis allergic, Eczema, Eczema asteatotic, Erythema, Generalised erythema, Intertrigo, Palmar erythema, Prurigo, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Skin irritation, Stasis dermatitis
#
Liver Test Abnormalities includes the following preferred terms:
Alanine aminotransferase increased, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Hyperbilirubinaemia, Liver function test abnormal, Transaminases increased
Þ
Fatigue includes the following preferred terms: Fatigue, Malaise
ß
Anaemia includes the following preferred terms: Anaemia, Haemoglobin decreased
à
Neutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased
è
Edema includes the following preferred terms containing:
Acute pulmonary edema, Allergic edema, Angioedema, Bone marrow edema, Circumoral edema, Eyelid edema, Eye edema, Face edema, Gastrointestinal edema, Localised edema, Edema, Edema peripheral, Periorbital edema, Pharyngeal edema, Pulmonary edema, Scrotal edema, Testicular edema, Tongue edema, Weight increased
ð
Renal impairment includes the following preferred terms: Acute kidney injury, Acute prerenal failure, Anuria, Blood creatinine abnormal, Blood creatinine increased, Chronic kidney disease, Oliguria, Prerenal failure, Renal failure, Renal impairment
ø
Leukopenia includes the following preferred terms: Leukopenia, White blood cell count decreased
ý
Chest pain included the following preferred terms: Chest pain, chest discomfort.
Diarrhea 85 9 76 4
Nausea 47 1 48 2
Abdominal Pain 42 2 31 6
Thrombocytopenia 40 26 45 39
Respiratory tract infection§ 39 5 38 12
Vomiting 37 3 43 3
Rash 42 8 38 4
Liver test abnormalities# 26 9 20 10
FatigueÞ 26 2 21 5
Anemiaß 27 11 38 27
Pyrexia 23 <1 37 2
Headache 21 <1 17 4
Cough 22 0 22 0
Neutropeniaà 18 12 22 20
Edemaè 20 1 17 2
Arthralgia 17 <1 14 0
Decreased appetite 14 <1 13 0
Renal impairmentð 13 2 13 5
Back pain 13 <1 8 1
Asthenia 13 2 10 <1
Pruritus 12 <1 7 0
Dizziness 11 0 13 <1
Dyspnea 12 2 20 6
Pleural effusion 12 4 9 4
Leukopeniaø 10 4 15 12
Chest painý 7 1 12 1

In the single-arm Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.

Table 4 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 1/2 CML safety population based on long-term follow-up.

Table 4: Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities in Patients with CML in Study 1, Safety Population*
Chronic Phase CML
N=403
n (%)
Advanced Phase CML
N=143
n (%)
All CP and AdvP CML
N=546
n (%)
*
Based on a Minimum of 48 Months of Follow-up
Hematology Parameters
  Platelet Count (Low) less than 50×109/L 105 (26) 82 (57) 187 (34)
  Absolute Neutrophil Count less than 1×109/L 65 (16) 55 (39) 120 (22)
  Hemoglobin (Low) less than 80 g/L 51 (13) 54 (38) 105 (19)
 
Biochemistry Parameters
  SGPT/ALT greater than 5.0×ULN 43 (11) 8 (6) 51 (9)
  SGOT/AST greater than 5.0×ULN 19 (5) 5 (4) 24 (4)
  Lipase greater than 2×ULN 42 (10) 9 (6) 51 (9)
  Phosphorus (Low) less than 0.6 mmol/L 30 (7) 10 (7) 40 (7)
 Total Bilirubin greater than 3.0×ULN 3 (1) 4 (3) 7 (1)

Additional Adverse Reactions from Multiple Clinical Trials

The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF-treated patients). They represent an evaluation of the adverse reaction data from 881 patients with Ph+ leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.

Blood and Lymphatic System Disorders: 1% and less than 10% - febrile neutropenia; less than 1% - granulocytopenia

Cardiac Disorders: 1% and less than 10% - pericardial effusion; 0.1% and less than 1% - pericarditis

Ear and Labyrinth Disorders: 1% and less than 10% - tinnitus

Vascular Disorders: 1% and less than 10% - hypertension

Gastrointestinal Disorders: 1% and less than 10% - gastritis, gastrointestinal hemorrhage (Anal hemorrhage, Gastric hemorrhage, Gastrointestinal hemorrhage, Hematemesis, Hematochezia, Intestinal hemorrhage, Lower gastrointestinal hemorrhage, Melena, Rectal hemorrhage, Upper gastrointestinal hemorrhage); 0.1% and less than 1% - acute pancreatitis

General Disorders and Administrative Site Conditions: 1% and less than 10% - pain

Hepatobiliary Disorders: 1% and less than 10% - hepatotoxicity (includes Allergic hepatitis, Ascites, Cholestasis, Drug-induced liver injury, Hepatic steatosis, Hepatitis toxic, Hepatocellular injury, Hepatotoxicity, Liver disorder, Liver injury)

Immune System Disorders: 1% and less than 10% - drug hypersensitivity; 0.1% and less than 1% - anaphylactic shock

Investigations: 1% and less than 10% - electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome), blood creatine phosphokinase increased, amylase increased.

Metabolism and Nutrition Disorder: 1% and less than 10% - hyperkalemia, dehydration, hypophosphatemia

Musculoskeletal and Connective Tissue Disorder: 1% and less than 10% - myalgia

Nervous System Disorders: 1% and less than 10% - dysgeusia

Respiratory, Thoracic and Mediastinal Disorders: 0.1% and less than 1% - respiratory failure, pulmonary hypertension

Skin and Subcutaneous Disorders: 1% and less than 10% - urticaria, pruritus; 0.1% and less than 1% - erythema multiforme, exfoliative rash, drug eruption

6.2 Post-Marketing Experience

The following additional adverse reactions have been identified during post-approval use of BOSULIF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome

1 INDICATIONS AND USAGE

BOSULIF is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.

CAMPTOSAR® (irinotecan HCl)

These highlights do not include all the information needed to use CAMPTOSAR safety and effectively. See full prescribing information for CAMPTOSAR.

WARNING: DIARRHEA and MYELOSUPPRESSION

  • Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt CAMPTOSAR and reduce subsequent doses if severe diarrhea occurs.
  • Severe myelosuppression may occur.

4 CONTRAINDICATIONS

  • CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.

5 WARNINGS AND PRECAUTIONS

5.1 Diarrhea and Cholinergic Reactions

Early diarrhea (occurring during or shortly after infusion of CAMPTOSAR) is usually transient and infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Bradycardia may also occur. Early diarrhea and other cholinergic symptoms may be prevented or treated. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). These symptoms are expected to occur more frequently with higher irinotecan doses.

Late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Grade 3–4 late diarrhea occurred in 23–31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. One dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication. Patients must not be treated with CAMPTOSAR until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of CAMPTOSAR should be decreased [see Dosage and Administration (2)].

Avoid diuretics or laxatives in patients with diarrhea.

5.2 Myelosuppression

Deaths due to sepsis following severe neutropenia have been reported in patients treated with CAMPTOSAR. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia. Manage febrile neutropenia promptly with antibiotic support [see Warnings and Precautions (5.2)]. Hold CAMPTOSAR if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm3. After recovery to an absolute neutrophil count ≥1000/mm3, subsequent doses of CAMPTOSAR should be reduced [see Dosage and Administration (2)].

When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation (48% [13/27] versus 24% [67/277]; p=0.04). Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of CAMPTOSAR. Based on sparse available data, the concurrent administration of CAMPTOSAR with irradiation is not recommended.

Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/266]; p<0.001). Patients with deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome, may be at greater risk of myelosuppression when receiving therapy with CAMPTOSAR.

5.3 Patients With Reduced UGT1A1 Activity

Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of CAMPTOSAR treatment.

In a study of 66 patients who received single-agent CAMPTOSAR (350 mg/m2 once-every-3-weeks), the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50%, and in patients heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%. No grade 4 neutropenia was observed in patients homozygous for the wild-type allele (UGT1A1 6/6 genotype).

In a prospective study (n=250) to investigate the role of UGT1A1*28 polymorphism in the development of toxicity in patients treated with CAMPTOSAR (180 mg/m2) in combination with infusional 5-FU/LV, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 4.5%, and in patients heterozygous for this allele the incidence was 5.3%. Grade 4 neutropenia was observed in 1.8% of patients homozygous for the wild-type allele.

In another study in which 109 patients were treated with CAMPTOSAR (100–125 mg/m2) in combination with bolus 5-FU/LV, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 18.2%, and in patients heterozygous for this allele the incidence was 11.1%. Grade 4 neutropenia was observed in 6.8% of patients homozygous for the wild-type allele.

When administered in combination with other agents or as a single-agent, a reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment [see Dosage and Administration (2)].

UGT1A1 Testing

A laboratory test is available to determine the UGT1A1 status of patients. Testing can detect the UGT1A1 6/6, 6/7 and 7/7 genotypes.

5.4 Hypersensitivity

Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue CAMPTOSAR if anaphylactic reaction occurs.

5.5 Renal Impairment/Renal Failure

Renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea.

5.6 Pulmonary Toxicity

Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred in patients receiving irinotecan (in combination and as monotherapy). Risk factors include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during CAMPTOSAR therapy. In Japanese studies, a reticulonodular pattern on chest x-ray was observed in a small percentage of patients. New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation. If IPD is diagnosed, CAMPTOSAR and other chemotherapy should be discontinued and appropriate treatment instituted as needed [see Adverse Reactions (6.1)].

5.7 Toxicity of the 5 Day Regimen

Outside of a well-designed clinical study, CAMPTOSAR Injection should not be used in combination with a regimen of 5-FU/LV administered for 4–5 consecutive days every 4 weeks because of reports of increased toxicity, including toxic deaths. CAMPTOSAR should be used as recommended in Table 2 [see Dosage and Administration (2)].

5.8 Increased Toxicity in Patients with Performance Status 2

In patients receiving either irinotecan/5-FU/LV or 5-FU/LV in the clinical trials, higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle treatment discontinuation, and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance status of 0 or 1.

5.9 Embryofetal Toxicity

CAMPTOSAR can cause fetal harm when administered to a pregnant woman. Irinotecan was embryotoxic in rats and rabbits at doses significantly lower than those administered to humans on a mg/m2 basis. In rats, at exposures approximately 0.2 times those achieved in humans at the 125 mg/m2 dose, irinotecan was embryotoxic and resulted in decreased learning ability and female fetal body weight in surviving pups; the drug was teratogenic at lower exposures (approximately 0.025 times the AUC in humans at the 125 mg/m2 dose). There are no adequate and well-controlled studies of irinotecan in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with CAMPTOSAR.

5.10 Patients with Hepatic Impairment

The use of CAMPTOSAR in patients with significant hepatic impairment has not been established. In clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin >2.0 mg/dL, or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >5 times the upper limit of normal with liver metastasis. In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first-cycle, grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/226]; p<0.001) [see Dosage and Administration (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Common adverse reactions (≥30%) observed in combination therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, and alopecia.

Common adverse reactions (≥30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia.

Serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia.

First-Line Combination Therapy

A total of 955 patients with metastatic colorectal cancer received the recommended regimens of irinotecan in combination with 5-FU/LV, 5-FU/LV alone, or irinotecan alone. In the two phase 3 studies, 370 patients received irinotecan in combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients received irinotecan alone [see Dosage and Administration (2)].

In Study 1, 49 (7.3%) patients died within 30 days of last study treatment: 21 (9.3%) received irinotecan in combination with 5-FU/LV, 15 (6.8%) received 5-FU/LV alone, and 13 (5.8%) received irinotecan alone. Deaths potentially related to treatment occurred in 2 (0.9%) patients who received irinotecan in combination with 5-FU/LV (2 neutropenic fever/sepsis), 3 (1.4%) patients who received 5-FU/LV alone (1 neutropenic fever/sepsis, 1 CNS bleeding during thrombocytopenia, 1 unknown) and 2 (0.9%) patients who received irinotecan alone (2 neutropenic fever). Deaths from any cause within 60 days of first study treatment were reported for 15 (6.7%) patients who received irinotecan in combination with 5-FU/LV, 16 (7.3%) patients who received 5-FU/LV alone, and 15 (6.7%) patients who received irinotecan alone. Discontinuations due to adverse events were reported for 17 (7.6%) patients who received irinotecan in combination with 5FU/LV, 14 (6.4%) patients who received 5-FU/LV alone, and 26 (11.7%) patients who received irinotecan alone.

In Study 2, 10 (3.5%) patients died within 30 days of last study treatment: 6 (4.1%) received irinotecan in combination with 5-FU/LV and 4 (2.8%) received 5-FU/LV alone. There was one potentially treatment-related death, which occurred in a patient who received irinotecan in combination with 5-FU/LV (0.7%, neutropenic sepsis). Deaths from any cause within 60 days of first study treatment were reported for 3 (2.1%) patients who received irinotecan in combination with 5-FU/LV and 2 (1.4%) patients who received 5-FU/LV alone. Discontinuations due to adverse events were reported for 9 (6.2%) patients who received irinotecan in combination with 5FU/LV and 1 (0.7%) patient who received 5-FU/LV alone.

The most clinically significant adverse events for patients receiving irinotecan-based therapy were diarrhea, nausea, vomiting, neutropenia, and alopecia. The most clinically significant adverse events for patients receiving 5-FU/LV therapy were diarrhea, neutropenia, neutropenic fever, and mucositis. In Study 1, grade 4 neutropenia, neutropenic fever (defined as grade 2 fever and grade 4 neutropenia), and mucositis were observed less often with weekly irinotecan/5-FU/LV than with monthly administration of 5-FU/LV.

Tables 5 and 6 list the clinically relevant adverse events reported in Studies 1 and 2, respectively.

Table 5. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies*
Adverse Event Study 1
Irinotecan + Bolus 5-FU/LV weekly × 4 every 6 weeks
N=225
Bolus 5-FU/LV daily × 5 every 4 weeks
N=219
Irinotecan weekly × 4 every 6 weeks
N=223
Grade 1–4 Grade 3&4 Grade 1–4 Grade 3&4 Grade 1–4 Grade 3&4
*
Severity of adverse events based on NCI CTC (version 1.0)
Complete hair loss = Grade 2
Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder.
TOTAL Adverse Events 100 53.3 100 45.7 99.6 45.7
GASTROINTESTINAL
  Diarrhea 84.9 22.7 69.4 13.2 83.0 31.0
    late -- 15.1 -- 5.9 -- 18.4
      grade 3 -- 7.6 -- 7.3 -- 12.6
      grade 4 45.8 4.9 31.5 1.4 43.0 6.7
    early
  Nausea 79.1 15.6 67.6 8.2 81.6 16.1
  Abdominal pain 63.1 14.6 50.2 11.5 67.7 13.0
  Vomiting 60.4 9.7 46.1 4.1 62.8 12.1
  Anorexia 34.2 5.8 42.0 3.7 43.9 7.2
  Constipation 41.3 3.1 31.5 1.8 32.3 0.4
  Mucositis 32.4 2.2 76.3 16.9 29.6 2.2
HEMATOLOGIC
  Neutropenia 96.9 53.8 98.6 66.7 96.4 31.4
    grade 3 -- 29.8 -- 23.7 -- 19.3
    grade 4 -- 24.0 -- 42.5 -- 12.1
  Leukopenia 96.9 37.8 98.6 23.3 96.4 21.5
  Anemia 96.9 8.4 98.6 5.5 96.9 4.5
  Neutropenic fever -- 7.1 -- 14.6 -- 5.8
  Thrombocytopenia 96.0 2.6 98.6 2.7 96.0 1.7
  Neutropenic infection -- 1.8 -- 0 -- 2.2
BODY AS A WHOLE
  Asthenia 70.2 19.5 64.4 11.9 69.1 13.9
  Pain 30.7 3.1 26.9 3.6 22.9 2.2
  Fever 42.2 1.7 32.4 3.6 43.5 0.4
  Infection 22.2 0 16.0 1.4 13.9 0.4
METABOLIC & NUTRITIONAL
  Bilirubin 87.6 7.1 92.2 8.2 83.9 7.2
DERMATOLOGIC 0.9 0 3.2 0.5 0 0
  Exfoliative dermatitis 19.1 0 26.5 0.9 14.3 0.4
  Rash 43.1 -- 26.5 -- 46.1 --
  Alopecia
RESPIRATORY
  Dyspnea 27.6 6.3 16.0 0.5 22.0 2.2
  Cough 26.7 1.3 18.3 0 20.2 0.4
  Pneumonia 6.2 2.7 1.4 1.0 3.6 1.3
NEUROLOGIC
  Dizziness 23.1 1.3 16.4 0 21.1 1.8
  Somnolence 12.4 1.8 4.6 1.8 9.4 1.3
  Confusion 7.1 1.8 4.1 0 2.7 0
CARDIOVASCULAR 9.3 0.9 5.0 0 9.0 0
  Vasodilatation 5.8 1.3 2.3 0.5 5.8 1.7
  Hypotension 9.3 -- 11.4 -- 5.4 --
  Thromboembolic events
Table 6. Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies*
Adverse Event Study 2
Irinotecan + 5-FU/LV infusional days 1&2 every 2 weeks
N= 145
5-FU/LV infusional days 1&2 every 2 weeks
N=143
Grades 1–4 Grades 3&4 Grades 1–4 Grades 3&4
*
Severity of adverse events based on NCI CTC (version 1.0)
Includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan)
Complete hair loss = Grade 2
§
Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder.
TOTAL Adverse Events 100 72.4 100 39.2
GASTROINTESTINAL
  Diarrhea 72.4 14.4 44.8 6.3
    late -- 10.3 -- 4.2
      grade 3 -- 4.1 -- 2.1
      grade 4 28.3 1.4 0.7 0
  Cholinergic syndrome
  Nausea 66.9 2.1 55.2 3.5
  Abdominal pain 17.2 2.1 16.8 0.7
  Vomiting 44.8 3.5 32.2 2.8
  Anorexia 35.2 2.1 18.9 0.7
  Constipation 30.3 0.7 25.2 1.4
  Mucositis 40.0 4.1 28.7 2.8
HEMATOLOGIC
  Neutropenia 82.5 46.2 47.9 13.4
    grade 3 -- 36.4 -- 12.7
    grade 4 -- 9.8 -- 0.7
  Leukopenia 81.3 17.4 42.0 3.5
  Anemia 97.2 2.1 90.9 2.1
  Neutropenic fever -- 3.4 -- 0.7
  Thrombocytopenia 32.6 0 32.2 0
  Neutropenic infection -- 2.1 -- 0
BODY AS A WHOLE
  Asthenia 57.9 9.0 48.3 4.2
  Pain 64.1 9.7 61.5 8.4
  Fever 22.1 0.7 25.9 0.7
  Infection 35.9 7.6 33.6 3.5
METABOLIC AND NUTRITIONAL
  Bilirubin 19.1 3.5 35.9 10.6
DERMATOLOGIC 10.3 0.7 12.6 0.7
  Hand and foot syndrome 17.2 0.7 20.3 0
  Cutaneous signs 56.6 -- 16.8 --
  Alopecia
RESPIRATORY
  Dyspnea 9.7 1.4 4.9 0
CARDIOVASCULAR 3.4 1.4 0.7 0
  Hypotension 11.7 -- 5.6 --
  Thromboembolic events§

Second-Line Single-Agent Therapy

Weekly Dosage Schedule

In three clinical studies evaluating the weekly dosage schedule, 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5-FU-based therapy were treated with CAMPTOSAR. Seventeen of the patients died within 30 days of the administration of CAMPTOSAR; in five cases (1.6%, 5/304), the deaths were potentially drug-related. One of the patients died of neutropenic sepsis without fever. Neutropenic fever occurred in nine (3.0%) other patients; these patients recovered with supportive care.

One hundred nineteen (39.1%) of the 304 patients were hospitalized because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be related to administration of CAMPTOSAR. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea and/or vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever (8.2%); and nausea and/or vomiting (4.9%).

The first dose of at least one cycle of CAMPTOSAR was reduced for 67% of patients who began the studies at the 125-mg/m2 starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m2 dose level. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with CAMPTOSAR because of adverse events. The adverse events in Table 7 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies (14.1).

Table 7. Adverse Events Occurring in >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectum*
% of Patients Reporting
Body System & Event NCI Grades 1–4 NCI Grades 3 & 4
*
Severity of adverse events based on NCI CTC (version 1.0)
Occurring >24 hours after administration of CAMPTOSAR
Occurring ≤24 hours after administration of CAMPTOSAR
§
Primarily upper respiratory infections
Not applicable; complete hair loss = NCI grade 2
GASTROINTESTINAL
  Diarrhea (late) 88 31
    7–9 stools/day (grade 3) (16)
    ≥10 stools/day (grade 4) (14)
  Nausea 86 17
  Vomiting 67 12
  Anorexia 55 6
  Diarrhea (early) 51 8
  Constipation 30 2
  Flatulence 12 0
  Stomatitis 12 1
  Dyspepsia 10 0
HEMATOLOGIC
  Leukopenia 63 28
  Anemia 60 7
  Neutropenia 54 26
    500 to <1000/mm3 (grade 3) (15)
    <500/mm3 (grade 4) (12)
BODY AS A WHOLE
  Asthenia 76 12
  Abdominal cramping/pain 57 16
  Fever 45 1
  Pain 24 2
  Headache 17 1
  Back pain 14 2
  Chills 14 0
  Minor infection§ 14 0
  Edema 10 1
  Abdominal enlargement 10 0
METABOLIC AND NUTRITIONAL
  ↓ Body weight 30 1
  Dehydration 15 4
  ↑ Alkaline phosphatase 13 4
  ↑ SGOT 10 1
DERMATOLOGIC
  Alopecia 60 NA
  Sweating 16 0
  Rash 13 1
RESPIRATORY
  Dyspnea 22 4
  ↑ Coughing 17 0
  Rhinitis 16 0
NEUROLOGIC
  Insomnia 19 0
  Dizziness 15 0
CARDIOVASCULAR
  Vasodilation (flushing) 11 0

Once-Every-3-Week Dosage Schedule

A total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days of treatment. In three cases (1%, 3/316), the deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. One (0.8%, 1/129) patient treated with 5-FU died within 30 days of treatment; this death was attributed to grade 4 diarrhea.

Hospitalizations due to serious adverse events occurred at least once in 60% (188/316) of patients who received irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129) who received 5-FU-based therapy. Eight percent of patients treated with irinotecan and 7% treated with 5-FU-based therapy discontinued treatment due to adverse events.

Of the 316 patients treated with irinotecan, the most clinically significant adverse events (all grades, 1–4) were diarrhea (84%), alopecia (72%), nausea (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). Table 8 lists the grade 3 and 4 adverse events reported in the patients enrolled to all treatment arms of the two studies described in Clinical Studies (14.1).

Table 8: Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan Therapy*
Study 1 Study 2
Adverse Event Irinotecan
N=189
BSC
N=90
Irinotecan
N=127
5-FU
N=129
*
Severity of adverse events based on NCI CTC (version 1.0)
BSC = best supportive care
Hepatic includes events such as ascites and jaundice
§
Cutaneous signs include events such as rash
Respiratory includes events such as dyspnea and cough
#
Neurologic includes events such as somnolence
Þ
Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction
ß
Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss
TOTAL Grade 3/4 Adverse Events 79 67 69 54
GASTROINTESTINAL
  Diarrhea 22 6 22 11
  Vomiting 14 8 14 5
  Nausea 14 3 11 4
  Abdominal pain 14 16 9 8
  Constipation 10 8 8 6
  Anorexia 5 7 6 4
  Mucositis 2 1 2 5
HEMATOLOGIC
  Leukopenia/Neutropenia 22 0 14 2
  Anemia 7 6 6 3
  Hemorrhage 5 3 1 3
  Thrombocytopenia 1 0 4 2
Infection
  without grade 3/4 neutropenia 8 3 1 4
  with grade 3/4 neutropenia 1 0 2 0
Fever
  without grade 3/4 neutropenia 2 1 2 0
  with grade 3/4 neutropenia 2 0 4 2
BODY AS A WHOLE
  Pain 19 22 17 13
  Asthenia 15 19 13 12
METABOLIC AND NUTRITIONAL
Hepatic 9 7 9 6
DERMATOLOGIC
  Hand and foot syndrome 0 0 0 5
  Cutaneous signs § 2 0 1 3
RESPIRATORY 10 8 5 7
NEUROLOGIC # 12 13 9 4
CARDIOVASCULAR Þ 9 3 4 2
OTHER ß 32 28 12 14

The incidence of akathisia in clinical trials of the weekly dosage schedule was greater (8.5%, 4/47 patients) when prochlorperazine was administered on the same day as CAMPTOSAR than when these drugs were given on separate days (1.3%, 1/80 patients). The 8.5% incidence of akathisia, however, is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of CAMPTOSAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Myocardial ischemic events have been observed following CAMPTOSAR therapy. Thromboembolic events have been observed in patients receiving CAMPTOSAR.

Symptomatic pancreatitis, asymptomatic pancreatic enzyme elevation have been reported. Increases in serum levels of transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis have been observed.

Hyponatremia, mostly with diarrhea and vomiting, has been reported.

Transient dysarthria has been reported in patients treated with CAMPTOSAR; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.

Interaction between CAMPTOSAR and neuromuscular blocking agents cannot be ruled out. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized.

1 INDICATIONS AND USAGE

  • CAMPTOSAR Injection is indicated as a component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum.
  • CAMPTOSAR is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.

ELLENCE® (epirubicin HCl)

These highlights do not include all the information needed to use ELLENCE safety and effectively. See full prescribing information for ELLENCE.

WARNING: RISK OF TISSUE NECROSIS, CARDIAC TOXICITY, SECONDARY ACUTE MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION

  1. Severe local tissue necrosis will occur if there is extravasation during administration. ELLENCE must not be given by the intramuscular or subcutaneous route [see Warnings and Precautions (5.9)].
  2. Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with ELLENCE or months to years after termination of therapy. The probability of developing clinically evident CHF is estimated as approximately 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. In the adjuvant treatment of breast cancer, the maximum cumulative dose used in clinical trials was 720 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of ELLENCE in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with ELLENCE may occur at lower cumulative doses whether or not cardiac risk factors are present [see Warnings and Precautions (5.3)].
  3. Secondary acute myelogenous leukemia (AML) has been reported in patients with breast cancer treated with anthracyclines, including epirubicin. The occurrence of refractory secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. The cumulative risk of developing treatment-related AML or myelodysplastic syndrome (MDS), in 7110 patients with breast cancer who received adjuvant treatment with ELLENCE-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years [see Warnings and Precautions (5.4)].
  4. Severe myelosuppression may occur [see Warnings and Precautions (5.2)].

4 CONTRAINDICATIONS

Patients should not be treated with ELLENCE Injection if they have any of the following conditions:

Cardiomyopathy and/or heart failure, recent myocardial infarction or severe arrhythmias [see Warnings and Precautions (5.3)]

Previous treatment with maximum cumulative dose of anthracyclines [see Warnings and Precautions (5)].

Hypersensitivity to ELLENCE, other anthracyclines, or anthracenediones [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

Administer ELLENCE Injection only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before beginning treatment with ELLENCE, patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment. Also, precede initial treatment with ELLENCE by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Carefully monitor patients during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to ELLENCE.

5.1 Injection-Related Reactions

ELLENCE Injection is administered by intravenous infusion. Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Extravasation of ELLENCE during the infusion may cause local pain, severe tissue lesions (vesication, severe cellulitis), and necrosis. Administer ELLENCE slowly into the tubing of a freely running intravenous infusion. Patients receiving initial therapy at the recommended starting doses of 100–120 mg/m2 should generally have ELLENCE infused over 15–20 minutes. For patients who require lower ELLENCE starting doses due to organ dysfunction or who require modification of ELLENCE doses during therapy, the ELLENCE infusion time may be proportionally decreased, but should not be less than 3 minutes [see Dosage and Administration (2.3)]. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Immediately terminate infusion and restart in another vein if a burning or stinging sensation indicates perivenous infiltration. Perivenous infiltration may occur without causing pain. Facial flushing, as well as local erythematous streaking along the vein, may be indicative of excessively rapid administration. It may precede local phlebitis or thrombophlebitis. Give prophylactic antibiotic therapy to patients administered the 120-mg/m2 regimen of ELLENCE as a component of combination chemotherapy [see Clinical Studies (14.1) and Dosage and Administration 2.1)].

5.2 Hematologic

Ellence can suppress bone marrow function as manifested by leukopenia, thrombocytopenia and anemia [see Adverse Reactions (6.1)], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [see Dosage and Administration (2.2, 2.3)].

5.3 Cardiac

Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiac toxicity may be manifested by early (or acute) or late (delayed) events. Early cardiac toxicity of ELLENCE consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes, but tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not considered an indication for the suspension of ELLENCE treatment. Delayed cardiac toxicity results from a characteristic cardiomyopathy that is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, hepatomegaly, ascites, pleural effusion, gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy. This toxicity appears to be dependent on the cumulative dose of ELLENCE and represents the cumulative dose-limiting toxicity of the drug. If it occurs, delayed cardiotoxicity usually develops late in the course of therapy with ELLENCE or within 2 to 3 months after completion of treatment, but later events (several months to years after treatment termination) have been reported.

Given the risk of cardiomyopathy, exceed a cumulative dose of 900 mg/m2 ELLENCE only with extreme caution. Risk factors [active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs, especially those with long half-lives (e.g., trastuzumab)] may increase the risk of ELLENCE cardiotoxicity [see Drug Interaction (7.4) and Dosage and Administration (2)]. Although not formally tested, it is probable that the toxicity of ELLENCE and other anthracyclines or anthracenediones is additive. Cardiac toxicity with ELLENCE may occur at lower cumulative doses whether or not cardiac risk factors are present.

Although endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy, this invasive examination is not practically performed on a routine basis. ECG changes such as dysrhythmias, a reduction of the QRS voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity. The risk of serious cardiac impairment may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of ELLENCE at the first sign of impaired function. The preferred method for repeated assessment of cardiac function is evaluation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Perform repeated MUGA or ECHO determinations of LVEF, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with ELLENCE in patients with impaired cardiac function must be carefully evaluated.

Do not administer ELLENCE in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving ELLENCE after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity [see Dosage and Administration (2)].

5.4 Secondary Leukemia

The occurrence of secondary acute myelogenous leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines. Secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a short 1- to 3-year latency period.

ELLENCE is mutagenic, clastogenic, and carcinogenic in animals [see Nonclinical Toxicology (13.1)].

5.5 Hepatic

The major route of elimination of epirubicin is the hepatobiliary system [see Clinical Pharmacology (12.3)]. Evaluate serum total bilirubin and AST levels before and during treatment with ELLENCE. Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients [see Dosage and Administration (2.2)]. Patients with severe hepatic impairment have not been evaluated; therefore, do not use ELLENCE in this patient population.

5.6 Renal

Assess serum creatinine before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL [see Dosage and Administration (2.2)]. Patients undergoing dialysis have not been studied.

5.7 Tumor-Lysis Syndrome

As with other cytotoxic agents, ELLENCE may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of highly chemosensitive neoplastic cells (tumor-lysis syndrome). Other metabolic abnormalities may also occur. While not generally a problem in patients with breast cancer, consider the potential for tumor-lysis syndrome in potentially susceptible patients and consider monitoring serum uric acid, potassium, calcium, phosphate, and creatinine immediately after initial chemotherapy administration. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome.

5.8 Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections. Avoid vaccination with a live vaccine in patients receiving ELLENCE. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

5.9 Gastrointestinal

ELLENCE is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of ELLENCE, particularly when given in conjunction with other emetigenic drugs [see Adverse Reactions (6.2)].

5.10 Thrombophlebitis and Thromboembolic Phenomena

As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of ELLENCE.

5.11 Coadministration with Cimetidine

Cimetidine increased the AUC of epirubicin by 50%. Stop Cimetidine treatment during treatment with ELLENCE [see Clinical Pharmacology (12.3)].

5.12 Pregnancy

ELLENCE can cause fetal harm when administered to a pregnant woman. Epirubicin was embryolethal and teratogenic in rats and rabbits. There are no adequate and well-controlled studies of ELLENCE in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods [see Use In Specific Populations (8.1)].

5.13 Male Fertility and Reproductive Outcomes

Males with female sexual partners of childbearing potential should use contraception during and after cessation of ELLENCE therapy. ELLENCE may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain [see Nonclinical Toxicology (13.1)].

5.14 Laboratory Testing

Assess blood counts, including absolute neutrophil counts, and liver function before and during each cycle of therapy with ELLENCE. Perform repeated evaluations of LVEF during therapy [see Warnings and Precautions (5.5 and 5.6)].

5.15 Inflammation following Irradiation

As with other anthracyclines, administration of ELLENCE after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Integrated safety data are available from two studies (Studies MA-5 and GFEA-05) [see Clinical Studies (14.1)] evaluating ELLENCE-containing combination regimens in patients with early breast cancer. Of the 1260 patients treated in these studies, 620 patients received the higher-dose ELLENCE regimen (FEC-100/CEF-120), 280 patients received the lower-dose ELLENCE regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant acute adverse events are summarized in Table 1.

Table 1. Clinically Relevant Acute Adverse Events in Patients with Early Breast Cancer
Event % of Patients
FEC-100/CEF-120 FEC-50 CMF
(N=620) (N=280) (N=360)
Grades 1–4 Grades 3/4 Grades 1–4 Grades 3/4 Grades 1–4 Grades 3/4
FEC & CEF = cyclophosphamide + ELLENCE + fluorouracil; CMF = cyclophosphamide + methotrexate + fluorouracil; NA = not available
Grade 1 or 2 changes in transaminase levels were observed but were more frequently seen with CMF than with CEF.
Hematologic
  Leukopenia 80.3 58.6 49.6 1.5 98.1 60.3
  Neutropenia 80.3 67.2 53.9 10.5 95.8 78.1
  Anemia 72.2 5.8 12.9 0 70.9 0.9
  Thrombocytopenia 48.8 5.4 4.6 0 51.4 3.6
Endocrine
  Amenorrhea 71.8 0 69.3 0 67.7 0
  Hot flashes 38.9 4.0 5.4 0 69.1 6.4
Body as a Whole
  Lethargy 45.8 1.9 1.1 0 72.7 0.3
  Fever 5.2 0 1.4 0 4.5 0
Gastrointestinal
  Nausea/vomiting 92.4 25.0 83.2 22.1 85.0 6.4
  Mucositis 58.5 8.9 9.3 0 52.9 1.9
  Diarrhea 24.8 0.8 7.1 0 50.7 2.8
  Anorexia 2.9 0 1.8 0 5.8 0.3
Infection
  Infection 21.5 1.6 15.0 0 25.9 0.6
  Febrile neutropenia NA 6.1 0 0 NA 1.1
Ocular
  Conjunctivitis/keratitis 14.8 0 1.1 0 38.4 0
Skin
  Alopecia 95.5 56.6 69.6 19.3 84.4 6.7
  Local toxicity 19.5 0.3 2.5 0.4 8.1 0
  Rash/itch 8.9 0.3 1.4 0 14.2 0
  Skin changes 4.7 0 0.7 0 7.2 0

Delayed Events

Table 2 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials.

Table 2. Long-Term Adverse Events in Patients with Early Breast Cancer
Event % of Patients
FEC-100/CEF-120
(N=620)
FEC-50
(N=280)
CMF
(N=360)
*
In study MA-5, cardiac function was not monitored after 5 years.
Cardiac events
Asymptomatic drops in LVEF 2.1* 1.4 0.8*
CHF 1.5 0.4 0.3
Leukemia
AML 0.8 0 0.3

Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving ELLENCE. However, an association between anthracyclines such as ELLENCE and ALL has not been clearly established.

6.2 Overview of Acute and Delayed Toxicities

Hematologic

Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with ELLENCE and represents the most common acute dose-limiting toxicity of this drug. In most cases, the white blood cell (WBC) nadir is reached 10 to 14 days from drug administration. Leukopenia/neutropenia is usually transient, with WBC and neutrophil counts generally returning to normal values by Day 21 after drug administration. As with other cytotoxic agents, ELLENCE at the recommended dose in combination with cyclophosphamide and fluorouracil can produce severe leukopenia and neutropenia. Severe thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, septicemia, septic shock, hemorrhage, tissue hypoxia, symptomatic anemia, or death. If myelosuppressive complications occur, use appropriate supportive measures (e.g., intravenous antibiotics, colony-stimulating factors, transfusions). Myelosuppression requires careful monitoring. Assess total and differential WBC, red blood cell (RBC), and platelet counts before and during each cycle of therapy with ELLENCE [see Warnings and Precautions (5.2)].

Gastrointestinal

A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with ELLENCE. Clinical manifestations of mucositis may include a pain or burning sensation, erythema, erosions, ulcerations, bleeding, or infections. Mucositis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations; most patients recover from this adverse event by the third week of therapy. Hyperpigmentation of the oral mucosa may also occur. Nausea, vomiting, and occasionally diarrhea and abdominal pain can also occur. Severe vomiting and diarrhea may produce dehydration. Antiemetics may reduce nausea and vomiting; consider prophylactic use of antiemetics before therapy [see Warnings and Precautions (5.10)].

Cutaneous and Hypersensitivity Reactions

Alopecia occurs frequently, but is usually reversible, with hair regrowth occurring within 2 to 3 months from the termination of therapy. Flushes, skin and nail hyperpigmentation, photosensitivity, and hypersensitivity to irradiated skin (radiation-recall reaction) have been observed. Urticaria and anaphylaxis have been reported in patients treated with ELLENCE; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock.

Cardiovascular

In a retrospective survey, including 9144 patients, mostly with solid tumors in advanced stages, the probability of developing CHF increased with increasing cumulative doses of ELLENCE (Figure 1). The estimated risk of ELLENCE-treated patients developing clinically evident CHF was 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an ELLENCE cumulative dose of 900 mg/m2 [see Warnings and Precautions (5.4)].

Figure 1. Risk of CHF in 9144 Patients Treated with ELLENCE

Figure 1

In another retrospective survey of 469 ELLENCE-treated patients with metastatic or early breast cancer, the reported risk of CHF was comparable to that observed in the larger study of over 9000 patients [see Warnings and Precautions (5.3)].

Other serious drug-related cardiovascular adverse events that occurred during clinical trials with ELLENCE, administered in different indications, include ventricular tachycardia, AV block, bundle branch block, bradycardia and thromboembolism.

Secondary Leukemia

An analysis of 7110 patients who received adjuvant treatment with ELLENCE in controlled clinical trials as a component of poly-chemotherapy regimens for early breast cancer, showed a cumulative risk of secondary acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) of about 0.27% (approximate 95% CI, 0.14–0.40) at 3 years, 0.46% (approximate 95% CI, 0.28–0.65) at 5 years, and 0.55% (approximate 95% CI, 0.33–0.78) at 8 years. The risk of developing AML/MDS increased with increasing ELLENCE cumulative doses as shown in Figure 2.

Figure 2. Risk of AML/MDS in 7110 Patients Treated with ELLENCE

Figure 2

The cumulative probability of developing AML/MDS was found to be particularly increased in patients who received more than the maximum recommended cumulative dose of ELLENCE (720 mg/m2) or cyclophosphamide (6,300 mg/m2), as shown in Table 3.

Table 3. Cumulative Probability of AML/MDS in Relation to Cumulative Doses of ELLENCE and Cyclophosphamide
Years from Treatment Start Cumulative Probability of Developing AML/MDS
% (95% CI)
Cyclophosphamide Cumulative Dose
≤6,300 mg/m2
Cyclophosphamide Cumulative Dose
>6,300 mg/m2
ELLENCE Cumulative Dose
≤720 mg/m2
N=4760
ELLENCE Cumulative Dose
>720 mg/m2
N=111
ELLENCE Cumulative Dose
≤720 mg/m2
N=890
ELLENCE Cumulative Dose
>720 mg/m2
N=261
3 0.12 (0.01–0.22) 0.00 (0.00–0.00) 0.12 (0.00–0.37) 4.37 (1.69–7.05)
5 0.25 (0.08–0.42) 2.38 (0.00–6.99) 0.31 (0.00–0.75) 4.97 (2.06–7.87)
8 0.37 (0.13–0.61) 2.38 (0.00–6.99) 0.31 (0.00–0.75) 4.97 (2.06–7.87)

Injection-Site Reactions [see Warnings and Precautions (5.9)].

6.3 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of ELLENCE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and infestations: sepsis, pneumonia

Immune system disorders: anaphylaxis

Metabolism and nutrition disorders: dehydration, hyperuricemia

Vascular disorders: shock, haemorrhage, embolism arterial, thrombophlebitis, phlebitis

Respiratory, thoracic and mediastinal disorders: pulmonary embolism

Gastrointestinal disorders: erosions, ulcerations, pain or burning sensation, bleeding, hyperpigmentation of the oral mucosa

Skin and subcutaneous tissue disorders: erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction), urticaria

Renal and urinary disorders: red coloration of urine for 1 to 2 days after administration

General disorders and administration site conditions: fever, chills

Injury, poisoning and procedural complications: chemical cystitis (following intravesical administration)

1 INDICATIONS AND USAGE

ELLENCE Injection is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer [see Clinical Studies (14.1)].

IBRANCE® (palbociclib)

These highlights do not include all the information needed to use IBRANCE safety and effectively. See full prescribing information for IBRANCE.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Neutropenia

Neutropenia was the most frequently reported adverse reaction in Study 1 (PALOMA-2) with an incidence of 80% and Study 2 (PALOMA-3) with an incidence of 83%. A Grade ≥3 decrease in neutrophil counts was reported in 66% of patients receiving IBRANCE plus letrozole in Study 1 and 66% of patients receiving IBRANCE plus fulvestrant in Study 2. In Study 1 and 2, the median time to first episode of any grade neutropenia was 15 days and the median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions (6.1)].

Monitor complete blood counts prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration (2.2)].

Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across Studies 1 and 2. One death due to neutropenic sepsis was observed in Study 2. Physicians should inform patients to promptly report any episodes of fever [see Patient Counseling Information (17)].

5.2 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of palbociclib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal exposures that were ≥4 times the human clinical exposure based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least 3 weeks after the last dose [see Use in Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

The following topic is described below and elsewhere in the labeling:

6.1 Clinical Studies Experience

Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Study 1: IBRANCE plus Letrozole

Patients with estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy

The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus placebo plus letrozole was evaluated in Study 1 (PALOMA-2). The data described below reflect exposure to IBRANCE in 444 out of 666 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of IBRANCE plus letrozole in Study 1. The median duration of treatment for IBRANCE plus letrozole was 19.8 months while the median duration of treatment for placebo plus letrozole arm was 13.8 months.

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1.

Permanent discontinuation associated with an adverse reaction occurred in 43 of 444 (9.7%) patients receiving IBRANCE plus letrozole and in 13 of 222 (5.9%) patients receiving placebo plus letrozole. Adverse reactions leading to permanent discontinuation for patients receiving IBRANCE plus letrozole included neutropenia (1.1%) and alanine aminotransferase increase (0.7%).

The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm by descending frequency were neutropenia, infections, leukopenia, fatigue, nausea, alopecia, stomatitis, diarrhea, anemia, rash, asthenia, thrombocytopenia, vomiting, decreased appetite, dry skin, pyrexia, and dysgeusia.

The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia.

Adverse reactions (≥10%) reported in patients who received IBRANCE plus letrozole or placebo plus letrozole in Study 1 are listed in Table 4.

Table 4. Adverse Reactions (≥10%) in Study 1
IBRANCE plus Letrozole
(N=444)
Placebo plus Letrozole
(N=222)
Adverse Reaction All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable;
*
Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations.
Most common infections (≥1%) include: nasopharyngitis, upper respiratory tract infection, urinary tract infection, oral herpes, sinusitis, rhinitis, bronchitis, influenza, pneumonia, gastroenteritis, conjunctivitis, herpes zoster, pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth infection, gingivitis, skin infection, gastroenteritis viral, respiratory tract infection, respiratory tract infection viral, and folliculitis.
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis.
§
Grade 1 events – 30%; Grade 2 events – 3%.
Grade 1 events – 15%; Grade 2 events – 1%.
#
Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.
Infections and infestations
  Infections* 60 6 1 42 3 0
Blood and lymphatic system disorders
  Neutropenia 80 56 10 6 1 1
  Leukopenia 39 24 1 2 0 0
  Anemia 24 5 <1 9 2 0
  Thrombocytopenia 16 1 <1 1 0 0
Metabolism and nutrition disorders
  Decreased appetite 15 1 0 9 0 0
Nervous system disorders
  Dysgeusia 10 0 0 5 0 0
Gastrointestinal disorders
  Stomatitis 30 1 0 14 0 0
  Nausea 35 <1 0 26 2 0
  Diarrhea 26 1 0 19 1 0
  Vomiting 16 1 0 17 1 0
Skin and subcutaneous tissue disorders
  Alopecia 33§ N/A N/A 16 N/A N/A
  Rash# 18 1 0 12 1 0
  Dry skin 12 0 0 6 0 0
General disorders and administration site conditions
  Fatigue 37 2 0 28 1 0
  Asthenia 17 2 0 12 0 0
  Pyrexia 12 0 0 9 0 0

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus letrozole in Study 1 included alanine aminotransferase increased (9.9%), aspartate aminotransferase increased (9.7%), epistaxis (9.2%), lacrimation increased (5.6%), dry eye (4.1%), vision blurred (3.6%), and febrile neutropenia (2.5%).

Table 5. Laboratory Abnormalities in Study 1
IBRANCE plus Letrozole
(N=444)
Placebo plus Letrozole
(N=222)
Laboratory Abnormality All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
N=number of patients; WBC=white blood cells.
WBC decreased 97 35 1 25 1 0
Neutrophils decreased 95 56 12 20 1 1
Anemia 78 6 0 42 2 0
Platelets decreased 63 1 1 14 0 0
Aspartate aminotransferase increased 52 3 0 34 1 0
Alanine aminotransferase increased 43 2 <1 30 0 0

Study 2: IBRANCE plus Fulvestrant

Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease progression on or after prior adjuvant or metastatic endocrine therapy

The safety of IBRANCE (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in Study 2 (PALOMA-3). The data described below reflect exposure to IBRANCE in 345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose of IBRANCE plus fulvestrant in Study 2. The median duration of treatment for IBRANCE plus fulvestrant was 10.8 months while the median duration of treatment for placebo plus fulvestrant arm was 4.8 months.

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus fulvestrant. No dose reduction was allowed for fulvestrant in Study 2.

Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving IBRANCE plus fulvestrant, and in 6 of 172 (3%) patients receiving placebo plus fulvestrant. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus fulvestrant included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%).

The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus fulvestrant arm by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia.

The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus fulvestrant in descending frequency were neutropenia and leukopenia.

Adverse reactions (≥10%) reported in patients who received IBRANCE plus fulvestrant or placebo plus fulvestrant in Study 2 are listed in Table 6.

Table 6. Adverse Reactions (≥10%) in Study 2
Adverse Reaction IBRANCE plus Fulvestrant
(N=345)
Placebo plus Fulvestrant
(N=172)
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
% % % % % %
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
*
Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations.
Most common infections (≥1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection, bronchitis, rhinitis, influenza, conjunctivitis, sinusitis, pneumonia, cystitis, oral herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, and paronychia.
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
§
Grade 1 events – 17%; Grade 2 events – 1%.
Grade 1 events – 6%.
#
Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, toxic skin eruption.
Infections and infestations
  Infections* 47 3 1 31 3 0
Blood and lymphatic system disorders
  Neutropenia 83 55 11 4 1 0
  Leukopenia 53 30 1 5 1 1
  Anemia 30 4 0 13 2 0
  Thrombocytopenia 23 2 1 0 0 0
Metabolism and nutrition disorders
  Decreased appetite 16 1 0 8 1 0
Gastrointestinal disorders
  Nausea 34 0 0 28 1 0
  Stomatitis 28 1 0 13 0 0
  Diarrhea 24 0 0 19 1 0
  Vomiting 19 1 0 15 1 0
Skin and subcutaneous tissue disorders
  Alopecia 18§ N/A N/A 6 N/A N/A
  Rash# 17 1 0 6 0 0
General disorders and administration site conditions
  Fatigue 41 2 0 29 1 0
  Pyrexia 13 <1 0 5 0 0

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus fulvestrant in Study 2 included asthenia (7.5%), aspartate aminotransferase increased (7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation increased (6.4%), dry skin (6.1%), alanine aminotransferase increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile neutropenia (0.9%).

Table 7. Laboratory Abnormalities in Study 2
Laboratory Abnormality IBRANCE plus Fulvestrant
(N=345)
Placebo plus Fulvestrant
(N=172)
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
N=number of patients; WBC=white blood cells.
WBC decreased 99 45 1 26 0 1
Neutrophils decreased 96 56 11 14 0 1
Anemia 78 3 0 40 2 0
Platelets decreased 62 2 1 10 0 0
Aspartate aminotransferase increased 43 4 0 48 4 0
Alanine aminotransferase increased 36 2 0 34 0 0

1 INDICATIONS AND USAGE

IBRANCE is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in combination with:

  • an aromatase inhibitor as initial endocrine based therapy in postmenopausal women; or
  • fulvestrant in women with disease progression following endocrine therapy.

IDAMYCIN® (idarubicin hydrochloride)

These highlights do not include all the information needed to use IDAMYCIN safety and effectively. See full prescribing information for IDAMYCIN.

WARNINGS

  1. IDAMYCIN (idarubicin hydrochloride for injection, USP) should be given slowly into a freely flowing intravenous infusion. It must never be given intramuscularly or subcutaneously. Severe local tissue necrosis can occur if there is extravasation during administration.
  2. As is the case with other anthracyclines the use of IDAMYCIN can cause myocardial toxicity leading to congestive heart failure. Cardiac toxicity is more common in patients who have received prior anthracyclines or who have pre-existing cardiac disease.
  3. As is usual with antileukemic agents, severe myelosuppression occurs when IDAMYCIN is used at effective therapeutic doses.
  4. It is recommended that IDAMYCIN be administered only under the supervision of a physician who is experienced in leukemia chemotherapy and in facilities with laboratory and supportive resources adequate to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The physician and institution must be capable of responding rapidly and completely to severe hemorrhagic conditions and/or overwhelming infection.
  5. Dosage should be reduced in patients with impaired hepatic or renal function. (See DOSAGE AND ADMINISTRATION.)

WARNINGS

IDAMYCIN (idarubicin hydrochloride for injection, USP) is intended for administration under the supervision of a physician who is experienced in leukemia chemotherapy.

IDAMYCIN is a potent bone marrow suppressant. IDAMYCIN should not be given to patients with pre-existing bone marrow suppression induced by previous drug therapy or radiotherapy unless the benefit warrants the risk.

Severe myelosuppression will occur in all patients given a therapeutic dose of this agent for induction, consolidation or maintenance. Careful hematologic monitoring is required. Deaths due to infection and/or bleeding have been reported during the period of severe myelosuppression. Facilities with laboratory and supportive resources adequate to monitor drug tolerability and protect and maintain a patient compromised by drug toxicity should be available. It must be possible to treat rapidly and completely a severe hemorrhagic condition and/or a severe infection.

Pre-existing heart disease and previous therapy with anthracyclines at high cumulative doses or other potentially cardiotoxic agents are co-factors for increased risk of idarubicin-induced cardiac toxicity and the benefit to risk ratio of idarubicin therapy in such patients should be weighed before starting treatment with IDAMYCIN.

Myocardial toxicity as manifested by potentially fatal congestive heart failure, acute life-threatening arrhythmias or other cardiomyopathies may occur following therapy with IDAMYCIN. Appropriate therapeutic measures for the management of congestive heart failure and/or arrhythmias are indicated.

Cardiac function should be carefully monitored during treatment in order to minimize the risk of cardiac toxicity of the type described for other anthracycline compounds. The risk of such myocardial toxicity may be higher following concomitant or previous radiation to the mediastinal-pericardial area or in patients with anemia, bone marrow depression, infections, leukemic pericarditis and/or myocarditis, active or dormant cardiovascular disease, previous therapy with other anthracyclines or anthracenediones, and concomitant use of drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab, cyclophosphamide and paclitaxel). Do not administer anthracyclines including idarubicin with other cardiotoxic agents unless the patient's cardiac function is monitored frequently. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives, may also be at an increased risk of developing cardiotoxicity. Avoid use of anthracycline-based therapy for at least 5 half-lives after discontinuation of the cardiotoxic agent. If anthracyclines are used before this time, carefully monitor the cardiac function. While there are no reliable means for predicting congestive heart failure, cardiomyopathy induced by anthracyclines is usually associated with a decrease of the left ventricular ejection fraction (LVEF) from pretreatment baseline values.

Since hepatic and/or renal function impairment can affect the disposition of IDAMYCIN, liver and kidney function should be evaluated with conventional clinical laboratory tests (using serum bilirubin and serum creatinine as indicators) prior to and during treatment. In a number of Phase III clinical trials, treatment was not given if bilirubin and/or creatinine serum levels exceeded 2 mg%. However, in one Phase III trial, patients with bilirubin levels between 2.6 and 5 mg% received the anthracycline with a 50% reduction in dose. Dose reduction of IDAMYCIN should be considered if the bilirubin and/or creatinine levels are above the normal range. (See DOSAGE AND ADMINISTRATION.)

Pregnancy Category D

Idarubicin was embryotoxic and teratogenic in the rat at a dose of 1.2 mg/m2/day or one tenth the human dose, which was nontoxic to dams. Idarubicin was embryotoxic but not teratogenic in the rabbit even at a dose of 2.4 mg/m2/day or two tenths the human dose, which was toxic to dams.

There is no conclusive information about idarubicin adversely affecting human fertility or causing teratogenesis. There has been one report of a fetal fatality after maternal exposure to idarubicin during the second trimester.

There are no adequate and well-controlled studies in pregnant women. If IDAMYCIN is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid pregnancy.


PRECAUTIONS

General

Therapy with IDAMYCIN (idarubicin hydrochloride for injection, USP) requires close observation of the patient and careful laboratory monitoring. Hyperuricemia secondary to rapid lysis of leukemic cells may be induced. Appropriate measures must be taken to prevent hyperuricemia and to control any systemic infection before beginning therapy.

Extravasation of IDAMYCIN can cause severe local tissue necrosis. Extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If signs or symptoms of extravasation occur the injection or infusion should be terminated immediately and restarted in another vein. (See DOSAGE AND ADMINISTRATION.)

Laboratory Tests

Frequent complete blood counts and monitoring of hepatic and renal function tests are recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Formal long-term carcinogenicity studies have not been conducted with idarubicin. Idarubicin and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models (including bacterial systems, mammalian cells in culture and female Sprague-Dawley rats).

In male dogs given 1.8 mg/m2/day 3 times/week (about one seventh the weekly human dose on a mg/m2 basis) for 13 weeks, or 3 times the human dose, testicular atrophy was observed with inhibition of spermatogenesis and sperm maturation with few or no mature sperm. These effects were not readily reversed after a recovery of 8 weeks.

Pregnancy Category D

(See WARNINGS.)

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from idarubicin, mothers should discontinue nursing prior to taking this drug.

Pediatric Use

Safety and effectiveness in children have not been established.

Geriatric Use

Patients over 60 years of age who were undergoing induction therapy experienced congestive heart failure, serious arrhythmias, chest pain, myocardial infarction, and asymptomatic declines in LVEF more frequently than younger patients (see ADVERSE REACTIONS).

ADVERSE REACTIONS

Approximately 550 patients with AML have received IDAMYCIN (idarubicin hydrochloride for injection, USP) in combination with cytarabine in controlled clinical trials worldwide. In addition, over 550 patients with acute leukemia have been treated in uncontrolled trials utilizing IDAMYCIN as a single agent or in combination. The table below lists the adverse experiences reported in U.S. Study 2 (see CLINICAL STUDIES) and is representative of the experiences in other studies. These adverse experiences constitute all reported or observed experiences, including those not considered to be drug related. Patients undergoing induction therapy for AML are seriously ill due to their disease, are receiving multiple transfusions, and concomitant medications including potentially toxic antibiotics and antifungal agents. The contribution of the study drug to the adverse experience profile is difficult to establish.

Induction Phase Percentage of Patients
  IDR DNR
Adverse Experiences (N=110) (N=118)
  Infection 95% 97%
  Nausea & Vomiting 82% 80%
  Hair Loss 77% 72%
  Abdominal Cramps/Diarrhea 73% 68%
  Hemorrhage 63% 65%
  Mucositis 50% 55%
  Dermatologic 46% 40%
  Mental Status 41% 34%
  Pulmonary-Clinical 39% 39%
  Fever (not elsewhere classified) 26% 28%
  Headache 20% 24%
  Cardiac-Clinical 16% 24%
  Neurologic-Peripheral Nerves 7% 9%
  Pulmonary Allergy 2% 4%
  Seizure 4% 5%
  Cerebellar 4% 4%

The duration of aplasia and incidence of mucositis were greater on the IDR arm than the DNR arm, especially during consolidation in some U.S. controlled trials (see CLINICAL STUDIES).

The following information reflects experience based on U.S. controlled clinical trials.

Myelosuppression

Severe myelosuppression is the major toxicity associated with IDAMYCIN therapy, but this effect of the drug is required in order to eradicate the leukemic clone. During the period of myelosuppression, patients are at risk of developing infection and bleeding which may be life-threatening or fatal.

Gastrointestinal

Nausea and/or vomiting, mucositis, abdominal pain and diarrhea were reported frequently, but were severe (equivalent to WHO Grade 4) in less than 5% of patients. Severe enterocolitis with perforation has been reported rarely. The risk of perforation may be increased by instrumental intervention. The possibility of perforation should be considered in patients who develop severe abdominal pain and appropriate steps for diagnosis and management should be taken.

Dermatologic

Alopecia was reported frequently and dermatologic reactions including generalized rash, urticaria and a bullous erythrodermatous rash of the palms and soles have occurred. The dermatologic reactions were usually attributed to concomitant antibiotic therapy. Local reactions including hives at the injection site have been reported. Recall of skin reaction due to prior radiotherapy has occurred with IDAMYCIN administration.

Hepatic and Renal

Changes in hepatic and renal function tests have been observed. These changes were usually transient and occurred in the setting of sepsis and while patients were receiving potentially hepatotoxic and nephrotoxic antibiotics and antifungal agents. Severe changes in renal function (equivalent to WHO Grade 4) occurred in no more than 1% of patients, while severe changes in hepatic function (equivalent to WHO Grade 4) occurred in less than 5% of patients.

Cardiac

Congestive heart failure (frequently attributed to fluid overload), serious arrhythmias including atrial fibrillation, chest pain, myocardial infarction and asymptomatic declines in LVEF have been reported in patients undergoing induction therapy for AML. Myocardial insufficiency and arrhythmias were usually reversible and occurred in the setting of sepsis, anemia and aggressive intravenous fluid administration. The events were reported more frequently in patients over age 60 years and in those with pre-existing cardiac disease.

INDICATIONS AND USAGE

IDAMYCIN (idarubicin hydrochloride for injection, USP) in combination with other approved antileukemic drugs is indicated for the treatment of acute myeloid leukemia (AML) in adults. This includes French-American- British (FAB) classifications M1 through M7.

INLYTA® (axitinib)

These highlights do not include all the information needed to use INLYTA safety and effectively. See full prescribing information for INLYTA.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Hypertension and Hypertensive Crisis

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)].

Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension [see Dosage and Administration (2.2)].

5.2 Arterial Thromboembolic Events

In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)].

In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident.

Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.

5.3 Venous Thromboembolic Events

In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism.

Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months.

5.4 Hemorrhage

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.

INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

5.5 Cardiac Failure

In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.

5.6 Gastrointestinal Perforation and Fistula Formation

In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%).

Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA.

5.7 Thyroid Dysfunction

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib [see Adverse Reactions (6.1)].

Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.

5.8 Wound Healing Complications

No formal studies of the effect of INLYTA on wound healing have been conducted.

Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing.

5.9 Reversible Posterior Leukoencephalopathy Syndrome

In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)]. There were two additional reports of RPLS in other clinical trials with INLYTA.

RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known.

5.10 Proteinuria

In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib [see Adverse Reactions (6.1)].

Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

5.11 Elevation of Liver Enzymes

In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm.

Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA.

5.12 Hepatic Impairment

The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

5.13 Pregnancy

INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described [see Adverse Reactions (6.1)] reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib [see Clinical Studies (14)].

The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label [see Warnings and Precautions (5.1–5.13)]: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, cardiac failure, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, hepatic impairment and fetal development.

6.1 Clinical Trials Experience

The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib.

The most common (≥20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. Table 1 presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib.

Table 1. Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib
Adverse Reaction* INLYTA Sorafenib
(N=359) (N=355)
All Grades Grade 3/4 All Grades Grade 3/4
% % % %
*
Percentages are treatment-emergent, all-causality events
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0
Diarrhea 55 11 53 7
Hypertension 40 16 29 11
Fatigue 39 11 32 5
Decreased appetite 34 5 29 4
Nausea 32 3 22 1
Dysphonia 31 0 14 0
Palmar-plantar erythrodysesthesia syndrome 27 5 51 16
Weight decreased 25 2 21 1
Vomiting 24 3 17 1
Asthenia 21 5 14 3
Constipation 20 1 20 1
Hypothyroidism 19 <1 8 0
Cough 15 1 17 1
Mucosal inflammation 15 1 12 1
Arthralgia 15 2 11 1
Stomatitis 15 1 12 <1
Dyspnea 15 3 12 3
Abdominal pain 14 2 11 1
Headache 14 1 11 0
Pain in extremity 13 1 14 1
Rash 13 <1 32 4
Proteinuria 11 3 7 2
Dysgeusia 11 0 8 0
Dry skin 10 0 11 0
Dyspepsia 10 0 2 0
Pruritus 7 0 12 0
Alopecia 4 0 32 0
Erythema 2 0 10 <1

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).

Table 2 presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib.

Table 2. Laboratory Abnormalities Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib
Laboratory Abnormality N INLYTA N Sorafenib
All Grades* Grade 3/4 All Grades* Grade 3/4
% % % %
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase
*
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0
Hematology
Hemoglobin decreased 320 35 <1 316 52 4
Lymphocytes (absolute) decreased 317 33 3 309 36 4
Platelets decreased 312 15 <1 310 14 0
White blood cells decreased 320 11 0 315 16 <1
Chemistry
Creatinine increased 336 55 0 318 41 <1
Bicarbonate decreased 314 44 <1 291 43 0
Hypocalcemia 336 39 1 319 59 2
ALP increased 336 30 1 319 34 1
Hyperglycemia 336 28 2 319 23 2
Lipase increased 338 27 5 319 46 15
Amylase increased 338 25 2 319 33 2
ALT increased 331 22 <1 313 22 2
AST increased 331 20 <1 311 25 1
Hypernatremia 338 17 1 319 13 1
Hypoalbuminemia 337 15 <1 319 18 1
Hyperkalemia 333 15 3 314 10 3
Hypoglycemia 336 11 <1 319 8 <1
Hyponatremia 338 13 4 319 11 2
Hypophosphatemia 336 13 2 318 49 16

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib) and hypercalcemia (6% for INLYTA versus 2% for sorafenib).

1 INDICATIONS AND USAGE

INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

SUTENT® (sunitinib malate)

These highlights do not include all the information needed to use SUTENT safety and effectively. See full prescribing information for SUTENT.

WARNING: HEPATOTOXICITY

Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported. [See Warnings and Precautions (5.1)]

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

SUTENT has been associated with hepatotoxicity, which may result in liver failure or death. Liver failure has been observed in clinical trials (7/2281 [0.3%]) and post-marketing experience. Liver failure signs include jaundice, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (ALT, AST, bilirubin) before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure.

Safety in patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN has not been established.

5.2 Pregnancy

SUTENT can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of SUTENT should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of SUTENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SUTENT.

5.3 Cardiovascular Events

In the presence of clinical manifestations of congestive heart failure (CHF), discontinuation of SUTENT is recommended. The dose of SUTENT should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline.

Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been reported. Use SUTENT with caution in patients who are at risk for, or who have a history of, these events. For GIST and RCC, more patients treated with SUTENT experienced decline in left ventricular ejection fraction (LVEF) than patients receiving either placebo or interferon-α (IFN-α). In the double-blind treatment phase of GIST Study A, 22/209 patients (11%) on SUTENT and 3/102 patients (3%) on placebo had treatment-emergent LVEF values below the lower limit of normal (LLN). Nine of 22 GIST patients on SUTENT with LVEF changes recovered without intervention. Five patients had documented LVEF recovery following intervention (dose reduction: one patient; addition of antihypertensive or diuretic medications: four patients). Six patients went off study without documented recovery. Additionally, three patients on SUTENT had Grade 3 reductions in left ventricular systolic function to LVEF <40%; two of these patients died without receiving further study drug. No GIST patients on placebo had Grade 3 decreased LVEF. In the double-blind treatment phase of GIST Study A, 1 patient on SUTENT and 1 patient on placebo died of diagnosed heart failure; 2 patients on SUTENT and 2 patients on placebo died of treatment-emergent cardiac arrest.

In the treatment-naïve RCC study, 103/375 (27%) and 54/360 (15%) patients on SUTENT and IFN-α, respectively, had an LVEF value below the LLN. Twenty-six patients on SUTENT (7%) and seven on IFN-α (2%) experienced declines in LVEF to >20% below baseline and to below 50%. Left ventricular dysfunction was reported in four patients (1%) and CHF in two patients (<1%) who received SUTENT.

In the Phase 3 pNET study, cardiac failure leading to death was reported in 2/83 (2%) patients on SUTENT and no patients on placebo.

Patients who presented with cardiac events within 12 months prior to SUTENT administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from SUTENT clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing drug-related left ventricular dysfunction. Physicians are advised to weigh this risk against the potential benefits of the drug. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving SUTENT. Baseline and periodic evaluations of LVEF should also be considered while these patients are receiving SUTENT. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.

5.4 QT Interval Prolongation and Torsade de Pointes

SUTENT has been shown to prolong the QT interval in a dose dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes has been observed in <0.1% of SUTENT-exposed patients.

SUTENT should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using SUTENT, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium) should be considered. Concomitant treatment with strong CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and dose reduction of SUTENT should be considered [see Dosage and Administration (2.2)].

5.5 Hypertension

Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled.

Of patients receiving SUTENT for treatment-naïve RCC, 127/375 patients (34%) receiving SUTENT compared with 13/360 patients (4%) on IFN-α experienced hypertension. Grade 3 hypertension was observed in 50/375 treatment-naïve RCC patients (13%) on SUTENT compared to 1/360 patients (<1%) on IFN-α. While all-grade hypertension was similar in GIST patients on SUTENT compared to placebo, Grade 3 hypertension was reported in 9/202 GIST patients on SUTENT (4%), and none of the GIST patients on placebo. Of patients receiving SUTENT in the Phase 3 pNET study, 22/83 patients (27%) on SUTENT and 4/82 patients (5%) on placebo experienced hypertension. Grade 3 hypertension was reported in 8/83 pNET patients (10%) on SUTENT, and 1/82 patient (1%) on placebo. No Grade 4 hypertension was reported. SUTENT dosing was reduced or temporarily delayed for hypertension in 21/375 patients (6%) on the treatment-naive RCC study and 7/83 pNET patients (8%). Four treatment-naïve RCC patients, including one with malignant hypertension, one patient with pNET, and no GIST patients discontinued treatment due to hypertension. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 8/202 GIST patients on SUTENT (4%), 1/102 GIST patients on placebo (1%), in 32/375 treatment-naïve RCC patients (9%) on SUTENT, in 3/360 patients (1%) on IFN-α, and in 8/80 pNET patients (10%) on SUTENT and 2/76 pNET patients (3%) on placebo.

5.6 Hemorrhagic Events

Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included GI, respiratory, tumor, urinary tract and brain hemorrhages. In patients receiving SUTENT in a clinical trial for treatment-naïve RCC, 140/375 patients (37%) had bleeding events compared with 35/360 patients (10%) receiving IFN-α. Bleeding events occurred in 37/202 patients (18%) receiving SUTENT in the double-blind treatment phase of GIST Study A, compared to 17/102 patients (17%) receiving placebo. Epistaxis was the most common hemorrhagic adverse event reported. Bleeding events, excluding epistaxis, occurred in 18/83 patients (22%) receiving SUTENT in the Phase 3 pNET study, compared to 8/82 patients (10%) receiving placebo. Epistaxis was reported in 17/83 patients (20%) receiving SUTENT for pNET and 4 patients (5%) receiving placebo. Less common bleeding events in GIST, RCC and pNET patients included rectal, gingival, upper gastrointestinal, genital, and wound bleeding. In the double-blind treatment phase of GIST Study A, 14/202 patients (7%) receiving SUTENT and 9/102 patients (9%) on placebo had Grade 3 or 4 bleeding events. In addition, one patient in GIST Study A taking placebo had a fatal gastrointestinal bleeding event during Cycle 2. Most events in RCC patients were Grade 1 or 2; there was one Grade 5 event of gastric bleed in a treatment-naïve patient. In the pNET study, 1/83 patients (1%) receiving SUTENT had Grade 3 epistaxis, and no patients had other Grade 3 or 4 bleeding events. In pNET patients receiving placebo, 3/82 patients (4%) had Grade 3 or 4 bleeding events.

Tumor-related hemorrhage has been observed in patients treated with SUTENT. These events may occur suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Cases of pulmonary hemorrhage, some with a fatal outcome, have been observed in clinical trials and have been reported in post-marketing experience in patients treated with SUTENT for MRCC, GIST and metastatic lung cancer. SUTENT is not approved for use in patients with lung cancer. Treatment-emergent Grade 3 and 4 tumor hemorrhage occurred in 5/202 patients (3%) with GIST receiving SUTENT on Study A. Tumor hemorrhages were observed as early as Cycle 1 and as late as Cycle 6. One of these five patients received no further drug following tumor hemorrhage. None of the other four patients discontinued treatment or experienced dose delay due to tumor hemorrhage. No patients with GIST in the Study A placebo arm were observed to undergo intratumoral hemorrhage. Clinical assessment of these events should include serial complete blood counts (CBCs) and physical examinations.

Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, have occurred rarely in patients with intra-abdominal malignancies treated with SUTENT.

5.7 Tumor Lysis Syndrome (TLS)

Cases of TLS, some fatal, have been observed in clinical trials and have been reported in post-marketing experience, primarily in patients with RCC or GIST treated with SUTENT. Patients generally at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and treated as clinically indicated.

5.8 Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, has been reported in clinical trials and in post-marketing experience of SUTENT as monotherapy and in combination with bevacizumab. Discontinue SUTENT in patients developing TMA. Reversal of the effects of TMA has been observed after treatment was discontinued.

5.9 Proteinuria

Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Monitor patients for the development or worsening of proteinuria. Perform baseline and periodic urinalyses during treatment, with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt SUTENT and dose reduce for 24-hour urine protein ≥ 3 grams. Discontinue SUTENT for patients with nephrotic syndrome or repeat episodes of urine protein ≥ 3 grams despite dose reductions. The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated.

5.10 Dermatologic Toxicities

Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of SJS, TEN, or EM (e.g., progressive skin rash often with blisters or mucosal lesions) are present, SUTENT treatment should be discontinued. If a diagnosis of SJS or TEN is suspected, SUTENT treatment must not be re-started.

Necrotizing fasciitis, including fatal cases, has been reported in patients treated with Sutent, including of the perineum and secondary to fistula formation. Discontinue Sutent in patients who develop necrotizing fasciitis.

5.11 Thyroid Dysfunction

Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of SUTENT treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, on SUTENT treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.

Treatment-emergent acquired hypothyroidism was noted in eight GIST patients (4%) on SUTENT versus one (1%) on placebo. Hypothyroidism was reported as an adverse reaction in sixty-one patients (16%) on SUTENT in the treatment-naïve RCC study and in three patients (1%) in the IFN-α arm. Hypothyroidism was reported as an adverse reaction in 6/83 patients (7%) on SUTENT in the Phase 3 pNET study and in 1/82 patients (1%) in the placebo arm.

Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience.

5.12 Hypoglycemia

SUTENT has been associated with symptomatic hypoglycemia, which may result in loss of consciousness, or require hospitalization. Hypoglycemia has occurred in clinical trials in 2% of the patients treated with SUTENT for RCC and GIST and in approximately 10% of the patients treated with SUTENT for pNET. For patients being treated with SUTENT for pNET, pre-existing abnormalities in glucose homeostasis were not present in all patients who experienced hypoglycemia. Reductions in blood glucose levels may be worse in diabetic patients. Check blood glucose levels regularly during and after discontinuation of treatment with SUTENT. Assess if anti-diabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

5.13 Osteonecrosis of the Jaw (ONJ)

ONJ has been observed in clinical trials and has been reported in post-marketing experience in patients treated with sunitinib. Concomitant exposure to other risk factors, such as bisphosphonates or dental disease, may increase the risk of osteonecrosis of the jaw.

5.14 Wound Healing

Cases of impaired wound healing have been reported during SUTENT therapy. Temporary interruption of SUTENT therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume SUTENT therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery.

5.15 Adrenal Function

Physicians prescribing SUTENT are advised to monitor for adrenal insufficiency in patients who experience stress such as surgery, trauma or severe infection.

Adrenal toxicity was noted in non-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at plasma exposures as low as 0.7 times the AUC observed in clinical studies. Histological changes of the adrenal gland were characterized as hemorrhage, necrosis, congestion, hypertrophy and inflammation. In clinical studies, CT/MRI obtained in 336 patients after exposure to one or more cycles of SUTENT demonstrated no evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately 400 patients across multiple clinical trials of SUTENT. Among patients with normal baseline ACTH stimulation testing, one patient developed consistently abnormal test results during treatment that are unexplained and may be related to treatment with SUTENT. Eleven additional patients with normal baseline testing had abnormalities in the final test performed, with peak cortisol levels of 12–16.4 mcg/dL (normal >18 mcg/dL) following stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency.

5.16 Laboratory Tests

CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT.

6 ADVERSE REACTIONS

The data described below reflect exposure to SUTENT in 660 patients who participated in the double-blind treatment phase of a placebo-controlled trial (n=202) for the treatment of GIST [see Clinical Studies (14.1)], an active-controlled trial (n=375) for the treatment of RCC [see Clinical Studies (14.2)] or a placebo-controlled trial (n=83) for the treatment of pNET [see Clinical Studies (14.3)]. The GIST and RCC patients received a starting oral dose of 50 mg daily on Schedule 4/2 in repeated cycles, and the pNET patients received a starting oral dose of 37.5 mg daily without scheduled off-treatment periods.

The most common adverse reactions (≥20%) in patients with GIST, RCC or pNET are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, and bleeding. The potentially serious adverse reactions of hepatotoxicity, left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, and adrenal function are discussed in Warnings and Precautions (5). Other adverse reactions occurring in GIST, RCC and pNET studies are described below.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Adverse Reactions in GIST Study A

Median duration of blinded study treatment was two cycles for patients on SUTENT (mean 3.0, range 1–9) and one cycle (mean 1.8, range 1–6) for patients on placebo at the time of the interim analysis. Dose reductions occurred in 23 patients (11%) on SUTENT and none on placebo. Dose interruptions occurred in 59 patients (29%) on SUTENT and 31 patients (30%) on placebo. The rates of treatment-emergent, non-fatal adverse reactions resulting in permanent discontinuation were 7% and 6% in the SUTENT and placebo groups, respectively.

Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 56% versus 51% of patients on SUTENT versus placebo, respectively, in the double-blind treatment phase of the trial. Table 1 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT and reported more commonly in patients receiving SUTENT than in patients receiving placebo.

Table 1. Adverse Reactions Reported in Study A in at Least 10% of GIST Patients who Received SUTENT in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo*
Adverse Reaction,n (%) GIST
SUTENT (n=202) Placebo (n=102)
All Grades Grade 3/4 All Grades Grade 3/4
*
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
Includes decreased appetite
Any 114 (56) 52 (51)
Gastrointestinal
  Diarrhea 81 (40) 9 (4) 27 (27) 0 (0)
  Mucositis/stomatitis 58 (29) 2 (1) 18 (18) 2 (2)
  Constipation 41 (20) 0 (0) 14 (14) 2 (2)
Cardiac
  Hypertension 31 (15) 9 (4) 11 (11) 0 (0)
Dermatology
  Skin discoloration 61 (30) 0 (0) 23 (23) 0 (0)
  Rash 28 (14) 2 (1) 9 (9) 0 (0)
  Hand-foot syndrome 28 (14) 9 (4) 10 (10) 3 (3)
Neurology
  Altered taste 42 (21) 0 (0) 12 (12) 0 (0)
Musculoskeletal
  Myalgia/limb pain 28 (14) 1 (1) 9 (9) 1 (1)
Metabolism/Nutrition
  Anorexia 67 (33) 1 (1) 30 (29) 5 (5)
  Asthenia 45 (22) 10 (5) 11 (11) 3 (3)

In the double-blind treatment phase of GIST Study A, oral pain other than mucositis/stomatitis occurred in 12 patients (6%) on SUTENT versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on SUTENT versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on SUTENT versus 2 (2%) on placebo.

Table 2 provides common (≥10%) treatment-emergent laboratory abnormalities.

Table 2. Laboratory Abnormalities Reported in Study A in at Least 10% of GIST Patients Who Received SUTENT or Placebo in the Double-Blind Treatment Phase*
Laboratory Parameter, n (%) GIST
SUTENT (n=202) Placebo (n=102)
All Grades* Grade 3/4* All Grades* Grade 3/4*
LVEF=Left ventricular ejection fraction
*
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
Grade 4 laboratory abnormalities in patients on SUTENT included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%).
Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%).
Any 68 (34) 22 (22)
Gastrointestinal
  AST / ALT 78 (39) 3 (2) 23 (23) 1 (1)
  Lipase 50 (25) 20 (10) 17 (17) 7 (7)
  Alkaline phosphatase 48 (24) 7 (4) 21 (21) 4 (4)
  Amylase 35 (17) 10 (5) 12 (12) 3 (3)
  Total bilirubin 32 (16) 2 (1) 8 (8) 0 (0)
  Indirect bilirubin 20 (10) 0 (0) 4 (4) 0 (0)
Cardiac
  Decreased LVEF 22 (11) 2 (1) 3 (3) 0 (0)
Renal/Metabolic
  Creatinine 25 (12) 1 (1) 7 (7) 0 (0)
  Potassium decreased 24 (12) 1 (1) 4 (4) 0 (0)
  Sodium increased 20 (10) 0 (0) 4 (4) 1 (1)
Hematology
  Neutrophils 107 (53) 20 (10) 4 (4) 0 (0)
  Lymphocytes 76 (38) 0 (0) 16 (16) 0 (0)
  Platelets 76 (38) 10 (5) 4 (4) 0 (0)
  Hemoglobin 52 (26) 6 (3) 22 (22) 2 (2)

After an interim analysis, the study was unblinded, and patients on the placebo arm were given the opportunity to receive open-label SUTENT treatment [see Clinical Studies (14.1)]. For 241 patients randomized to the SUTENT arm, including 139 who received SUTENT in both the double-blind and open-label treatment phases, the median duration of SUTENT treatment was 6 cycles (mean 8.5, range 1 – 44). For the 255 patients who ultimately received open-label SUTENT treatment, median duration of study treatment was 6 cycles (mean 7.8, range 1 – 37) from the time of the unblinding. A total of 118 patients (46%) required dosing interruptions, and a total of 72 patients (28%) required dose reductions. The incidence of treatment-emergent adverse reactions resulting in permanent discontinuation was 20%. The most common Grade 3 or 4 treatment-related adverse reactions experienced by patients receiving SUTENT in the open-label treatment phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%).

6.2 Adverse Reactions in the Treatment-Naïve RCC Study

The as-treated patient population for the treatment-naive RCC study included 735 patients, 375 randomized to SUTENT and 360 randomized to IFN-α. The median duration of treatment was 11.1 months (range: 0.4 – 46.1) for SUTENT treatment and 4.1 months (range: 0.1 – 45.6) for IFN-α treatment. Dose interruptions occurred in 202 patients (54%) on SUTENT and 141 patients (39%) on IFN-α. Dose reductions occurred in 194 patients (52%) on SUTENT and 98 patients (27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for SUTENT and 24% for IFN-α. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 77% versus 55% of patients on SUTENT versus IFN-α, respectively.

Table 3 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT versus IFN-α.

Table 3. Adverse Reactions Reported in at Least 10% of Patients with RCC Who Received SUTENT or IFN-α*
Adverse Reaction, n (%) Treatment-Naïve RCC
SUTENT (n=375) IFN-α (n=360)
All Grades Grade 3/4 All Grades Grade 3/4
*
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
Grade 4 ARs in patients on SUTENT included back pain (1%), arthralgia (<1%), dyspnea (<1%), asthenia (<1%), fatigue (<1%), limb pain (<1%) and rash (<1%).
Grade 4 ARs in patients on IFN-α included dyspnea (1%), fatigue (1%), abdominal pain (<1%) and depression (<1%).
§
Includes flank pain
Includes ageusia, hypogeusia and dysgeusia
#
Includes decreased appetite
Þ
Includes one patient with Grade 5 gastric hemorrhage
ß
Includes depressed mood
Any 372 (99) 290 (77) 355 (99) 197 (55)
Constitutional
  Fatigue 233 (62) 55 (15) 202 (56) 54 (15)
  Asthenia 96 (26) 42 (11) 81 (22) 21 (6)
  Fever 84 (22) 3 (1) 134 (37) 1 (<1)
  Weight decreased 60 (16) 1 (<1) 60 (17) 3 (1)
  Chills 53 (14) 3 (1) 111 (31) 0 (0)
  Chest Pain 50 (13) 7 (2) 24 (7) 3 (1)
  Influenza like illness 18 (5) 0 (0) 54 (15) 1 (<1)
Gastrointestinal
  Diarrhea 246 (66) 37 (10) 76 (21) 1 (<1)
  Nausea 216 (58) 21 (6) 147 (41) 6 (2)
  Mucositis/stomatitis 178 (47) 13 (3) 19 (5) 2 (<1)
  Vomiting 148 (39) 19 (5) 62 (17) 4 (1)
  Dyspepsia 128 (34) 8 (2) 16 (4) 0 (0)
  Abdominal pain§ 113 (30) 20 (5) 42 (12) 5 (1)
  Constipation 85 (23) 4 (1) 49 (14) 1 (<1)
  Dry mouth 50 (13) 0 (0) 27 (7) 1 (<1)
  GERD/reflux esophagitis 47 (12) 1 (<1) 3 (1) 0(0)
  Flatulence 52 (14) 0 (0) 8 (2) 0 (0)
  Oral pain 54 (14) 2 (<1) 2 (1) 0 (0)
  Glossodynia 40 (11) 0 (0) 2 (1) 0 (0)
  Hemorrhoids 38 (10) 0 (0) 6 (2) 0 (0)
Cardiac
  Hypertension 127 (34) 50 (13) 13 (4) 1 (<1)
  Edema, peripheral 91 (24) 7 (2) 17 (5) 2 (1)
  Ejection fraction decreased 61 (16) 10 (3) 19 (5) 6 (2)
Dermatology
  Rash 109 (29) 6 (2) 39 (11) 1 (<1)
  Hand-foot syndrome 108 (29) 32 (8) 3 (1) 0 (0)
  Skin discoloration/ yellow skin 94 (25) 1 (<1) 0 (0) 0 (0)
  Dry skin 85 (23) 1 (<1) 26 (7) 0 (0)
  Hair color changes 75 (20) 0 (0) 1 (<1) 0 (0)
  Alopecia 51 (14) 0 (0) 34 (9) 0 (0)
  Erythema 46 (12) 2 (<1) 5 (1) 0 (0)
  Pruritus 44 (12) 1 (<1) 24 (7) 1 (<1)
Neurology
  Altered taste 178 (47) 1 (<1) 54 (15) 0 (0)
  Headache 86 (23) 4 (1) 69 (19) 0 (0)
  Dizziness 43 (11) 2 (<1) 50 (14) 2 (1)
Musculoskeletal
  Back pain 105 (28) 19 (5) 52 (14) 7 (2)
  Arthralgia 111 (30) 10 (3) 69 (19) 4 (1)
  Pain in extremity/ limb discomfort 150 (40) 19 (5) 107 (30) 7 (2)
Endocrine
  Hypothyroidism 61 (16) 6 (2) 3 (1) 0 (0)
Respiratory
  Cough 100 (27) 3 (1) 51 (14) 1 (<1)
  Dyspnea 99 (26) 24 (6) 71 (20) 15 (4)
  Nasopharyngitis 54 (14) 0 (0) 8 (2) 0 (0)
  Oropharyngeal Pain 51 (14) 2 (<1) 9 (2) 0 (0)
  Upper respiratory tract infection 43 (11) 2 (<1) 9 (2) 0 (0)
Metabolism/Nutrition
  Anorexia# 182 (48) 11 (3) 153 (42) 7 (2)
Hemorrhage/Bleeding
  Bleeding, all sites 140 (37) 16 (4)Þ 35 (10) 3 (1)
Psychiatric
  Insomnia 57 (15) 3 (<1) 37 (10) 0 (0)
  Depressionß 40 (11) 0 (0) 51 (14) 5 (1)

Treatment-emergent Grade 3/4 laboratory abnormalities are presented in Table 4.

Table 4. Laboratory Abnormalities Reported in at Least 10% of Treatment-Naïve RCC Patients Who Received SUTENT or IFN-α
Laboratory Parameter, n (%) Treatment-Naïve RCC
SUTENT (n=375) IFN-α (n=360)
All Grades* Grade 3/4* All Grades* Grade 3/4*
*
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
Grade 4 laboratory abnormalities in patients on SUTENT included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (<1%), creatine kinase (<1%), creatinine (<1%), glucose increased (<1%), calcium decreased (<1%), phosphorous (<1%), potassium increased (<1%), and sodium decreased (<1%).
Grade 4 laboratory abnormalities in patients on IFN-α included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%), and hemoglobin (<1%).
Gastrointestinal
  AST 211 (56) 6 (2) 136 (38) 8 (2)
  ALT 192 (51) 10 (3) 144 (40) 9 (2)
  Lipase 211 (56) 69 (18) 165 (46) 29 (8)
  Alkaline phosphatase 171 (46) 7 (2) 132 (37) 6 (2)
  Amylase 130 (35) 22 (6) 114 (32) 12 (3)
  Total bilirubin 75 (20) 3 (1) 8 (2) 0 (0)
  Indirect bilirubin 49 (13) 4 (1) 3 (1) 0 (0)
Renal/Metabolic
  Creatinine 262 (70) 2 (<1) 183 (51) 1 (<1)
  Creatine kinase 183 (49) 9 (2) 40 (11) 4 (1)
  Uric acid 173 (46) 54 (14) 119 (33) 29 (8)
  Calcium decreased 156 (42) 4 (1) 145 (40) 4 (1)
  Phosphorus 116 (31) 22 (6) 87 (24) 23 (6)
  Albumin 106 (28) 4 (1) 72 (20) 0 (0)
  Glucose increased 86 (23) 21 (6) 55 (15) 22 (6)
  Sodium decreased 75 (20) 31 (8) 55 (15) 13 (4)
  Glucose decreased 65 (17) 0 (0) 43 (12) 1 (<1)
  Potassium increased 61 (16) 13 (3) 61 (17) 15 (4)
  Calcium increased 50 (13) 2 (<1) 35 (10) 5 (1)
  Potassium decreased 49 (13) 3 (1) 7 (2) 1 (<1)
  Sodium increased 48 (13) 0 (0) 38 (10) 0 (0)
Hematology
  Neutrophils 289 (77) 65 (17) 178 (49) 31 (9)
  Hemoglobin 298 (79) 29 (8) 250 (69) 18 (5)
  Platelets 255 (68) 35 (9) 85 (24) 2 (1)
  Lymphocytes 256 (68) 66 (18) 245 (68) 93 (26)
  Leukocytes 293 (78) 29 (8) 202 (56) 8 (2)

6.3 Adverse Reactions in the Phase 3 pNET Study

The median number of days on treatment was 139 days (range 13–532 days) for patients on SUTENT and 113 days (range 1–614 days) for patients on placebo. Nineteen patients (23%) on SUTENT and 4 patients (5%) on placebo were on study for >1 year. Dose interruptions occurred in 25 patients (30%) on SUTENT and 10 patients (12%) on placebo. Dose reductions occurred in 26 patients (31%) on SUTENT and 9 patients (11%) on placebo. Discontinuation rates due to adverse reactions were 22% for SUTENT and 17% for placebo.

Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 54% versus 50% of patients on SUTENT versus placebo, respectively. Table 5 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT and reported more commonly in patients receiving SUTENT than in patients receiving placebo.

Table 5. Adverse Reactions Reported in the Phase 3 pNET Study in at Least 10% of Patients who Received SUTENT and More Commonly Than in Patients Given Placebo*
Adverse Reaction, n (%) pNET
SUTENT (n=83) Placebo (n=82)
All Grades Grade 3/4 All Grades Grade 3/4
*
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
Grade 4 ARs in patients on SUTENT included fatigue (1%).
Includes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth.
§
Includes abdominal discomfort, abdominal pain, and abdominal pain upper.
Includes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia.
Any 82 (99) 45 (54) 78 (95) 41 (50)
Constitutional
  Asthenia 28 (34) 4 (5) 22 (27) 3 (4)
  Fatigue 27 (33) 4 (5) 22 (27) 7 (9)
  Weight decreased 13 (16) 1(1) 9 (11) 0 (0)
Gastrointestinal
  Diarrhea 49 (59) 4 (5) 32 (39) 2 (2)
  Stomatitis/oral syndromes 40 (48) 5 (6) 15 (18) 0 (0)
  Nausea 37 (45) 1 (1) 24 (29) 1 (1)
  Abdominal pain§ 32 (39) 4 (5) 28 (34) 8 (10)
  Vomiting 28 (34) 0 (0) 25 (31) 2 (2)
  Dyspepsia 12 (15) 0 (0) 5 (6) 0 (0)
Cardiac
  Hypertension 22 (27) 8 (10) 4 (5) 1 (1)
Dermatology
  Hair color changes 24 (29) 1 (1) 1 (1) 0 (0)
  Hand-foot syndrome 19 (23) 5 (6) 2 (2) 0 (0)
  Rash 15 (18) 0 (0) 4 (5) 0 (0)
  Dry skin 12 (15) 0 (0) 9 (11) 0 (0)
Neurology
  Dysgeusia 17 (21) 0 (0) 4 (5) 0 (0)
  Headache 15 (18) 0 (0) 11 (13) 1 (1)
Musculoskeletal
  Arthralgia 12 (15) 0 (0) 5 (6) 0 (0)
Psychiatric
  Insomnia 15 (18) 0 (0) 10 (12) 0 (0)
Hemorrhage/Bleeding
  Bleeding events 18 (22) 0 (0) 8 (10) 3 (4)
  Epistaxis 17 (21) 1 (1) 4 (5) 0 (0)

Table 6 provides common (≥10%) treatment-emergent laboratory abnormalities.

Table 6. Laboratory Abnormalities Reported in the Phase 3 pNET Study in at Least 10% of Patients Who Received SUTENT
Laboratory Parameter, n (%) pNET
SUTENT Placebo
N All Grades* Grade 3/4* N All Grades* Grade 3/4*
*
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
Grade 4 laboratory abnormalities in patients on SUTENT included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%) and total bilirubin (1%).
Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%) and lipase (1%).
Gastrointestinal
  AST increased 82 59 (72) 4 (5) 80 56 (70) 2 (3)
  ALT increased 82 50 (61) 3 (4) 80 44 (55) 2 (3)
  Alkaline phosphatase increased 82 52 (63) 8 (10) 80 56 (70) 9 (11)
  Total bilirubin increased 82 30 (37) 1 (1) 80 22 (28) 3 (4)
  Amylase increased 74 15 (20) 3 (4) 74 7 (10) 1 (1)
  Lipase increased 75 13 (17) 4 (5) 72 8 (11) 3 (4)
Renal/Metabolic
  Glucose increased 82 58 (71) 10 (12) 80 62 (78) 14 (18)
  Albumin decreased 81 33 (41) 1 (1) 79 29 (37) 1 (1)
  Phosphorus decreased 81 29 (36) 6 (7) 77 17 (22) 4 (5)
  Calcium decreased 82 28 (34) 0 (0) 80 15 (19) 0 (0)
  Sodium decreased 82 24 (29) 2 (2) 80 27 (34) 2 (3)
  Creatinine increased 82 22 (27) 4 (5) 80 22 (28) 4 (5)
  Glucose decreased 82 18 (22) 2 (2) 80 12 (15) 3 (4)
  Potassium decreased 82 17 (21) 3 (4) 80 11 (14) 0 (0)
  Magnesium decreased 52 10 (19) 0 (0) 39 4 (10) 0 (0)
  Potassium increased 82 15 (18) 1 (1) 80 9 (11) 1 (1)
Hematology
  Neutrophils decreased 82 58 (71) 13 (16) 80 13 (16) 0 (0)
  Hemoglobin decreased 82 53 (65) 0 (0) 80 44 (55) 1 (1)
  Platelets decreased 82 49 (60) 4 (5) 80 12 (15) 0 (0)
  Lymphocytes decreased 82 46 (56) 6 (7) 80 28 (35) 3 (4)

6.4 Venous Thromboembolic Events

Seven patients (3%) on SUTENT and none on placebo in the double-blind treatment phase of GIST Study A experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT), and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of DVT.

Thirteen (3%) patients receiving SUTENT for treatment-naïve RCC had venous thromboembolic events reported. Seven (2%) of these patients had pulmonary embolism, one was Grade 2 and six were Grade 4, and six (2%) patients had DVT, including three Grade 3. One patient was permanently withdrawn from SUTENT due to pulmonary embolism; dose interruption occurred in two patients with pulmonary embolism and one with DVT. In treatment-naïve RCC patients receiving IFN-α, six (2%) venous thromboembolic events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolism, all Grade 4. One patient (1%) receiving SUTENT for pNET had a venous thromboembolic event reported compared to 5 patients (6%) receiving placebo. The SUTENT patient had Grade 2 thrombosis. Two placebo patients had DVT, one was Grade 3, two placebo patients had pulmonary embolism, one was Grade 3 and one was Grade 4, and one placebo patient had Grade 3 jugular thrombosis.

6.5 Reversible Posterior Leukoencephalopathy Syndrome

There have been reports (<1%), some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness should be controlled with medical management including control of hypertension. Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

6.6 Pancreatic and Hepatic Function

If symptoms of pancreatitis or hepatic failure are present, patients should have SUTENT discontinued. Pancreatitis was observed in 5 (1%) patients receiving SUTENT for treatment-naïve RCC compared to 1 (<1%) patient receiving IFN-α. Pancreatitis was observed in 1 (1%) patient receiving SUTENT for pNET and 1 (1%) patient receiving placebo. Hepatotoxicity was observed in patients receiving SUTENT [see Boxed Warning and Warnings and Precautions (5.1)].

6.7 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of SUTENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: hemorrhage associated with thrombocytopenia1. Suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

Gastrointestinal disorders: esophagitis.

Hepatobiliary disorders: cholecystitis, particularly acalculous cholecystitis.

Immune system disorders: hypersensitivity reactions, including angioedema.

Infections and infestations: serious infection (with or without neutropenia)1. The infections most commonly observed with sunitinib treatment include respiratory, urinary tract, skin infections, sepsis/septic shock.

Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression1; myopathy and/or rhabdomyolysis with or without acute renal failure1. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.

Renal and urinary disorders: renal impairment and/or failure1.

Respiratory disorders: pulmonary embolism1.

Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive dechallenges.

Vascular disorders: arterial thromboembolic events1. The most frequent events included cerebrovascular accident, transient ischemic attack and cerebral infarction.


1
including some fatalities

1 INDICATIONS AND USAGE

1.1 Gastrointestinal Stromal Tumor (GIST)

SUTENT is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.

1.2 Advanced Renal Cell Carcinoma (RCC)

SUTENT is indicated for the treatment of advanced renal cell carcinoma.

1.3 Advanced Pancreatic Neuroendocrine Tumors (pNET)

SUTENT is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.

TORISEL® (temsirolimus)

These highlights do not include all the information needed to use TORISEL safety and effectively. See full prescribing information for TORISEL.

4 CONTRAINDICATIONS

TORISEL is contraindicated in patients with bilirubin >1.5×ULN [see Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity/Infusion Reactions

Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus. These reactions can occur very early in the first infusion, but may also occur with subsequent infusions. Patients should be monitored throughout the infusion and appropriate supportive care should be available. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.

TORISEL should be used with caution in persons with known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the excipients) of TORISEL.

An H1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. TORISEL should be used with caution in patients with known hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other medical reasons.

If a patient develops a hypersensitivity reaction during the TORISEL infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed with the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously administered [see Dosage and Administration (2.2)], and/or an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the TORISEL infusion. The infusion may then be resumed at a slower rate (up to 60 minutes).

A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions.

5.2 Hepatic Impairment

The safety and pharmacokinetics of TORISEL were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5×ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5×ULN when treated with TORISEL. The overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5×ULN due to increased risk of death [see Contraindications (4)].

Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week [see Dosage and Administration (2.4)].

5.3 Hyperglycemia/Glucose Intolerance

The use of TORISEL is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving TORISEL had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with TORISEL. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.

5.4 Infections

The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections [see Adverse Reactions (6.1)].

Pneumocystis jiroveci pneumonia (PJP), including fatalities, has been reported in patients who received temsirolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis of PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.

5.5 Interstitial Lung Disease

Cases of interstitial lung disease, some resulting in death, occurred in patients who received TORISEL. Some patients were asymptomatic, or had minimal symptoms, with infiltrates detected on computed tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms.

It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of TORISEL therapy. Follow such assessments periodically, even in the absence of clinical respiratory symptoms.

It is recommended that patients be followed closely for occurrence of clinical respiratory symptoms. If clinically significant respiratory symptoms develop, consider withholding TORISEL administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Empiric treatment with corticosteroids and/or antibiotics may be considered. Opportunistic infections such as PJP should be considered in the differential diagnosis. For patients who require use of corticosteroids, prophylaxis of PJP may be considered.

5.6 Hyperlipemia

The use of TORISEL is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving TORISEL had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value. This may require initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with TORISEL.

5.7 Bowel Perforation

Cases of fatal bowel perforation occurred in patients who received TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening abdominal pain or blood in their stools.

5.8 Renal Failure

Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. Some of these cases were not responsive to dialysis.

5.9 Wound Healing Complications

Use of TORISEL has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of TORISEL in the perioperative period.

5.10 Intracerebral Hemorrhage

Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL.

5.11 Co-administration with Inducers or Inhibitors of CYP3A Metabolism

Agents Inducing CYP3A Metabolism:

Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, and rifampacin may decrease exposure of the active metabolite, sirolimus. If alternative treatment cannot be administered, a dose adjustment should be considered. St. John's Wort may decrease TORISEL plasma concentrations unpredictably. Patients receiving TORISEL should not take St. John's Wort concomitantly [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

Agents Inhibiting CYP3A Metabolism:

Strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be administered, a dose adjustment should be considered [see Dosage and Administration (2.4) and Drug Interactions (7.2)].

5.12 Concomitant use of TORISEL with sunitinib

The combination of TORISEL and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization) were observed in two out of three patients treated in the first cohort of a phase 1 study at doses of TORISEL 15 mg IV per week and sunitinib 25 mg oral per day (Days 1–28 followed by a 2-week rest).

5.13 Vaccinations

The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with TORISEL. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

5.14 Use in Pregnancy

There are no adequate and well-controlled studies of TORISEL in pregnant women. However, based on its mechanism of action, TORISEL may cause fetal harm when administered to a pregnant woman. Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after TORISEL therapy has stopped [see Use in Specific Populations (8.1)].

Men should be counseled regarding the effects of TORISEL on the fetus and sperm prior to starting treatment [see Nonclinical Toxicology (13.1)]. Men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for 3 months after the last dose of TORISEL.

5.15 Elderly Patients

Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia [see Use in Specific Populations (8.5)].

5.16 Monitoring Laboratory Tests

In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician's discretion.

6 ADVERSE REACTIONS

The following serious adverse reactions have been associated with TORISEL in clinical trials and are discussed in greater detail in other sections of the label [see Warnings and Precautions (5)].

The most common (≥30%) adverse reactions observed with TORISEL are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with TORISEL are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, TORISEL alone, and TORISEL and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received TORISEL 25 mg weekly, and 208 patients received a combination of TORISEL and IFN-α weekly [see Clinical Studies (14)].

Treatment with the combination of TORISEL 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone.

Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received TORISEL 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison:

Table 1 – Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TORISEL or IFN-α in the Randomized Trial
Adverse Reaction TORISEL
25 mg
n = 208
IFN-α

n = 200
All Grades*
n (%)
Grades 3&4*
n (%)
All Grades*
n (%)
Grades 3&4*
n (%)
*
Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0.
Includes edema, facial edema, and peripheral edema
Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis
§
Includes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster
Includes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection
#
Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash
Þ
Includes taste loss and taste perversion
General disorders
  Asthenia 106 (51) 23 (11) 127 (64) 52 (26)
  Edema 73 (35) 7 (3) 21 (11) 1 (1)
  Pain 59 (28) 10 (5) 31 (16) 4 (2)
  Pyrexia 50 (24) 1 (1) 99 (50) 7 (4)
  Weight Loss 39 (19) 3 (1) 50 (25) 4 (2)
  Headache 31 (15) 1 (1) 30 (15) 0 (0)
  Chest Pain 34 (16) 2 (1) 18 (9) 2 (1)
  Chills 17 (8) 1 (1) 59 (30) 3 (2)
Gastrointestinal disorders
  Mucositis 86 (41) 6 (3) 19 (10) 0 (0)
  Anorexia 66 (32) 6 (3) 87 (44) 8 (4)
  Nausea 77 (37) 5 (2) 82 (41) 9 (5)
  Diarrhea 56 (27) 3 (1) 40 (20) 4 (2)
  Abdominal Pain 44 (21) 9 (4) 34 (17) 3 (2)
  Constipation 42 (20) 0 (0) 36 (18) 1 (1)
  Vomiting 40 (19) 4 (2) 57 (29) 5 (3)
Infections
  Infections§ 42 (20) 6 (3) 19 (10) 4 (2)
  Urinary tract infection 31 (15) 3 (1) 24 (12) 3 (2)
  Pharyngitis 25 (12) 0 (0) 3 (2) 0 (0)
  Rhinitis 20 (10) 0 (0) 4 (2) 0 (0)
Musculoskeletal and connective tissue disorders
  Back Pain 41 (20) 6 (3) 28 (14) 7 (4)
  Arthralgia 37 (18) 2 (1) 29 (15) 2 (1)
  Myalgia 16 (8) 1 (1) 29 (15) 2 (1)
Respiratory, thoracic and mediastinal disorders
  Dyspnea 58 (28) 18 (9) 48 (24) 11 (6)
  Cough 53 (26) 2 (1) 29 (15) 0 (0)
  Epistaxis 25 (12) 0 (0) 7 (4) 0 (0)
Skin and subcutaneous tissue disorders
  Rash# 97 (47) 10 (5) 14 (7) 0 (0)
  Pruritus 40 (19) 1 (1) 16 (8) 0 (0)
  Nail Disorder 28 (14) 0 (0) 1 (1) 0 (0)
  Dry Skin 22 (11) 1 (1) 14 (7) 0 (0)
  Acne 21 (10) 0 (0) 2 (1) 0 (0)
Nervous system disorders
  DysgeusiaÞ 41 (20) 0 (0) 17 (9) 0 (0)
  Insomnia 24 (12) 1 (1) 30 (15) 0 (0)
  Depression 9 (4) 0 (0) 27 (14) 4 (2)

The following selected adverse reactions were reported less frequently (<10%).

Gastrointestinal Disorders – Gastrointestinal hemorrhage (1%), rectal hemorrhage (1%).

Eye Disorders – Conjunctivitis (including lacrimation disorder) (8%).

Immune System – Angioneurotic edema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received TORISEL and ACE inhibitors concomitantly.

Infections – Pneumonia (8%), upper respiratory tract infection (7%), wound infection/post-operative wound infection (1%), sepsis (1%).

General Disorders and Administration Site Conditions - Diabetes mellitus (5%).

Respiratory, Thoracic and Mediastinal Disorders – Pleural effusion (4%).

Vascular – Hypertension (7%), venous thromboembolism (including deep vein thrombosis and pulmonary embolus [including fatal outcomes]) (2%), thrombophlebitis (1%), pericardial effusion (1%).

Nervous System Disorders – Convulsion (1%).

Table 2 – Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV TORISEL or IFN-α in the Randomized Trial
Laboratory Abnormality TORISEL
25 mg
n = 208
IFN-α

n = 200
All Grades*
n (%)
Grades 3&4*
n (%)
All Grades*
n (%)
Grades 3&4*
n (%)
*
NCI CTC version 3.0
Grade 1 toxicity may be under-reported for lymphocytes and neutrophils
Any 208 (100) 162 (78) 195 (98) 144 (72)
Hematology
  Hemoglobin Decreased 195 (94) 41 (20) 180 (90) 43 (22)
  Lymphocytes Decreased 110 (53) 33 (16) 106 (53) 48 (24)
  Neutrophils Decreased 39 (19) 10 (5) 58 (29) 19 (10)
  Platelets Decreased 84 (40) 3 (1) 51 (26) 0 (0)
  Leukocytes Decreased 67 (32) 1 (1) 93 (47) 11 (6)
Chemistry
  Alkaline Phosphatase Increased 141 (68) 7 (3) 111 (56) 13 (7)
  AST Increased 79 (38) 5 (2) 103 (52) 14 (7)
  Creatinine Increased 119 (57) 7 (3) 97 (49) 2 (1)
  Glucose Increased 186 (89) 33 (16) 128 (64) 6 (3)
  Phosphorus Decreased 102 (49) 38 (18) 61 (31) 17 (9)
  Total Bilirubin Increased 16 (8) 2 (1) 25 (13) 4 (2)
  Total Cholesterol Increased 181 (87) 5 (2) 95 (48) 2 (1)
  Triglycerides Increased 173 (83) 92 (44) 144 (72) 69 (35)
  Potassium Decreased 43 (21) 11 (5) 15 (8) 0 (0)

6.2 Post-marketing and Other Clinical Experience

The following adverse reactions have been identified during post approval use of TORISEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been observed in patients receiving temsirolimus: rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome (reflex sympathetic dystrophy), pancreatitis, cholecystitis, and cholelithiasis.

There are also post-marketing reports of temsirolimus extravasations resulting in swelling, pain, warmth, and erythema.

1 INDICATIONS AND USAGE

TORISEL is indicated for the treatment of advanced renal cell carcinoma.

XALKORI® (crizotinib)

These highlights do not include all the information needed to use XALKORI safety and effectively. See full prescribing information for XALKORI.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

Drug-induced hepatotoxicity with fatal outcome occurred in 2 (0.1%) of the 1719 patients treated with XALKORI across clinical trials. Concurrent elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3 times the upper limit of normal (ULN) and total bilirubin greater than or equal to 2 times the ULN, with normal alkaline phosphatase, occurred in 10 patients (<1%) treated with XALKORI. Elevations in ALT or AST greater than 5 times the ULN occurred in 187 (11.2%) and 95 (5.7%) patients, respectively. Seventeen patients (1.0%) required permanent discontinuation due to elevated transaminases. Transaminase elevations generally occurred within the first 2 months of treatment.

Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as described in Table 2 [see Dosage and Administration (2.3) and Adverse Reactions (6)].

5.2 Interstitial Lung Disease (Pneumonitis)

Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1719), 50 XALKORI-treated patients (2.9%) had ILD of any grade, 18 patients (1.0%) had Grade 3 or 4 ILD, and 8 patients (0.5%) had fatal ILD. Interstitial lung disease generally occurred within 3 months after the initiation of XALKORI.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related ILD/pneumonitis [see Dosage and Administration (2.3) and Adverse Reactions (6)].

5.3 QT Interval Prolongation

QTc prolongation can occur in patients treated with XALKORI. Across clinical trials, 34 of 1616 patients (2.1%) had QTcF (corrected QT for heart rate by the Fridericia method) greater than or equal to 500 ms and 79 of 1582 patients (5.0%) had an increase from baseline QTcF greater than or equal to 60 ms by automated machine-read evaluation of ECGs.

Avoid use of XALKORI in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc greater than 500 ms on at least 2 separate ECGs until recovery to a QTc less than or equal to 480 ms, then resume XALKORI at a reduced dose as described in Table 2 [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2)].

5.4 Bradycardia

Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia occurred in 219 (12.7%) of 1719 patients treated with XALKORI. Grade 3 syncope occurred in 2.4% of XALKORI-treated patients and in 0.6% of the chemotherapy-treated patients.

Avoid using XALKORI in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring [see Dosage and Administration (2.3) and Adverse Reactions (6)].

5.5 Severe Visual Loss

Across all clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% (4/1719). Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss.

Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for new onset of severe visual loss. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume XALKORI should consider the potential benefits to the patient.

5.6 Embryo-Fetal Toxicity

Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days following the final dose [see Use in Specific Populations (8.1, 8.3)]. Advise male patients with female partners of reproductive potential to use condoms during treatment with XALKORI and for at least 90 days after the final dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data in the Warnings and Precautions section reflect exposure to XALKORI in 1719 patients who received XALKORI 250 mg twice daily enrolled on Studies 1 (including an additional 109 patients who crossed over from the control arm), 2, 3, a single arm trial (n=1063) of ALK-positive NSCLC, and an additional ALK-positive NSCLC expansion cohort of a dose finding study (n=154) [see Warnings and Precautions (5)].

The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg twice daily from 2 open-label, randomized, active-controlled trials (Studies 1 and 2). The safety of XALKORI was also evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study (Study 3).

The most common adverse reactions (≥25%) of XALKORI are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.

Previously Untreated ALK-Positive Metastatic NSCLC - Study 1

The data in Table 3 are derived from 340 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 169 patients in the chemotherapy arm received pemetrexed 500 mg/m2 in combination with cisplatin 75 mg/m2 (n=91) or carboplatin at a dose calculated to produce an area under the concentration-time curve (AUC) of 5 or 6 mg min/mL (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression.

The median duration of study treatment was 10.9 months for patients in the XALKORI arm and 4.1 months for patients in the chemotherapy arm. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 340 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian.

Serious adverse events were reported in 58 patients (34%) treated with XALKORI. The most frequent serious adverse events reported in patients treated with XALKORI were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis.

Dose reductions due to adverse reactions were required in 6.4% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in these patients were nausea (1.8%) and elevated transaminases (1.8%).

Permanent discontinuation of XALKORI treatment for adverse reactions was 8.2%. The most frequent adverse reactions that led to permanent discontinuation in XALKORI-treated patients were elevated transaminases (1.2%), hepatotoxicity (1.2%), and ILD (1.2%).

Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 3. Adverse Reactions Reported at a Higher Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3–4) with XALKORI than Chemotherapy in Study 1*
Adverse Reaction XALKORI
(N=171)
Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)
(N=169)
All Grades
(%)
Grade 3–4
(%)
All Grades
(%)
Grade 3–4
(%)
*
Adverse reactions were graded using NCI CTCAE version 4.0.
Includes cases reported within the clustered terms:
Bradycardia (Bradycardia, Sinus bradycardia).
Vision Disorder (Diplopia, Photophobia, Photopsia, Reduced visual acuity, Blurred vision, Vitreous floaters, Visual impairment).
§
Abdominal pain (Abdominal discomfort, Abdominal pain, Lower abdominal pain, Upper abdominal pain, Abdominal tenderness).
Esophagitis (Esophagitis, Esophageal ulcer).
#
Edema (Edema, Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital edema).
Þ
Upper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
ß
Dizziness (Balance disorder, Dizziness, Postural dizziness, Presyncope).
Cardiac Disorders
  Electrocardiogram QT prolonged 6 2 2 0
  Bradycardia 14 1 1 0
Eye Disorders
  Vision disorder 71 1 10 0
Gastrointestinal Disorders
  Vomiting 46 2 36 3
  Diarrhea 61 2 13 1
  Constipation 43 2 30 0
  Dyspepsia 14 0 2 0
  Dysphagia 10 1 2 1
  Abdominal pain§ 26 0 12 0
  Esophagitis 6 2 1 0
General Disorders and Administration Site Conditions
  Edema# 49 1 12 1
  Pyrexia 19 0 11 1
Infections and Infestations
  Upper respiratory infectionÞ 32 0 12 1
Investigations
  Increased weight 8 1 2 0
Musculoskeletal and Connective Tissue Disorders
  Pain in extremity 16 0 7 0
  Muscle spasm 8 0 2 1
Nervous System Disorders
  Dizzinessß 18 0 10 1
  Dysgeusia 26 0 5 0
  Headache 22 1 15 0

Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%; gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash (11%), renal cyst (5%), ILD (1%; ILD, pneumonitis), syncope (1%), and decreased blood testosterone (1%; hypogonadism).

Table 4. Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients in Study 1
Laboratory Abnormality XALKORI Chemotherapy
Any Grade
(%)
Grade 3–4
(%)
Any Grade
(%)
Grade 3–4
(%)
Additional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any Grade: 99%; Grade 3: 2%; Grade 4: 0%) compared to the chemotherapy arm (Any Grade: 92%; Grade 3: 0%; Grade 4: 1%).
Hematology
  Neutropenia 52 11 59 16
  Lymphopenia 48 7 53 13
Chemistry
  ALT elevation 79 15 33 2
  AST elevation 66 8 28 1
  Hypophosphatemia 32 10 21 6

Previously Treated ALK-Positive Metastatic NSCLC - Study 2

The data in Table 5 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). Patients in the XALKORI arm (n=172) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m2 (n=99) or docetaxel 75 mg/m2 (n=72) by intravenous infusion every 3 weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment.

The median duration of study treatment was 7.1 months for patients who received XALKORI and 2.8 months for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343 received at least 1 dose of study treatment), the median age was 50 years; 14% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian.

Serious adverse reactions were reported in 64 patients (37.2%) treated with XALKORI and 40 patients (23.4%) in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 9 (5%) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, ILD, respiratory failure, and sepsis.

Dose reductions due to adverse reactions were required in 16% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were ALT elevation (7.6%) including some patients with concurrent AST elevation, QTc prolongation (2.9%), and neutropenia (2.3%).

XALKORI was discontinued for adverse reactions in 15% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (1.7%), ALT and AST elevation (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%).

Tables 5 and 6 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 5. Adverse Reactions Reported at a Higher Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3/4) with XALKORI than Chemotherapy in Study 2*
Adverse Reaction XALKORI
(N=172)
Chemotherapy
(Pemetrexed or Docetaxel)
(N=171)
All Grades
(%)
Grade 3–4
(%)
All Grades
(%)
Grade 3–4
(%)
*
Adverse reactions were graded using NCI CTCAE version 4.0.
Includes cases reported within the clustered terms:
Dizziness (Balance disorder, Dizziness, Postural dizziness).
Vision Disorder (Diplopia, Photophobia, Photopsia, Blurred vision, Reduced visual acuity, Visual impairment, Vitreous floaters).
§
Bradycardia (Bradycardia, Sinus bradycardia).
Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
#
Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism).
Þ
Edema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Peripheral edema, Periorbital edema).
Nervous System Disorders
  Dizziness 22 1 8 0
  Dysgeusia 26 0 9 0
  Syncope 3 3 0 0
Eye Disorders
  Vision disorder 60 0 9 0
Cardiac Disorders
  Electrocardiogram QT prolonged 5 3 0 0
  Bradycardia§ 5 0 0 0
Investigations
  Decreased weight 10 1 4 0
Gastrointestinal Disorders
  Vomiting 47 1 18 0
  Nausea 55 1 37 1
  Diarrhea 60 0 19 1
  Constipation 42 2 23 0
  Dyspepsia 8 0 3 0
Infections and Infestations
  Upper respiratory infection 26 0 13 1
Respiratory, Thoracic and Mediastinal Disorders
  Pulmonary embolism# 6 5 2 2
General Disorders and Administration Site Conditions
  EdemaÞ 31 0 16 0

Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with XALKORI included decreased appetite (27%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, paresthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), esophagitis (2%), hepatic failure (1%), and decreased blood testosterone (1%; hypogonadism).

Table 6. Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients in Study 2
Laboratory Abnormality XALKORI Chemotherapy
Any Grade
(%)
Grade 3–4
(%)
Any Grade
(%)
Grade 3–4
(%)
Additional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any Grade: 96%; Grade 3: 1%; Grade 4: 0%) compared to the chemotherapy arm (Any Grade: 72%; Grade 3: 0%; Grade 4: 0%).
Hematology
  Neutropenia 49 12 28 12
  Lymphopenia 51 9 60 25
Chemistry
  ALT elevation 76 17 38 4
  AST elevation 61 9 33 0
  Hypokalemia 18 4 10 1
  Hypophosphatemia 28 5 25 6

ROS1-Positive Metastatic NSCLC - Study 3

The safety profile of XALKORI from Study 3, which was evaluated in 50 patients with ROS1-positive metastatic NSCLC, was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC (n=1669). Vision disorders occurred in 92% of patients in Study 3; 90% were Grade 1 and 2% were Grade 2. The median duration of exposure to XALKORI was 34.4 months.

Description of Selected Adverse Drug Reactions

Vision disorders

Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 1084 (63.1%) of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. There were 13 (0.8%) patients with Grade 3 and 4 (0.2%) patients with Grade 4 visual impairment.

Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies 1 and 2 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4–7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured in the VSAQ-ALK questionnaire.

Neuropathy

Neuropathy, most commonly sensory in nature, occurred in 435 (25%) of 1719 patients. Most events (95%) were Grade 1 or Grade 2 in severity.

Renal cysts

Renal cysts were experienced by 52 (3%) of 1719 patients.

The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests.

Renal impairment

The estimated glomerular filtration rate (eGFR) decreased from a baseline median of 96.42 mL/min/1.73 m2 (n=1681) to a median of 80.23 mL/min/1.73 m2 at 2 weeks (n=1499) in patients with ALK-positive advanced NSCLC who received XALKORI in clinical trials. No clinically relevant changes occurred in median eGFR from 12 to 104 weeks of treatment. Median eGFR slightly increased (83.02 mL/min/1.73 m2) 4 weeks after the last dose of XALKORI. Overall, 76% of patients had a decrease in eGFR to <90 mL/min/1.73 m2, 38% had a decrease to eGFR to <60 mL/min/1.73 m2, and 3.6% had a decrease to eGFR to <30 mL/min/1.73 m2.

1 INDICATIONS AND USAGE

1.1 ALK-Positive Metastatic NSCLC

XALKORI is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test [see Clinical Studies (14.1)].

1.2 ROS1-Positive Metastatic NSCLC

XALKORI is indicated for the treatment of patients with metastatic NSCLC whose tumors are ROS1-positive [see Clinical Studies (14.2)].

ZINECARD® (dexrazoxane)

These highlights do not include all the information needed to use ZINECARD safety and effectively. See full prescribing information for ZINECARD.

4 CONTRAINDICATIONS

Do not use ZINECARD with non-anthracycline chemotherapy regimens.

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

ZINECARD may add to the myelosuppression caused by chemotherapeutic agents. Obtain a complete blood count prior to and during each course of therapy, and administer ZINECARD and chemotherapy only when adequate hematologic parameters are met.

5.2 Concomitant Chemotherapy

Only use ZINECARD in those patients who have received a cumulative doxorubicin dose of 300 mg/m2 and are continuing with doxorubicin therapy. Do not use with chemotherapy initiation as ZINECARD may interfere with the antitumor activity of the chemotherapy regimen. In a trial conducted in patients with metastatic breast cancer who were treated with fluorouracil, doxorubicin, and cyclophosphamide (FAC) with or without ZINECARD starting with their first cycle of FAC therapy, patients who were randomized to receive ZINECARD had a lower response rate (48% vs. 63%) and shorter time to progression than patients who were randomized to receive placebo.

5.3 Cardiac Toxicity

Treatment with ZINECARD does not completely eliminate the risk of anthracycline-induced cardiac toxicity. Monitor cardiac function before and periodically during therapy to assess left ventricular ejection fraction (LVEF). In general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage.

5.4 Secondary Malignancies

Secondary malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been reported in studies of pediatric patients who have received ZINECARD in combination with chemotherapy. ZINECARD is not indicated for use in pediatric patients. Some adult patients who received ZINECARD in combination with anti-cancer agents known to be carcinogenic have also developed secondary malignancies, including AML and MDS.

Razoxane is the racemic mixture, of which dexrazoxane is the S(+)-enantiomer. Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with oral razoxane. In these patients, the total cumulative dose of razoxane ranged from 26 to 480 grams and the duration of treatment was from 42 to 319 weeks. One case of T-cell lymphoma, one case of B-cell lymphoma, and six to eight cases of cutaneous basal cell or squamous cell carcinoma have also been reported in patients treated with razoxane. Long-term administration of razoxane to rodents was associated with the development of malignancies [see Nonclinical Toxicology (13.1)].

5.5 Embryo-Fetal Toxicity

ZINECARD can cause fetal harm when administered to pregnant women. Dexrazoxane administration during the period of organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity in rats and rabbits at doses significantly lower than the clinically recommended dose [see Use in Specific Populations (8.1)]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment [see Use in Specific Populations (8.6)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

The adverse reaction profile described in this section was identified from randomized, placebo-controlled, double-blind studies in patients with metastatic breast cancer who received the combination of the FAC chemotherapy regimen with or without ZINECARD. The dose of doxorubicin was 50 mg/m2 in each of these trials. Treatment was administered every three weeks until disease progression or cardiac toxicity.

Patients in clinical trials who received FAC with ZINECARD experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without ZINECARD [see Warnings and Precautions (5.1)].

Table 1 below lists the incidence of adverse reactions for patients receiving FAC with either ZINECARD or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving ZINECARD or placebo with FAC beginning with their first course of therapy (columns 1 and 3, respectively). Adverse experiences occurring at course 7 and beyond for patients who received placebo with FAC during the first six courses and who then received either ZINECARD or placebo with FAC are also displayed (columns 2 and 4, respectively).

The adverse reactions listed below in Table 1 demonstrate that the frequency of adverse reaction "Pain on Injection" has been greater for ZINECARD arm, as compared to placebo.

Table 1
Adverse Reaction Percentage (%) of Breast Cancer Patients With Adverse Reaction
FAC + ZINECARD FAC + Placebo
Courses 1–6
N = 413
Courses ≥ 7
N = 102
Courses 1–6
N = 458
Courses ≥ 7
N = 99
Alopecia 94 100 97 98
Nausea 77 51 84 60
Vomiting 59 42 72 49
Fatigue/Malaise 61 48 58 55
Anorexia 42 27 47 38
Stomatitis 34 26 41 28
Fever 34 22 29 18
Infection 23 19 18 21
Diarrhea 21 14 24 7
Pain on Injection 12 13 3 0
Sepsis 17 12 14 9
Neurotoxicity 17 10 13 5
Streaking/Erythema 5 4 4 2
Phlebitis 6 3 3 5
Esophagitis 6 3 7 4
Dysphagia 8 0 10 5
Hemorrhage 2 3 2 1
Extravasation 1 3 1 2
Urticaria 2 2 2 0
Recall Skin Reaction 1 1 2 0

1 INDICATIONS AND USAGE

ZINECARD is indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain tumor control. Do not use with the initiation of doxorubicin therapy [see Warnings and Precautions (5.2)].