Oxaliplatin

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. Oxaliplatin injection 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 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 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 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 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. Permanently discontinue oxaliplatin 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 Injection Dosage Modifications Peripheral Sensory Neuropathy [see Warnings and Precautions (5.2)] Persistent Grade 2 Consider reducing oxaliplatin injection dose to 75 mg/m 2 . Persistent Grade 3 Consider discontinuing oxaliplatin injection. Grade 4 Discontinue oxaliplatin 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 injection dose to 75 mg/m 2 . Grade 3 to 4 thrombocytopenia Gastrointestinal Adverse Reactions [see Adverse Reactions (6.1)] Grade 3 to 4 After recovery, reduce oxaliplatin 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 Injection Dosage Modifications Neuropathy [see Warnings and Precautions (5.2)] Persistent Grade 2 Consider reducing oxaliplatin injection dose to 65 mg/m 2 . Persistent Grade 3 Consider discontinuing oxaliplatin injection. Grade 4 Discontinue oxaliplatin injection. Myelosuppression [see Warnings and Precautions (5.3), Adverse Reactions (6.1)] Grade 4 neutropenia or febrile neut …

3 DOSAGE FORMS AND STRENGTHS Oxaliplatin injection, USP: 50 mg/10 mL (5 mg/mL) or 100 mg/20 mL (5 mg/mL) sterile, clear, colorless solution in a single-dose vial. Injection: 50 mg/10 mL (5 mg/mL) or 100 mg/20 mL (5 mg/mL) in a single-dose vial ( 3 )

4 CONTRAINDICATIONS Oxaliplatin 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 )

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 Accord Healthcare Inc. at 1-866-941-7875 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 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 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 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 injection arm. Grade 3 or 4 adverse reactions occurred in 70% of patients in the Oxaliplatin 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 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 Injection + FU/LV N=1108 FU/LV N=1111 Adverse reaction * All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) * Event coded in WHO-ART dictionary † Includes thrombosis related to the catheter 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 † 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: Adverse Reactions Reported in P …

7 DRUG INTERACTIONS 7.1 Drugs that Prolong the QT Interval QT interval prolongation and ventricular arrhythmias can occur with Oxaliplatin injection [see Warnings and Precautions (5.7) ] . Avoid coadministration of Oxaliplatin injection with medicinal products with a known potential to prolong the QT interval. 7.2 Use with Nephrotoxic Product 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 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 injection with fluorouracil/leucovorin while on anticoagulants [see Warnings and Precautions (5.9) , Adverse Reactions (6.2) ] . Increase frequency of monitoring in patients who are receiving Oxaliplatin injection with fluorouracil/leucovorin and oral anticoagulants.

8 USE IN SPECIFIC POPULATIONS Females: Advise female patients of reproductive potential to use effective contraception while receiving Oxaliplatin injection and for 9 months after the final dose. (8.3) 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 injection and for 6 months after the final dose [ see Nonclinical Toxicology (13.1) ]. 8.1 Pregnancy Risk Summary Based on its direct interaction with DNA, Oxaliplatin 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 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 injection and for 3 months after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating Oxaliplatin injection [see Use in Specific Populations (8.1) ] . Contraception Oxaliplatin injection can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Females Advise female patients of reproductive potential to use effective contraception while receiving Oxaliplatin injection and for 9 months after the final dose. 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 injection and for 6 months after the final dose [see Nonclinical Toxicology (13.1) ] . Infertility Based on animal studies, Oxaliplatin injection may impair fertility in males and females [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of Oxaliplatin injection 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/m 2 . 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/m 2 . No responses were observed. In an open-label, single-agent study (ARD5021), …

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]).

11 DESCRIPTION Oxaliplatin Injection, USP is a platinum-based drug with the molecular formula C 8 H 14 N 2 O 4 Pt 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 for intravenous use after dilution. Each mL contains 5 mg of Oxaliplatin with 0.03 mg Tartaric Acid, NF and 0.0123 mg Sodium Hydroxide, NF used in combination as a buffering system and Water for Injection, USP. Chemical Structure

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 injection. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Oxaliplatin injection is supplied in clear, glass, single-dose vials with gray elastomeric stoppers and aluminum flip-off seals containing 50 mg or 100 mg or 200 mg of oxaliplatin as a clear, colorless, sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. NDC 16729-332-03: 50 mg/10 mL single-dose vial with green flip-off seal individually packaged in a carton. NDC 16729-332-05: 100 mg/20 mL single-dose vial with dark blue flip-off seal individually packaged in a carton. NDC 16729-332-35: 200 mg/40 mL single-dose vial with orange flip-off seal individually packaged in a carton. Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Do not freeze and protect from light (keep in original outer carton). Discard unused portion. Oxaliplatin injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 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.