ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed in greater detail in other sections of the label: Anaphylaxis and Allergic reactions [see Boxed Warning, Warnings and Precautions (5.1)] Neuropathy [see Warnings and Precautions (5.2)] Severe Neutropenia [see Warnings and Precautions (5.3)] Pulmonary Toxicities [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Cardiovascular Toxicities [see Warnings and Precautions (5.6)] Rhabdomyolysis [see Warnings and Precautions (5.7)] Anaphylaxis and Allergic reactions [see Boxed Warning, Warnings and Precautions (5.1)] Neuropathy [see Warnings and Precautions (5.2)] Severe Neutropenia [see Warnings and Precautions (5.3)] Pulmonary Toxicities [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Cardiovascular Toxicities [see Warnings and Precautions (5.6)] Rhabdomyolysis [see Warnings and Precautions (5.7)] Most common adverse reactions (incidence >= 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 oxaliplatin. 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 5 )]. Combination Adjuvant Therapy with Oxaliplatin and Infusional Fluorouracil/Leucovorin in Patients with Colon CancerOne 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 clinical study with oxaliplatin in combination with infusional fluorouracil/leucovorin [see Clinical Studies 14 )]. The incidence of Grade or adverse reactions was 70% on the oxaliplatin combination arm, and 31% on the infusional fluorouracil/leucovorin arm. The adverse reactions in this trial are shown in the tables below. Discontinuation of treatment due to adverse reactions occurred in 15% of the patients receiving oxaliplatin and infusional fluorouracil/leucovorin. Both fluorouracil/leucovorin and oxaliplatin are associated with gastrointestinal or hematologic adverse reactions. When oxaliplatin is administered in combination with infusional fluorouracil/leucovorin, 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 oxaliplatin combination and infusional fluorouracil/leucovorin arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the oxaliplatin combination and infusional fluorouracil/leucovorin arms, respectively. On the oxaliplatin combination arm, deaths were due to sepsis/neutropenic sepsis, from intracerebral bleeding and one from eosinophilic pneumonia. On the fluorouracil/leucovorin arm, one death was due to suicide, from Stevens-Johnson syndrome (1 patient also had sepsis), unknown cause, anoxic cerebral infarction and probable abdominal aorta rupture. The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies 14 )] by body system and decreasing order of frequency in the oxaliplatin and infusional fluorouracil/leucovorin arm for events with overall incidences >= 5% and for NCI Grade 3/4 events with incidences >= 1%.Table 3: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (>= 5% of all patients and with >= 1% NCI Grade 3/4 events)Oxaliplatin FU/LVN 1108FU/LVN 1111Adverse reaction(WHO/Pref)All Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)Any Event100709931Allergy/ImmunologyAllergic Reaction 1032< 1Constitutional Symptoms/PainFatigue444381Abdominal Pain181172Dermatology/SkinSkin Disorder322362Injection Site Reaction1 113103GastrointestinalNausea745612Diarrhea5611487Vomiting476241Stomatitis423402Anorexia1318< 1Fever/InfectionFever271121Infection254253NeurologyOverall Peripheral Sensory Neuropathy 921216< 1. Includes thrombosis related to the catheterThe following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies (14)] by body system and decreasing order of frequency in the oxaliplatin and infusional fluorouracil/leucovorin arm for events with overall incidences >= 5% but with incidences 1% NCI Grade 3/4 events. Table 4: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (>= 5% of all patients, but with 1% NCI Grade 3/4 events)Oxaliplatin +FU/LVN 1108FU/LVN 1111Adverse reaction(WHO/Pref)All Grades (%)All Grades (%)Allergy/ImmunologyRhinitis 68Constitutional Symptoms/Pain/Ocular/VisualEpistaxis1612Weight Increase1010Conjunctivitis915Headache75Dyspnea53Pain55Lacrimation Abnormal412Dermatology/SkinAlopecia3028GastrointestinalConstipation2219Taste Perversion128Dyspepsia85MetabolicPhosphate Alkaline increased4220NeurologySensory Disturbance81Although specific events can vary, the overall frequency of adverse reactions 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 reactions were reported in >= 2% and 5% of the patients in the oxaliplatin and infusional fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): pain, leukopenia, weight decrease, coughing.The number of patients who developed secondary malignancies was similar; 62 in the oxaliplatin combination arm and 68 in the infusional fluorouracil/leucovorin arm. An exploratory analysis showed that the number of deaths due to secondary malignancies was 1.96% in the oxaliplatin combination arm and 0.98% in infusional fluorouracil/leucovorin arm. In addition, the number of cardiovascular deaths was 1.4% in the oxaliplatin combination arm as compared to 0.7% in the infusional fluorouracil/leucovorin arm. Clinical significance of these findings is unknown.Patients Previously Untreated for Advanced Colorectal Cancer Two hundred and fifty-nine patients were treated in the oxaliplatin and fluorouracil/leucovorin combination arm of the randomized trial in patients previously untreated for advanced colorectal cancer [see Clinical Studies (14)]. The adverse reaction 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 fluorouracil and oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin is administered in combination with fluorouracil, 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 oxaliplatin and fluorouracil/leucovorin combination, 5% with irinotecan plus fluorouracil/leucovorin, and 3% with oxaliplatin plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the oxaliplatin and fluorouracil/leucovorin combination, 5.1% with irinotecan plus fluorouracil/leucovorin, and 3.1% with oxaliplatin plus irinotecan. The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study [see Clinical Studies (14)] by body system and decreasing order of frequency in the oxaliplatin and fluorouracil/leucovorin combination arm for events with overall incidences >= 5% and for Grade 3/4 events with incidences >= 1%. Table 5: Adverse Reactions Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial (>= 5% of all patients and with >= 1% NCI Grade 3/4 events)Oxaliplatin +FU/LVN 259Irinotecan +FU/LVN 256Oxaliplatin +IrinotecanN 258Adverse reaction(WHO/Pref)All Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)Any Event998298709976Allergy/ImmunologyHypersensitivity1225061CardiovascularThrombosis656633Hypotension536343Constitutional Symptoms/Pain/Ocular/VisualFatigue70758116616Abdominal Pain2983173910Myalgia1426092Pain715161Vision abnormal502161Neuralgia500021Dermatology/SkinSkin reaction hand/foot712110Injection site reaction601041GastrointestinalNausea71667158319Diarrhea561265297625Vomiting41443136423Stomatitis380251191Anorexia352254275Constipation324272212Diarrhea-colostomy132167163Gastrointestinal NOS524232Hematology/InfectionInfection normal ANC1045172Infection low ANC88121198Lymphopenia624152Febrile neutropenia4415141211Hepatic/Metabolic/Laboratory/RenalHyperglycemia142113123Hypokalemia1137462Dehydration951611147Hypoalbuminemia805291Hyponatremia827441Urinary frequency512131NeurologyOverall Neuropathy8219182697Paresthesias7718162626Pharyngo-laryngeal dysesthesias38210281Neuro-sensory1212091Neuro NOS101010PulmonaryCough351252171Dyspnea187143112Hiccups512032 Not otherwise specified Absolute neutrophil countThe following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study [see Clinical Studies (14)] by body system and decreasing order of frequency in the oxaliplatin and fluorouracil/leucovorin combination arm for events with overall incidences >= 5% but with incidences 1% NCI Grade 3/4 events.Table 6: Adverse Reactions Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial (>= 5% of all patients but with 1% NCI Grade 3/4 events)Adverse reaction(WHO/Pref)Oxaliplatin +FU/LVN 259Irinotecan +FU/LVN 256Oxaliplatin +IrinotecanN=258All Grades(%)All Grades(%)All Grades(%)Allergy/ImmunologyRash1147Rhinitis allergic1066CardiovascularEdema151310Constitutional Symptoms/Pain/Ocular/VisualHeadache1369Weight Loss119 11Epistaxis1022Tearing912Rigors827Dysphasia533Sweating 5612Arthralgia558Dermatology/SkinAlopecia384467Flushing725Pruritis642Dry Skin625GastrointestinalTaste perversion1468Dyspepsia1275Flatulence965Mouth Dryness523Hematology/InfectionFever normal ANC1699Hepatic/Metabolic/Laboratory/RenalHypocalcemia754Elevated Creatinine445NeurologyInsomnia13911Depression957Dizziness8610Anxiety526 Absolute neutrophil countAdverse reactions 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 reactions, at least possibly related to treatment and potentially important, were reported in >= 2% and 5% of the patients in the oxaliplatin and fluorouracil/leucovorin 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 oxaliplatin and fluorouracil/leucovorin) were studied in randomized trial in patients with refractory and relapsed colorectal cancer [see Clinical Studies (14)]. The adverse reaction 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 oxaliplatin and fluorouracil/leucovorin combination arm and 18% in the fluorouracil/leucovorin arm of the previously treated study had to discontinue treatment because of adverse effects related to gastrointestinal, or hematologic adverse reactions, or neuropathies. Both fluorouracil and oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin is administered in combination with fluorouracil, 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 oxaliplatin and fluorouracil/leucovorin combination, 8% with oxaliplatin alone, and 7% with fluorouracil/leucovorin. Of the deaths that occurred on the oxaliplatin and fluorouracil/leucovorin combination arm within 30 days of stopping treatment, may have been treatment related, associated with gastrointestinal bleeding or dehydration. The following table provides adverse reactions reported in the previously treated study [see Clinical Studies (14)] by body system and in decreasing order of frequency in the oxaliplatin and fluorouracil/leucovorin 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 7: Adverse Reactions Reported in Previously Treated Colorectal Cancer Clinical Trial (>= 5% of all patients and with >= 1% NCI Grade 3/4 events)FU/LV(N 142)Oxaliplatin(N 153)Oxaliplatin +FU/LV(N 150)Adverse reaction(WHO/Pref)All Grades (%)Grade 3/4(%)All Grades(%)Grade 3/4(%)All Grades (%)Grade 3/4(%)Any Event9841100469973CardiovascularDyspnea112137204Coughing90110191Edema131101151Thromboembolism422198Chest Pain415181Constitutional Symptoms/PainFatigue526619687Back Pain164110193Pain93143152Dermatology/SkinInjection Site Reaction5190103GastrointestinalDiarrhea4434646711Nausea5946446511Vomiting274374409Stomatitis323140373Abdominal Pain315317334Anorexia201202293Gastroesophageal Reflux301052Hematology/InfectionFever231251291Febrile Neutropenia110066Hepatic/Metabolic/Laboratory/RenalHypokalemia313294Dehydration645383NeurologyNeuropathy170767747 Acute100655562 Persistent90433486The following table provides adverse reactions reported in the previously treated study [see Clinical Studies (14)] by body system and in decreasing order of frequency in the oxaliplatin and fluorouracil/leucovorin combination arm for events with overall incidences >= 5% but with incidences 1% NCI Grade 3/4 events.Table 8: Adverse Reactions Reported in Previously Treated Colorectal Cancer Clinical Trial (>= 5% of all patients but with 1% NCI Grade 3/4 events)Adverse reaction(WHO/Pref)FU/LV(N 142)Oxaliplatin(N 153)Oxaliplatin +FU/LV(N 150)All Grades(%)All Grades(%)All Grades(%)Allergy/ImmunologyRhinitis4615Allergic Reaction1310Rash559CardiovascularPeripheral Edema11510Constitutional Symptoms/Pain/Ocular/VisualHeadache81317Arthralgia10710Epistaxis129Abnormal Lacrimation617Rigors697Dermatology/SkinHand-Foot Syndrome13111Flushing2310Alopecia337GastrointestinalConstipation233132Dyspepsia10714Taste Perversion1513Mucositis1027Flatulence635Hepatic/Metabolic/Laboratory/RenalHematuria406Dysuria116NeurologyDizziness8713Insomnia4119PulmonaryUpper Resp Tract Infection4710Pharyngitis1029Hiccup025Adverse reactions 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 reactions, at least possibly related to treatment and potentially important, were reported in >= 2% and 5% of the patients in the oxaliplatin and fluorouracil/leucovorin 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 ChangesThe 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 Reactions in Patients with Colon Cancer Receiving Adjuvant Therapy (>= 5% of patients)Oxaliplatin FU/LV(N 1108)FU/LV(N 1111)Hematology ParameterAll Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)Anemia76167< 1Neutropenia7941405Thrombocytopenia77219< 1Table 10: Adverse Hematologic Reactions in Patients Previously Untreated for Advanced Colorectal Cancer (>= 5% of patients)Oxaliplatin +FU/LVN 259Irinotecan +FU/LVN 256Oxaliplatin IrinotecanN 258Hematology ParameterAll Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)Anemia273284253Leukopenia852084237624Neutropenia815377447136Thrombocytopenia715262444Table 11: Adverse Hematologic Reactions in Previously Treated Patients (>= 5% of patients)FU/LV(N 142)Oxaliplatin(N 153)Oxaliplatin +FU/LV(N 150)Hematology ParameterAll Grades(%)Grade3/4(%)All Grades(%)Grade3/4(%)All Grades(%)Grade3/4(%)Anemia682641812Leukopenia3411307619Neutropenia255707344Thrombocytopenia200303644Thrombocytopenia and BleedingThrombocytopenia was frequently reported with the combination of oxaliplatin and infusional fluorouracil/leucovorin. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the oxaliplatin combination arm compared to the infusional fluorouracil/leucovorin arm. These events included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant trial, two patients died from intracerebral 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% to 5%, and the incidence of these events was greater for the combination of oxaliplatin and fluorouracil/leucovorin over the irinotecan plus fluorouracil/leucovorin or fluorouracil/leucovorin control groups. Grade 3/4 gastrointestinal bleeding was reported in 0.2% of adjuvant patients receiving oxaliplatin and fluorouracil/leucovorin. In the previously untreated patients, the incidence of epistaxis was 10% in the oxaliplatin and fluorouracil/leucovorin arm, and 2% and 1%, respectively, in the irinotecan plus fluorouracil/leucovorin or irinotecan plus oxaliplatin arms.NeutropeniaNeutropenia was frequently observed with the combination of oxaliplatin and fluorouracil/leucovorin, with Grade and events reported in 29% and 12% of adjuvant patients with colon cancer, respectively. In the adjuvant trial, patients died from sepsis/neutropenic sepsis. Grade and events were reported in 35% and 18% of the patients previously untreated for advanced colorectal cancer, respectively. Grade and 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 oxaliplatin and fluorouracil/leucovorin arm. The incidence of febrile neutropenia in the patients previously untreated for advanced colorectal cancer was 15% (3% of cycles) in the irinotecan plus fluorouracil/leucovorin arm and 4% (less than 1% of cycles) in the oxaliplatin and fluorouracil/leucovorin combination arm. Additionally, in this same population, infection with Grade or neutropenia was 12% in the irinotecan plus fluorouracil/leucovorin, and 8% in the oxaliplatin and fluorouracil/leucovorin combination. The incidence of febrile neutropenia in the previously treated patients was 1% in the fluorouracil/leucovorin arm and 6% (less than 1% of cycles) in the oxaliplatin and fluorouracil/leucovorin combination arm.Gastrointestinal In patients receiving the combination of oxaliplatin plus infusional fluorouracil/leucovorin for adjuvant treatment for colon cancer the incidence of Grade 3/4 nausea and vomiting was greater than those receiving infusional fluorouracil/leucovorin alone (see table). In patients previously untreated for advanced colorectal cancer receiving the combination of oxaliplatin and fluorouracil/leucovorin, the incidence of Grade and vomiting and diarrhea was less compared to irinotecan plus fluorouracil/leucovorin controls (see table). In previously treated patients receiving the combination of oxaliplatin and fluorouracil/leucovorin, the incidence of Grade and nausea, vomiting, diarrhea, and mucositis/stomatitis increased compared to fluorouracil/leucovorin controls (see table).The incidence of gastrointestinal adverse reactions 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 oxaliplatin to fluorouracil/leucovorin, 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 Oxaliplatin Injection.DermatologicOxaliplatin did not increase the incidence of alopecia compared to fluorouracil/leucovorin alone. No complete alopecia was reported. The incidence of Grade 3/4 skin disorders was 2% in both the oxaliplatin plus infusional fluorouracil/leucovorin and the infusional fluorouracil/leucovorin 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 fluorouracil/leucovorin arm and 7% in the oxaliplatin and fluorouracil/leucovorin combination arm. The incidence of hand-foot syndrome in previously treated patients was 13% in the fluorouracil/leucovorin arm and 11% in the oxaliplatin and fluorouracil/leucovorin combination arm.Intravenous Site ReactionsExtravasation, in some cases including necrosis, has been reported. Injection site reaction, including redness, swelling, and pain, has been reported.Anticoagulation and HemorrhageThere have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received oxaliplatin plus fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin Injection plus fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.RenalAbout 5% to 10% of patients in all groups had some degree of elevation of serum creatinine. The incidence of Grade 3/4 elevations in serum creatinine in the oxaliplatin and fluorouracil/leucovorin combination arm was 1% in the previously treated patients. Serum creatinine measurements were not reported in the adjuvant trial.HepaticHepatotoxicity (defined as elevation of liver enzymes) appears to be related to oxaliplatin combination therapy [see Warnings and Precautions (5.6)]. The following tables list the clinical chemistry changes associated with hepatic toxicity occurring in >= 5% of patients, based on adverse reactions 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 Reactions in Patients with Stage II or III Colon Cancer Receiving Adjuvant Therapy (>= 5% of patients)Oxaliplatin +FU/LV(N 1108)FU/LV(N 1111)Hepatic ParameterAll Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)Increase in transaminases572341ALP increased42< 120< 1Bilirubinaemia204205Table 13: Adverse Hepatic Reactions Clinical Chemistry Abnormalities in Patients Previously Untreated for Advanced Colorectal Cancer (>= 5% of patients)Oxaliplatin +FU/LVN 259Irinotecan +FU/LVN 256Oxaliplatin IrinotecanN 258ClinicalChemistryAll Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)ALT(SGPT-ALAT)612052AST(SGOT-ASAT)17121111Alkaline Phosphatase16080142Total Bilirubin613132Table 14: Adverse Hepatic Reactions Clinical Chemistry Abnormalities in Previously Treated Patients (>= 5% of patients)FU/LV(N 142)Oxaliplatin(N 153)Oxaliplatin +FU/LV(N 150)ClinicalChemistryAll Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)All Grades(%)Grade 3/4(%)ALT (SGPT-ALAT)283361310AST (SGOT-ASAT)392544470Total Bilirubin226135131ThromboembolismThe incidence of thromboembolic events in adjuvant patients with colon cancer was 6% (1.8% Grade 3/4) in the infusional fluorouracil/leucovorin arm and 6% (1.2% grade 3/4) in the oxaliplatin and infusional fluorouracil/leucovorin combined arm, respectively. The incidence was and 9% of the patients previously untreated for advanced colorectal cancer and previously treated patients in the oxaliplatin and fluorouracil/leucovorin combination arm, respectively.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of oxaliplatin. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Body as wholeangioedema, anaphylactic shockCardiovascular disordersQT prolongation leading to ventricular arrhythmias including fatal Torsade de PointesCentral and peripheral nervous system disordersloss of deep tendon reflexes, dysarthria, Lhermittes sign, cranial nerve palsies, fasciculations, convulsion, Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES).Hearing and vestibular system disordersdeafnessInfectionsseptic shock, including fatal outcomesInfusion reactions/hypersensitivitylaryngospasmLiver and gastrointestinal system disorderssevere diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile 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.Musculoskeletal and connective tissue disordersrhabdomyolysis, including fatal outcomes.Platelet, bleeding, and clotting disordersimmuno-allergic thrombocytopenia, prolongation of prothrombin time and of INR in patients receiving anticoagulantsRed blood cell disordershemolytic uremic syndrome, immuno-allergic hemolytic anemiaRenal disordersAcute tubular necrosis, acute interstitial nephritis and acute renal failure.Respiratory system disorderspulmonary fibrosis, and other interstitial lung diseases (sometimes fatal)Vision disordersdecrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation).

BOXED WARNING SECTION.

WARNING: ANAPHYLACTIC REACTIONS. Anaphylactic reactions to oxaliplatin have been reported, and may occur within minutes of oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms of anaphylaxis [see Warnings and Precautions (5.1)]. WARNING: ANAPHYLACTIC REACTIONSSee full prescribing information for complete boxed warning.Anaphylactic reactions to oxaliplatin have been reported, and may occur within minutes of oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).In fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or mg/kg/day for five days every 21 days for total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. dose of mg/kg/day (less than one-seventh the recommended human dose on body surface area basis) did not affect pregnancy rate, but resulted in 97% postimplantation loss (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).The evaluation of ovaries and testes from mice that received oxaliplatin in single intraperitoneal dose of 15 mg/kg (approximately one-half the recommended human dose based on body surface area) showed decreased number of growing follicles in the ovaries month after dosing and decreased spermatagonia, spermatocyte numbers, and sperm mobility in testes week after dosing. Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day (approximately one-sixth of the recommended human dose on body surface area basis) 5 days every 28 days for three cycles. no effect level was not identified.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models [HT29 (colon), GR (mammary), and L1210 (leukemia)].. 12.3 Pharmacokinetics. The reactive oxaliplatin derivatives are present as fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t1/2; 0.43 hours and t1/2; 16.8 hours) and long terminal elimination phase (t1/2; 391 hours). Pharmacokinetic parameters obtained after single 2-hour intravenous infusion of oxaliplatin at dose of 85 mg/m2 expressed as ultrafilterable platinum were Cmax of 0.814 mcg/mL and volume of distribution of 440 L.Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0-48hr) assessed over cycles was moderate to low (23% and 6%, respectively). pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.DistributionAt the end of 2-hour infusion of oxaliplatin, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every two weeks.MetabolismOxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro.Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and number of noncytotoxic, conjugated species.EliminationThe major route of platinum elimination is renal excretion. At five days after single 2-hour infusion of oxaliplatin, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at rate (10 to 17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with GFR.Pharmacokinetics in Special PopulationsRenal ImpairmentA study was conducted in 38 patients with advanced GI cancer and varying degrees of renal impairment. Patients in the normal (creatinine clearance (CrCL) 80 mL/min, N=11), mild (CrCL=50 to 80 mL/min, N=13), and moderate (CrCL=30 to 49 mL/min, N=10) groups were treated with 85 mg/m2 oxaliplatin and those in the severe (CrCL 30 mL/min, N=4) group were treated with 65 mg/m2 oxaliplatin. The mean AUC of unbound platinum was 40%, 95%, and 342% higher in the mild, moderate, and severe groups, respectively, than in the normal group. Mean Cmax of unbound platinum appeared to be similar among the normal, mild and moderate renal function groups, but was 38% higher in the severe group than in the normal group. Caution should be exercised in renally impaired patients [see Use in Specific Populations (8.6 )]. The starting dose of Oxaliplatin Injection should be reduced in patients with severe renal impairment [see Dosage and Administration 2.2 )].Drug Drug InteractionsNo pharmacokinetic interaction between 85 mg/m2 of oxaliplatin and infusional fluorouracil has been observed in patients treated every weeks, but increases of fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 of oxaliplatin administered every weeks. In vitro, platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome P450 isoenzymes. No P450-mediated drug-drug interactions are therefore anticipated in patients. Since platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds, although this has not been specifically studied.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Combination Adjuvant Therapy withOxaliplatin and Infusional Fluorouracil/Leucovorin in Patients with ColonCancer. An international, multicenter, randomized study compared the efficacy and evaluated the safety of oxaliplatin in combination with an infusional schedule of fluorouracil/leucovorin to infusional fluorouracil/leucovorin alone, in patients with Stage II (Dukes B2) or III (Dukes C) colon cancer who had undergone complete resection of the primary tumor. The primary objective of the study was to compare the 3-year disease-free survival (DFS) in patients receiving oxaliplatin and infusional fluorouracil/leucovorin to those receiving fluorouracil/leucovorin alone. Patients were to be treated for total of months (i.e., 12 cycles). total of 2246 patients were randomized; 1123 patients per study arm. Patients in the study had to be between 18 and 75 years of age, have histologically proven Stage II (T3 to T4 N0 M0; Dukes B2) or III (any N1-2 M0; Dukes C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., >= 15 cm from the anal margin) and undergone (within weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease. Patients had to have had no prior chemotherapy, immunotherapy or radiotherapy, and have an ECOG performance status of 0, 1, or (KPS >= 60%), absolute neutrophil count (ANC) 1.5 109/L, platelets >= 100 109/L, serum creatinine <= 1.25 ULN total bilirubin 2 ULN, AST/ALT 2 ULN and carcinoembyrogenic antigen (CEA) 10 ng/mL. Patients with preexisting peripheral neuropathy (NCI Grade >= 1) were ineligible for this trial.The following table shows the dosing regimens for the two arms of the study.Table 15: Dosing Regimens in Adjuvant Therapy StudyTreatment ArmDoseRegimenOxaliplatin FU/LV (FOLFOX4) (N 1123)Day 1: Oxaliplatin: 85 mg/m2 (2-hour infusion) LV: 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion) Day 2: LV: 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)every weeks 12 cyclesFU/LV (N 1123)Day 1: LV: 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)Day 2: LV: 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)every weeks 12 cyclesThe following tables show the baseline characteristics and dosing of the patient population entered into this study. The baseline characteristics were well balanced between arms.Table 16: Patient Characteristics in Adjuvant Therapy Study Oxaliplatin +InfusionalFU/LVN 1123 InfusionalFU/LVN 1123Sex: Male (%)56.152.4Female (%)43.947.6Median age (years)6160< 65 years of age (%)64.466.2>= 65 years of age (%)35.633.8Karnofsky Performance Status (KPS) (%)10029.730.59052.253.9804.43.37013.211.9<= 600.60.4Primary site (%)Colon including cecum54.654.4Sigmoid31.933.8Recto sigmoid12.910.9Other including rectum0.60.9Bowel obstruction (%)Yes17.919.3Perforation (%)Yes6.96.9Stage at Randomization (%)II (T 3,4 = 0, = 0)40.139.9III (T any, = 1,2, = 0)59.659.3IV (T any, = any, = 1)0.40.8Staging T (%)T10.50.7T24.54.8T37675.9T41918.5Staging N (%)N040.239.9N139.439.4N220.420.7Staging M (%)M10.40.8Table 17: Dosing in Adjuvant Therapy Study Oxaliplatin InfusionalFU/LVN 1108 InfusionalFU/LVN 1111Median Relative Dose Intensity (%)FU84.497.7Oxaliplatin80.5N/AMedian Number of Cycles1212Median Number of cycles With Oxaliplatin11N/AThe following table and figures summarize the disease-free survival (DFS) results in the overall randomized population and in patients with Stage II and III disease based on an ITT analysis. The median duration of follow-up was approximately 77 months.Table 18: Summary of DFS analysis ITT analysis Oxaliplatin +Infusional FU/LV InfusionalFU/LVParameterOverallN 11231123Number of events relapse or death (%)304 (27.1)360 (32.1)Disease-free survival [95% CI] 73.3 [70.7, 76]67.4 [64.6, 70.2]Hazard ratio [95% CI] 0.80 [0.68, 0.93]Stratified Logrank testp 0.003Stage III (Dukes C)N672675Number of events relapse or death (%)226 (33.6)271 (40.1)Disease-free survival [95% CI] 66.4 [62.7, 70]58.9 [55.2, 62.7]Hazard ratio [95% CI] 0.78 [0.65, 0.93]Logrank testp 0.005Stage II (Dukes B2)N451448Number of events relapse or death (%)78 (17.3)89 (19.9)Disease-free survival [95% CI] 83.7 [80.2, 87.1]79.9 [76.2, 83.7]Hazard ratio [95% CI] 0.84 [0.62, 1.14]Logrank testp 0.258Data cut off for disease free survival June 2006Disease-free survival at yearsA hazard ratio of less than favors Oxaliplatin Infusional fluorouracil/leucovorinIn the overall and Stage III colon cancer populations DFS was statistically significantly improved in the oxaliplatin combination arm compared to infusional fluorouracil/leucovorin alone. However, statistically significant improvement in DFS was not noted in Stage II patients.Figure shows the DFS Kaplan-Meier curves for the comparison of oxaliplatin and infusional fluorouracil/leucovorin combination and infusional fluorouracil/leucovorin alone for the overall population (ITT analysis). Figure shows the DFS Kaplan-Meier curves for the comparison of oxaliplatin and infusional fluorouracil/leucovorin combination and infusional fluorouracil/leucovorin alone in Stage III patients.Figure 2: DFS Kaplan-Meier Curves by Treatment Arm (cutoff: June 2006) ITT Population Figure 3: DFS Kaplan-Meier Curves by Treatment Arm in Stage III Patients (cutoff: June 2006) ITT PopulationThe following table summarizes the overall survival (OS) results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis.Table 19: Summary of OS Analysis ITT Analysis Parameter Oxaliplatin InfusionalFU/LV InfusionalFU/LVOverallN11231123Number of death events (%)245 (21.8)283 (25.2)Hazard ratio [95% CI]0.84 [0.71, 1]Stage III (Dukes C)N672675Number of death events (%)182 (27.1)220 (32.6)Hazard ratio [95% CI]0.80 [0.65, 0.97]Stage II (Dukes B2)N451448Number of death events (%)63 (14)63 (14.1)Hazard ratio [95% CI]1 [0.70, 1.41]Data cut off for overall survival 16 January 2007A hazard ratio of less than favors oxaliplatin infusional fluorouracil/leucovorin. Figure 2. Figure 3. 14.2 Combination Therapy withOxaliplatin and Fluorouracil/Leucovorin in Patients Previously Untreated forAdvanced Colorectal Cancer. North American, multicenter, open-label, randomized controlled study was sponsored by the National Cancer Institute (NCI) as an intergroup study led by the North Central Cancer Treatment Group (NCCTG). The study had arms at different times during its conduct, four of which were closed due to either changes in the standard of care, toxicity, or simplification. During the study, the control arm was changed to irinotecan plus fluorouracil/leucovorin. The results reported below compared the efficacy and safety of two experimental regimens, oxaliplatin in combination with infusional fluorouracil/leucovorin and combination of oxaliplatin plus irinotecan, to an approved control regimen of irinotecan plus fluorouracil/leucovorin in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. After completion of enrollment, the dose of irinotecan plus fluorouracil/leucovorin was decreased due to toxicity. Patients had to be at least 18 years of age, have known locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy with curative intent, histologically proven colorectal adenocarcinoma, measurable or evaluable disease, with an ECOG performance status 0, 1, or 2. Patients had to have granulocyte count >= 1.5 109/L, platelets >= 100 109/L, hemoglobin >= gm/dL, creatinine <= 1.5 ULN, total bilirubin <= 1.5 mg/dL, AST <= x ULN, and alkaline phosphatase <= x ULN. Patients may have received adjuvant therapy for resected Stage II or III disease without recurrence within 12 months. The patients were stratified for ECOG performance status (0, vs. 2), prior adjuvant chemotherapy (yes vs. no), prior immunotherapy (yes vs. no), and age (< 65 vs. >= 65 years). Although no post study treatment was specified in the protocol, 65% to 72% of patients received additional post study chemotherapy after study treatment discontinuation on all arms. Fifty-eight percent of patients on the oxaliplatin plus fluorouracil/leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus fluorouracil/leucovorin arm received oxaliplatin-containing regimens. Oxaliplatin was not commercially available during the trial.The following table presents the dosing regimens of the three arms of the study.Table 20: Dosing Regimens in Patients Previously Untreated for Advanced Colorectal Cancer Clinical TrialTreatment ArmDoseRegimenOxaliplatin FU/LV (FOLFOX4) (N 267)Day 1: Oxaliplatin: 85 mg/m2 (2-hour infusion) LV 200 mg/m2 (2-hour infusion), followed byFU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)Day 2: LV 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)every weeksIrinotecan FU/LV (IFL) (N 264)Day 1: irinotecan 125 mg/m2 as 90-min infusion LV 20 mg/m2 as 15 minute infusion or intravenous push, followed by FU 500 mg/m2 intravenous bolus weekly 4every weeksOxaliplatin Irinotecan (IROX) (N 264)Day 1: Oxaliplatin: 85 mg/m2 intravenous (2-hour infusion) irinotecan 200 mg/m2 intravenous over 30 minutesevery weeksThe following table presents the demographics of the patient population entered into this study.Table 21: Patient Demographics in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial Oxaliplatin +FU/LVN 267 Irinotecan +FU/LVN 264 Oxaliplatin +IrinotecanN 264Sex: Male (%)58.865.261 Female (%)41.234.839Median age (years)616161< 65 years of age (%)616263>= 65 years of age (%)393837ECOG (%)0 to 194.495.594.725.64.55.3Involved organs (%) Colon only0.70.80.4 Liver only39.344.339 Liver other41.238.640.9 Lung only6.43.85.3 Other (including lymph nodes)11.61112.9 Not reported0.71.51.5Prior radiation (%)31.53Prior surgery (%)74.579.281.8Prior adjuvant (%)15.714.815.2The length of treatment cycle was weeks for the oxaliplatin and fluorouracil/leucovorin regimen; weeks for the irinotecan plus fluorouracil/leucovorin regimen; and weeks for the oxaliplatin plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the oxaliplatin and fluorouracil/leucovorin regimen, (23.6 weeks) for the irinotecan plus fluorouracil/leucovorin regimen, and (21 weeks) for the oxaliplatin plus irinotecan regimen. Patients treated with the oxaliplatin and fluorouracil/leucovorin combination had significantly longer time to tumor progression based on investigator assessment, longer overall survival, and significantly higher confirmed response rate based on investigator assessment compared to patients given irinotecan plus fluorouracil/leucovorin. The following table summarizes the efficacy results.Table 22: Summary of Efficacy Oxaliplatin +FU/LVN 267Irinotecan +FU/LVN 264 Oxaliplatin +Irinotecan = 264Survival (ITT)Number of deaths (%)155 (58.1)192 (72.7)175 (66.3)Median survival (months)19.414.617.6Hazard Ratio and (95% confidence interval)0.65 (0.53 to 0.80) -P-value< 0.0001--TTP (ITT, investigator assessment)Percentage of progressors82.881.889.4Median TTP (months)8.76.96.5Hazard Ratio and (95% confidence interval) 0.74 (0.61 to 0.89) P-value0.0014--Response Rate (investigator assessment) Patients with measurable disease210212215Complete response (%)13 (6.2)5 (2.4)7 (3.3)Partial response (%)82 (39)64 (30.2)67 (31.2)Complete and partial response (%)95 (45.2)69 (32.5)74 (34.4)95% confidence interval(38.5 to 52)(26.2 to 38.9)(28.1 to 40.8)P-value0.0080--Compared to irinotecan plus fluorouracil/leucovorin (IFL) armBased on all patients with measurable disease at baselineThe numbers in the response rate and TTP analysis are based on unblinded investigator assessment.A hazard ratio of less than favors Oxaliplatin Infusional fluorouracil/leucovorinFigure illustrates the Kaplan-Meier survival curves for the comparison of oxaliplatin and fluorouracil/leucovorin combination and oxaliplatin plus irinotecan to irinotecan plus fluorouracil/leucovorin. Log rank test comparing oxaliplatin plus FU/LV to irinotecan plus FU/LV.Figure 4: Kaplan-Meier Overall Survival by Treatment Arm descriptive subgroup analysis demonstrated that the improvement in survival for oxaliplatin plus fluorouracil/leucovorin compared to irinotecan plus fluorouracil/leucovorin appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in oxaliplatin plus fluorouracil/leucovorin versus irinotecan plus fluorouracil/leucovorin was seen in both genders; however it was greater among women than men. Insufficient subgroup sizes prevented analysis by race.. Figure 4. 14.3 Combination Therapy with Oxaliplatin and Fluorouracil/Leucovorin in Previously Treated Patients with Advanced Colorectal Cancer. multicenter, open-label, randomized, three-arm controlled study was conducted in the US and Canada comparing the efficacy and safety of oxaliplatin in combination with an infusional schedule of fluorouracil/leucovorin to the same dose and schedule of fluorouracil/leucovorin alone and to single agent oxaliplatin in patients with advanced colorectal cancer who had relapsed/progressed during or within months of first-line therapy with bolus fluorouracil/leucovorin and irinotecan. The study was intended to be analyzed for response rate after 450 patients were enrolled. Survival will be subsequently assessed in all patients enrolled in the completed study. Accrual to this study is complete, with 821 patients enrolled. Patients in the study had to be at least 18 years of age, have unresectable, measurable, histologically proven colorectal adenocarcinoma, with Karnofsky performance status 50%. Patients had to have SGOT(AST) and SGPT(ALT) <= 2x the institutions upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case <= 5x ULN was permitted. Patients had to have alkaline phosphatase <= 2x the institutions ULN, unless liver metastases were present and documented at baseline by CT or MRI scan, in which cases <= 5x ULN was permitted. Prior radiotherapy was permitted if it had been completed at least weeks before randomization.The dosing regimens of the three arms of the study are presented in the table below.Table 23: Dosing Regimens in Refractory and Relapsed Colorectal Cancer Clinical Trial Treatment Arm Dose RegimenOxaliplatin FU/LV (N 152)Day 1: Oxaliplatin: 85 mg/m2 (2-hour infusion) LV 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)Day 2: LV 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)every weeksFU/LV (N 151)Day 1: LV 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)Day 2: LV 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)every weeksOxaliplatin (N 156)Day 1: Oxaliplatin 85 mg/m2 (2-hour infusion)every weeksPatients entered into the study for evaluation of response must have had at least one unidimensional lesion measuring >= 20mm using conventional CT or MRI scans, or >= 10mm using spiral CT scan. Tumor response and progression were assessed every cycles (6 weeks) using the Response Evaluation Criteria in Solid Tumors (RECIST) until radiological documentation of progression or for 13 months following the first dose of study drug(s), whichever came first. Confirmed responses were based on two tumor assessments separated by at least weeks.The demographics of the patient population entered into this study are shown in the table below.Table 24: Patient Demographics in Refractory and Relapsed Colorectal Cancer Clinical TrialFU/LV(N 151) Oxaliplatin (N 156) Oxaliplatin +FU/LV (N 152)Sex: Male (%)54.360.957.2 Female (%)45.739.142.8Median age (years)606159 Range21 to 8027 to 7922 to 88Race (%) Caucasian87.484.688.8 Black7.97.15.9 Asian1.32.62.6 Other3.35.82.6KPS (%) 70 to 10094.792.395.4 50 to 602.64.52 Not reported2.63.22.6Prior radiotherapy (%)25.219.225Prior pelvic radiation (%)18.513.521.1Number of metastatic sites (%) 127.231.425.7 >= 272.267.974.3Liver involvement (%) Liver only22.525.618.4 Liver other60.35953.3The median number of cycles administered per patient was for the oxaliplatin and fluorouracil/leucovorin combination and each for fluorouracil/leucovorin alone and oxaliplatin alone.Patients treated with the combination of oxaliplatin and fluorouracil/leucovorin had an increased response rate compared to patients given fluorouracil/leucovorin or oxaliplatin alone. The efficacy results are summarized in the tables below.Table 25: Response Rates (ITT Analysis) Best ResponseFU/LV (N 151) Oxaliplatin (N 156) Oxaliplatin +FU/LV (N 152)CR000PR02 (1%)13 (9%)P-value0.0002 for FU/LV vs. Oxaliplatin FU/LV95% CI0 to 2.4%0.2 to 4.6%4.6 to 14.2%Table 26: Summary of Radiographic Time to Progression ArmFU/LV (N 151) Oxaliplatin (N 156) Oxaliplatin +FU/LV (N 152)No. of Progressors7410150No. of patients with no radiological evaluation beyond baseline22 (15%)16 (10%)17 (11%)Median TTP (months)2.71.64.695% CI1.8 to 31.4 to 2.74.2 to 6.1This is not an ITT analysis. Events were limited to radiographic disease progression documented by independent review of radiographs. Clinical progression was not included in this analysis, and 18% of patients were excluded from the analysis based on unavailability of the radiographs for independent review.At the time of the interim analysis 49% of the radiographic progression events had occurred. In this interim analysis an estimated 2-month increase in median time to radiographic progression was observed compared to fluorouracil/leucovorin alone.Of the 13 patients who had tumor response to the combination of oxaliplatin and fluorouracil/leucovorin, were female and were male, and responders included patients 65 years old and >= 65 years old. The small number of non-Caucasian participants made efficacy analyses in these populations uninterpretable.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Oxaliplatin Injection should not be administered to patients with history of known allergy to oxaliplatin or other platinum compounds [see Warnings and Precautions 5.1 )]. Known allergy to oxaliplatin or other platinum compounds. (4, 5.1). Known allergy to oxaliplatin or other platinum compounds. (4, 5.1).

DESCRIPTION SECTION.

11 DESCRIPTION. Oxaliplatin is platinum-based drug with the chemical name of cis-[(1 R,2 R)-1,2-cyclohexanediamine-N,N] [oxalato(2-)- O,O] platinum. Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane(DACH) and with an oxalate ligand as leaving group.C8H14N2O4Pt M.W. 397.3 Oxaliplatin is slightly soluble in water at mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone.Oxaliplatin Injection for intravenous use is supplied in single-dose vial containing 50 mg or 100 mg of oxaliplatin as sterile, preservative-free, aqueous solution at concentration of mg/mL. The pH is 4.0 to 6.0. Lactose monohydrate is present as an inactive ingredient at 450 mg and 900 mg in the 50 mg and 100 mg dosage strengths, respectively. Water for Injection, USP is also present as an inactive ingredient. Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer Oxaliplatin Injection under the supervision of qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. Administer Oxaliplatin Injection in combination with fluorouracil/leucovorin every weeks. (2.1): Day 1: Oxaliplatin Injection 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection both given over 120 minutes at the same time in separate bags using Y-line, followed by fluorouracil 400 mg/m2 intravenous bolus given over to minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as 22-hour continuous infusion. Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m2 intravenous bolus given over to minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as 22-hour continuous infusion. Reduce the dose of Oxaliplatin Injection to 75 mg/m2 (adjuvant setting) or 65 mg/m2 (advanced colorectal cancer) (2.2): if there are persistent Grade neurosensory events that do not resolve.after recovery from Grade 3/4 gastrointestinal toxicities (despite prophylactic treatment) or Grade neutropenia or febrile neutropenia or Grade 3/4 thrombocytopenia. Delay next dose until neutrophils >= 1.5 109/L and platelets >= 75 109/L. For patients with severe renal impairment (creatinine clearance 30 mL/min), the initial recommended dose is 65 mg/m2. (2.2) Discontinue Oxaliplatin Injection if there are persistent Grade neurosensory events. (2.2)Never prepare final dilution with sodium chloride solution or other chloride-containing solutions. (2.3). Administer Oxaliplatin Injection in combination with fluorouracil/leucovorin every weeks. (2.1): Day 1: Oxaliplatin Injection 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection both given over 120 minutes at the same time in separate bags using Y-line, followed by fluorouracil 400 mg/m2 intravenous bolus given over to minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as 22-hour continuous infusion. Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m2 intravenous bolus given over to minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as 22-hour continuous infusion. Day 1: Oxaliplatin Injection 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection both given over 120 minutes at the same time in separate bags using Y-line, followed by fluorouracil 400 mg/m2 intravenous bolus given over to minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as 22-hour continuous infusion. Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m2 intravenous bolus given over to minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as 22-hour continuous infusion.. Reduce the dose of Oxaliplatin Injection to 75 mg/m2 (adjuvant setting) or 65 mg/m2 (advanced colorectal cancer) (2.2): if there are persistent Grade neurosensory events that do not resolve.after recovery from Grade 3/4 gastrointestinal toxicities (despite prophylactic treatment) or Grade neutropenia or febrile neutropenia or Grade 3/4 thrombocytopenia. Delay next dose until neutrophils >= 1.5 109/L and platelets >= 75 109/L. if there are persistent Grade neurosensory events that do not resolve.. after recovery from Grade 3/4 gastrointestinal toxicities (despite prophylactic treatment) or Grade neutropenia or febrile neutropenia or Grade 3/4 thrombocytopenia. Delay next dose until neutrophils >= 1.5 109/L and platelets >= 75 109/L. For patients with severe renal impairment (creatinine clearance 30 mL/min), the initial recommended dose is 65 mg/m2. (2.2) Discontinue Oxaliplatin Injection if there are persistent Grade neurosensory events. (2.2). Never prepare final dilution with sodium chloride solution or other chloride-containing solutions. (2.3). 2.1 Dosage. Administer Oxaliplatin Injection in combination with fluorouracil/leucovorin every weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for total of months (12 cycles):Day 1: Oxaliplatin Injection 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection both given over 120 minutes at the same time in separate bags using Y-line, followed by fluorouracil 400 mg/m2 intravenous bolus given over to minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as 22-hour continuous infusion.Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m2 intravenous bolus given over to minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as 22-hour continuous infusion.Figure 1The administration of Oxaliplatin Injection does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.For information on fluorouracil and leucovorin, see the respective package inserts.. Figure 1. 2.2 Dose Modification Recommendations. Prior to subsequent therapy cycles, evaluate patients for clinical toxicities and recommended laboratory tests [see Warnings and Precautions 5.9 )]. Prolongation of infusion time for Oxaliplatin Injection from hours to hours may mitigate acute toxicities. The infusion times for fluorouracil and leucovorin do not need to be changed.Adjuvant Therapy in Patients with Stage III Colon CancerNeuropathy and other toxicities were graded using the NCI CTC scale version [see Warnings and Precautions 5.2 )]. For patients who experience persistent Grade neurosensory events that do not resolve, consider dose reduction of Oxaliplatin Injection to 75 mg/m2. For patients with persistent Grade neurosensory events, consider discontinuing therapy. The infusional fluorouracil/leucovorin regimen need not be altered. dose reduction of Oxaliplatin Injection to 75 mg/m2 and infusional fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from Grade 3/4 gastrointestinal (despite prophylactic treatment), or Grade neutropenia, or febrile neutropenia, or Grade 3/4 thrombocytopenia. Delay the next dose until: neutrophils >= 1.5 109/L and platelets >= 75 109/L.Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal CancerNeuropathy was graded using study-specific neurotoxicity scale [see Warnings and Precautions 5.2 )]. Other toxicities were graded by the NCI CTC, Version 2.0.For patients who experience persistent Grade neurosensory events that do not resolve, consider dose reduction of Oxaliplatin Injection to 65 mg/m2. For patients with persistent Grade neurosensory events, consider discontinuing therapy. The fluorouracil/leucovorin regimen need not be altered.A dose reduction of Oxaliplatin Injection to 65 mg/m2 and fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from Grade 3/4 gastrointestinal (despite prophylactic treatment), or Grade neutropenia, or febrile neutropenia, or Grade 3/4 thrombocytopenia. Delay the next dose until: neutrophils >= 1.5 109/L and platelets >= 75 109/L.Dose Modifications in Therapy for Patients with Renal Impairment In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin Injection is 85 mg/m2. In patients with severe renal impairment, the recommended Oxaliplatin Injection dose is 65 mg/m2 [see Use in Specific Populations 8.6) and Clinical Pharmacology (12.3)]. 2.3 Preparation of Infusion Solution. Oxaliplatin Injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Do not freeze and protect from light the concentrated solution.A final dilution must never be performed with sodium chloride solution or other chloride-containing solutions.The solution must be further diluted in an infusion solution of 250 to 500 mL of 5% Dextrose Injection.After dilution with 250 to 500 mL of 5% Dextrose Injection, the shelf life is hours at room temperature [20C to 25C (68F to 77F)] or up to 24 hours under refrigeration [2C to 8C (36F to 46F)]. After final dilution, protection from light is not required.Oxaliplatin Injection is incompatible in solution with alkaline medications or media (such as basic solutions of fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection prior to administration of any concomitant medication. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin Injection should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.Discard unused portion.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 50 mg/10 mL (5 mg/mL) and 100 mg/20 mL (5 mg/mL) as sterile, preservative-free, aqueous solution in single-dose vials.. Injection: 50 mg/10 mL and 100 mg/20 mL in single-dose vials. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 oxaliplatin and fluorouracil/leucovorin has been observed in patients treated every weeks. Increases of fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 oxaliplatin dosed every 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 (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. No significant effect of age on the clearance of ultrafilterable platinum has been observed. In the adjuvant therapy colon cancer randomized clinical trial, [see Clinical Studies 14 )] 723 patients treated with oxaliplatin and infusional fluorouracil/leucovorin were 65 years and 400 patients were >= 65 years. descriptive subgroup analysis demonstrated that the improvement in DFS for the oxaliplatin combination arm compared to the infusional fluorouracil/leucovorin alone arm appeared to be maintained across genders. The effect of oxaliplatin in patients >= 65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race. Patients >= 65 years of age receiving the oxaliplatin combination therapy experienced more Grade to granulocytopenia than patients 65 years of age (45% versus 39%).In the previously untreated for advanced colorectal cancer randomized clinical trial [see Clinical Studies 14 )] of oxaliplatin, 160 patients treated with oxaliplatin and fluorouracil/leucovorin were 65 years and 99 patients were >= 65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the >= 65 year old patients as in the overall study population. In the previously treated for advanced colorectal cancer randomized clinical trial [see Clinical Studies 14 )] of oxaliplatin, 95 patients treated with oxaliplatin and fluorouracil/leucovorin were 65 years and 55 patients were >= 65 years. The rates of overall adverse reactions, including Grade and events, were similar across and within arms in the different age groups in all studies. The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope were higher in patients >= 65 years old. No adjustment to starting dose was required in patients >= 65 years old.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Oxaliplatin injection is sterile, preservative-free, aqueous solution for intravenous use supplied as single-dose vials with gray elastomeric stopper and an aluminum flip-off seal with red cap in the following strengths.NDC 0703-3985-01 50 mg/10 mL (5 mg/mL) individually packaged in cartonNDC 0703-3986-01 100 mg/20 mL (5 mg/mL) individually packaged in carton Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F). [See USP Controlled Room Temperature].DO NOT FREEZE.PROTECT FROM LIGHT.Keep in original outer carton.Oxaliplatin Injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1 The use of gloves is recommended. If solution of oxaliplatin contacts the skin, wash the skin immediately and thoroughly with soap and water. If solution of oxaliplatin contacts the mucous membranes, flush thoroughly with water.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Oxaliplatin Injection, used in combination with infusional fluorouracil/leucovorin, is indicated for:adjuvant treatment of Stage III colon cancer in patients who have undergone complete resection of the primary tumor. treatment of advanced colorectal cancer.. adjuvant treatment of Stage III colon cancer in patients who have undergone complete resection of the primary tumor. treatment of advanced colorectal cancer.. Oxaliplatin Injection is platinum-based drug used in combination with infusional fluorouracil/leucovorin, which is indicated for:adjuvant treatment of Stage III colon cancer in patients who have undergone complete resection of the primary tumor. (1)treatment of advanced colorectal cancer. (1). adjuvant treatment of Stage III colon cancer in patients who have undergone complete resection of the primary tumor. (1). treatment of advanced colorectal cancer. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients: To expect side effects of Oxaliplatin Injection, particularly its neurologic effects, both the acute, reversible effects and the persistent neurosensory toxicity. Patients should be informed that the acute neurosensory toxicity may be precipitated or exacerbated by exposure to cold or cold objects.To avoid cold drinks, use of ice, and to cover exposed skin prior to exposure to cold temperature or cold objects. Of the risk of low blood cell counts and to contact their physician immediately should fever develop, particularly if associated with persistent diarrhea, or other evidence of infection. To contact their physician if persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties occur, or signs of allergic reaction appear. To exercise caution when driving and using machines. No studies of the effects of oxaliplatin treatment on the ability to operate cars and machines have been performed; however, an increased risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to minor or moderate influence on the ability to drive and use machines. Of the potential effects of vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), which may affect patients ability to drive and use machines. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions 5.8 ), Use in Specific Populations 8.1 )]. Advise females of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for months after the final dose [see Use in Specific Populations 8.3 )]. Advise males with female partners of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for months after the final dose [see Use in Specific Populations 8.3 ), Nonclinical Toxicology 13.1 )]. Lactation Advise women not to breastfeed during treatment with Oxaliplatin Injection and for months after the final dose [see Use in Specific Populations 8.2 )]. Infertility Advise females and males of reproductive potential that Oxaliplatin Injection may impair fertility [see Use in Specific Populations 8.3 ), Nonclinical Toxicology 13.1 )]. Rev. 1/2020Manufactured In The Netherlands By:Pharmachemie B.V.Haarlem, The NetherlandsManufactured For: Teva Pharmaceuticals USA, Inc.North Wales, PA 19454. To expect side effects of Oxaliplatin Injection, particularly its neurologic effects, both the acute, reversible effects and the persistent neurosensory toxicity. Patients should be informed that the acute neurosensory toxicity may be precipitated or exacerbated by exposure to cold or cold objects.. To avoid cold drinks, use of ice, and to cover exposed skin prior to exposure to cold temperature or cold objects. Of the risk of low blood cell counts and to contact their physician immediately should fever develop, particularly if associated with persistent diarrhea, or other evidence of infection. To contact their physician if persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties occur, or signs of allergic reaction appear. To exercise caution when driving and using machines. No studies of the effects of oxaliplatin treatment on the ability to operate cars and machines have been performed; however, an increased risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to minor or moderate influence on the ability to drive and use machines. Of the potential effects of vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), which may affect patients ability to drive and use machines. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions 5.8 ), Use in Specific Populations 8.1 )]. Advise females of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for months after the final dose [see Use in Specific Populations 8.3 )]. Advise males with female partners of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for months after the final dose [see Use in Specific Populations 8.3 ), Nonclinical Toxicology 13.1 )]. Advise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions 5.8 ), Use in Specific Populations 8.1 )]. Advise females of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for months after the final dose [see Use in Specific Populations 8.3 )]. Advise males with female partners of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for months after the final dose [see Use in Specific Populations 8.3 ), Nonclinical Toxicology 13.1 )]. Lactation Advise women not to breastfeed during treatment with Oxaliplatin Injection and for months after the final dose [see Use in Specific Populations 8.2 )]. Advise women not to breastfeed during treatment with Oxaliplatin Injection and for months after the final dose [see Use in Specific Populations 8.2 )]. Infertility Advise females and males of reproductive potential that Oxaliplatin Injection may impair fertility [see Use in Specific Populations 8.3 ), Nonclinical Toxicology 13.1 )]. Advise females and males of reproductive potential that Oxaliplatin Injection may impair fertility [see Use in Specific Populations 8.3 ), Nonclinical Toxicology 13.1 )].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of oxaliplatin or its metabolites in human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Oxaliplatin Injection and for months after the final dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models [HT29 (colon), GR (mammary), and L1210 (leukemia)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).In fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or mg/kg/day for five days every 21 days for total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. dose of mg/kg/day (less than one-seventh the recommended human dose on body surface area basis) did not affect pregnancy rate, but resulted in 97% postimplantation loss (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).The evaluation of ovaries and testes from mice that received oxaliplatin in single intraperitoneal dose of 15 mg/kg (approximately one-half the recommended human dose based on body surface area) showed decreased number of growing follicles in the ovaries month after dosing and decreased spermatagonia, spermatocyte numbers, and sperm mobility in testes week after dosing. Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day (approximately one-sixth of the recommended human dose on body surface area basis) 5 days every 28 days for three cycles. no effect level was not identified.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no known antidote for oxaliplatin overdose. In addition to thrombocytopenia, the anticipated complications of an oxaliplatin overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhea and neurotoxicity. Several cases of overdoses have been reported with oxaliplatin. Adverse reactions observed were Grade thrombocytopenia (< 25,000/mm3) without any bleeding, anemia, sensory neuropathy such as paresthesia, dysesthesia, laryngospasm and facial muscle spasms, gastrointestinal disorders such as nausea, vomiting, stomatitis, flatulence, abdomen enlarged and Grade intestinal obstruction, Grade dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia and death. Patients suspected of receiving an overdose should be monitored, and supportive treatment should be administered. The maximum dose of oxaliplatin that has been administered in single infusion is 825 mg.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel. image. Oxaliplatin Injection mg/mL, 10 mL Single Use Vial Carton Text. NDC 0703-3985-01 Rx onlyOxaliplatinInjection50 mg/10 mL(5 mg/mL)For Intravenous Use OnlySterile Aqueous Solution Preservative Free Single Use Vial -Discard Unused PortionMust Be Diluted Prior to Use with 5% Dextrose InjectionCaution: Contains Cytotoxic AgentPHARMACIST: PLEASE DISPENSE WITHATTACHED PATIENT INFORMATIONLEAFLETTEVA.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The effectiveness of Oxaliplatin Injection in children has not been established. Oxaliplatin has been tested in Phase and Phase trials in 235 patients ages months to 22 years with solid tumors and no significant activity observed. In Phase 1/2 study, oxaliplatin was administered as 2-hour intravenous infusion on Days 1, and 15 every weeks (1 cycle), for maximum of cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight pediatric patients in the Phase study received oxaliplatin at dose levels starting at 40 mg/m2 with escalation to 110 mg/m2. The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m2 dose. Fifteen patients received oxaliplatin at dose of 90 mg/m2 intravenous in the Phase portion of the study. At this dose, paresthesia (60%, G3/4: 7%), fever (40%, G3/4: 7%) and thrombocytopenia (40%, G3/4: 27%) were the main adverse reactions. No responses were observed. In second Phase study, oxaliplatin was administered to 26 pediatric patients as 2-hour intravenous infusion on day every weeks (1 cycle) at dose levels starting at 100 mg/m2 with escalation to 160 mg/m2, for maximum of cycles. In separate cohort, oxaliplatin 85 mg/m2 was administered on day every weeks, for maximum of doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma. No responses were observed. The DLT was sensory neuropathy at the 160 mg/m2 dose. Based on these studies, oxaliplatin 130 mg/m2 as 2-hour intravenous infusion on day every weeks (1 cycle) was used in subsequent Phase II studies. dose of 85 mg/m2 on day every weeks was also found to be tolerable. In one Phase study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m2 every weeks for maximum of 12 months in absence of progressive disease or unacceptable toxicity. In patients 10 kg the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were leukopenia (67%, G3/4: 12%), anemia (65%, G3/4: 5%), thrombocytopenia (65%, G3/4: 26%), vomiting (65%, G3/4: 7%), neutropenia (58%, G3/4: 16%) and sensory neuropathy (40%, G3/4: 5%). One partial response was observed. In second Phase study, 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, Ewing sarcoma or peripheral PNET, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors of interest received oxaliplatin 130 mg/m2 every weeks for maximum of 12 months or 17 cycles. In patients <= 12 months old the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were sensory neuropathy (52%, G3/4: 12%), thrombocytopenia (37%, G3/4: 17%), anemia (37%, G3/4: 9%), vomiting (26%, G3/4: 4%), ALT increased (24%, G3/4: 6%), AST increased (24%, G3/4: 2%), and nausea (23%, G3/4: 3%). Two partial responses were observed. The pharmacokinetic parameters of ultrafiltrable platinum have been evaluated in 105 pediatric patients during the first cycle. The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h. The inter-patient variability of platinum clearance in pediatric cancer patients was 41%. Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 +- 0.24 mcg/mL, AUC0-48 of 7.52 +- 5.07 mcgoh/mL and AUCinf of 8.83 +- 1.57 mcgoh/mL at 85 mg/m2 of oxaliplatin and Cmax of 1.10 +- 0.43 mcg/mL, AUC0-48 of 9.74 +- 2.52 mcgoh/mL and AUCinf of 17.3 +- 5.34 mcgoh/mL at 130 mg/m2 of oxaliplatin.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The reactive oxaliplatin derivatives are present as fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t1/2; 0.43 hours and t1/2; 16.8 hours) and long terminal elimination phase (t1/2; 391 hours). Pharmacokinetic parameters obtained after single 2-hour intravenous infusion of oxaliplatin at dose of 85 mg/m2 expressed as ultrafilterable platinum were Cmax of 0.814 mcg/mL and volume of distribution of 440 L.Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0-48hr) assessed over cycles was moderate to low (23% and 6%, respectively). pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.DistributionAt the end of 2-hour infusion of oxaliplatin, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every two weeks.MetabolismOxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro.Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and number of noncytotoxic, conjugated species.EliminationThe major route of platinum elimination is renal excretion. At five days after single 2-hour infusion of oxaliplatin, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at rate (10 to 17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with GFR.Pharmacokinetics in Special PopulationsRenal ImpairmentA study was conducted in 38 patients with advanced GI cancer and varying degrees of renal impairment. Patients in the normal (creatinine clearance (CrCL) 80 mL/min, N=11), mild (CrCL=50 to 80 mL/min, N=13), and moderate (CrCL=30 to 49 mL/min, N=10) groups were treated with 85 mg/m2 oxaliplatin and those in the severe (CrCL 30 mL/min, N=4) group were treated with 65 mg/m2 oxaliplatin. The mean AUC of unbound platinum was 40%, 95%, and 342% higher in the mild, moderate, and severe groups, respectively, than in the normal group. Mean Cmax of unbound platinum appeared to be similar among the normal, mild and moderate renal function groups, but was 38% higher in the severe group than in the normal group. Caution should be exercised in renally impaired patients [see Use in Specific Populations (8.6 )]. The starting dose of Oxaliplatin Injection should be reduced in patients with severe renal impairment [see Dosage and Administration 2.2 )].Drug Drug InteractionsNo pharmacokinetic interaction between 85 mg/m2 of oxaliplatin and infusional fluorouracil has been observed in patients treated every weeks, but increases of fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 of oxaliplatin administered every weeks. In vitro, platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome P450 isoenzymes. No P450-mediated drug-drug interactions are therefore anticipated in patients. Since platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds, although this has not been specifically studied.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on direct interaction with DNA, Oxaliplatin Injection can cause fetal harm when administered to pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area (see Data). Advise pregnant woman of the potential hazard to fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal DataPregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days (GD) to (preimplantation), GD to 10, or GD 11 to 16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on GD to 10 and GD 11 to 16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on GD to 10.

REFERENCES SECTION.

15 REFERENCES. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients [see Pharmacokinetics (12.3)]. Caution and close monitoring should be exercised when Oxaliplatin Injection is administered to patients with renal impairment. The starting Oxaliplatin Injection dose does not need to be reduced in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal impairment. However, the starting dose of Oxaliplatin Injection should be reduced in patients with severe renal impairment (creatinine clearance 30 mL/min) [see Dosage and Administration 2.2 )].

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationOXALIPLATIN (ox-Al-ah-platin)Injectionfor intravenous useRead this Patient Information leaflet carefully before you start receiving Oxaliplatin Injection. There may be new information. It will help you learn more about Oxaliplatin Injection. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment. Ask your doctor about any questions you have. What is the most important information should know about Oxaliplatin Injection Oxaliplatin Injection can cause serious allergic reactions, including allergic reactions that can lead to death. Oxaliplatin Injection is platinum base medicine. Serious allergic reactions including death can happen in people who take oxaliplatin and who have had previous allergic reactions to platinum medicines. Serious allergic reactions can happen within few minutes of your Oxaliplatin Injection infusion or any time during your treatment with Oxaliplatin Injection.Get emergency help right away if you:have trouble breathingfeel like your throat is closing upCall your doctor right away if you have any of the following signs or symptoms of an allergic reaction:rashflushed facehivesitchingswelling of your lips or tonguesudden coughdizziness or feel faintsweatingchest painSee What are the possible side effects of Oxaliplatin Injection for information about other serious side effects.What is Oxaliplatin InjectionOxaliplatin Injection is an anti-cancer (chemotherapy) medicine that is used with other anti-cancer medicines called fluorouracil and leucovorin to treat people with:Stage III colon cancer after surgery to remove the tumoradvanced colon or rectal cancer (colorectal cancer)It is not known if Oxaliplatin Injection is effective in children. Who should not receive Oxaliplatin Injection Do not receive Oxaliplatin Injection if you are allergic to any of the ingredients in Oxaliplatin Injection or other medicines that contain platinum. See the end of this leaflet for complete list of the ingredients in Oxaliplatin Injection. Ask your doctor if you are not sure if you take medicine that contains platinum.What should tell my doctor before receiving Oxaliplatin InjectionBefore receiving Oxaliplatin Injection, tell your doctor about all of your medical conditions, including if you:have an infectionhave lung, liver, or kidney problemshave or had heart problems such as an abnormal heart test called an electrocardiogram (ECG or EKG), condition called long QT syndrome, an irregular or slow heartbeat, or family history of heart problems.have had changes in the level of certain blood salt (electrolytes) levels, including potassium, magnesium, and calciumare pregnant or plan to become pregnant. Oxaliplatin Injection may harm your unborn baby. Females who are able to become pregnant should avoid becoming pregnant and should use effective birth control during treatment with Oxaliplatin Injection and for months after the last dose of Oxaliplatin Injection. Males with female sexual partners who are able to become pregnant should use effective birth control during treatment with Oxaliplatin Injection and for months after the last dose of Oxaliplatin Injection.are breastfeeding or plan to breastfeed. It is not known if Oxaliplatin Injection passes into your breast milk. You and your doctor should decide if you will receive Oxaliplatin Injection or breastfeed. You should not do both.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of them and show it to your doctor and pharmacist when you get new medicine.How will receive Oxaliplatin InjectionOxaliplatin Injection is given to you into your vein through an intravenous (IV) tube.Your doctor will prescribe Oxaliplatin Injection in dose that is right for you.Your doctor may change how often you receive Oxaliplatin Injection, your dose, or how long your infusion will take.You and your doctor will decide how many Oxaliplatin Injection treatments you will receive.It is very important that you do exactly what your doctor and nurse tell you to do.Some medicines may be given to you before Oxaliplatin Injection to help prevent nausea and vomiting.Each treatment course is given to you over days. You will receive Oxaliplatin Injection on the first day only.There are usually 14 days between each chemotherapy treatment course.It is important for you to keep all of your medical appointments. Call your doctor if you miss an appointment. There may be special instructions for you.Treatment Day 1:Oxaliplatin Injection and leucovorin will be given through thin plastic tube into vein (intravenous infusion or IV) and given for hours. You will be watched by healthcare provider during this time.Right after the Oxaliplatin Injection and leucovorin are given, doses of fluorouracil will be given. The first dose is given right away into your IV tube. The second dose will be given into your IV tube over the next 22 hours, using pump device.Treatment Day 2:You will not get Oxaliplatin Injection on Day 2. Leucovorin and fluorouracil will be given the same way as on Day 1.The fluorouracil will be given through your IV with pump. If you have any problems with the pump or the tube, call your doctor, your nurse, or the person who is responsible for your pump. Do not let anyone other than healthcare provider touch your infusion pump or tubing.What should avoid while receiving Oxaliplatin InjectionAvoid cold temperatures and cold objects. Cover your skin if you must go outside in cold temperatures.Do not drink cold drinks or use ice cubes in drinks.Do not put ice or ice packs on your body.Oxaliplatin Injection can cause dizziness, vision problems, or vision loss that can affect your ability to drive or use machines. You should not drive or operate machinery if you develop these symptoms while receiving Oxaliplatin Injection.See How can reduce the side effects caused by cold temperatures for more information.Talk with your doctor and nurse about your level of activity during treatment with Oxaliplatin Injection. Follow their instructions.What are the possible side effects of Oxaliplatin InjectionOxaliplatin Injection can cause serious side effects, including:See What is the most important information should know about Oxaliplatin InjectionNerve problems. Oxaliplatin Injection can affect how your nerves work and make you feel. Nerve problems may happen with the first treatment or within two days after your treatment of Oxaliplatin Injection. Nerve problems may last short time (acute) or may become persistent. Symptoms may improve after stopping treatment with Oxaliplatin Injection. Exposure to cold or cold objects may cause or worsen nerve problems. Tell your doctor right away if you get any signs of nerve problems, including:very sensitive to cold temperatures and cold objectstrouble breathing, swallowing, or saying words, jaw tightness, odd feelings in your tongue, or chest pressurepain, tingling, burning (pins and needles, numb feeling) in your hands, feet, or around your mouth or throat, which may cause problems walking or performing activities of daily living.For information on ways to lessen or help with the nerve problems, see the end of this leaflet, How can reduce the side effects caused by cold temperaturesReversible Posterior Leukoencephalopathy (RPLS). RPLS is rare condition that affects the brain. Tell your doctor right away if you have any of the following signs and symptoms of RPLS: headacheconfusion or change in the way you thinkseizuresvision problems, such as blurriness or vision lossLow white blood cell counts (neutropenia). Oxaliplatin Injection can cause low white blood cells counts. Low blood cell counts are common with Oxaliplatin Injection and can lead to serious infection and death. Tell your doctor right away if you have fever greater than 100.9oF (38.3C) or prolonged fever greater than 100.4oF (38C) for more than one hour (febrile neutropenia). Call your doctor right away if you get any of the following signs of infection:chills or shiveringpain on swallowingsore throat cough that brings up mucusburning or pain on urinationredness or swelling at intravenous sitepersistent diarrheaLung problems (interstitial fibrosis). Oxaliplatin Injection can cause lung problems that may lead to death. Tell your doctor right away if you get dry cough and have trouble breathing (shortness of breath) before your next treatment. These may be signs of serious lung disease.Liver problems (hepatotoxicity). Your doctor will do blood tests to check your liver.Heart problems. Oxaliplatin Injection can cause heart problems that have led to death. Your doctor may do blood and heart tests during treatment with Oxaliplatin Injection if you have certain heart problems. If you faint (lose consciousness) or have an irregular heartbeat or chest pain during treatment with Oxaliplatin Injection, tell your doctor right away as this may be sign of serious heart condition.Muscle problems. Oxaliplatin Injection can cause muscle damage (rhabdomyolysis) which can lead to death. Tell your doctor right away if you have muscle pain and swelling, along with weakness, fever, or red brown urine.Harm to an unborn baby. See What should tell my doctor before treatment with Oxaliplatin InjectionThe most common side effects of Oxaliplatin Injection include:Numbness, pain, tingling, and/or burning along the nervesLow white blood cells (neutropenia)Low platelet count (important for clotting and to control bleeding)Low red blood cells (blood cells that carry oxygen to the tissues)NauseaChanges in liver function testsDiarrheaVomitingTirednessMouth soresTell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Oxaliplatin Injection. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How can reduce the side effects caused by cold temperaturesCover yourself with blanket while you are getting your Oxaliplatin Injection infusion.Do not breathe deeply when exposed to cold air.Wear warm clothing in cold weather at all times. Cover your mouth and nose with scarf or pull-down cap (ski cap) to warm the air that goes to your lungs.Wear gloves when taking things from the freezer or refrigerator.Drink fluids warm or at room temperature.Always drink through straw.Do not use ice chips if you have nausea or mouth sores. Ask your doctor about what you can use.Be aware that most metals are cold to touch, especially in the winter. These include your car door and mailbox. Wear gloves to touch cold objects.Do not run the air-conditioning at high levels in the house or in the car in hot weather.If your body gets cold, warm-up the affected part. If your hands get cold, wash them with warm water.Always let your healthcare provider or doctor know before your next treatment how well you did since your last visit.Your doctor may have other useful tips for helping you with these side effects.General information about the safe and effective use of Oxaliplatin InjectionMedicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet.This Patient Information leaflet summarizes the most important information about Oxaliplatin Injection. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Oxaliplatin Injection that is written for health professionals.What are the ingredients in Oxaliplatin InjectionActive ingredient: oxaliplatinConcentrate for solution for infusion inactive ingredients: lactose monohydrate and water for injection.This Patient Information has been approved by the U.S. Food and Drug Administration.Rev. 1/2020Manufactured In The Netherlands By:Pharmachemie B.V.Haarlem, The NetherlandsManufactured For: Teva Pharmaceuticals USA, Inc.North Wales, PA 19454. have trouble breathing. feel like your throat is closing up. rash. flushed face. hives. itching. swelling of your lips or tongue. sudden cough. dizziness or feel faint. sweating. chest pain. Stage III colon cancer after surgery to remove the tumor. advanced colon or rectal cancer (colorectal cancer). have an infection. have lung, liver, or kidney problems. have or had heart problems such as an abnormal heart test called an electrocardiogram (ECG or EKG), condition called long QT syndrome, an irregular or slow heartbeat, or family history of heart problems.. have had changes in the level of certain blood salt (electrolytes) levels, including potassium, magnesium, and calcium. are pregnant or plan to become pregnant. Oxaliplatin Injection may harm your unborn baby. Females who are able to become pregnant should avoid becoming pregnant and should use effective birth control during treatment with Oxaliplatin Injection and for months after the last dose of Oxaliplatin Injection. Males with female sexual partners who are able to become pregnant should use effective birth control during treatment with Oxaliplatin Injection and for months after the last dose of Oxaliplatin Injection.. are breastfeeding or plan to breastfeed. It is not known if Oxaliplatin Injection passes into your breast milk. You and your doctor should decide if you will receive Oxaliplatin Injection or breastfeed. You should not do both.. Oxaliplatin Injection is given to you into your vein through an intravenous (IV) tube.. Your doctor will prescribe Oxaliplatin Injection in dose that is right for you.. Your doctor may change how often you receive Oxaliplatin Injection, your dose, or how long your infusion will take.. You and your doctor will decide how many Oxaliplatin Injection treatments you will receive.. It is very important that you do exactly what your doctor and nurse tell you to do.. Some medicines may be given to you before Oxaliplatin Injection to help prevent nausea and vomiting.. Each treatment course is given to you over days. You will receive Oxaliplatin Injection on the first day only.. There are usually 14 days between each chemotherapy treatment course.. It is important for you to keep all of your medical appointments. Call your doctor if you miss an appointment. There may be special instructions for you.. Oxaliplatin Injection and leucovorin will be given through thin plastic tube into vein (intravenous infusion or IV) and given for hours. You will be watched by healthcare provider during this time.. Right after the Oxaliplatin Injection and leucovorin are given, doses of fluorouracil will be given. The first dose is given right away into your IV tube. The second dose will be given into your IV tube over the next 22 hours, using pump device.. Avoid cold temperatures and cold objects. Cover your skin if you must go outside in cold temperatures.. Do not drink cold drinks or use ice cubes in drinks.. Do not put ice or ice packs on your body.. Oxaliplatin Injection can cause dizziness, vision problems, or vision loss that can affect your ability to drive or use machines. You should not drive or operate machinery if you develop these symptoms while receiving Oxaliplatin Injection.. See What is the most important information should know about Oxaliplatin Injection. Nerve problems. Oxaliplatin Injection can affect how your nerves work and make you feel. Nerve problems may happen with the first treatment or within two days after your treatment of Oxaliplatin Injection. Nerve problems may last short time (acute) or may become persistent. Symptoms may improve after stopping treatment with Oxaliplatin Injection. Exposure to cold or cold objects may cause or worsen nerve problems. Tell your doctor right away if you get any signs of nerve problems, including:very sensitive to cold temperatures and cold objectstrouble breathing, swallowing, or saying words, jaw tightness, odd feelings in your tongue, or chest pressurepain, tingling, burning (pins and needles, numb feeling) in your hands, feet, or around your mouth or throat, which may cause problems walking or performing activities of daily living.. very sensitive to cold temperatures and cold objects. trouble breathing, swallowing, or saying words, jaw tightness, odd feelings in your tongue, or chest pressure. pain, tingling, burning (pins and needles, numb feeling) in your hands, feet, or around your mouth or throat, which may cause problems walking or performing activities of daily living.. Reversible Posterior Leukoencephalopathy (RPLS). RPLS is rare condition that affects the brain. Tell your doctor right away if you have any of the following signs and symptoms of RPLS: headacheconfusion or change in the way you thinkseizuresvision problems, such as blurriness or vision loss. headache. confusion or change in the way you think. seizures. vision problems, such as blurriness or vision loss. Low white blood cell counts (neutropenia). Oxaliplatin Injection can cause low white blood cells counts. Low blood cell counts are common with Oxaliplatin Injection and can lead to serious infection and death. Tell your doctor right away if you have fever greater than 100.9oF (38.3C) or prolonged fever greater than 100.4oF (38C) for more than one hour (febrile neutropenia). Call your doctor right away if you get any of the following signs of infection:. chills or shivering. pain on swallowing. sore throat cough that brings up mucus. burning or pain on urination. redness or swelling at intravenous site. persistent diarrhea. Lung problems (interstitial fibrosis). Oxaliplatin Injection can cause lung problems that may lead to death. Tell your doctor right away if you get dry cough and have trouble breathing (shortness of breath) before your next treatment. These may be signs of serious lung disease.. Liver problems (hepatotoxicity). Your doctor will do blood tests to check your liver.. Heart problems. Oxaliplatin Injection can cause heart problems that have led to death. Your doctor may do blood and heart tests during treatment with Oxaliplatin Injection if you have certain heart problems. If you faint (lose consciousness) or have an irregular heartbeat or chest pain during treatment with Oxaliplatin Injection, tell your doctor right away as this may be sign of serious heart condition.. Muscle problems. Oxaliplatin Injection can cause muscle damage (rhabdomyolysis) which can lead to death. Tell your doctor right away if you have muscle pain and swelling, along with weakness, fever, or red brown urine.. Harm to an unborn baby. See What should tell my doctor before treatment with Oxaliplatin Injection. Numbness, pain, tingling, and/or burning along the nerves. Low white blood cells (neutropenia). Low platelet count (important for clotting and to control bleeding). Low red blood cells (blood cells that carry oxygen to the tissues). Nausea. Changes in liver function tests. Diarrhea. Vomiting. Tiredness. Mouth sores. Cover yourself with blanket while you are getting your Oxaliplatin Injection infusion.. Do not breathe deeply when exposed to cold air.. Wear warm clothing in cold weather at all times. Cover your mouth and nose with scarf or pull-down cap (ski cap) to warm the air that goes to your lungs.. Wear gloves when taking things from the freezer or refrigerator.. Drink fluids warm or at room temperature.. Always drink through straw.. Do not use ice chips if you have nausea or mouth sores. Ask your doctor about what you can use.. Be aware that most metals are cold to touch, especially in the winter. These include your car door and mailbox. Wear gloves to touch cold objects.. Do not run the air-conditioning at high levels in the house or in the car in hot weather.. If your body gets cold, warm-up the affected part. If your hands get cold, wash them with warm water.. Always let your healthcare provider or doctor know before your next treatment how well you did since your last visit.

SPL UNCLASSIFIED SECTION.

2.1 Dosage. Administer Oxaliplatin Injection in combination with fluorouracil/leucovorin every weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for total of months (12 cycles):Day 1: Oxaliplatin Injection 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection both given over 120 minutes at the same time in separate bags using Y-line, followed by fluorouracil 400 mg/m2 intravenous bolus given over to minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as 22-hour continuous infusion.Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m2 intravenous bolus given over to minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as 22-hour continuous infusion.Figure 1The administration of Oxaliplatin Injection does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.For information on fluorouracil and leucovorin, see the respective package inserts.. Figure 1.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2) 8.1 Pregnancy. Risk SummaryBased on direct interaction with DNA, Oxaliplatin Injection can cause fetal harm when administered to pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area (see Data). Advise pregnant woman of the potential hazard to fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal DataPregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days (GD) to (preimplantation), GD to 10, or GD 11 to 16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on GD to 10 and GD 11 to 16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on GD to 10. 8.2 Lactation. Risk SummaryThere are no data on the presence of oxaliplatin or its metabolites in human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Oxaliplatin Injection and for months after the final dose.. 8.3 Females and Males ofReproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating Oxaliplatin Injection [see Use in Specific Populations 8.1 )].ContraceptionOxaliplatin Injection can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1 )].FemalesAdvise females of reproductive potential to use effective contraception while receiving Oxaliplatin Injection and for months after the final dose. MalesBased on its mechanism action as genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving Oxaliplatin Injection and for months after the final dose [see Nonclinical Toxicology 13.1 )].InfertilityBased on animal studies, Oxaliplatin Injection may impair fertility in males and females [see Nonclinical Toxicology 13.1 )].. 8.4 Pediatric Use. The effectiveness of Oxaliplatin Injection in children has not been established. Oxaliplatin has been tested in Phase and Phase trials in 235 patients ages months to 22 years with solid tumors and no significant activity observed. In Phase 1/2 study, oxaliplatin was administered as 2-hour intravenous infusion on Days 1, and 15 every weeks (1 cycle), for maximum of cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight pediatric patients in the Phase study received oxaliplatin at dose levels starting at 40 mg/m2 with escalation to 110 mg/m2. The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m2 dose. Fifteen patients received oxaliplatin at dose of 90 mg/m2 intravenous in the Phase portion of the study. At this dose, paresthesia (60%, G3/4: 7%), fever (40%, G3/4: 7%) and thrombocytopenia (40%, G3/4: 27%) were the main adverse reactions. No responses were observed. In second Phase study, oxaliplatin was administered to 26 pediatric patients as 2-hour intravenous infusion on day every weeks (1 cycle) at dose levels starting at 100 mg/m2 with escalation to 160 mg/m2, for maximum of cycles. In separate cohort, oxaliplatin 85 mg/m2 was administered on day every weeks, for maximum of doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma. No responses were observed. The DLT was sensory neuropathy at the 160 mg/m2 dose. Based on these studies, oxaliplatin 130 mg/m2 as 2-hour intravenous infusion on day every weeks (1 cycle) was used in subsequent Phase II studies. dose of 85 mg/m2 on day every weeks was also found to be tolerable. In one Phase study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m2 every weeks for maximum of 12 months in absence of progressive disease or unacceptable toxicity. In patients 10 kg the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were leukopenia (67%, G3/4: 12%), anemia (65%, G3/4: 5%), thrombocytopenia (65%, G3/4: 26%), vomiting (65%, G3/4: 7%), neutropenia (58%, G3/4: 16%) and sensory neuropathy (40%, G3/4: 5%). One partial response was observed. In second Phase study, 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, Ewing sarcoma or peripheral PNET, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors of interest received oxaliplatin 130 mg/m2 every weeks for maximum of 12 months or 17 cycles. In patients <= 12 months old the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were sensory neuropathy (52%, G3/4: 12%), thrombocytopenia (37%, G3/4: 17%), anemia (37%, G3/4: 9%), vomiting (26%, G3/4: 4%), ALT increased (24%, G3/4: 6%), AST increased (24%, G3/4: 2%), and nausea (23%, G3/4: 3%). Two partial responses were observed. The pharmacokinetic parameters of ultrafiltrable platinum have been evaluated in 105 pediatric patients during the first cycle. The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h. The inter-patient variability of platinum clearance in pediatric cancer patients was 41%. Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 +- 0.24 mcg/mL, AUC0-48 of 7.52 +- 5.07 mcgoh/mL and AUCinf of 8.83 +- 1.57 mcgoh/mL at 85 mg/m2 of oxaliplatin and Cmax of 1.10 +- 0.43 mcg/mL, AUC0-48 of 9.74 +- 2.52 mcgoh/mL and AUCinf of 17.3 +- 5.34 mcgoh/mL at 130 mg/m2 of oxaliplatin.. 8.5 Geriatric Use. No significant effect of age on the clearance of ultrafilterable platinum has been observed. In the adjuvant therapy colon cancer randomized clinical trial, [see Clinical Studies 14 )] 723 patients treated with oxaliplatin and infusional fluorouracil/leucovorin were 65 years and 400 patients were >= 65 years. descriptive subgroup analysis demonstrated that the improvement in DFS for the oxaliplatin combination arm compared to the infusional fluorouracil/leucovorin alone arm appeared to be maintained across genders. The effect of oxaliplatin in patients >= 65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race. Patients >= 65 years of age receiving the oxaliplatin combination therapy experienced more Grade to granulocytopenia than patients 65 years of age (45% versus 39%).In the previously untreated for advanced colorectal cancer randomized clinical trial [see Clinical Studies 14 )] of oxaliplatin, 160 patients treated with oxaliplatin and fluorouracil/leucovorin were 65 years and 99 patients were >= 65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the >= 65 year old patients as in the overall study population. In the previously treated for advanced colorectal cancer randomized clinical trial [see Clinical Studies 14 )] of oxaliplatin, 95 patients treated with oxaliplatin and fluorouracil/leucovorin were 65 years and 55 patients were >= 65 years. The rates of overall adverse reactions, including Grade and events, were similar across and within arms in the different age groups in all studies. The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope were higher in patients >= 65 years old. No adjustment to starting dose was required in patients >= 65 years old.. 8.6 Renal Impairment. The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients [see Pharmacokinetics (12.3)]. Caution and close monitoring should be exercised when Oxaliplatin Injection is administered to patients with renal impairment. The starting Oxaliplatin Injection dose does not need to be reduced in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal impairment. However, the starting dose of Oxaliplatin Injection should be reduced in patients with severe renal impairment (creatinine clearance 30 mL/min) [see Dosage and Administration 2.2 )].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Allergic Reactions: Monitor for development of rash, urticaria, erythema, pruritus, bronchospasm, and hypotension. (5.1)Neuropathy: Reduce the dose or discontinue Oxaliplatin Injection if necessary. (5.2)Severe Neutropenia: Delay Oxaliplatin Injection until neutrophils are >=1.5 109/L. Withhold Oxaliplatin Injection for sepsis. (5.3)Pulmonary Toxicity: May need to discontinue Oxaliplatin Injection until interstitial lung disease or pulmonary fibrosis are excluded. (5.4)Hepatotoxicity: Monitor liver function tests. (5.5)Cardiovascular Toxicity: Correct hypokalemia or hypomagnesemia prior to initiating Oxaliplatin Injection. (5.6)Rhabdomyolysis: Discontinue Oxaliplatin Injection if rhabdomyolysis occurs. (5.7)Embryo-Fetal Toxicity: Can cause fetal harm. Advise pregnant women of the potential risk to fetus. Advise males and females of reproductive potential to use an effective method of contraception. (5.8, 8.1, 8.3). Allergic Reactions: Monitor for development of rash, urticaria, erythema, pruritus, bronchospasm, and hypotension. (5.1). Neuropathy: Reduce the dose or discontinue Oxaliplatin Injection if necessary. (5.2). Severe Neutropenia: Delay Oxaliplatin Injection until neutrophils are >=1.5 109/L. Withhold Oxaliplatin Injection for sepsis. (5.3). Pulmonary Toxicity: May need to discontinue Oxaliplatin Injection until interstitial lung disease or pulmonary fibrosis are excluded. (5.4). Hepatotoxicity: Monitor liver function tests. (5.5). Cardiovascular Toxicity: Correct hypokalemia or hypomagnesemia prior to initiating Oxaliplatin Injection. (5.6). Rhabdomyolysis: Discontinue Oxaliplatin Injection if rhabdomyolysis occurs. (5.7). Embryo-Fetal Toxicity: Can cause fetal harm. Advise pregnant women of the potential risk to fetus. Advise males and females of reproductive potential to use an effective method of contraception. (5.8, 8.1, 8.3). 5.1 Allergic Reactions. Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin has been observed in 2% to 3% of colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy. Rechallenge is contraindicated in these patients [see Contraindications (4)]. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.. 5.2 Neurologic Toxicity. NeuropathyOxaliplatin is associated with two types of neuropathyAn acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing. The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and feeling of chest pressure have also been observed. The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received oxaliplatin with fluorouracil/leucovorin. In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. In adjuvant patients the median cycle of onset for Grade peripheral sensory neuropathy was in the previously treated patients the median number of cycles administered on the oxaliplatin with fluorouracil/leucovorin combination arm was 6.An acute syndrome of pharyngolaryngeal dysesthesia seen in 1% to 2% (Grade 3/4) of patients previously untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of oxaliplatin because cold temperature can exacerbate acute neurological symptoms. persistent (> 14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception). These forms of neuropathy occurred in 48% of the study patients receiving oxaliplatin with fluorouracil/leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed Grade persistent neuropathy progressed from prior Grade or events. These symptoms may improve in some patients upon discontinuation of oxaliplatin. In the adjuvant colon cancer trial, neuropathy was graded using prelisted module derived from the Neuro-Sensory section of the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale, Version 1, as follows:Table 1: NCI CTC Grading for Neuropathy in Adjuvant PatientsGradeDefinitionGrade 0No change or noneGrade 1Mild paresthesias, loss of deep tendon reflexesGrade 2Mild or moderate objective sensory loss, moderate paresthesiasGrade 3Severe objective sensory loss or paresthesias that interfere with functionGrade 4Not applicablePeripheral sensory neuropathy was reported in adjuvant patients treated with the oxaliplatin combination with frequency of 92% (all grades) and 13% (Grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at months follow-up (Grade 1=31%, Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, Grade 3=1%).In the advanced colorectal cancer studies, neuropathy was graded using study-specific neurotoxicity scale, which was different from the NCI CTC scale, Version 2.0 (see below). Table 2: Grading Scale for Paresthesias/Dysesthesias in Advanced Colorectal Cancer PatientsGradeDefinitionGrade 1Resolved and did not interfere with functioningGrade 2Interfered with function but not daily activitiesGrade 3Pain or functional impairment that interfered with daily activitiesGrade 4Persistent impairment that is disabling or life-threateningOverall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (Grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (Grade 3/4) events. Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer.Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension [see Adverse Reactions (6.2)]. Diagnosis of RPLS is based upon confirmation by brain imaging. 5.3 Severe Neutropenia. Grade or neutropenia occurred in 41 to 44% of patients with colorectal cancer treated with oxaliplatin in combination with flurouracil (FU) and leucovorin compared to 5% with FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin, including fatal outcomes [see Adverse Reactions 6.1)].Delay Oxaliplatin Injection until neutrophils are >= 1.5 109/L. Withhold Oxaliplatin Injection for sepsis or septic shock. Reduce the dose of Oxaliplatin Injection after recovery from Grade neutropenia or febrile neutropenia [see Dosage and Administration 2.2 )].. 5.4 Pulmonary Toxicity. Oxaliplatin has been associated with pulmonary fibrosis (< 1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) and 1% (Grade 3) with no Grade events in the oxaliplatin plus infusional fluorouracil/leucovorin arm compared to 4.5% (any grade) and no Grade and 0.1% Grade events in the infusional fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the oxaliplatin combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (Grade and 4) in the oxaliplatin plus fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (Grade and 4) in the irinotecan plus fluorouracil/leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, Oxaliplatin Injection should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.. 5.5 Hepatotoxicity. Hepatotoxicity as evidenced in the adjuvant study by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the oxaliplatin combination arm than in the control arm. The incidence of increased bilirubin was similar in both arms. Changes noted on liver biopsies included: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension which cannot be explained by liver metastases [see Clinical Trials Experience 6.1 )]. 5.6 Cardiovascular Toxicity. QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been reported in postmarketing experiences following oxaliplatin administration. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating Oxaliplatin Injection and monitor these electrolytes periodically during therapy. Avoid Oxaliplatin Injection in patients with congenital long QT syndrome [see Adverse Reactions 6.2 )].. 5.7 Rhabdomyolysis. Rhabdomyolysis, including fatal cases, has been reported in patients treated with oxaliplatin. Discontinue Oxaliplatin Injection if any signs or symptoms of rhabdomyolysis occur [see Adverse Reactions 6.2)].. 5.8 Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, Oxaliplatin Injection can cause fetal harm when administered to pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for at least months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for months after the final dose [see Use in Specific Populations 8.1 8.3 )]. 5.9 Recommended Laboratory Tests. Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each Oxaliplatin Injection cycle [see Dosage and Administration 2 )]. There have been reports while on study and from postmarketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received oxaliplatin plus fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin Injection plus fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.