Oxaliplatin Injection: Indications, Dosage, Precautions, Adverse Effects
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Oxaliplatin Injection - Product Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Colorectal Carcinoma (Colorectal Cancer), Colorectal Cancer
Class: Alkylating agents
Form: Liquid solution, Intravenous (IV)
Ingredients: Oxaliplatin, water.

Indications and Usage

Oxaliplatin Injection, USP, used in combination with infusional 5-fluorouracil/leucovorin, is indicated for:

  • adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary
  • treatment of advanced colorectal

Dosage and Administration

Oxaliplatin Injection, USP should be administered under the supervision of a 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.

Dosage

Administer Oxaliplatin Injection, USP in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

Day 1: Oxaliplatin injection, USP 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

The administration of oxaliplatin injection, USP does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

For information on 5-fluorouracil and leucovorin, see the respective package inserts.

Dose Modification Recommendations

Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions]. Prolongation of infusion time for oxaliplatin injection, USP from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

Adjuvant Therapy in Patients with Stage III Colon Cancer

Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions].

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5- fluorouracil/leucovorin regimen need not be altered.

A dose reduction of oxaliplatin injection, USP to 75 mg/m2 and infusional 5-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 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.

Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer

Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions]. Other toxicities were graded by the NCI CTC, Version 2.0.

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin injection, USP to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5- fluorouracil/leucovorin regimen need not be altered.

A dose reduction of oxaliplatin injection, USP to 65 mg/m2 and 5-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 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 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 is 85 mg/m2. In patients with severe renal impairment, the initial recommended oxaliplatin injection, USP dose should be reduced to 65 mg/m2 [see Use in Specific Populations and Clinical Pharmacology].

Preparation of Infusion Solution

Do not freeze and protect from light the concentrated solution.

A final dilution must never be performed with a 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, USP.

After dilution with 250 to 500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20° to 25°C (68° to 77°F)] or up to 24 hours under refrigeration [2° to 8°C (36° to 46°F)]. After final dilution, protection from light is not required.

Oxaliplatin injection, USP is incompatible in solution with alkaline medications or media (such as basic solutions of 5-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, USP 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 should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

Dosage Forms and Strengths

Oxaliplatin Injection, USP is supplied in single-use vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL.

Contraindications

Oxaliplatin Injection, USP should not be administered to patients with a history of known allergy to oxaliplatin or other platinum compounds [see Warnings and Precautions].

Warnings and Precautions

WARNING: ANAPHYLACTIC REACTIONS

Anaphylactic reactions to Oxaliplatin have been reported, and may occur within minutes of Oxaliplatin adminis tration. Epinephrine, corticos teroids, and antihis tamines have been employed to alleviate symptoms of anaphylaxis.

Allergic Reactions

See boxed warning

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]. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.

Neurologic Toxicity

Neuropathy

Oxaliplatin is associated with two types of neuropathy:

An 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 a 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 5-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 3 peripheral sensory neuropathy was 9 in the previously treated patients the median number of cycles administered on the oxaliplatin with 5-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.

A 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 5□fluorouracil/leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of oxaliplatin.

In the adjuvant colon cancer trial, neuropathy was graded using a 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 Patients
GradeDefinition
Grade 0No change or none
Grade 1Mild paresthesias, loss of deep tendon reflexes
Grade 2Mild or moderate objective sensory loss, moderate paresthesias
Grade 3Severe objective sensory loss or paresthesias that interfere with function
Grade 4Not applicable

Peripheral sensory neuropathy was reported in adjuvant patients treated with the oxaliplatin combination with a 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 6 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 a 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 Patients
GradeDefinition
Grade 1Resolved and did not interfere with functioning
Grade 2Interfered with function but not daily activities
Grade 3Pain or functional impairment that interfered with daily activities
Grade 4Persistent impairment that is disabling or life-threatening

Overall, 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]. Diagnosis of RPLS is based upon confirmation by brain imaging.

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 4 events in the oxaliplatin plus infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-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 3 and 4) in the oxaliplatin plus 5-fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-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 should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

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 on both arms. Changes noted on liver biopsies include: 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].

Use in Pregnancy

Pregnancy Category D

Oxaliplatin may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of oxaliplatin in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with oxaliplatin [see Use In Specific Populations].

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 cycle [see Dosage and Administration].

There 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 5- fluorouracil/leucovorin while on anticoagulants. Patients receiving oxaliplatin plus 5- fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.

Adverse Reactions

The following serious adverse reactions are discussed in greater detail in other sections of the label:

  • Anaphylaxis and Allergic reactions [see Warnings and Precautions.]
  • Neuropathy [see Warnings and Precautions.]
  • Pulmonary Toxicities [see Warnings and Precautions.]
  • Hepatotoxicity [see Warnings and Precautions.]

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 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].

Combination Adjuvant Therapy with Oxaliplatin and Infusional 5-Fluorouracil/Leucovorin in Patients with Colon Cancer

One thousand one hundred and eight patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, have been treated in a clinical study with oxaliplatin in combination with infusional 5-fluorouracil/leucovorin [see Clinical Studies]. The incidence of grade 3 or 4 adverse reactions was 70% on the oxaliplatin combination arm, and 31% on the infusional 5-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 5□fluorouracil/leucovorin. Both 5-fluorouracil/leucovorin and oxaliplatin are associated with gastrointestinal or hematologic adverse reactions. When oxaliplatin is administered in combination with infusional 5-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 5-fluorouracil/leucovorin arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the oxaliplatin combination and infusional 5- fluorouracil/leucovorin arms, respectively. On the oxaliplatin combination arm, 3 deaths were due to sepsis/neutropenic sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia. On the 5□fluorouracil/leucovorin arm, one death was due to suicide, 2 from Stevens - Johnson syndrome (1 patient also had sepsis), 1 unknown cause, 1 anoxic cerebral infarction and 1 probable abdominal aorta rupture.

The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies] by body system and decreasing order of frequency in the oxaliplatin and infusional 5-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)
Adverse Reaction
(WHO/Pref)
Oxaliplatin + 5-FU/LV
N=1108
5-FU/LV
N=1111
All GradesGrade 3/4All GradesGrade 3/4
(%)(%)(%)(%)
Any Event100709931
Allergy/Immunology
Allergic Reaction1032<1
Constitutional Symptoms/Pain
Fatigue444381
Abdominal Pain181172
Dermatology/Skin
Skin Disorder322362
Injection Site Reaction*113103
Gastrointestinal
Nausea745612
Diarrhea5611487
Vomiting476241
Stomatitis423402
Anorexia1318<1
Fever/Infection
Fever271121
Infection254253
Neurology
Overall Peripheral Sensory Neuropathy921216<1

*Includes thrombosis related to the catheter

The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies] by body system and decreasing order of frequency in the oxaliplatin and infusional 5-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)
Adverse Reaction (WHO/Pref)Oxaliplatin + 5-FU/LV
N=1108
5-FU/LV
N=1111
All Grades (%)All Grades (%)
Allergy/Immunology
Rhinitis68
Constitutional Symptoms/Pain/Ocular/Visual
Epistaxis1612
Weight Increase1010
Conjunctivitis915
Headache75
Dyspnea53
Pain55
Lacrimation Abnormal412
Dermatology/Skin
Alopecia3028
Gastrointestinal
Constipation2219
Taste Perversion128
Dyspepsia85
Metabolic
Phosphate Alkaline increased4220
Neurology
Sensory Disturbance81

Although 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 5-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 5-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 5-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 5-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 5□fluorouracil/leucovorin combination arm of the randomized trial in patients previously untreated for advanced colorectal cancer [see Clinical Studies]. 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 5-fluorouracil and oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin is administered in combination with 5-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 5□fluorouracil/leucovorin combination, 5% with irinotecan plus 5-fluorouracil/leucovorin, and 3% with oxaliplatin plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the oxaliplatin and 5- fluorouracil/leucovorin combination, 5.1% with irinotecan plus 5-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] by body system and decreasing order of frequency in the oxaliplatin and 5-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)
Adverse Reaction
(WHO/Pref)
Oxaliplatin + 5-FU/LV
N=259
Irinotecan + 5-FU/LV
N=256
Oxaliplatin + irinotecan
N=258
All Grades
(%)
Grade
3/4
(%)
All Grades
(%)
Grade
3/4
(%)
All Grades
(%)
Grade
3/4
(%)
Any Event998298709976
Allergy/Immunology
Hypersensitivity1225061
Cardiovascular
Thrombosis656633
Hypotension536343
Constitutional Symptoms/Pain/Ocular/Visual
Fatigue70758116616
Abdominal Pain2983173910
Myalgia1426092
Pain715161
Vision abnormal502161
Neuralgia500021
Dermatology/Skin
Skin reaction – hand/foot712110
Injection site reaction601041
Gastrointestinal
Nausea71667158319
Diarrhea561265297625
Vomiting41443136423
Stomatitis380251191
Anorexia352254275
Constipation324272212
Diarrhea-colostomy132167163
Gastrointestinal NOS*524232
Hematology/Infection
Infection normal ANC1045172
Infection low ANC88121198
Lymphopenia624152
Febrile neutropenia4415141211
Hepatic/Metabolic/Laboratory/Renal
Hyperglycemia142113123
Hypokalemia1137462
Dehydration951611147
Hypoalbuminemia805291
Hyponatremia827441
Urinary frequency512131
Neurology
Overall Neuropathy8219182697
Paresthesias7718162626
Pharyngo-laryngeal dysesthesias38210281
Neuro-sensory1212091
Neuro NOS*101010
Pulmonary
Cough351252171
Dyspnea187143112
Hiccups512032

*Not otherwise specified

Absolute neutrophil count

The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study [see Clinical Studies] by body system and decreasing order of frequency in the oxaliplatin and 5-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 +
5-FU/LV
N=259
irinotecan +
5-FU/LV
N=256
Oxaliplatin +
irinotecan
N=258
All Grades
(%)
All Grades
(%)
All Grades
(%)
Allergy/Immunology
Rash1147
Rhinitis allergic1066
Cardiovascular
Edema151310
Constitutional  Symptoms/Pain/Ocular/Visual
Headache1369
Weight loss11911
Epistaxis1022
Tearing912
Rigors827
Dysphasia533
Sweating5612
Arthralgia558
Dermatology/Skin
Alopecia384467
Flushing725
Pruritus642
Dry Skin625
Gastrointestinal
Taste perversion1468
Dyspepsia1275
Flatulence965
Mouth Dryness523
Hematology/Infection
Fever normal ANC*1699
Hepatic/Metabolic/Laboratory/Renal
Hypocalcemia754
Elevated Creatinine445
Neurology
Insomnia13911
Depression957
Dizziness8610
Anxiety526

*Absolute neutrophil count

Adverse 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 5-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 5-fluorouracil/leucovorin) were studied in a randomized trial in patients with refractory and relapsed colorectal cancer [see Clinical Studies]. 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 5-fluorouracil/leucovorin combination arm and 18% in the 5-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 5-fluorouracil and oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin is administered in combination with 5-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 5-fluorouracil/leucovorin combination, 8% with oxaliplatin alone, and 7% with 5-fluorouracil/leucovorin. Of the 7 deaths that occurred on the oxaliplatin and 5- fluorouracil/leucovorin combination arm within 30 days of stopping treatment, 3 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] by body system and in decreasing order of frequency in the oxaliplatin and 5- 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)
Adverse Reaction
(WHO/Pref)
5-FU/LVN
(N = 142)
Oxaliplatin
(N = 153)
Oxaliplatin +
5-FU/LV
(N = 150)
All
Grades
(%)
Grade
3/4
(%)
All
Grades
(%)
Grade
3/4
(%)
All
Grades
(%)
Grade
3/4
(%)
Any Event9841100469973
Cardiovascular
Dyspnea112137204
Coughing90110191
Edema131101151
Thromboembolism422198
Chest Pain415181
Constitutional Symptoms/Pain
Fatigue526619687
Back Pain164110193
Pain93143152
Dermatology/Skin
Injection Site Reaction5190103
Gastrointestinal
Diarrhea4434646711
Nausea5946446511
Vomiting274374409
Stomatitis323140373
Abdominal Pain315317334
Anorexia201202293
Gastroesophageal Reflux301052
Hematology/Infection
Fever231251291
Febrile Neutropenia110066
Hepatic/Metabolic/Laboratory/Renal
Hypokalemia313294
Dehydration645383
Neurology
Neuropathy170767747
Acute100655562
Persistent90433486

The following table provides adverse reactions reported in the previously treated study [see Clinical Studies] by body system and in decreasing order of frequency in the oxaliplatin and 5- 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)5-FU/LV
(N = 142)
Oxaliplatin
(N = 153)
Oxaliplatin +
5-FU/LV
(N = 150)
All Grades (%)All Grades (%)All Grades (%)
Allergy/Immunology
Rhinitis4615
Allergic Reaction1310
Rash559
Cardiovascular
Peripheral Edema11510
Constitutional Symptoms/Pain/Ocular/Visual
Headache81317
Arthralgia10710
Epistaxis129
Abnormal Lacrimation617
Rigors697
Dermatology/Skin
Hand-Foot Syndrome13111
Flushing2310
Alopecia337
Gastrointestinal
Constipation233132
Dyspepsia10714
Taste Perversion1513
Mucositis1027
Flatulence635
Hepatic/Metabolic/Laboratory/Renal
Hematuria406
Dysuria116
Neurology
Dizziness8713
Insomnia4119
Pulmonary
Upper Resp Tract Infection4710
Pharyngitis1029
Hiccup025

Adverse 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 5 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 Changes

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

Table 9 - Adverse Hematologic Reactions in Patients with Colon Cancer Receiving Adjuvant Therapy (≥5% of patients)
 Oxaliplatin + 5-FU/LV
(N=1108)
5-FU/LV
(N=1111)
Hematology ParameterAll Grades
(%)
Grade 3/4
(%)
All Grades
(%)
Grade 3/4
(%)
Anemia76167<1
Neutropenia7941405
Thrombocytopenia77219<1
Table 10 – Adverse Hematologic Reactions in Patients Previously Untreated for Advanced Colorectal Cancer (≥5% of patients)
 Oxaliplatin +
5-FU/LV
(N=259)
Irinotecan +
5-FU/LV
N=256
Oxaliplatin +
Irinotecan
N=258
Hematology ParameterAll Grades (%)Grade 3/4
(%)
All Grades (%)Grade
3/4
(%)
All Grades (%)Grade 3/4
(%)
Anemia273284253
Leukopenia852084237624
Neutropenia815377447136
Thrombocytopenia715262444
Table 11 – Adverse Hematologic Reactions in Previously Treated Patients (≥5% of patients)
 5-FU/LV
(N=142)
Oxaliplatin (N=153)Oxaliplatin +
5-FU/LV
(N=150)
Hematology ParameterAll
Grades
(%)
Grade
3/4
(%)
All
Grades
(%)
Grade
3/4
(%)
All
Grades
(%)
Grade
3/4
(%)
Anemia682641812
Leukopenia3411307619
Neutropenia255707344
Thrombocytopenia200303644

Thrombocytopenia and Bleeding

Thrombocytopenia was frequently reported with the combination of oxaliplatin and infusional 5- 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 5- 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 5- fluorouracil/leucovorin over the irinotecan plus 5□fluorouracil/leucovorin or 5- fluorouracil/leucovorin control groups. Grade 3/4 gastrointestinal bleeding was reported in 0.2% of adjuvant patients receiving oxaliplatin and 5fluorouracil/leucovorin. In the previously untreated patients, the incidence of epistaxis was 10% in the oxaliplatin and 5-fluorouracil/leucovorin arm, and 2% and 1%, respectively, in the irinotecan plus 5-fluorouracil/leucovorin or irinotecan plus oxaliplatin arms.

Neutropenia

Neutropenia was frequently observed with the combination of oxaliplatin and 5□fluorouracil/leucovorin, with Grade 3 and 4 events reported in 29% and 12% of adjuvant patients with colon cancer, respectively. In the adjuvant trial, 3 patients died from sepsis/neutropenic sepsis. Grade 3 and 4 events were reported in 35% and 18% of the patients previously untreated for advanced colorectal cancer, respectively.

Grade 3 and 4 events were reported in 27% and 17% of previously treated patients, respectively. In adjuvant patients the incidence of either febrile neutropenia (0.7%) or documented infection with concomitant grade 3/4 neutropenia (1.1%) was 1.8% in the oxaliplatin and 5-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 5-fluorouracil/leucovorin arm and 4% (less than 1% of cycles) in the oxaliplatin and 5-fluorouracil/leucovorin combination arm. Additionally, in this same population, infection with grade 3 or 4 neutropenia was 12% in the irinotecan plus 5- fluorouracil/leucovorin, and 8% in the oxaliplatin and 5□fluorouracil/leucovorin combination. The incidence of febrile neutropenia in the previously treated patients was 1% in the 5- fluorouracil/leucovorin arm and 6% (less than 1% of cycles) in the oxaliplatin and 5- fluorouracil/leucovorin combination arm.

Gastrointestinal

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

Dermatologic

Oxaliplatin did not increase the incidence of alopecia compared to 5-fluorouracil/leucovorin alone. No complete alopecia was reported. The incidence of Grade 3/4 skin disorders was 2% in both the oxaliplatin plus infusional 5-fluorouracil/leucovorin and the infusional 5□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 5-fluorouracil/leucovorin arm and 7% in the oxaliplatin and 5fluorouracil/leucovorin combination arm. The incidence of hand-foot syndrome in previously treated patients was 13% in the 5-fluorouracil/leucovorin arm and 11% in the oxaliplatin and 5-fluorouracil/leucovorin combination arm.

Intravenous Site Reactions

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

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

Anticoagulation and Hemorrhage

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

Renal

About 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 5□fluorouracil/leucovorin combination arm was 1% in the previously treated patients. Serum creatinine measurements were not reported in the adjuvant trial.

Hepatic

Hepatotoxicity (defined as elevation of liver enzymes) appears to be related to oxaliplatin combination therapy [see Warnings and Precautions]. The following tables list the clinical chemistry changes associated with hepatic toxicity occurring in ≥5% of patients, based on adverse 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 + 5-FU/LV
(N=1108)
5-FU/LV
(N=1111)
Hepatic ParameterAll Grades
(%)
Grade 3/4
(%)
All Grades
(%)
Grade 3/4
(%)
Increase in transaminases572341
ALP increased42<120<1
Bilirubinaemia204205
Table 13 – Adverse Hepatic – Clinical Chemistry Abnormalities in Patients Previously Untreated for Advanced Colorectal Cancer (≥5% of patients)
 Oxaliplatin +
5-FU/LV
N=259
irinotecan +
5-FU/LV
N=256
Oxaliplatin +
irinotecan
N=258
Clinical ChemistryAll
Grades
(%)
Grade 3/4
(%)
All
Grades
(%)
Grade 3/4
(%)
All
Grades
(%)
Grade 3/4
(%)
ALT (SGPT-ALAT)612052
AST (SGOT-ASAT)17121111
Alkaline Phosphatase16080142
Total Bilirubin613132
Table 14 – Adverse Hepatic – Clinical Chemistry Abnormalities in Previously Treated Patients (≥5% of patients)
 5-FU/LV
(N=142)
Oxaliplatin
(N=153)
Oxaliplatin +
5-FU/LV (N=150)
Clinical ChemistryAll
Grades
(%)
Grade 3/4
(%)
All
Grades
(%)
Grade 3/4
(%)
All
Grades
(%)
Grade 3/4
(%)
ALT (SGPT-ALAT)283361310
AST (SGOT-ASAT)392544470
Total Bilirubin226135131

Thromboembolism

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

Postmarketing Experience

The following adverse reactions have been identified during post-approval 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.

Body as a Whole

Angioedema, anaphylactic shock

Central and Peripheral Nervous System Disorders

Loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion, Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES).

Hearing and Vestibular System Disorders

Deafness

Infusion Reactions/Hypersensitivity

Laryngospasm

Liver and Gastrointestinal System Disorders

severe 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.

Platelet, Bleeding, and Clotting Disorders

Immuno-allergic thrombocytopenia

Prolongation of prothrombin time and of INR in patients receiving anticoagulants

Red Blood Cell Disorders

Hemolytic uremic syndrome, immuno-allergic hemolytic anemia

Renal Disorders

Acute tubular necrosis, acute interstitial nephritis and acute renal failure

Respiratory System Disorders

Pulmonary fibrosis, and other interstitial lung diseases (sometimes fatal)

Vision Disorders

Decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation).

Drug Interactions

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

Use in Specific Populations

Pregnancy

Pregnancy Category D

Based on direct interaction with DNA, oxaliplatin may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of oxaliplatin in pregnant women.

Reproductive toxicity studies in rats demonstrated adverse effects on fertility and embryo-fetal development at maternal doses that were below the recommended human dose based on body surface area. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant and use effective contraception while receiving treatment with oxaliplatin.

Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days 1 to 5 (pre-implantation), 6 to 10, or 11 to 16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6 to 10 and 11 to 16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6 to 10. Administration of oxaliplatin to male and female rats prior to mating resulted in 97% post-implantation loss in animals that received approximately one-seventh the recommended human dose based on the body surface area.

Nursing Mothers

It is not known whether oxaliplatin or its derivatives are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from oxaliplatin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase 1 and 2 Phase 2 trials in 235 patients ages 7 months to 22 years with solid tumors (see below) and no significant activity observed.

In a Phase 1/2 study, oxaliplatin was administered as a 2-hour intravenous infusion on Days 1, 8 and 15 every 4 weeks (1 cycle), for a maximum of 6 cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty-eight pediatric patients in the Phase 1 study received oxaliplatin at 6 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 a dose of 90 mg/m2 intravenous in the Phase 2 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 a second Phase 1 study, oxaliplatin was administered to 26 pediatric patients as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) at 5 dose levels starting at 100 mg/m2 with escalation to 160 mg/m2, for a maximum of 6 cycles. In a separate cohort, oxaliplatin 85 mg/m2 was administered on day 1 every 2 weeks, for a maximum of 9 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 a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) was used in subsequent Phase 2 studies. A dose of 85 mg/m2 on day 1 every 2 weeks was also found to be tolerable.

In one Phase 2 study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m2 every 3 weeks for a 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 a second Phase 2 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 3 weeks for a 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 mcg•h/mL and AUCinf of 8.83 ± 1.57 mcg•h/mL at 85 mg/mof oxaliplatin and Cmax of 1.1 ± 0.43 mcg/mL, AUC0-48 of 9.74 ± 2.52 mcg•h/mL and AUCinf of 17.3 ± 5.34 mcg•h/mL at 130 mg/m2 of oxaliplatin.

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] 723 patients treated with oxaliplatin and infusional 5-fluorouracil/leucovorin were <65 years and 400 patients were ≥65 years.

A descriptive subgroup analysis demonstrated that the improvement in DFS for the oxaliplatin combination arm compared to the infusional 5-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 3-4 granulocytopenia than patients < 65 years of age (45% versus 39%).

In the previously untreated for advanced colorectal cancer randomized clinical trial [see Clinical Studies] of oxaliplatin, 160 patients treated with oxaliplatin and 5-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] of oxaliplatin, 95 patients treated with oxaliplatin and 5-fluorouracil/leucovorin were <65 years and 55 patients were ≥65 years. The rates of overall adverse reactions, including grade 3 and 4 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.

Patients with Renal Impairment

The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients [see Pharmacokinetics]. Caution and close monitoring should be exercised when oxaliplatin is administered to patients with renal impairment. The starting oxaliplatin 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 should be reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min) [see Dosage and Administration].

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 4 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 4 intestinal obstruction, Grade 4 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 a single infusion is 825 mg.

How Supplied/Storage and Handling

How Supplied

Oxaliplatin Injection, USP is supplied in clear, glass, single-use vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. Water for injection is present as inactive ingredient.

Product
No.
NDC
No.
Strength 
77501063323-750-050 mg per 10 mL
(5 mg per mL)
10 mL single-use vial, packaged individually.
77501763323-750-750 mg per 10 mL
(5 mg per mL)
10 mL single-use vials packaged individually in a carton of ten.
77502063323-750-0100 mg per 20 mL
(5 mg per mL)
20 mL single-use vial, packaged individually.
77502763323-750-7100 mg per 20 mL
(5 mg per mL)
20 mL single-use vials packaged individually in a carton of ten.

This container closure is not made with natural rubber latex.

Storage

Store at 20°C to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not freeze and protect from light (keep in original outer carton).

Handling and Disposal

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from oxaliplatin injection. The use of gloves is recommended. If a solution of oxaliplatin injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If oxaliplatin injection contacts the mucous membranes, flush thoroughly with water.

Procedures for the handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published [see References]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Patient Counseling Information

Advise patients:

  • To expect side effects of oxaliplatin, 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 should 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, particularly if associated with persistent diarrhea, or evidence of infection develop.
  • 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 on the effects of the ability to operate cars and machines have been performed; however, oxaliplatin treatment resulting in an increase risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to a 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.

Manufactured For

Fresenius Kabi USA, LLC

Lake Zurich, IL 60047

Made in India

For Product Inquiry:

1-800-551-7176 or www.fresenius-kabi.us

451426/Issued: May 2015