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oxaliplatin injection Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in labeling:

6.1 Clinical Trials Experience

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

More than 1,100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer were treated in trials with Oxaliplatin. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant treatment were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. The most common adverse reactions in previously untreated and treated patients with advanced colorectal cancer were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea.

Adjuvant Treatment

The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor in the adjuvant treatment trial [see Clinical Studies (14.1)].

Fatal adverse reactions in patients who received Oxaliplatin in the combination arm included sepsis/neutropenic sepsis (n=3), intracerebral hemorrhage (n=2) and eosinophilic pneumonia (n=1).

Thromboembolic events occurred in 6% (grade 3–4, 1.2%) of patients in the Oxaliplatin arm.

Grade 3 or 4 adverse reactions occurred in 70% of patients in the Oxaliplatin arm. Grade 3–4 gastrointestinal bleeding occurred in 0.2% of patients. Febrile neutropenia occurred in 0.7% and documented infection with concomitant grade 3–4 neutropenia occurred in 1.1%.

Discontinuation due to an adverse reaction occurred in 15% of the patients in the Oxaliplatin arm.

Tables 5, 6, and 7 summarize the adverse reactions reported in patients with colon cancer receiving adjuvant treatment.

Table 5: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=1108
FU/LV
N=1111
All Grades
(%)
Grade 3–4
(%)
All Grades
(%)
Grade 3–4
(%)
*
Event coded in WHO-ART dictionary
Includes thrombosis related to the catheter
Neurology
Peripheral Sensory Neuropathy921216<1
Gastrointestinal
Nausea745612
Diarrhea5611487
Vomiting476241
Stomatitis423402
Anorexia1318<1
Constitutional Symptoms/Pain
Fatigue444381
Abdominal Pain181172
Dermatology/Skin
Skin Disorder322362
Injection Site Reaction113103
Fever/Infection
Fever271121
Infection254253
Allergy/Immunology
Allergic Reaction1032<1
Table 6: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients but with less than 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=1108
FU/LV
N=1111
All Grades
(%)
All Grades
(%)
*
Event coded in WHO-ART dictionary
No complete alopecia was reported.
Dermatology/Skin
Alopecia3028
Gastrointestinal
Constipation2219
Taste Perversion128
Dyspepsia85
Constitutional Symptoms/Pain/Ocular/Visual
Epistaxis 1612
Weight Increase 1010
Conjunctivitis915
Headache75
Dyspnea 53
Pain55
Abnormal Lacrimation412
Neurology
Sensory Disturbance81
Allergy/Immunology
Rhinitis68

In females, the following grade 3–4 adverse reactions were more frequent: diarrhea, fatigue, neutropenia, nausea, and vomiting.

In patients greater than or equal to 65 years old, the incidence of grade 3–4 diarrhea and neutropenia was higher than in younger adults.

Clinically relevant adverse reactions were reported in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin arm (listed in decreasing order of frequency) were pain, leukopenia, weight loss, and cough.

Table 7: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Colon Cancer Receiving Adjuvant Treatment
Laboratory-Related Adverse ReactionOxaliplatin with FU/LV
N=1108
FU/LV N=1111
All Grades
(%)
Grades 3–4
(%)
All Grades
(%)
Grades 3–4
(%)
Hematology
Neutropenia7941405
Thrombocytopenia77219<1
Anemia76167<1
Hepatic
Increased Transaminases572341
Increased Alkaline Phosphatase42<120<1
Hyperbilirubinemia204205

Previously Untreated Advanced Colorectal Cancer

The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial of patients with previously untreated advanced colorectal cancer [see Clinical Studies (14.2)]. The adverse reaction profile in this trial was similar to that seen in other trials.

Tables 8, 9, and 10 summarize the adverse reactions reported in the previously untreated advanced colorectal cancer trial.

Table 8: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=259
Irinotecan + FU/LV
N=256
Oxaliplatin + Irinotecan
N=258
All Grades
(%)
Grades 3–4
(%)
All Grades
(%)
Grades 3–4
(%)
All Grades
(%)
Grades 3–4
(%)
*
Event coded in WHO-ART dictionary
Not otherwise specified
Absolute neutrophil count
Neurology
Neuropathy8219182697
Paresthesias7718162626
Pharyngo-laryngeal Dysesthesias38210281
Neuro-sensory1212091
Neuro NOS101010
Gastrointestinal
Nausea71667158319
Diarrhea561265297625
Vomiting41443136423
Stomatitis380251191
Anorexia352254275
Constipation324272212
Diarrhea-colostomy132167163
Gastrointestinal NOS524232
Constitutional Symptoms/Pain/Ocular/Visual
Fatigue70758116616
Abdominal Pain2983173910
Myalgia1426092
Pain715161
Abnormal Vision502161
Neuralgia500021
Pulmonary
Cough351252171
Dyspnea187143112
Hiccups512032
Hepatic/Metabolic/Laboratory/Renal
Hyperglycemia142113123
Hypokalemia1137462
Dehydration951611147
Hypoalbuminemia805291
Hyponatremia827441
Urinary Frequency512131
Hematology/Infection
Infection Normal ANC1045172
Infection Low ANC88121198
Lymphopenia624152
Febrile Neutropenia4415141211
Dermatology/Skin
Hand/Foot Syndrome712110
Injection Site Reaction601041
Cardiovascular
Thrombosis656633
Hypotension536343
Table 9: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients but with less than 1% grade 3–4)
Adverse Reaction*Oxaliplatin + 5-FU/LV
N=259
Irinotecan + 5-FU/LV
N=256
Oxaliplatin + Irinotecan
N=258
All Grades
(%)
All Grades
(%)
All Grades
(%)
*
Event coded in WHO-ART dictionary
No complete alopecia was reported.
Absolute neutrophil count
Dermatology/Skin
Alopecia384467
Flushing725
Pruritus642
Dry Skin625
Hematology/Infection
Fever Normal ANC1699
Cardiovascular
Edema151310
Gastrointestinal
Taste Perversion1468
Dyspepsia1275
Flatulence965
Mouth Dryness 523
Constitutional Symptoms/Pain/Ocular/Visual
Headache1369
Weight Loss11911
Epistaxis1022
Tearing912
Rigors827
Dysphasia533
Sweating5612
Arthralgia558
Neurology
Insomnia13911
Depression957
Dizziness8610
Anxiety526
Allergy/Immunology
Rash1147
Rhinitis Allergic1066
Hepatic/Metabolic/Laboratory/Renal
Hypocalcemia754
Elevated Creatinine445

Clinically relevant adverse reactions that occurred in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: metabolic, pneumonitis, catheter infection, vertigo, prothrombin time, pulmonary, rectal bleeding, dysuria, nail changes, chest pain, rectal pain, syncope, hypertension, hypoxia, unknown infection, bone pain, pigmentation changes, and urticaria.

Table 10: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients in the Previously Untreated Advanced Colorectal Cancer Trial
Laboratory-Related Adverse ReactionOxaliplatin and FU/LV N=259Irinotecan and FU/LV
N=256
Oxaliplatin and Irinotecan
N=258
All Grades
(%)
Grades 3–4
(%)
All Grades
(%)
Grades 3–4
(%)
All Grades
(%)
Grades 3–4
(%)
*
Aspartate transaminase
Alanine transaminase
Hematology
Leukopenia852084237624
Neutropenia815377447136
Thrombocytopenia715262444
Anemia273284253
Hepatic
Increased AST*17121111
Increased Alkaline Phosphatase16080142
Hyperbilirubinemia613132
Increased ALT612052

Previously Treated Advanced Colorectal Cancer

The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial in patients with refractory and relapsed colorectal cancer [see Clinical Studies (14.3)]. The adverse reaction profile in this trial was similar to that seen in other trials.

Three patients who received Oxaliplatin in the combination arm experienced fatal adverse reactions: gastrointestinal bleeding and dehydration.

Grade 3 and 4 neutropenia were reported in 27% and 17% of patients, respectively, in the Oxaliplatin with fluorouracil/leucovorin combination arm. Grade 3–4 increased serum creatinine occurred in 1% of patients in the Oxaliplatin with combination fluorouracil/leucovorin arm.

Thirteen percent of patients in the Oxaliplatin with fluorouracil/leucovorin combination arm discontinued treatment; the most frequent reasons were gastrointestinal adverse reactions, hematologic adverse reactions and neuropathies.

Tables 11, 12, and 13 summarize the adverse reactions reported in the previously treated advanced colorectal cancer trial.

Table 11: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=150
Oxaliplatin
N=153
FU/LV
N=142
All Grades
(%)
Grades 3–4
(%)
All Grades
(%)
Grades 3–4
(%)
All Grades
(%)
Grades 3–4
(%)
*
Event coded in WHO-ART dictionary
Neurology
Neuropathy747767170
  Acute562655100
  Persistent48643390
Constitutional Symptoms/Pain
Fatigue687619526
Back Pain193110164
Pain15214393
Gastrointestinal
Diarrhea6711464443
Nausea6511644594
Vomiting409374274
Stomatitis373140323
Abdominal Pain334317315
Anorexia293202201
Gastroesophageal Reflux521030
Hematology/Infection
Fever291251231
Febrile Neutropenia660011
Cardiovascular
Dyspnea204137112
Coughing19111090
Edema151101131
Thromboembolism982142
Chest Pain815141
Dermatology/Skin
Injection Site Reaction1039051
Hepatic/Metabolic/Laboratory/Renal
Hypokalemia943231
Dehydration835364
Table 12: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients but with less than 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=150
Oxaliplatin
N=153
5-FU/LV
N=142
All Grades
(%)
All Grades
(%)
All Grades
(%)
*
Event coded in WHO-ART dictionary
No complete alopecia was reported.
Gastrointestinal
Constipation323123
Dyspepsia14710
Taste Perversion1351
Mucositis7210
Flatulence536
Constitutional Symptoms/Pain/Ocular/Visual
Headache17138
Arthralgia10710
Epistaxis921
Abnormal Lacrimation716
Rigors796
Allergy/Immunology
Rhinitis1564
Allergic Reaction1031
Rash955
Neurology
Dizziness1378
Insomnia9114
Dermatology/Skin
Hand-Foot Syndrome11113
Flushing1032
Alopecia733
Pulmonary
Upper Respiratory Tract Infection1074
Pharyngitis9210
Cardiovascular
Peripheral Edema10511
Hepatic/Metabolic/Laboratory/Renal
Hematuria604
Dysuria611

Clinically relevant adverse reactions in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: anxiety, myalgia, erythematous rash, increased sweating, conjunctivitis, weight decrease, dry mouth, rectal hemorrhage, depression, ataxia, ascites, hemorrhoids, muscle weakness, nervousness, tachycardia, abnormal micturition frequency, dry skin, pruritus, hemoptysis, purpura, vaginal hemorrhage, melena, somnolence, pneumonia, proctitis, involuntary muscle contractions, intestinal obstruction, gingivitis, tenesmus, hot flashes, enlarged abdomen, and urinary incontinence.

Table 13: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Previously Treated Advanced Colorectal Cancer
Laboratory-Related Adverse ReactionOxaliplatin and FU/LV
N=150
Oxaliplatin
N=153
FU/LV
N=142
All Grades
(%)
Grades 3–4
(%)
All Grades
(%)
Grades 3–4
(%)
All Grades
(%)
Grades 3–4
(%)
*
Alanine transaminase
Aspartate transaminase
Hematology
Anemia812641682
Leukopenia7619130341
Neutropenia734470255
Thrombocytopenia644303200
Hepatic
Increased ALT*310361283
Increased AST470544392
Increased Bilirubin131135226

Additional Adverse Reactions

The following adverse reactions were observed across clinical trials.

Intravenous site reactions

Injection site reaction, including redness, swelling, and pain, can occur with Oxaliplatin. In some cases, skin necrosis has occurred with extravasation.

PRES

PRES occurred in less than 0.1% of patients.

Pulmonary fibrosis and interstitial lung disease

Pulmonary fibrosis, which may be fatal, occurred in less than 1% of patients.

6.2 Postmarketing Experience

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

  • General: angioedema, anaphylactic shock
  • Cardiovascular: QT prolongation leading to ventricular arrhythmias, including fatal torsade de pointes; bradyarrhythmia
  • Neurological: loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion
  • Hearing and vestibular system: deafness
  • Infections: septic shock, including fatal outcomes
  • Infusion-related reactions and hypersensitivity reactions: laryngospasm
  • Hepatic and gastrointestinal: severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis, ileus, intestinal obstruction, pancreatitis, sinusoidal obstruction syndrome, perisinusoidal fibrosis which rarely may progress, esophagitis
  • Musculoskeletal and connective tissue: rhabdomyolysis, including fatal outcomes
  • Platelet, bleeding, and clotting disorders: immuno-allergic thrombocytopenia, prolonged prothrombin time and INR in patients receiving anticoagulants
  • Blood disorders: secondary leukemia
  • Red blood cell: hemolytic uremic syndrome, immuno-allergic hemolytic anemia
  • Renal: acute tubular necrosis, acute interstitial nephritis, acute renal failure
  • Respiratory: interstitial lung diseases (sometimes fatal) and pneumonia (including fatal outcomes)
  • Vision: decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following treatment discontinuation)
  • Injury, poisoning, and procedural complications: fall-related injuries
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