oxaliplatin 50 MG Injection

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 )

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 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 65 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 65 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 . 2.3 Dose 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/m 2 [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 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.

WARNINGS AND PRECAUTIONS Peripheral Sensory Neuropathy : Acute and delayed neuropathy can occur. Avoid topical application of ice. Reduce the dose or permanently discontinue oxaliplatin as recommended. ( 5.2 ) Severe Myelosuppression : Delay oxaliplatin 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 sepsis or septic shock. Dose reduce after recovery from grade 4 neutropenia, febrile neutropenia, or grade 3 to 4 thrombocytopenia as recommended. ( 5.3 ) Posterior Reversible Encephalopathy Syndrome (PRES) : Permanently discontinue oxaliplatin in patients who develop PRES. ( 5.4 ) Pulmonary Toxicity : Withhold oxaliplatin 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 and periodically during treatment. ( 5.7 ) Rhabdomyolysis : Permanently discontinue oxaliplatin if rhabdomyolysis occurs. ( 5.8 ) Hemorrhage : Increase frequency of monitoring in patients who are receiving oxaliplatin 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 within minutes of administration and during any cycle. Grade 3 to 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 ( 2.2 )] . 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 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. 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. Adjuvant treatment In the adjuvant treatment trial, neuropathy was graded using NCI CTC, version 1 as summarized in Table 3 . Table 3: Grading for Neuropathy in Adjuvant Treatment Trial Grade Definition 0 No change or none 1 Mild paresthesias, loss of deep tendon reflexes 2 Mild or moderate objective sensory loss, moderate paresthesias 3 Severe objective sensory loss or paresthesias that interfere with function 4 Not applicable 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%). Advanced colorectal cancer In the advanced colorectal cancer trials, neuropathy was graded using the neurotoxicity scale summarized in Table 4 . Table 4: Grading for Neuropathy in Advanced Colorectal Cancer Trials Grade Definition 1 Resolved and did not interfere with functioning 2 Interfered with function but not daily activities 3 Pain or functional impairment that interfered with daily activities 4 Persistent impairment that is disabling or life-threatening Neuropathy occurred in 82% (all grades) of patients previously untreated for advanced colorectal cancer, including 19% grade 3 to 4; and in 74% (all grades) of patients previously treated for advanced colorectal cancer, including 7% grade 3 to 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 × 10 9 /L and platelets are greater than or equal to 75 × 10 9 /L. Withhold oxaliplatin for sepsis or septic shock. Dose reduce oxaliplatin after recovery from grade 4 neutropenia, febrile neutropenia or grade 3 to 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

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 )

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 injection at a dose of 85 mg/m 2 , pharmacokinetic parameters expressed as ultrafiltrable platinum were C max of 0.814 mcg/mL and volume of distribution of 440 L. Interpatient and intrapatient variability in ultrafiltrable platinum exposure (AUC 0-48hr ) assessed over 3 cycles was 23% and 6%, respectively. Distribution At the end of a 2-hour infusion of oxaliplatin injection, 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 injection administration is triphasic, including two distribution phases (t 1/2α ; 0.43 hours and t 1/2β ; 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/m 2 every two weeks. Elimination The decline of ultrafiltrable platinum concentrations from plasma is characterized by a long terminal elimination phase (t 1/2y ; 391 hour). 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. Excretion The major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of oxaliplatin injection, 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 (10-17 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. Special Populations Sex There was no significant effect of sex on the clearance of ultrafiltrable platinum. Patients with renal impairment Patients with normal function (CLcr greater than 80 mL/min) and patients with mild (CLcr=50­80 mL/min) and moderate (CLcr equal to 30-49 mL/min) renal impairment received oxaliplatin injection 85 mg/m 2 and those with severe (CLcr less than 30 mL/min) renal impairment received oxaliplatin injection 65 mg/m 2 . 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 C max 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)] . Drug Interaction Studies No pharmacokinetic interaction between oxaliplatin injection 85 mg/m 2 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/m 2 of oxaliplatin injection 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.