Oxaliplatin Drug Information

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.

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.

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

Dose Modifications for Adverse Reactions Prolongation of infusion time for oxaliplatin injection from 2 hours to 6 hours may mitigate acute toxicities, such as non-life-threatening infusion-related reactions. Dosage Modifications for Adjuvant Treatment Dosage modifications for adverse reactions for adjuvant treatment are presented in Table 1. Table 2: Dosage Modifications for Advanced Colorectal Cancer

Dose Modifications for Patients with Renal Impairment

In patients with severe renal impairment (creatinine clearance less than 30 mL/min, calculated by the Cockcroft-Gault equation), reduce the oxaliplatin injection dose to 65 mg/m 2.

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. Protection from light is not required.

Visually inspect for particulate matter and discoloration prior to administration and discard if present. Do not mix oxaliplatin injection or administer oxaliplatin injection 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 injection. Aluminum has been reported to cause degradation of platinum compounds. Administer oxaliplatin injection as an intravenous infusion over 120 minutes concurrently with leucovorin over 120 minutes in separate bags.

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 were treated in trials with oxaliplatin. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant treatment were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis.

The most common adverse reactions in previously untreated and treated patients with advanced colorectal cancer were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea. Adjuvant Treatment The safety of oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor in the adjuvant treatment trial. 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).

Grade 3 or 4 adverse reactions occurred in 70% of patients in the oxaliplatin arm. Grade 3 to 4 gastrointestinal bleeding occurred in 0.2% of patients. 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. In patients greater than or equal to 65 years old, the incidence of grade 3 to 4 diarrhea and neutropenia was higher than in younger adults. Clinically relevant adverse reactions were reported in greater than or equal to 2% and less than 5% of the patients in the oxaliplatin arm (listed in decreasing order of frequency) were pain, leukopenia, weight loss, and cough.

Table 7: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Colon Cancer Receiving Adjuvant Treatment 5 Previously Untreated Advanced Colorectal Cancer The safety of oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial of patients with previously untreated advanced colorectal cancer. The adverse reaction profile in this trial was similar to that seen in other trials. Tables 8, 9, and 10 summarize the adverse reactions reported in the previously untreated advanced colorectal cancer trial.

Table 8: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial greater than or equal to 5% of all patients and with greater than or equal to 1% grade Table 9: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial greater than or equal to 5% of all patients but with less than 1% grade Clinically relevant adverse reactions that occurred in greater than or equal to 2% and less than 5% of the patients in the oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: metabolic, pneumonitis, catheter infection, vertigo, prothrombin time, pulmonary, rectal bleeding, dysuria, nail changes, chest pain, rectal pain, syncope, hypertension, hypoxia, unknown infection, bone pain, pigmentation changes, and urticaria. Table 10: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients in the Previously Untreated Advanced Colorectal Cancer Trial 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. Three patients who received oxaliplatin in the combination arm experienced fatal adverse reactions: gastrointestinal bleeding and dehydration.

Grade 3 to 4 increased serum creatinine occurred in 1% of patients in the oxaliplatin with combination fluorouracil/leucovorin arm. Thirteen percent of patients in the oxaliplatin with fluorouracil/leucovorin combination arm discontinued treatment; the most frequent reasons were gastrointestinal adverse reactions, hematologic adverse reactions and neuropathies. Tables 11, 12, and 13 summarize the adverse reactions reported in the previously treated advanced colorectal cancer trial.

Table 11: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3 to 4): Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Clinical Trial greater than or equal to 5% of all patients but with less than 1% grade Clinically relevant adverse reactions in greater than or equal to 2% and less than 5% of the patients in the oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: anxiety, myalgia, erythematous rash, increased sweating, conjunctivitis, weight decrease, dry mouth, rectal hemorrhage, depression, ataxia, ascites, hemorrhoids, muscle weakness, nervousness, tachycardia, abnormal micturition frequency, dry skin, pruritus, hemoptysis, purpura, vaginal hemorrhage, melena, somnolence, pneumonia, proctitis, involuntary muscle contractions, intestinal obstruction, gingivitis, tenesmus, hot flashes, enlarged abdomen, and urinary incontinence. Table 13: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Previously Treated Advanced Colorectal Cancer 6 Additional Adverse Reactions The following adverse reactions were observed across clinical trials. Intravenous site reactions Injection site reaction, including redness, swelling, and pain, can occur with oxaliplatin.

In some cases, skin necrosis has occurred with extravasation. PRES PRES occurred in less than 0.1% of patients. Pulmonary fibrosis and interstitial lung disease Pulmonary fibrosis, which may be fatal, occurred in less than 1% of patients.

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, focal nodular hyperplasia, 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

Drugs that Prolong the QT Interval

QT interval prolongation and ventricular arrhythmias can occur with oxaliplatin. Avoid coadministration of oxaliplatin with medicinal products with a known potential to prolong the QT interval.

Use with Nephrotoxic Products

Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds. Avoid coadministration of oxaliplatin with medicinal products known to cause nephrotoxicity.

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. Increase frequency of monitoring in patients who are receiving oxaliplatin with fluorouracil/leucovorin and oral anticoagulants.

Pregnancy 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 respectively.

Pediatric Use The safety and effectiveness of oxaliplatin in pediatrics have not been established. 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/m 2.

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. 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. 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 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%).

Oxaliplatin is contraindicated in patients with a history of a hypersensitivity reaction to oxaliplatin or other platinum-based drugs. Reactions have included anaphylaxis.

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/mm 3 ) 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.