The following clinically significant adverse reactions are described elsewhere in 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.
More than 1,100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer were treated in trials with Oxaliplatin. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant treatment 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 with advanced colorectal cancer were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea.
Adjuvant Treatment
The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor in the adjuvant treatment trial [see Clinical Studies (14.1)].
Fatal adverse reactions in patients who received Oxaliplatin in the combination arm included sepsis/neutropenic sepsis (n=3), intracerebral hemorrhage (n=2), and eosinophilic pneumonia (n=1).
Thromboembolic events occurred in 6% (grade 3–4, 1.2%) of patients in the Oxaliplatin arm.
Grade 3 or 4 adverse reactions occurred in 70% of patients in the Oxaliplatin arm. Grade 3–4 gastrointestinal bleeding occurred in 0.2% of patients. Febrile neutropenia occurred in 0.7% and documented infection with concomitant grade 3–4 neutropenia occurred in 1.1%.
Discontinuation due to an adverse reaction occurred in 15% of the patients in the Oxaliplatin arm.
Tables 5, 6, and 7 summarize the adverse reactions reported in patients with colon cancer receiving adjuvant treatment.
Table 5: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)Adverse Reaction* | Oxaliplatin + FU/LV N=1,108 | FU/LV N=1,111 |
---|
All Grades (%) | Grade 3–4 (%) | All Grades (%) | Grade 3–4 (%) |
---|
|
Neurology |
Peripheral Sensory Neuropathy | 92 | 12 | 16 | <1 |
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 |
Constitutional Symptoms/Pain |
Fatigue | 44 | 4 | 38 | 1 |
Abdominal Pain | 18 | 1 | 17 | 2 |
Dermatology/Skin |
Skin Disorder | 32 | 2 | 36 | 2 |
Injection Site Reaction† | 11 | 3 | 10 | 3 |
Fever/Infection |
Fever | 27 | 1 | 12 | 1 |
Infection | 25 | 4 | 25 | 3 |
Allergy/Immunology |
Allergic Reaction | 10 | 3 | 2 | <1 |
Table 6: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients but with less than 1% grade 3–4)Adverse Reaction* | Oxaliplatin + FU/LV N=1,108 | FU/LV N=1,111 |
---|
All Grades (%) | All Grades (%) |
---|
|
Dermatology/Skin |
Alopecia† | 30 | 28 |
Gastrointestinal |
Constipation | 22 | 19 |
Taste Perversion | 12 | 8 |
Dyspepsia | 8 | 5 |
Constitutional Symptoms/Pain/Ocular/Visual |
Epistaxis | 16 | 12 |
Weight Increase | 10 | 10 |
Conjunctivitis | 9 | 15 |
Headache | 7 | 5 |
Dyspnea | 5 | 3 |
Pain | 5 | 5 |
Abnormal Lacrimation | 4 | 12 |
Neurology |
Sensory Disturbance | 8 | 1 |
Allergy/Immunology |
Rhinitis | 6 | 8 |
In females, the following grade 3–4 adverse reactions were more frequent: diarrhea, fatigue, neutropenia, nausea, and vomiting.
In patients greater than or equal to 65 years old, the incidence of grade 3–4 diarrhea and neutropenia was higher than in younger adults.
Clinically relevant adverse reactions were reported in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin arm (listed in decreasing order of frequency) were pain, leukopenia, weight loss, and cough.
Table 7: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Colon Cancer Receiving Adjuvant TreatmentLaboratory-Related Adverse Reaction | Oxaliplatin with FU/LV N=1,108 | FU/LV N=1,111 |
---|
All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) |
---|
Hematology |
Neutropenia | 79 | 41 | 40 | 5 |
Thrombocytopenia | 77 | 2 | 19 | <1 |
Anemia | 76 | 1 | 67 | <1 |
Hepatic |
Increased Transaminases | 57 | 2 | 34 | 1 |
Increased Alkaline Phosphatase | 42 | <1 | 20 | <1 |
Hyperbilirubinemia | 20 | 4 | 20 | 5 |
Previously Untreated Advanced Colorectal Cancer
The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial of patients with previously untreated advanced colorectal cancer [see Clinical Studies (14.2)]. The adverse reaction profile in this trial was similar to that seen in other trials.
Tables 8, 9, and 10 summarize the adverse reactions reported in the previously untreated advanced colorectal cancer trial.
Table 8: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)Adverse Reaction* | Oxaliplatin + FU/LV N=259 | Irinotecan + FU/LV N=256 | Oxaliplatin + Irinotecan N=258 |
---|
All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) |
---|
|
Neurology |
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 |
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 |
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 |
Abnormal Vision | 5 | 0 | 2 | 1 | 6 | 1 |
Neuralgia | 5 | 0 | 0 | 0 | 2 | 1 |
Pulmonary |
Cough | 35 | 1 | 25 | 2 | 17 | 1 |
Dyspnea | 18 | 7 | 14 | 3 | 11 | 2 |
Hiccups | 5 | 1 | 2 | 0 | 3 | 2 |
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 |
Hematology/Infection |
Infection Normal ANC‡ | 10 | 4 | 5 | 1 | 7 | 2 |
Infection Low ANC‡ | 8 | 8 | 12 | 11 | 9 | 8 |
Lymphopenia | 6 | 2 | 4 | 1 | 5 | 2 |
Febrile Neutropenia | 4 | 4 | 15 | 14 | 12 | 11 |
Dermatology/Skin |
Hand/Foot Syndrome | 7 | 1 | 2 | 1 | 1 | 0 |
Injection Site Reaction | 6 | 0 | 1 | 0 | 4 | 1 |
Cardiovascular |
Thrombosis | 6 | 5 | 6 | 6 | 3 | 3 |
Hypotension | 5 | 3 | 6 | 3 | 4 | 3 |
Table 9: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients but with less than 1% grade 3–4)Adverse Reaction* | Oxaliplatin + FU/LV N=259 | Irinotecan + FU/LV N=256 | Oxaliplatin + Irinotecan N=258 |
---|
All Grades (%) | All Grades (%) | All Grades (%) |
---|
|
Dermatology/Skin |
Alopecia† | 38 | 44 | 67 |
Flushing | 7 | 2 | 5 |
Pruritus | 6 | 4 | 2 |
Dry Skin | 6 | 2 | 5 |
Hematology/Infection |
Fever Normal ANC‡ | 16 | 9 | 9 |
Cardiovascular |
Edema | 15 | 13 | 10 |
Gastrointestinal |
Taste Perversion | 14 | 6 | 8 |
Dyspepsia | 12 | 7 | 5 |
Flatulence | 9 | 6 | 5 |
Mouth Dryness | 5 | 2 | 3 |
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 |
Neurology |
Insomnia | 13 | 9 | 11 |
Depression | 9 | 5 | 7 |
Dizziness | 8 | 6 | 10 |
Anxiety | 5 | 2 | 6 |
Allergy/Immunology |
Rash | 11 | 4 | 7 |
Rhinitis Allergic | 10 | 6 | 6 |
Hepatic/Metabolic/Laboratory/Renal |
Hypocalcemia | 7 | 5 | 4 |
Elevated Creatinine | 4 | 4 | 5 |
Clinically relevant adverse reactions that occurred in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: 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.
Table 10: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients in the Previously Untreated Advanced Colorectal Cancer TrialLaboratory-Related Adverse Reaction | Oxaliplatin and FU/LV N=259 | Irinotecan and FU/LV N=256 | Oxaliplatin and Irinotecan N=258 |
---|
All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) |
---|
|
Hematology |
Leukopenia | 85 | 20 | 84 | 23 | 76 | 24 |
Neutropenia | 81 | 53 | 77 | 44 | 71 | 36 |
Thrombocytopenia | 71 | 5 | 26 | 2 | 44 | 4 |
Anemia | 27 | 3 | 28 | 4 | 25 | 3 |
Hepatic |
Increased AST* | 17 | 1 | 2 | 1 | 11 | 1 |
Increased Alkaline Phosphatase | 16 | 0 | 8 | 0 | 14 | 2 |
Hyperbilirubinemia | 6 | 1 | 3 | 1 | 3 | 2 |
Increased ALT† | 6 | 1 | 2 | 0 | 5 | 2 |
Previously Treated Advanced Colorectal Cancer
The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial in patients with refractory and relapsed colorectal cancer [see Clinical Studies (14.3)]. The adverse reaction profile in this trial was similar to that seen in other trials.
Three patients who received Oxaliplatin in the combination arm experienced fatal adverse reactions: gastrointestinal bleeding and dehydration.
Grade 3 and 4 neutropenia were reported in 27% and 17% of patients, respectively, in the Oxaliplatin with fluorouracil/leucovorin combination arm. Grade 3–4 increased serum creatinine occurred in 1% of patients in the Oxaliplatin with combination fluorouracil/leucovorin arm.
Thirteen percent of patients in the Oxaliplatin with fluorouracil/leucovorin combination arm discontinued treatment; the most frequent reasons were gastrointestinal adverse reactions, hematologic adverse reactions and neuropathies.
Tables 11, 12, and 13 summarize the adverse reactions reported in the previously treated advanced colorectal cancer trial.
Table 11: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)Adverse Reaction* | Oxaliplatin + FU/LV N=150 | Oxaliplatin N=153 | FU/LV N=142 |
---|
All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) |
---|
|
Neurology |
Neuropathy | 74 | 7 | 76 | 7 | 17 | 0 |
Acute | 56 | 2 | 65 | 5 | 10 | 0 |
Persistent | 48 | 6 | 43 | 3 | 9 | 0 |
Constitutional Symptoms/Pain |
Fatigue | 68 | 7 | 61 | 9 | 52 | 6 |
Back Pain | 19 | 3 | 11 | 0 | 16 | 4 |
Pain | 15 | 2 | 14 | 3 | 9 | 3 |
Gastrointestinal |
Diarrhea | 67 | 11 | 46 | 4 | 44 | 3 |
Nausea | 65 | 11 | 64 | 4 | 59 | 4 |
Vomiting | 40 | 9 | 37 | 4 | 27 | 4 |
Stomatitis | 37 | 3 | 14 | 0 | 32 | 3 |
Abdominal Pain | 33 | 4 | 31 | 7 | 31 | 5 |
Anorexia | 29 | 3 | 20 | 2 | 20 | 1 |
Gastroesophageal Reflux | 5 | 2 | 1 | 0 | 3 | 0 |
Hematology/Infection |
Fever | 29 | 1 | 25 | 1 | 23 | 1 |
Febrile Neutropenia | 6 | 6 | 0 | 0 | 1 | 1 |
Cardiovascular |
Dyspnea | 20 | 4 | 13 | 7 | 11 | 2 |
Coughing | 19 | 1 | 11 | 0 | 9 | 0 |
Edema | 15 | 1 | 10 | 1 | 13 | 1 |
Thromboembolism | 9 | 8 | 2 | 1 | 4 | 2 |
Chest Pain | 8 | 1 | 5 | 1 | 4 | 1 |
Dermatology/Skin |
Injection Site Reaction | 10 | 3 | 9 | 0 | 5 | 1 |
Hepatic/Metabolic/Laboratory/Renal |
Hypokalemia | 9 | 4 | 3 | 2 | 3 | 1 |
Dehydration | 8 | 3 | 5 | 3 | 6 | 4 |
Table 12: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients but with less than 1% grade 3–4)Adverse Reaction* | Oxaliplatin + FU/LV N=150 | Oxaliplatin N=153 | FU/LV N=142 |
---|
All Grades (%) | All Grades (%) | All Grades (%) |
---|
|
Gastrointestinal |
Constipation | 32 | 31 | 23 |
Dyspepsia | 14 | 7 | 10 |
Taste Perversion | 13 | 5 | 1 |
Mucositis | 7 | 2 | 10 |
Flatulence | 5 | 3 | 6 |
Constitutional Symptoms/Pain/Ocular/Visual |
Headache | 17 | 13 | 8 |
Arthralgia | 10 | 7 | 10 |
Epistaxis | 9 | 2 | 1 |
Abnormal Lacrimation | 7 | 1 | 6 |
Rigors | 7 | 9 | 6 |
Allergy/Immunology |
Rhinitis | 15 | 6 | 4 |
Allergic Reaction | 10 | 3 | 1 |
Rash | 9 | 5 | 5 |
Neurology |
Dizziness | 13 | 7 | 8 |
Insomnia | 9 | 11 | 4 |
Dermatology/Skin |
Hand-Foot Syndrome | 11 | 1 | 13 |
Flushing | 10 | 3 | 2 |
Alopecia† | 7 | 3 | 3 |
Pulmonary |
Upper Respiratory Tract Infection | 10 | 7 | 4 |
Pharyngitis | 9 | 2 | 10 |
Cardiovascular |
Peripheral Edema | 10 | 5 | 11 |
Hepatic/Metabolic/Laboratory/Renal |
Hematuria | 6 | 0 | 4 |
Dysuria | 6 | 1 | 1 |
Clinically relevant adverse reactions in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: 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, and urinary incontinence.
Table 13: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Previously Treated Advanced Colorectal CancerLaboratory-Related Adverse Reaction | Oxaliplatin and FU/LV N=150 | Oxaliplatin N=153 | FU/LV N=142 |
---|
All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) |
---|
|
Hematology |
Anemia | 81 | 2 | 64 | 1 | 68 | 2 |
Leukopenia | 76 | 19 | 13 | 0 | 34 | 1 |
Neutropenia | 73 | 44 | 7 | 0 | 25 | 5 |
Thrombocytopenia | 64 | 4 | 30 | 3 | 20 | 0 |
Hepatic |
Increased ALT* | 31 | 0 | 36 | 1 | 28 | 3 |
Increased AST† | 47 | 0 | 54 | 4 | 39 | 2 |
Increased Bilirubin | 13 | 1 | 13 | 5 | 22 | 6 |
Additional Adverse Reactions
The following adverse reactions were observed across clinical trials.
Intravenous site reactions
Injection site reaction, including redness, swelling, and pain, can occur with Oxaliplatin. In some cases, skin necrosis has occurred with extravasation.
PRES
PRES occurred in less than 0.1% of patients.
Pulmonary fibrosis and interstitial lung disease
Pulmonary fibrosis, which may be fatal, occurred in less than 1% of patients.