ADVERSE REACTIONS
More than 1100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer have been treated in clinical studies with ELOXATIN either as a single agent or in combination with other medications. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy, were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. The most common adverse reactions in previously untreated and treated patients were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea (see PRECAUTIONS).
Combination Adjuvant Therapy with ELOXATIN and infusional 5-FU/LV in Patients with Stage II or III Colon Cancer
One thousand one hundred and eight patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, have been treated in a clinical study with ELOXATIN in combination with infusional 5-FU/LV (See CLINICAL STUDIES). The incidence of grade 3 or 4 adverse events was 70% on the ELOXATIN combination arm, and 31% on the infusional 5-FU/LV arm. The adverse reactions in this trial are shown in the tables below. Discontinuation of treatment due to adverse events occurred in 15% of the patients receiving ELOXATIN and infusional 5-FU/LV. Both 5-FU/LV and ELOXATIN are associated with gastrointestinal or hematologic adverse events. When ELOXATIN is administered in combination with infusional 5-FU/LV, the incidence of these events is increased.
The incidence of death within 28 days of last treatment, regardless of causality, was 0.5% (n=6) in both the ELOXATIN combination and infusional 5-FU/LV arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the ELOXATIN combination and infusional 5-FU/LV arms, respectively. On the ELOXATIN combination arm, 3 deaths were due to sepsis/neutropenic sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia. On the 5-FU/LV arm, one death was due to suicide, 2 from Steven-Johnson Syndrome (1 patient also had sepsis), 1 unknown cause, 1 anoxic cerebral infarction and 1 probable abdominal aorta rupture.
The following table provides adverse events reported in the adjuvant therapy colon cancer clinical trial (see CLINICAL STUDIES) by body system and decreasing order of frequency in the ELOXATIN and infusional 5-FU/LV arm for events with overall incidences ≥ 5% and for NCI grade 3/4 events with incidences ≥ 1%. This table does not include hematologic and blood chemistry abnormalities; these are shown separately below.
Table 13 - Adverse Experiences Reported in Patients with Stage II or III Colon Cancer receiving Adjuvant Treatment (≥5% of all patients and with ≥1% NCI Grade 3/4 events) | ELOXATIN + 5-FU/LV
N=1108 | 5-FU/LV
N=1111 |
|---|
| Adverse Event (WHO/Pref) | All Grades (%) | Grade 3/4 (%) | All Grades (%) | Grade 3/4 (%) |
|---|
| Any Event | 100 | 70 | 99 | 31 |
| Allergy/Immunology |
| Allergic Reaction | 10 | 3 | 2 | <1 |
| Constitutional Symptoms/Pain |
| Fatigue | 44 | 4 | 38 | 1 |
| Abdominal Pain | 18 | 1 | 17 | 2 |
| Dermatology/Skin |
| Skin Disorder | 32 | 2 | 36 | 2 |
| Injection Site ReactionIncludes thrombosis related to the catheter | 11 | 3 | 10 | 3 |
| Gastrointestinal |
| Nausea | 74 | 5 | 61 | 2 |
| Diarrhea | 56 | 11 | 48 | 7 |
| Vomiting | 47 | 6 | 24 | 1 |
| Stomatitis | 42 | 3 | 40 | 2 |
| Anorexia | 13 | 1 | 8 | <1 |
| Fever/Infection |
| Fever | 27 | 1 | 12 | 1 |
| Infection | 25 | 4 | 25 | 3 |
| Neurology |
| Overall Peripheral Sensory Neuropathy | 92 | 12 | 16 | <1 |
The following table provides adverse events reported in the adjuvant therapy colon cancer clinical trial (see CLINICAL STUDIES) by body system and decreasing order of frequency in the ELOXATIN and infusional 5-FU/LV arm for events with overall incidences ≥ 5% but with incidences <1% NCI grade 3/4 events.
Table 14 - Adverse Experiences Reported in Patients with Stage II or III Colon Cancer receiving Adjuvant Treatment (≥ 5% of all patients, but with <1% NCI Grade 3/4 events) | eloxatin + 5-FU/LV
N=1108 | 5-FU/LV
N=1111 |
|---|
Adverse Event
(WHO/Pref) | All Grades (%) | All Grades (%) |
|---|
| Allergy/Immunology |
| Rhinitis | 6 | 8 |
| Constitutional Symptoms/Pain/Ocular/Visual |
| Epistaxis | 16 | 12 |
| Weight Increase | 10 | 10 |
| Conjunctivitis | 9 | 15 |
| Headache | 7 | 5 |
| Dyspnea | 5 | 3 |
| Pain | 5 | 5 |
| Lacrimation Abnormal | 4 | 12 |
| Dermatology/Skin |
| Alopecia | 30 | 28 |
| Gastrointestinal |
| Constipation | 22 | 19 |
| Taste Perversion | 12 | 8 |
| Dyspepsia | 8 | 5 |
| Metabolic |
| Phosphate Alkaline increased | 42 | 20 |
| Neurology |
| Sensory Disturbance | 8 | 1 |
Although specific events can vary, the overall frequency of adverse events was similar in men and women and in patients <65 and ≥65 years. However, the following grade 3/4 events were more common in females: diarrhea, fatigue, granulocytopenia, nausea and vomiting. In patients ≥65 years old, the incidence of grade 3/4 diarrhea and granulocytopenia was higher than in younger patients. Insufficient subgroup sizes prevented analysis of safety by race. The following additional adverse events, were reported in ≥2% and <5% of the patients in the ELOXATIN and infusional 5-FU/LV combination arm (listed in decreasing order of frequency): pain, leukopenia, weight decrease, coughing.
Patients Previously Untreated for Advanced Colorectal Cancer
Two hundred and fifty-nine patients were treated in the ELOXATIN and 5-FU/LV combination arm of the randomized trial in patients previously untreated for advanced colorectal cancer (see CLINICAL STUDIES). The adverse event profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below.
Both 5-FU and ELOXATIN are associated with gastrointestinal and hematologic adverse events. When ELOXATIN is administered in combination with 5-FU, the incidence of these events is increased.
The incidence of death within 30 days of treatment in the previously untreated for advanced colorectal cancer study, regardless of causality, was 3% with the ELOXATIN and 5-FU/LV combination, 5% with irinotecan plus 5-FU/LV, and 3% with ELOXATIN plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the ELOXATIN and 5-FU/LV combination, 5.1% with irinotecan plus 5-FU/LV, and 3.1% with ELOXATIN plus irinotecan.
The following table provides adverse events reported in the previously untreated for advanced colorectal cancer study (see CLINICAL STUDIES) by body system and decreasing order of frequency in the ELOXATIN and 5-FU/LV combination arm for events with overall incidences ≥5% and for grade 3/4 events with incidences ≥1%. This table does not include hematologic and blood chemistry abnormalities; these are shown separately below.
Table 15 – Adverse Experiences Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial (≥5% of all patients and with ≥1% NCI Grade 3/4 events) | ELOXATIN + 5-FU/LV
N=259 | irinotecan + 5-FU/LV
N=256 | ELOXATIN + irinotecan
N=258 |
|---|
| Adverse Event (WHO/Pref) | All Grades (%) | Grade 3/4 (%) | All Grades (%) | Grade 3/4 (%) | All Grades (%) | Grade 3/4 (%) |
|---|
| Any Event | 99 | 82 | 98 | 70 | 99 | 76 |
| Allergy/Immunology |
| Hypersensitivity | 12 | 2 | 5 | 0 | 6 | 1 |
| Cardiovascular |
| Thrombosis | 6 | 5 | 6 | 6 | 3 | 3 |
| Hypotension | 5 | 3 | 6 | 3 | 4 | 3 |
| Constitutional Symptoms/Pain/Ocular/Visual |
| Fatigue | 70 | 7 | 58 | 11 | 66 | 16 |
| Abdominal Pain | 29 | 8 | 31 | 7 | 39 | 10 |
| Myalgia | 14 | 2 | 6 | 0 | 9 | 2 |
| Pain | 7 | 1 | 5 | 1 | 6 | 1 |
| Vision abnormal | 5 | 0 | 2 | 1 | 6 | 1 |
| Neuralgia | 5 | 0 | 0 | 0 | 2 | 1 |
| Dermatology/Skin |
| Skin reaction – hand/foot | 7 | 1 | 2 | 1 | 1 | 0 |
| Injection site reaction | 6 | 0 | 1 | 0 | 4 | 1 |
| Gastrointestinal |
| Nausea | 71 | 6 | 67 | 15 | 83 | 19 |
| Diarrhea | 56 | 12 | 65 | 29 | 76 | 25 |
| Vomiting | 41 | 4 | 43 | 13 | 64 | 23 |
| Stomatitis | 38 | 0 | 25 | 1 | 19 | 1 |
| Anorexia | 35 | 2 | 25 | 4 | 27 | 5 |
| Constipation | 32 | 4 | 27 | 2 | 21 | 2 |
| Diarrhea-colostomy | 13 | 2 | 16 | 7 | 16 | 3 |
| Gastrointestinal NOS | 5 | 2 | 4 | 2 | 3 | 2 |
| Hematology/Infection |
| Infection no ANC | 10 | 4 | 5 | 1 | 7 | 2 |
| Infection –ANC | 8 | 8 | 12 | 11 | 9 | 8 |
| Lymphopenia | 6 | 2 | 4 | 1 | 5 | 2 |
| Febrile neutropenia | 4 | 4 | 15 | 14 | 12 | 11 |
| Hepatic/Metabolic/Laboratory/Renal |
| Hyperglycemia | 14 | 2 | 11 | 3 | 12 | 3 |
| Hypokalemia | 11 | 3 | 7 | 4 | 6 | 2 |
| Dehydration | 9 | 5 | 16 | 11 | 14 | 7 |
| Hypoalbuminemia | 8 | 0 | 5 | 2 | 9 | 1 |
| Hyponatremia | 8 | 2 | 7 | 4 | 4 | 1 |
| Urinary frequency | 5 | 1 | 2 | 1 | 3 | 1 |
| Neurology |
| Overall Neuropathy | 82 | 19 | 18 | 2 | 69 | 7 |
| Paresthesias | 77 | 18 | 16 | 2 | 62 | 6 |
| Pharyngo-laryngeal dysesthesias | 38 | 2 | 1 | 0 | 28 | 1 |
| Neuro-sensory | 12 | 1 | 2 | 0 | 9 | 1 |
| Neuro NOS | 1 | 0 | 1 | 0 | 1 | 0 |
| Pulmonary |
| Cough | 35 | 1 | 25 | 2 | 17 | 1 |
| Dyspnea | 18 | 7 | 14 | 3 | 11 | 2 |
| Hiccups | 5 | 1 | 2 | 0 | 3 | 2 |
The following table provides adverse events reported in the previously untreated for advanced colorectal cancer study (see CLINICAL STUDIES) by body system and decreasing order of frequency in the ELOXATIN and 5-FU/LV combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events.
Table 16 - Adverse Experiences Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial (≥5% of all patients but with < 1% NCI Grade 3/4 events) | ELOXATIN + 5-FU/LV
N=259 | irinotecan + 5-FU/LV
N=256 | ELOXATIN + irinotecan
N=258 |
|---|
| Adverse Event (WHO/Pref) | All Grades (%) | All Grades (%) | All Grades (%) |
|---|
| Allergy/Immunology |
| Rash | 11 | 4 | 7 |
| Rhinitis allergic | 10 | 6 | 6 |
| Cardiovascular |
| Edema | 15 | 13 | 10 |
| Constitutional Symptoms/Pain/Ocular/Visual |
| Headache | 13 | 6 | 9 |
| Weight loss | 11 | 9 | 11 |
| Epistaxis | 10 | 2 | 2 |
| Tearing | 9 | 1 | 2 |
| Rigors | 8 | 2 | 7 |
| Dysphasia | 5 | 3 | 3 |
| Sweating | 5 | 6 | 12 |
| Arthralgia | 5 | 5 | 8 |
| Dermatology/Skin |
| Alopecia | 38 | 44 | 67 |
| Flushing | 7 | 2 | 5 |
| Pruritis | 6 | 4 | 2 |
| Dry Skin | 6 | 2 | 5 |
| Gastrointestinal |
| Taste perversion | 14 | 6 | 8 |
| Dyspepsia | 12 | 7 | 5 |
| Flatulence | 9 | 6 | 5 |
| Mouth Dryness | 5 | 2 | 3 |
| Hematology/Infection |
| Fever no ANC | 16 | 9 | 9 |
| Hepatic/Metabolic/Laboratory/Renal |
| Hypocalcemia | 7 | 5 | 4 |
| Elevated Creatinine | 4 | 4 | 5 |
| Neurology |
| Insomnia | 13 | 9 | 11 |
| Depression | 9 | 5 | 7 |
| Dizziness | 8 | 6 | 10 |
| Anxiety | 5 | 2 | 6 |
Adverse events were similar in men and women and in patients <65 and ≥ 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope. The following additional adverse events, at least possibly related to treatment and potentially important, were reported in ≥ 2% and <5% of the patients in the ELOXATIN and 5-FU/LV combination arm (listed in decreasing order of frequency): metabolic, pneumonitis, catheter infection, vertigo, prothrombin time, pulmonary, rectal bleeding, dysuria, nail changes, chest pain, rectal pain, syncope, hypertension, hypoxia, unknown infection, bone pain, pigmentation changes, and urticaria.
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