Oxaliplatin

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

2 DOSAGE AND ADMINISTRATION Administer oxaliplatin for injection 85 mg/m 2 as an intravenous infusion over 120 minutes concurrently with leucovorin over 120 minutes in separate bags, followed by fluorouracil on Day 1 of each 14-day cycle. Administer fluorouracil and leucovorin on Day 2 as recommended. ( 2.1 ) Adjuvant Treatment : Continue treatment for up to 12 cycles or unacceptable toxicity. ( 2.1 ) Advanced Colorectal Cancer : Continue treatment until disease progression or unacceptable toxicity. ( 2.1 ) 2.1 Recommended Dosage Administer oxaliplatin for 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. Day 1 Administer oxaliplatin for injection 85 mg/m 2 as an intravenous infusion over 120 minutes and leucovorin 200 mg/m 2 as an intravenous infusion over 120 minutes at the same time in separate bags, followed by fluorouracil 400 mg/m 2 as intravenous bolus over 2-4 minutes, followed by fluorouracil 600 mg/m 2 as a 22-hour continuous infusion. Day 2 Administer leucovorin 200 mg/m 2 as an intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m 2 as intravenous bolus over 2-4 minutes, followed by fluorouracil 600 mg/m 2 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 for injection from 2 hours to 6 hours may mitigate acute toxicities, such as non-life threatening infusion-related reactions. Permanently discontinue oxaliplatin for injection for any of the following: 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 )] Refer to the fluorouracil and leucovorin prescribing information for dosage modifications for adverse reactions. Dosage Modifications for Adjuvant Treatment Dosage modifications for adverse reactions for adjuvant treatment are presented in Table 1. Table 1: Dosage Modifications for Adjuvant Treatment in Patients with Stage III Colon Cancer Adverse Reactions Severity Oxaliplatin for Injection Dosage Modifications Peripheral Sensory Neuropathy [see Warnings and Precautions ( 5.2 )] Persistent Grade 2 Consider reducing oxaliplatin for injection dose to 75 mg/m 2 . Persistent Grade 3 Consider discontinuing oxaliplatin for injection. Grade 4 Discontinue oxaliplatin for injection. Myelosuppression [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 )]. Grade 4 neutropenia or febrile neutropenia Delay the next dose until neutrophils greater than or equal to 1.5 × 10 9 /L and platelets greater than or equal to 75 × 10 9 /L. Reduce oxaliplatin for injection dose to 75 mg/m 2 Grade 3-4 thrombocytopenia Gastrointestinal Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3-4 After recovery, reduce oxaliplatin for injection dose to 75 mg/m 2 along with a dose reduction of fluorouracil to 300 mg/m 2 as an intravenous bolus and 500 mg/m 2 as a 22-hour continuous infusion. Dosage Modifications for Advanced Colorectal Cancer Dosage modifications for adverse reactions for advanced colorectal cancer are presented in Table 2. Table 2: Dosage Modifications for Advanced Colorectal Cancer Adverse Reactions Severity Oxaliplatin for Injection Dosage Modifications Neuropathy [see Warnings and Precautions ( 5.2 )] Persistent Grade 2 Consider reducing oxaliplatin for injection dose to 65 mg/m 2 . Persistent Grade 3 Consider discontinuing oxaliplatin for injection. Grade 4 Discontinue oxaliplatin for injection. Myelosuppression [see Warnings and Precautions ( 5.3 ), Adverse Rea…

5 WARNINGS AND PRECAUTIONS Peripheral Sensory Neuropathy : Acute and delayed neuropathy can occur. Avoid topical application of ice. Reduce the dose or permanently discontinue oxaliplatin for injection as recommended. ( 5.2 ) Severe Myelosuppression : Delay oxaliplatin for injection until neutrophils are greater than or equal to 1.5 × 10 9 /L and platelets are greater than or equal to 75 × 10 9 /L. Withhold oxaliplatin for injection for sepsis or septic shock. Dose reduce after recovery from grade 4 neutropenia, febrile neutropenia, or grade 3-4 thrombocytopenia as recommended. ( 5.3 ) Posterior Reversible Encephalopathy Syndrome (PRES): Permanently discontinue oxaliplatin for injection in patients who develop PRES. ( 5.4 ) Pulmonary Toxicity : Withhold oxaliplatin for injection until investigation excludes interstitial lung disease or pulmonary fibrosis. ( 5.5 ) Hepatotoxicity : Monitor liver function tests at baseline, before each subsequent cycle, and as clinically indicated. ( 5.6 ) QT Interval Prolongation : Avoid in patients with congenital long QT syndrome. Monitor electrocardiograms in patients with congestive heart failure, bradyarrhythmias, and electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Correct electrolyte abnormalities prior to initiating oxaliplatin for injection and periodically during treatment. ( 5.7 ) Rhabdomyolysis : Permanently discontinue oxaliplatin for injection if rhabdomyolysis occurs. ( 5.8 ) Hemorrhage : Increase frequency of monitoring in patients who are receiving oxaliplatin for injection with fluorouracil/leucovorin and oral anticoagulants ( 5.9 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise males and females of reproductive potential to use an effective method of contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 Hypersensitivity Reactions Serious and fatal hypersensitivity reactions, including anaphylaxis, can occur with oxaliplatin for injection 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 for injection. 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 for Injection is contraindicated in patients with hypersensitivity reactions to platinum-based drugs [see Contraindications ( 4 )] . Immediately and permanently discontinue oxaliplatin for injection for hypersensitivity reactions and administer appropriate treatment for management of hypersensitivity reactions. 5.2 Peripheral Sensory Neuropathy Oxaliplatin for Injection can cause acute and delayed neuropathy. Reduce the dose or permanently discontinue oxaliplatin for injection for persistent neurosensory reactions based on the severity of the adverse reaction [see Dosage and Administration ( 2.3 )] . 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 for injection ATIN 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…

4 CONTRAINDICATIONS Oxaliplatin for Injection 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 )] . History of hypersensitivity reaction to oxaliplatin or other platinum-based drugs. ( 4 , 5.1 )

7 DRUG INTERACTIONS 7.1 Drugs that Prolong the QT Interval QT interval prolongation and ventricular arrhythmias can occur with oxaliplatin for injection [see Warnings and Precautions ( 5.7 )] . Avoid coadministration of oxaliplatin for injection 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 for injection 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 for injection 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 for injection with fluorouracil/leucovorin and oral anticoagulants.

8.1 Pregnancy Risk Summary Based on its direct interaction with DNA, oxaliplatin for injection 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 for injection. 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. Data 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 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 for injection and for 3 months after the final dose.

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 )] Most common adverse reactions (incidence greater than or equal to 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact QILU PHARMA, INC. at 484-838-0633/ 484-875-3013 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 for injection. 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 for injection 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 for injection 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 for injection arm. Grade 3 or 4 adverse reactions occurred in 70% of patients in the oxaliplatin for injection 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 for injection arm. Tables 5, 6, and 7 summarize the adverse reactions reported in patients with colon cancer receiving adjuvant treatment. Table 5: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4) Oxaliplatin for Injection + FU/LV N=1108 FU/LV N=1111 Adverse Reaction Event coded in WHO-ART dictionary All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Neurology Peripheral Sensory Neuropathy 92 12 16 <1 Gastrointestinal Nausea 74 5 61 2 Diarrhea 56 11 48 7 Vomiting 47 6 24 1 Stomatitis 42 3 40 2 Anorexia 13 1 8 <1 Constitutional Symptoms/Pain Fatigue 44 4 38 1 Abdominal Pain 18 1 17 2 Dermatology/Skin Skin Disorder 32 2 36 2 Injection Site Reaction Includes thrombosis related to the catheter 11 3 10 3 Fever/Infection Fever 27 1 12 1 Infection 25 4 25 3 Allergy/Immunology Allergic Reaction 10 3 2 <1 Table 6…