Clinical Trials Experience

Serious adverse reactions including anaphylaxis and allergic reactions, neuropathy, pulmonary toxicities and hepatotoxicities can occur [See WARNINGS and PRECAUTIONS].

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.

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. 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 WARNINGS and PRECAUTIONS].

Combination Adjuvant Therapy with ELOXATIN and Infusional 5-FU/LV in Patients with 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 frominitiation 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 fromintracerebral bleeding and one fromeosinophilic pneumonia. On the 5-FU/LV arm, one death was due to suicide, 2 fromSteven-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 systemand decreasing order of frequency in the ELOXATIN and infusional 5-FU/LV armfor events with overall incidences ≥ 5% and for NCI grade 3/4 events with incidences ≥ 1%.

Table 3 - Adverse Experiences Reported in Patients with Colon Cancer receiving Adjuvant Treatment ( ≥ 5% of all patients and with ≥ 1% NCI Grade 3/4 events)

The following table provides adverse events reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies] by body systemand decreasing order of frequency in the ELOXATIN and infusional 5-FU/LV armfor events with overall incidences ≥ 5% but with incidences < 1% NCI grade 3/4 events.

Table 4 - Adverse Experiences Reported in Patients with Colon Cancer receiving Adjuvant Treatment ( ≥ 5% of all patients, but with < 1% NCI Grade 3/4 events)

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 armof 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 frominitiation 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 systemand decreasing order of frequency in the ELOXATIN and 5-FU/LV combination armfor events with overall incidences ≥ 5% and for grade 3/4 events with incidences ≥ 1%.

Table 5 – 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)

The following table provides adverse events reported in the previously untreated for advanced colorectal cancer study [see Clinical Studies]by body systemand decreasing order of frequency in the ELOXATIN and 5-FU/LV combination armfor events with overall incidences ≥ 5% but with incidences < 1% NCI Grade 3/4 events.

Table 6 - 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)

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.

Previously Treated Patients with Advanced Colorectal Cancer

Four hundred and fifty patients (about 150 receiving the combination of ELOXATIN and 5-FU/LV) were studied in a randomized trial in patients with refractory and relapsed 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. Thirteen percent of patients in the ELOXATIN and 5-FU/LV combination armand 18% in the 5-FU/LV armof the previously treated study had to discontinue treatment because of adverse effects related to gastrointestinal, or hematologic adverse events, or neuropathies. 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 treated study, regardless of causality, was 5% with the ELOXATIN and 5-FU/LV combination, 8% with ELOXATIN alone, and 7% with 5-FU/LV. Of the 7 deaths that occurred on the ELOXATIN and 5-FU/LV combination armwithin 30 days of stopping treatment, 3 may have been treatment related, associated with gastrointestinal bleeding or dehydration.

The following table provides adverse events reported in the previously treated study [see Clinical Studies ]by body systemand in decreasing order of frequency in the ELOXATIN and 5-FU/LV combination armfor 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 7 – Adverse Experiences Reported In Previously Treated Colorectal Cancer Clinical Trial ( ≥ 5% of all patients and with ≥ 1% NCI Grade 3/4 events)

The following table provides adverse events reported in the previously treated study [see Clinical Studies ] by body systemand in decreasing order of frequency in the ELOXATIN and 5-FU/LV combination armfor events with overall incidences ≥ 5% but with incidences < 1% NCI Grade 3/4 events.

Table 8 - Adverse Experiences Reported In Previously Treated Colorectal Cancer Clinical Trial ( ≥ 5% of all patients but with < 1% NCI Grade 3/4 events)

Adverse events were similar in men and women and in patients < 65 and ≥ 65 years, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia and fatigue. 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): anxiety, myalgia, erythematous rash, increased sweating, conjunctivitis, weight decrease, dry mouth, rectal hemorrhage, depression, ataxia, ascites, hemorrhoids, muscle weakness, nervousness, tachycardia, abnormal micturition frequency, dry skin, pruritus, hemoptysis, purpura, vaginal hemorrhage, melena, somnolence, pneumonia, proctitis, involuntary muscle contractions, intestinal obstruction, gingivitis, tenesmus, hot flashes, enlarged abdomen, urinary incontinence.

Hematologic Changes

The following tables list the hematologic changes occurring in ≥ 5% of patients, based on laboratory values and NCI grade, with the exception of those events occurring in adjuvant patients and anemia in the patients previously untreated for advanced colorectal cancer, respectively, which are based on AE reporting and NCI grade alone.

Table 9 - Adverse Hematologic Experiences in Patients with Colon Cancer Receiving Adjuvant Therapy ( ≥ 5% of patients)

Table 10 – Adverse Hematologic Experiences in Patients Previously Untreated for Advanced Colorectal Cancer ( ≥ 5% of patients)

Table 11 – Adverse Hematologic Experiences in Previously Treated Patients ( ≥ 5% of patients)

Thrombocytopenia and Bleeding

Thrombocytopenia was frequently reported with the combination of ELOXATIN and infusional 5-FU/LV. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the ELOXATIN combination armcompared to the infusional 5-FU/LV arm. These events included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant trial, two patients died fromintracerebral hemorrhages.

The incidence of Grade 3/4 thrombocytopenia was 2% in adjuvant patients with colon cancer. In patients treated for advanced colorectal cancer the incidence of Grade 3/4 thrombocytopenia was 3-5%, and the incidence of these events was greater for the combination of ELOXATIN and 5-FU/LV over the irinotecan plus 5-FU/LV or 5-FU/LV control groups. Grade 3/4 gastrointestinal bleeding was reported in 0.2% of adjuvant patients receiving ELOXATIN and 5-FU/LV. In the previously untreated patients, the incidence of epistaxis was 10% in the ELOXATIN and 5-FU/LV arm, and 2% and 1%, respectively, in the irinotecan plus 5-FU/LV or irinotecan plus ELOXATIN arms.

Neutropenia

Neutropenia was frequently observed with the combination of ELOXATIN and 5-FU/LV, with Grade 3 and 4 events reported in 29% and 12% of adjuvant patients with colon cancer, respectively. In the adjuvant trial, 3 patients died fromsepsis/neutropenic sepsis. Grade 3 and 4 events were reported in 35% and 18% of the patients previously untreated for advanced colorectal cancer, respectively. Grade 3 and 4 events were reported in 27% and 17% of previously treated patients, respectively. In adjuvant patients the incidence of either febrile neutropenia (0.7%) or documented infection with concomitant grade 3/4 neutropenia (1.1%) was 1.8% in the ELOXATIN and 5-FU/LV arm. The incidence of febrile neutropenia in the patients previously untreated for advanced colorectal cancer was 15% (3% of cycles) in the irinotecan plus 5-FU/LV armand 4% (less than 1% of cycles) in the ELOXATIN and 5-FU/LV combination arm. Additionally, in this same population, infection with grade 3 or 4 neutropenia was 12% in the irinotecan plus 5-FU/LV, and 8% in the ELOXATIN and 5-FU/LV combination.

The incidence of febrile neutropenia in the previously treated patients was 1% in the 5-FU/LV armand 6% (less than 1% of cycles) in the ELOXATIN and 5-FU/LV combination arm.

Gastrointestinal

In patients receiving the combination of ELOXATIN plus infusional 5-FU/LV for adjuvant treatment for colon cancer the incidence of Grade 3/4 nausea and vomiting was greater than those receiving infusional 5-FU/LV alone (see table). In patients previously untreated for advanced colorectal cancer receiving the combination of ELOXATIN and 5-FU/LV, the incidence of Grade 3 and 4 vomiting and diarrhea was less compared to irinotecan plus 5-FU/LV controls (see table). In previously treated patients receiving the combination of ELOXATIN and 5-FU/LV, the incidence of Grade 3 and 4 nausea, vomiting, diarrhea, and mucositis/stomatitis increased compared to 5-FU/LV controls (see table).

The incidence of gastrointestinal adverse events in the previously untreated and previously treated patients appears to be similar across cycles. Premedication with antiemetics, including 5-HT₃ blockers, is recommended. Diarrhea and mucositis may be exacerbated by the addition of ELOXATIN to 5-FU/LV, and should be managed with appropriate supportive care. Since cold temperature can exacerbate acute neurological symptoms, ice (mucositis prophylaxis) should be avoided during the infusion of ELOXATIN.

Dermatologic

ELOXATIN did not increase the incidence of alopecia compared to 5-FU/LV alone. No complete alopecia was reported. The incidence of Grade 3/4 skin disorders was 2% in both the ELOXATIN plus infusional 5-FU/LV and the infusional 5-FU/LV alone arms in the adjuvant colon cancer patients. The incidence of hand-foot syndrome in patients previously untreated for advanced colorectal cancer was 2% in the irinotecan plus 5-FU/LV armand 7% in the ELOXATIN and 5-FU/LV combination arm. The incidence of hand-foot syndrome in previously treated patients was 13% in the 5-FU/LV armand 11% in the ELOXATIN and 5-FU/LV combination arm.

Intravenous Site Reactions

Extravasation, in some cases including necrosis, has been reported.

Injection site reaction, including redness, swelling, and pain, has been reported.

Anticoagulation and Hemorrhage

There have been reports while on study and frompost-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received ELOXATIN plus 5-FU/LV while on anticoagulants. Patients receiving ELOXATIN plus 5-FU/LV and requiring oral anticoagulants may require closer monitoring.

Renal

About 5-10% of patients in all groups had some degree of elevation of serumcreatinine. The incidence of Grade 3/4 elevations in serumcreatinine in the ELOXATIN and 5-FU/LV combination armwas 1% in the previously treated patients. Serumcreatinine measurements were not reported in the adjuvant trial.

Hepatic

Hepatotoxicity (defined as elevation of liver enzymes) appears to be related to ELOXATIN combination therapy [see WARNINGS and PRECAUTIONS]. The following tables list the clinical chemistry changes associated with hepatic toxicity occurring in ≥ 5% of patients, based on adverse events reported and NCI CTC grade for adjuvant patients and patients previously untreated for advanced colorectal cancer, laboratory values and NCI CTC grade for previously treated patients.

Table 12 - Adverse Hepatic Experiences in Patients with Stage II or III Colon Cancer Receiving Adjuvant Therapy ( ≥ 5% of patients)

Table 13 – Adverse Hepatic – Clinical Chemistry Experience in Patients Previously Untreated for Advanced Colorectal Cancer ( ≥ 5% of patients)

Table 14 – Adverse Hepatic – Clinical Chemistry Experience in Previously Treated Patients ( ≥ 5% of patients)

Thromboembolism

The incidence of thromboembolic events in adjuvant patients with colon cancer was 6% (1.8% grade 3/4) in the infusional 5-FU/LV armand 6% (1.2% grade 3/4) in the ELOXATIN and infusional 5-FU/LV combined arm, respectively. The incidence was 6 and 9% of the patients previously untreated for advanced colorectal cancer and previously treated patients in the ELOXATIN and 5-FU/LV combination arm, respectively.

Postmarketing Experience

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

Body as a whole: angioedema, anaphylactic shock

Central and peripheral nervous systemdisorders: loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations

Liver and Gastrointestinal systemdisorders: severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridiumdifficile diarrhea), metabolic acidosis; ileus; intestinal obstruction, pancreatitis; veno-occlusive disease of liver also known as sinusoidal obstruction syndrome, and perisinusoidal fibrosis which rarely may progress.

Hearing and vestibular systemdisorders: deafness

Platelet, bleeding, and clotting disorders: immuno-allergic thrombocytopenia prolongation of prothrombin time and of INR in patients receiving anticoagulants

Red Blood Cell disorders: hemolytic uremic syndrome, immuno-allergic hemolytic anemia

Renal disorders: Acute tubulo-interstitial nephropathy leading to acute renal failure.

Respiratory systemdisorders: pulmonary fibrosis, and other interstitial lung diseases

Vision disorders: decrease of visual acuity, visual field disturbance, optic neuritis

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m² ELOXATIN and 5-FU/LV has been observed in patients treated every 2 weeks. Increases of 5-FU plasma concentrations by approximately 20% have been observed with doses of 130 mg/m² ELOXATIN dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds; although, this has not been specifically studied [see CLINICAL PHARMACOLOGY ]

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