Oxaliplatin

DOSAGE AND ADMINISTARTION (2.2) 10/2015 WARNINGS AND PRECAUTIONS (5.3,5.4,5.7,5.8,5.9) 10/2015

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 & ADMINISTRATION Oxaliplatin for injection should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. - Administer oxaliplatin for injection in combination with 5-fluorouracil/leucovorin every 2 weeks. (2.1): - Day 1: Oxaliplatin for injection 85 mg/m 2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection, USP and leucovorin 200 mg/m 2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m 2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m 2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion. - Day 2: leucovorin 200 mg/m 2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m 2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m 2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion. - Reduce the dose of oxaliplatin for injection to 75 mg/m 2 (adjuvant setting) or 65 mg/m 2 (advanced colorectal cancer) (2.2) : - if there are persistent grade 2 neurosensory events that do not resolve. - after recovery from grade 3/4 gastrointestinal toxicities (despite prophylactic treatment) or grade 4 neutropenia or febrile neutropenia or grade 3/4 thrombocytopenia. Delay next dose until neutrophils ≥1.5 x 10 9 /L and platelets ≥75 x 10 9 /L. - For patients with severe renal impairment (Creatinine clearance <30 mL/min), the initial recommended dose is 65 mg/m 2 . (2.2) - Discontinue oxaliplatin for injection if there are persistent Grade 3 neurosensory events. (2.2) - Never reconstitute or prepare final dilution with a sodium chloride solution or other chloride-containing solutions. (2.3) 2.1 Dosage Administer oxaliplatin for injection in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles): Day 1: Oxaliplatin for injection 85 mg/m 2 intravenous infusion in 250 to 500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m 2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m 2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m 2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion. Day 2: Leucovorin 200 mg/m 2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m 2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m 2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion. Figure 1 The administration of oxaliplatin for injection does not require prehydration. Premedication with antiemetics, including 5-HT 3 blockers with or without dexamethasone, is recommended. For information on 5-fluorouracil and leucovorin, see the respective package inserts. Oxaliplatin-image1 2.2 Dose Modification Recommendations Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.11)]. Prolongation of infusion time for oxaliplatin for injection from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed. Adjuvant Therapy in Patients with Stage III Colon Cancer Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)]. For patients who experience persistent …

3 DOSAGE FORMS & STRENGTHS Oxaliplatin for injection is supplied in single-dose vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free lyophilized powder for reconstitution. Single-dose vials of 50 mg or 100 mg oxaliplatin as a sterile, preservative-free lyophilized powder for reconstitution. (3)

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 )

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 …

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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Based on direct interaction with DNA, oxaliplatin for injection may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of oxaliplatin for injection in pregnant women. Reproductive toxicity studies in rats demonstrated adverse effects on fertility and embryo-fetal development at maternal doses that were below the recommended human dose based on body surface area. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant and use effective contraception while receiving treatment with oxaliplatin for injection. Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days 1 to 5 (pre-implantation), 6 to 10, or 11 to 16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6 to 10 and 11 to 16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6 to 10. Administration of oxaliplatin to male and female rats prior to mating resulted in 97% post-implantation loss in animals that received approximately one-seventh the recommended human dose based on the body surface area. 8.3 Nursing Mothers It is not known whether oxaliplatin for injection or its derivatives are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from oxaliplatin for injection, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase 1 and 2 Phase 2 trials in 235 patients ages 7 months to 22 years with solid tumors (see below) and no significant activity observed. In a Phase 1/2 study, oxaliplatin was administered as a 2-hour intravenous infusion on days 1, 8 and 15 every 4 weeks (1 cycle), for a maximum of 6 cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight pediatric patients in the Phase 1 study received oxaliplatin at 6 dose levels starting at 40 mg/m2 with escalation to 110 mg/m2. The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m2 dose. Fifteen patients received oxaliplatin at a dose of 90 mg/m2 intravenous in the Phase 2 portion of the study. At this dose, paresthesia (60%, G3/4: 7%), fever (40%, G3/4: 7%) and thrombocytopenia (40%, G3/4: 27%) were the main adverse reactions. No responses were observed. In a second Phase 1 study, oxaliplatin was administered to 26 pediatric patients as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) at 5 dose levels starting at 100 mg/m2 with escalation to 160 mg/m2, for a maximum of 6 cycles. In a separate cohort, oxaliplatin 85 mg/m2 was administered on day 1 every 2 weeks, for a maximum of 9 doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma. No responses were observed. The DLT was sensory neuropathy at the 160 mg/m2 dose. Based on these studies, oxaliplatin 130 mg/m2 as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) was used in subsequent Phase II studies. A dose of 85 mg/m2 on day 1 every 2 weeks was also found to be tolerable. In one Phase 2 study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months in absence of progressive disease or unacceptable toxicity. In patients < 10 kg the oxaliplatin dose used was 4.3 mg/kg. The most common adverse rea …

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 5-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 for injection USP is an antineoplastic agent 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 for injection, USP is supplied in vials containing 50 mg or 100 mg of Oxaliplatin, USP as a sterile, preservative-free lyophilized powder for reconstitution. Lactose monohydrate is present as an inactive ingredient at 450 mg and 900 mg in the 50 mg and 100 mg dosage strengths, respectively. Oxaliplatin-image2

10 OVERDOSAGE There is no known antidote for oxaliplatin for injection overdose. In addition to thrombocytopenia, the anticipated complications of an oxaliplatin for injection overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhea and neurotoxicity. Several cases of overdoses have been reported with oxaliplatin for injection. Adverse reactions observed were Grade 4 thrombocytopenia (<25,000/mm 3 ) without any bleeding, anemia, sensory neuropathy such as paresthesia, dysesthesia, laryngospasm and facial muscle spasms, gastrointestinal disorders such as nausea, vomiting, stomatitis, flatulence, abdomen enlarged and Grade 4 intestinal obstruction, Grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia and death. Patients suspected of receiving an overdose should be monitored, and supportive treatment should be administered. The maximum dose of oxaliplatin that has been administered in a single infusion is 825 mg.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Oxaliplatin for Injection USP is supplied in clear, glass, single-use vials with gray elastomeric stoppers and aluminum flip-off seals containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free lyophilized powder for reconstitution. Lactose monohydrate is also present as an inactive ingredient. NDC 68083-170-01: 50 mg single-use vial with red flip-off seal individually packaged in a carton. NDC 68083-171-01: 100 mg single-use vial with yellow flip-off seal individually packaged in a carton. 16.2 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C [See USP Controlled Room Temperature]. 16.3 Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from oxaliplatin for injection. The use of gloves is recommended. If a solution of oxaliplatin for injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If oxaliplatin for injection contacts the mucous membranes, flush thoroughly with water. Procedures for the handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published [ see References (15) ]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.