These highlights do not include all the information needed to use OXALIPLATIN INJECTION, USP safely and effectively. See full prescribing information for OXALIPLATIN INJECTION, USP.OXALIPLATIN Injection, for intravenous use Initial U.S. Approval: 2002

WARNING: HYPERSENSITIVITY REACTIONS, INCLUDING ANAPHYLAXIS

Serious and fatal hypersensitivity adverse reactions, including anaphylaxis, can occur with Oxaliplatin Injection within minutes of administration and during any cycle. Oxaliplatin Injection is contraindicated in patients with hypersensitivity reactions to oxaliplatin and other platinum-based drugs [see Contraindications (4)]. Immediately and permanently discontinue Oxaliplatin Injection for hypersensitivity reactions and administer appropriate treatment for management of the hypersensitivity reaction [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

Oxaliplatin Injection, in combination with infusional fluorouracil and 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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

Administer Oxaliplatin Injection in combination with fluorouracil and leucovorin every 2 weeks.

• For adjuvant treatment, continue treatment for up to 12 cycles or unacceptable toxicity.
• For advanced colorectal cancer, continue treatment until disease progression or unacceptable toxicity.

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Day 1

Administer Oxaliplatin 85 mg/m2 as an intravenous infusion over 120 minutes and leucovorin 200 mg/m2 as an intravenous infusion over 120 minutes at the same time in separate bags, followed by fluorouracil 400 mg/m2 as intravenous bolus over 2 to 4 minutes, followed by fluorouracil 600 mg/m2 as a 22-hour continuous infusion.

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Day 2

Administer leucovorin 200 mg/m2 as an intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m2 as intravenous bolus over 2 to 4 minutes, followed by fluorouracil 600 mg/m2 as a 22-hour continuous infusion.

Refer to the prescribing information for fluorouracil and leucovorin for additional information.

2.2 Dosage Modification for Adverse Reactions

Prolongation of infusion time for Oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities, such as non-life threatening infusion-related reactions.

Permanently discontinue Oxaliplatin for any of the following:

Refer to the fluorouracil and leucovorin prescribing information for dosage modifications for adverse reactions.

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.4)]
• Confirmed interstitial lung disease or pulmonary fibrosis [see Warnings and Precautions (5.5)]
• Rhabdomyolysis [see Warnings and Precautions (5.8)]

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Dosage Modifications for Adjuvant Treatment

Dosage modifications for adverse reactions for adjuvant treatment are presented in Table 1.

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Dosage Modifications for Advanced Colorectal Cancer

Dosage modifications for adverse reactions for advanced colorectal cancer are presented in Table 2.

2.3 Dosage Modifications for Patients with Renal Impairment

In patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min, calculated by the Cockcroft-Gault equation), reduce the Oxaliplatin Injection dose to 65 mg/m2 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.4 Preparation and Administration

• Oxaliplatin Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
• Do not freeze.
• Protect the concentrated solution from light.
• Dilute concentrated solution with 250 to 500 mL of 5% Dextrose Injection, USP. Do not dilute with sodium chloride solution or other chloride-containing solutions.
• Store diluted solution for no more than 6 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours under refrigeration (2°C to 8°C [36°F to 46°F]). Protection from light is not required.
• Visually inspect for particulate matter and discoloration prior to administration and discard if present.
• Do not mix Oxaliplatin or administer Oxaliplatin through the same infusion line concurrently with alkaline medications or media (such as basic solutions of fluorouracil).
• Flush the infusion line with 5% Dextrose Injection, USP prior to administration of any concomitant medication.
• Do not use needles or intravenous administration sets containing aluminum parts for the preparation or mixing of Oxaliplatin. Aluminum has been reported to cause degradation of platinum compounds.
• Administer Oxaliplatin as an intravenous infusion over 120 minutes concurrently with leucovorin over 120 minutes in separate bags.

3 DOSAGE FORMS AND STRENGTHS

Injection: 50 mg (5 mg/mL) or 100 mg (5 mg/mL) clear, colorless solution in a single-dose vial.

4 CONTRAINDICATIONS

Oxaliplatin is contraindicated in patients with a history of a hypersensitivity reaction to oxaliplatin or other platinum-based drugs. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Serious and fatal hypersensitivity reactions, including anaphylaxis, can occur with Oxaliplatin within minutes of administration and during any cycle. Grade 3-4 hypersensitivity reactions, including anaphylaxis, occurred in 2% to 3% of patients with colon cancer who received Oxaliplatin. Hypersensitivity reactions, including rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension, were similar in nature and severity to those reported with other platinum-based drugs.

Oxaliplatin is contraindicated in patients with hypersensitivity reactions to platinum-based drugs [see Contraindications (4)]. Immediately and permanently discontinue Oxaliplatin for hypersensitivity reactions and administer appropriate treatment for management of hypersensitivity reactions.

5.2 Peripheral Sensory Neuropathy

Oxaliplatin can cause acute and delayed neuropathy. Reduce the dose or permanently discontinue Oxaliplatin for persistent neurosensory reactions based on the severity of the adverse reaction [see Dosage and Administration (2.3)].

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Acute Neuropathy

Acute neuropathy typically presents as a reversible, primarily peripheral sensory neuropathy that occurs within hours or 2 days following a dose, resolves within 14 days, and frequently recurs with further dosing. The symptoms can 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 patients who received Oxaliplatin Injection with fluorouracil/leucovorin. In any individual cycle, acute neuropathy occurred in approximately 30% of patients. For grade 3 peripheral sensory neuropathy, the median time to onset was 9 cycles for adjuvant treatment and 6 cycles for previously treated advanced colorectal cancer.

An acute syndrome of pharyngolaryngeal dysesthesia occurred in 1% to 2% (grade 3 to 4) of patients previously untreated for advanced colorectal cancer. Subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing) occurred in patients previously treated for advanced colorectal cancer.

Avoid topical application of ice for mucositis prophylaxis or other conditions, because cold temperature can exacerbate acute neurological symptoms.

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Delayed Neuropathy

Delayed neuropathy typically presents as a persistent (greater than 14 days), primarily peripheral sensory neuropathy that is usually characterized by paresthesias, dysesthesias, and 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 patients receiving Oxaliplatin. Delayed neuropathy can occur without any prior acute neuropathy. Most patients (80%) who developed grade 3 persistent neuropathy progressed from prior grade 1 or 2 reactions. These symptoms may improve in some patients upon discontinuation of Oxaliplatin.

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Adjuvant treatment

In the adjuvant treatment trial, neuropathy was graded using NCI CTC, version 1 as summarized in Table 3.

Peripheral sensory neuropathy occurred in 92% of patients (all grades), including 13% of patients (grade 3) who received Oxaliplatin with fluorouracil/leucovorin. At the 28-day follow-up after the last treatment cycle, 60% of patients had any grade (grade 1=40%, grade 2=16%, grade 3=5%) peripheral sensory neuropathy, decreasing to 39% at 6 months of 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%).

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Advanced colorectal cancer

In the advanced colorectal cancer trials, neuropathy was graded using the neurotoxicity scale summarized in Table 4.

Neuropathy occurred in 82% (all grades) of patients previously untreated for advanced colorectal cancer, including 19% grade 3-4; and in 74% (all grades) of patients previously treated for advanced colorectal cancer, including 7% grade 3-4.

5.3 Severe Myelosuppression

Grade 3 or 4 neutropenia occurred in 41% to 44% of patients with colorectal cancer who received Oxaliplatin with fluorouracil/leucovorin. Sepsis, neutropenic sepsis and septic shock, including fatal outcomes, occurred in patients who received Oxaliplatin [see Adverse Reactions (6.1, 6.2)].

Grade 3 or 4 thrombocytopenia occurred in 2% to 5% of patients with colorectal cancer who received Oxaliplatin with fluorouracil/leucovorin.

Monitor complete blood cell count at baseline, before each subsequent cycle and as clinically indicated. Delay Oxaliplatin until neutrophils are greater than or equal to 1.5 × 109/L and platelets are greater than or equal to 75 × 109/L. Withhold Oxaliplatin for sepsis or septic shock. Dose reduce Oxaliplatin after recovery from grade 4 neutropenia, febrile neutropenia or grade 3-4 thrombocytopenia as recommended [see Dosage and Administration (2.2)].

5.4 Posterior Reversible Encephalopathy Syndrome

PRES occurred in less than 0.1% of patients across clinical trials [see Adverse Reactions (6.1)]. Signs and symptoms of PRES can include headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Confirm the diagnosis of PRES with magnetic resonance imaging. Permanently discontinue Oxaliplatin in patients who develop PRES.

5.5 Pulmonary Toxicity

Oxaliplatin has been associated with pulmonary fibrosis (less than 1% of patients), which may be fatal [see Adverse Reactions (6.1)].

In the adjuvant treatment trial, the combined incidence of cough and dyspnea was 7.4% (any grade), including less than 1% (grade 3) in the Oxaliplatin arm. One patient died from eosinophilic pneumonia in the Oxaliplatin arm.

In the previously untreated advanced colorectal cancer trial, the combined incidence of cough, dyspnea and hypoxia was 43% (any grade), including 7% (grade 3-4) in the Oxaliplatin with fluorouracil/leucovorin arm.

In case of unexplained respiratory symptoms, such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, withhold Oxaliplatin until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis. Permanently discontinue Oxaliplatin for confirmed interstitial lung disease or pulmonary fibrosis.

5.6 Hepatotoxicity

In the adjuvant treatment trial, increased transaminases (57% vs 34%) and alkaline phosphatase (42% vs 20%) occurred more commonly in the Oxaliplatin arm than in the fluorouracil/leucovorin arm [see Adverse Reactions (6.1)]. 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. Consider evaluating patients who develop abnormal liver tests or portal hypertension which cannot be explained by liver metastases, for hepatic vascular disorders. Monitor liver function tests at baseline, before each subsequent cycle and as clinically indicated.

5.7 QT Interval Prolongation and Ventricular Arrhythmias

QT prolongation and ventricular arrhythmias, including fatal torsade de pointes, have been reported with Oxaliplatin [see Adverse Reactions (6.2)].

Avoid Oxaliplatin in patients with congenital long QT syndrome. Monitor electrocardiograms (ECG) in patients with congestive heart failure, bradyarrhythmias, and electrolyte abnormalities and in patients taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics [see Drug Interactions (7.1)]. Monitor and correct electrolyte abnormalities prior to initiating Oxaliplatin and periodically during treatment.

5.8 Rhabdomyolysis

Rhabdomyolysis, including fatal cases, has been reported with Oxaliplatin [see Adverse Reactions (6.2)]. Permanently discontinue Oxaliplatin for any signs or symptoms of rhabdomyolysis.

5.9 Hemorrhage

The incidence of hemorrhage in clinical trials was higher on the Oxaliplatin combination arm compared to the fluorouracil/leucovorin arm. These reactions included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant treatment trial, 2 patients died from intracerebral hemorrhage [see Adverse Reactions (6.1)].

Prolonged prothrombin time and INR occasionally associated with hemorrhage have been reported in patients who received Oxaliplatin with fluorouracil/leucovorin while on anticoagulants [see Adverse Reactions (6.2)]. Increase frequency of monitoring in patients who are receiving Oxaliplatin with fluorouracil/leucovorin and oral anticoagulants [see Drug Interactions (7.3)].

Thrombocytopenia and immune-mediated thrombocytopenia have been observed with Oxaliplatin. Rapid onset of thrombocytopenia and greater risk of bleeding have been observed in immune-mediated thrombocytopenia. In this case, consider discontinuing Oxaliplatin.

5.10 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, Oxaliplatin can cause fetal harm when administered to a 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 a fetus. Advise females of reproductive potential to use effective contraception during treatment with Oxaliplatin and for at least 9 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Oxaliplatin and for 6 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

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

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Peripheral Sensory Neuropathy [see Warnings and Precautions (5.2)]
• Severe Myelosuppression [see Warnings and Precautions (5.3)]
• Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.4)]
• Pulmonary Toxicity [see Warnings and Precautions (5.5)]
• Hepatotoxicity [see Warnings and Precautions (5.6)]
• QT Interval Prolongation and Ventricular Arrhythmias [see Warnings and Precautions (5.7)]
• Rhabdomyolysis [see Warnings and Precautions (5.8)]
• Hemorrhage [see Warnings and Precautions (5.9)]

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.

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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.

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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.

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.

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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.

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.

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Additional Adverse Reactions

The following adverse reactions were observed across clinical trials.

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Intravenous site reactions

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

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PRES

PRES occurred in less than 0.1% of patients.

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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

7 DRUG INTERACTIONS

7.1 Drugs that Prolong the QT Interval

QT interval prolongation and ventricular arrhythmias can occur with Oxaliplatin [see Warnings and Precautions (5.7)]. Avoid coadministration of Oxaliplatin with medicinal products with a known potential to prolong the QT interval.

7.2 Use with Nephrotoxic Drugs

Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds [see Clinical Pharmacology (12.3)]. Avoid coadministration of Oxaliplatin with medicinal products known to cause nephrotoxicity.

7.3 Use with Anticoagulants

Prolonged prothrombin time and INR occasionally associated with hemorrhage have been reported in patients who received Oxaliplatin with fluorouracil/leucovorin while on anticoagulants [see Warnings and Precautions (5.10), Adverse Reactions (6.2)]. Increase frequency of monitoring in patients who are receiving Oxaliplatin with fluorouracil/leucovorin and oral anticoagulants.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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Risk Summary

Based on its direct interaction with DNA, Oxaliplatin can cause fetal harm when administered to a 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 a pregnant woman of the potential risk to a 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.

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Data

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Animal data

Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days (GD)1-5 (preimplantation), GD 6-10, or GD 11-16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days GD 6-10 and GD 11-16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days GD 6-10.

8.2 Lactation

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Risk Summary

There 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 and for 3 months after the final dose.

8.3 Females and Males of Reproductive Potential

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Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating Oxaliplatin [see Use in Specific Populations (8.1)].

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Contraception

Oxaliplatin can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

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Females

Advise female patients of reproductive potential to use effective contraception while receiving Oxaliplatin and for 9 months after the final dose.

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Males

Based on its mechanism action as a genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving Oxaliplatin and for 6 months after the final dose [see Nonclinical Toxicology (13.1)].

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Infertility

Based on animal studies, Oxaliplatin may impair fertility in males and females [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of Oxaliplatin in pediatrics have not been established. Safety and effectiveness were assessed across 4 open-label studies in 235 patients aged 7 months to 22 years with solid tumors.

In a multicenter, open-label, non-comparative, non-randomized study (ARD5531), oxaliplatin was administered to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. The dose limiting toxicity (DLT) was sensory neuropathy at a dose of 110 mg/m2. The main adverse reactions were: paresthesia (60%, grade 3-4: 7%), fever (40%, grade 3-4: 7%), and thrombocytopenia (40%, grade 3-4: 27%). No responses were observed.

In an open-label non-randomized study (DFI7434), oxaliplatin was administered to 26 pediatric patients with metastatic or unresectable solid tumors, mainly neuroblastoma and ganglioneuroblastoma. The DLT was sensory neuropathy at a dose of 160 mg/m2. No responses were observed.

In an open-label, single-agent study (ARD5021), oxaliplatin was administered to 43 pediatric patients with recurrent or refractory embryonal CNS tumors. The most common adverse reactions reported were: leukopenia (67%, grade 3-4: 12%), anemia (65%, grade 3-4: 5%), thrombocytopenia (65%, grade 3-4: 26%), vomiting (65%, grade 3-4: 7%), neutropenia (58%, grade 3-4: 16%), and sensory neuropathy (40%, grade 3-4: 5%).

In an open-label single-agent study (ARD5530), oxaliplatin was administered to 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. The most common adverse reactions reported were: sensory neuropathy (52%, grade 3-4: 12%), thrombocytopenia (37%, grade 3-4: 17%), anemia (37%, grade 3-4: 9%), vomiting (26%, grade 3-4: 4%), increased ALT (24%, grade 3-4: 6%), increased AST (24%, grade 3-4: 2%), and nausea (23%, grade 3-4: 3%).

The pharmacokinetic parameters of ultrafiltrable platinum were 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 (%CV, 41%). Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 ± 0.24 mcg/mL, AUC0-48h of 7.52 ± 5.07 mcg∙h/mL and AUCinf of 8.83 ± 1.57 mcg∙h/mL at 85 mg/m2 of oxaliplatin and Cmax of 1.10 ± 0.43 mcg/mL, AUC0-48h of 9.74 ± 2.52 mcg∙h/mL and AUCinf of 17.3 ± 5.34 mcg∙h/mL at 130 mg/m2 of oxaliplatin.

8.5 Geriatric Use

In the adjuvant treatment trial [see Clinical Studies (14.1)], 400 patients who received Oxaliplatin with fluorouracil/leucovorin were greater than or equal to 65 years. The effect of Oxaliplatin in patients greater than or equal to 65 years was not conclusive. Patients greater than or equal to 65 years receiving Oxaliplatin experienced more diarrhea and grade 3-4 neutropenia (45% vs 39%) compared to patients less than 65 years.

In the previously untreated advanced colorectal cancer trial [see Clinical Studies (14.2)], 99 patients who received Oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the greater than or equal to 65 years patients as in the overall study population. Adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope.

In the previously treated advanced colorectal cancer trial [see Clinical Studies (14.3)], 55 patients who received Oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. No overall differences in effectiveness were observed between these patients and younger adults. Adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, and fatigue.

No significant effect of age on the clearance of ultrafiltrable platinum has been observed [see Clinical Pharmacology (12.3)].

8.6 Patients with Renal Impairment

The AUC of unbound platinum in plasma ultrafiltrate was increased in patients with renal impairment [see Clinical Pharmacology (12.3)]. No dose reduction is recommended for patients with mild (creatinine clearance 50 to 79 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal impairment, calculated by Cockcroft-Gault equation. Reduce the dose of Oxaliplatin in patients with severe renal impairment (creatinine clearance less than 30 mL/min) [see Dosage and Administration (2.3)].

10 OVERDOSAGE

The maximum dose of oxaliplatin that has been administered in a single infusion is 825 mg. Several cases of overdoses have been reported with Oxaliplatin. Adverse reactions observed following an overdosage were grade 4 thrombocytopenia (less than 25,000/mm3) without bleeding, anemia, sensory neuropathy (including paresthesia, dysesthesia, laryngospasm and facial muscle spasms), gastrointestinal disorders (including nausea, vomiting, stomatitis, flatulence, abdomen enlarged and grade 4 intestinal obstruction), grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia and death.

Closely monitor patients suspected of receiving an overdose, including for the adverse reactions described above and administer appropriate supportive treatment.

11 DESCRIPTION

Oxaliplatin is a platinum-based drug with the molecular formula C8H14N2O4Pt and 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 a leaving group.

The molecular weight is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone.

Oxaliplatin Injection, USP, for intravenous use is supplied in 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, USP is present as an inactive ingredient.

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]).

12.2 Pharmacodynamics

A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.

12.3 Pharmacokinetics

The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. After a single 2-hour intravenous infusion of Oxaliplatin at a dose of 85 mg/m2, pharmacokinetic parameters expressed as ultrafiltrable platinum were Cmax of 0.814 mcg/mL and volume of distribution of 440 L.

Interpatient and intrapatient variability in ultrafiltrable platinum exposure (AUC0-48hr) assessed over 3 cycles was 23% and 6%, respectively.

SPL UNCLASSIFIED SECTION

Distribution

At the end of a 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. The decline of ultrafiltrable platinum levels following Oxaliplatin administration is triphasic, including two distribution phases (t1/2α; 0.43 hours and t1/2β; 16.8 hours).

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.

SPL UNCLASSIFIED SECTION

Elimination

The decline of ultrafiltrable platinum concentrations from plasma is characterized by a long terminal elimination phase (t1/2γ; 392 hours).

SPL UNCLASSIFIED SECTION

Metabolism

Oxaliplatin 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 a number of noncytotoxic, conjugated species.

SPL UNCLASSIFIED SECTION

Excretion

The major route of platinum elimination is renal excretion. At five days after a 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 a rate (10 to 17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). The renal clearance of ultrafiltrable platinum is significantly correlated with GFR.

SPL UNCLASSIFIED SECTION

Special Populations

SPL UNCLASSIFIED SECTION

Sex

There was no significant effect of sex on the clearance of ultrafiltrable platinum.

SPL UNCLASSIFIED SECTION

Patients with renal impairment

Patients with normal function (CLcr greater than 80 mL/min) and patients with mild (CLcr=50- 80 mL/min) and moderate (CLcr equal to 30-49 mL/min) renal impairment received Oxaliplatin 85 mg/m2 and those with severe (CLcr less than 30 mL/min) renal impairment received Oxaliplatin 65 mg/m2. Mean dose adjusted AUC of unbound platinum was 40%, 95%, and 342% higher for patients with mild, moderate, and severe renal impairment, respectively, compared to patients with normal renal function. Mean dose adjusted 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 [see Dosage and Administration (2.3)].

SPL UNCLASSIFIED SECTION

Drug Interaction Studies

No pharmacokinetic interaction between Oxaliplatin 85 mg/m2 and infusional fluorouracil has been observed in patients treated every 2 weeks, but increases of fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 of Oxaliplatin administered every 3 weeks.

In vitro platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel.

In vitro Oxaliplatin does not inhibit human cytochrome P450 isoenzymes.

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 a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a 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).

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 a body surface area basis) x 5 days every 28 days for three cycles. A no effect level was not identified.

14 CLINICAL STUDIES

14.1 Adjuvant Treatment with Oxaliplatin in Combination with Fluorouracil and Leucovorin

The efficacy of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in an international, multicenter, randomized (1:1) trial (The Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer [MOSAIC], NCT00275210) in patients with stage II (Dukes' B2) or III (Dukes' C) colon cancer who had undergone complete resection of the primary tumor. Patients were randomized to receive Oxaliplatin with fluorouracil/leucovorin or fluorouracil/leucovorin alone for a total of 6 months (i.e., 12 cycles). Table 14 shows the dosing regimens for the two arms.

Eligible patients were between 18 and 75 years of age, had histologically proven stage II (T3-T4 N0 M0; Dukes' B2) or III (any T N1-2 M0; Dukes' C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., greater than or equal to 15 cm from the anal margin) and had undergone (within 7 weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease and carcino-embyrogenic antigen (CEA) less than 10 ng/mL. Additional eligibility criteria were no prior chemotherapy, immunotherapy or radiotherapy; Eastern Cooperative Oncology Group performance status of 0, 1, or 2 (Karnofsky Performance Status greater than or equal to 60%); no pre-existing neuropathy; and absolute neutrophil count (ANC) greater than or equal to 1.5 × 109/L, platelets greater than or equal to 100 × 109/L, serum creatinine less than or equal to 1.25 × upper limit normal (ULN), total bilirubin less than 2 × ULN, and aspartate transaminase (AST)/alanine transaminase (ALT) less than 2 × ULN. The major efficacy outcome was 3-year disease-free survival (DFS).

There were 2,246 patients enrolled, of whom 1,347 (60%) had Stage III disease. Tables 15 and 16 show the baseline characteristics and exposure to Oxaliplatin.

The median duration of follow-up was approximately 77 months. In the overall and the stage III colon cancer populations, DFS was statistically significantly improved in the Oxaliplatin - containing arm compared to fluorouracil/leucovorin alone; however, a statistically significant improvement in DFS was not observed in Stage II patients. No significant differences in overall survival (OS) were detected in the overall population or those with Stage III disease. Table 17 and Figures 1 and 2 summarize the 5-year DFS rates in the overall randomized population and in patients with stage II and III disease based on an intention-to-treat (ITT) analysis.

Figure 1: Kaplan-Meier Curves of Disease-Free Survival (cutoff: 1 June 2006) in Adjuvant Treatment Trial – ITT Population

Figure 2: Kaplan-Meier Curves of Disease-Free Survival in Stage III Patients (cutoff: 1 June 2006) in Adjuvant Treatment Trial - ITT Population

Table 18 summarizes the OS results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis.

14.2 Previously Untreated Advanced Colorectal Cancer

The efficacy of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a North American, multicenter, open-label, randomized, active-controlled trial (A Randomized Phase III Trial of Three Different Regimens of CPT-11 Plus 5-Fluorouracil and Leucovorin Compared to 5-Fluorouracil and Leucovorin in Patients with Advanced Adenocarcinoma of the Colon and Rectum; NCT00003594). The trial included 7 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 trial, the control arm was changed to irinotecan with fluorouracil/leucovorin.

The results reported below compared the efficacy of Oxaliplatin with fluorouracil/leucovorin and Oxaliplatin with irinotecan to an approved control regimen of irinotecan with fluorouracil/leucovorin in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. Table 19 presents the dosing regimens for the three arms. After completion of enrollment, the dose of irinotecan with fluorouracil/leucovorin was decreased due to toxicity.

Eligible patients were at least 18 years of age; had known locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy; with an Eastern Cooperative Oncology Group (ECOG) performance status ≤0, 1, or 2. Patients had to have absolute neutrophil count (ANC) greater than or equal to 1.5 × 109/L, platelets greater than or equal to 100 × 109/L, hemoglobin greater than or equal to 9.0 g/dL, creatinine less than or equal to 1.5 × upper limit of normal (ULN), total bilirubin less than or equal to 1.5 mg/dL, aspartate transaminase (AST) less than or equal to 5 × ULN, and alkaline phosphatase less than or equal to 5 × ULN. Patients may have received adjuvant treatment for resected Stage II or III disease without recurrence within 12 months. Randomization was stratified by ECOG performance status (0, 1 vs 2), prior adjuvant chemotherapy (yes vs no), prior immunotherapy (yes vs no), and age (less than 65 vs greater than or equal to 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 with fluorouracil/leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan with fluorouracil/leucovorin arm received an oxaliplatin-containing regimen. The main efficacy outcome measure was 3-year disease-free survival (DFS) and additional efficacy outcome measures were overall survival (OS).

Table 20 presents the baseline characteristics.

The median number of cycles administered per patient was 10 (23.9 weeks) for the Oxaliplatin plus fluorouracil/leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus fluorouracil/leucovorin regimen, and 7 (21.0 weeks) for the Oxaliplatin plus irinotecan regimen.

Patients who received Oxaliplatin with fluorouracil/leucovorin had a significantly longer time to tumor progression based on investigator assessment, longer OS, and a significantly higher confirmed response rate based on investigator assessment compared to patients who received irinotecan with fluorouracil/leucovorin. Efficacy results are summarized in Table 21 and Figure 3.

Figure 3: Kaplan-Meier Curves for Overall Survival in Previously Untreated Advanced Colorectal Cancer Trial

*Log rank test comparing Oxaliplatin plus 5-FU/LV to irinotecan plus 5-FU/LV

In descriptive subgroup analyses, the improvement in overall survival (OS) for Oxaliplatin with fluorouracil/leucovorin compared to irinotecan with fluorouracil/leucovorin appeared to be maintained across age groups, prior adjuvant treatment, number of organs involved and both sexes; however, the effect appeared larger among women than men.

14.3 Previously Treated Advanced Colorectal Cancer

The efficacy of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a multicenter, open-label, randomized, three-arm controlled trial was conducted in the US and Canada in patients with advanced colorectal cancer who had relapsed/progressed during or within 6 months of first-line treatment with bolus fluorouracil/leucovorin and irinotecan (A multicenter, open-label, randomized, three-arm study of 5-fluorouracil (5-FU) + leucovorin (LV) or oxaliplatin or a combination of 5-FU/LV + oxaliplatin as second-line treatment of metastatic colorectal carcinoma: NCT00008281). Patients were randomized to one of three regimens; the dosing regimens are presented in Table 22. Eligible patients were at least 18 years of age, had unresectable, measurable, histologically proven colorectal adenocarcinoma, with a Karnofsky performance status (KPS) greater than 50%. Patients had to have aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase less than or equal to 2× upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case less than or equal to 5× ULN was permitted. Prior radiotherapy was permitted if it had been completed at least 3 weeks before randomization. The main efficacy outcome measure was 3-year disease-free survival (DFS) and an additional outcome measure was overall survival (OS).

Patients must have had at least one unidimensional lesion measuring greater than or equal to 20 mm using conventional CT or MRI scans or greater than or equal to10 mm using a spiral CT scan. Tumor response and progression were assessed every 3 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 4 weeks.

Baseline characteristics are shown in Table 23.

The median number of cycles administered per patient was 6 for the Oxaliplatin and fluorouracil/leucovorin combination and 3 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. Efficacy results are summarized in Tables 24 and 25.

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.

15 REFERENCES

• “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

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

The container closure is not made with natural rubber latex.

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).

Oxaliplatin is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 The use of gloves is recommended. If a solution of Oxaliplatin contacts the skin, wash the skin immediately and thoroughly with soap and water. If Oxaliplatin contacts the mucous membranes, flush thoroughly with water.

17 PATIENT COUNSELING INFORMATION

SPL UNCLASSIFIED SECTION

Hypersensitivity Reactions

Advise patients of the potential risk of hypersensitivity and that Oxaliplatin is contraindicated in patients with a history of hypersensitivity reactions to oxaliplatin and other platinum-based drugs. Instruct patients to seek immediate medical attention for signs of severe hypersensitivity reaction such as chest tightness; shortness of breath; wheezing; dizziness or faintness; or swelling of the face, eyelids, or lips [see Warnings and Precautions (5.1)].

SPL UNCLASSIFIED SECTION

Peripheral Sensory Neuropathy

Advise patients of the risk of acute reversible or persistent-type neurosensory toxicity. Advise patients to avoid cold drinks, use of ice, and exposure of skin to cold temperature or cold objects [see Warnings and Precautions (5.2)].

SPL UNCLASSIFIED SECTION

Myelosuppression

Inform patients that Oxaliplatin can cause low blood cell counts and the need for frequent monitoring of blood cell counts. Advise patients to contact their healthcare provider immediately for bleeding, fever, particularly if associated with persistent diarrhea, or symptoms of infection develop [see Warnings and Precautions (5.3)].

SPL UNCLASSIFIED SECTION

Posterior Reversible Encephalopathy Syndrome

Advise patients of the potential effects of vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), which may affect the patients' ability to drive and use machines [see Warnings and Precautions (5.4)].

SPL UNCLASSIFIED SECTION

Pulmonary Toxicity

Advise patients to report immediately to their healthcare provider any persistent or recurrent respiratory symptoms, such as non-productive cough and dyspnea [see Warnings and Precautions (5.5)].

SPL UNCLASSIFIED SECTION

Hepatotoxicity

Advise patients to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions (5.6)].

SPL UNCLASSIFIED SECTION

QT Interval Prolongation

Advise patients that Oxaliplatin can cause QTc interval prolongation and to inform their physician if they have any symptoms, such as syncope [see Warnings and Precautions (5.7)].

SPL UNCLASSIFIED SECTION

Rhabdomyolysis

Advise patients to contact their healthcare provider immediately for new or worsening signs or symptoms of muscle toxicity, dark urine, decreased urine output, or the inability to urinate [see Warnings and Precautions (5.8)].

SPL UNCLASSIFIED SECTION

Hemorrhage

Advise patients that Oxaliplatin may increase the risk of bleeding and to promptly inform their healthcare provider of any bleeding episodes [see Warnings and Precautions (5.9)].

SPL UNCLASSIFIED SECTION

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with Oxaliplatin and for 9 months after the final dose [see Use in Specific Populations (8.3)].

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Oxaliplatin and for 6 months after the final dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

SPL UNCLASSIFIED SECTION

Lactation

Advise women not to breastfeed during treatment with Oxaliplatin and for 3 months after the final dose [see Use in Specific Populations (8.2)].

SPL UNCLASSIFIED SECTION

Infertility

Advise females and males of reproductive potential that Oxaliplatin may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

SPL UNCLASSIFIED SECTION

Gastrointestinal

Advise patients to contact their healthcare provider for persistent vomiting, diarrhea, or signs of dehydration [see Adverse Reactions (6.1)].

SPL UNCLASSIFIED SECTION

Drug Interactions

Inform patients about the risk of drug interactions and the importance of providing a list of prescription and nonprescription drugs to their healthcare provider [see Drug Interactions (7)].

For Product Inquiry:1-800-551-7176 or www.fresenius-kabi.com/us451426C

SPL PATIENT PACKAGE INSERT SECTION

Patient Information

Oxaliplatin Injection (ox-AL-i-PLA-tin)

for intravenous use

What is the most important information I should know about Oxaliplatin Injection?

Oxaliplatin Injection can cause serious allergic reactions, including allergic reactions that can lead to death. Oxaliplatin is a platinum-based medicine. Serious allergic reactions including death can happen in people who take Oxaliplatin and who have had previous allergic reactions to platinum-based medicines. Serious allergic reactions can happen within a few minutes of your Oxaliplatin infusion or any time during your treatment with Oxaliplatin Injection.

Get emergency help right away if you:

Call your doctor right away if you have any of the following signs or symptoms of an allergic reaction:

See "What are the possible side effects of Oxaliplatin Injection?" for information about other serious side effects.

What is Oxaliplatin Injection?

Oxaliplatin is an anti-cancer (chemotherapy) medicine that is used with other anti-cancer medicines called fluorouracil and leucovorin to treat people with:

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 a complete list of the ingredients Oxaliplatin Injection.

Ask your doctor if you are not sure if you take a medicine that contains platinum.

What should I tell my doctor before receiving Oxaliplatin Injection?

Before receiving Oxaliplatin Injection, tell your doctor about all of your medical conditions, including if you:

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 a list of them and show it to your doctor and pharmacist when you get a new medicine.

How will I receive Oxaliplatin Injection?

Treatment Day 1:

Treatment Day 2:

You will not get Oxaliplatin 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 a 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 a healthcare provider touch your infusion pump or tubing.

What should I avoid while receiving Oxaliplatin Injection?

See “How can I 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 Injection?

Oxaliplatin Injection can cause serious side effects, including:

For information on ways to lessen or help with the nerve problems, see the end of this leaflet, “How can I reduce the side effects caused by cold temperatures?”

The most common side effects of Oxaliplatin Injection include:

Tell your doctor if you have any side effect that bothers your 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 I reduce the side effects caused by cold temperatures?

Your doctor may have other useful tips for helping you with side effects.

General information about the safe and effective use of Oxaliplatin Injection

Medicines 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 Injection?

Active ingredient: oxaliplatin

Inactive ingredient: water for injection

For Product Inquiry:1-800-551-7176 or www.fresenius-kabi.com/us451427CRevised: September 2021

This Patient Information has been approved by the U.S. Food and Drug Administration.

• have trouble breathing
• feel like your throat is closing up

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL PRINCIPAL DISPLAY PANEL- 50 mg per 10 mL- Vial Label

NDC 63323-750-10     775010Oxaliplatin Injection, USP50 mg per 10 mL (5 mg per mL)For intravenous use only.MUST BE DILUTED WITH 5% DEXTROSE INJECTION BEFORE USE. Preservative free. Cytotoxic agent.Do not mix or add to sodium chloride/chloride-containing solutions.

Rx only Single Dose Vial

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL PRINCIPAL DISPLAY PANEL- 50 mg per 10 mL- Vial Carton Panel NDC 63323-750-10     775010Oxaliplatin Injection, USP50 mg per 10 mL (5 mg per mL)For intravenous use only.MUST BE DILUTED WITH 5% DEXTROSE INJECTION BEFORE USE. Preservative free. Cytotoxic agent. Do not  mix or add to sodium chloride/chloride-containing solutions.

Single Dose Vial   Rx only