Vinorelbine

1 INDICATIONS AND USAGE Vinorelbine Injection is indicated: In combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) As a single agent for the treatment of patients with metastatic NSCLC Vinorelbine Injection is a vinca alkaloid indicated: In combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) ( 1 ) As a single agent for first-line treatment of patients with metastatic NSCLC ( 1 )

2 DOSAGE AND ADMINISTRATION In combination with cisplatin: 25 to 30 mg/m 2 as an intravenous injection or infusion once weekly ( 2.1 ) Single agent: 30 mg/m 2 as intravenously once a week ( 2.1 ) Adjust dose in patients with decreased neutrophil counts or elevated serum total bilirubin ( 2.2 ) 2.1 Recommended Dosage In Combination with Cisplatin 100 mg/m 2 The recommended dosage of Vinorelbine Injection is 25 mg/m 2 administered as an intravenous injection or infusion over 6 to 10 minutes on Days 1, 8, 15 and 22 of a 28-day cycle in combination with cisplatin 100 mg/m 2 on Day 1 only of each 28-day cycle. In Combination with Cisplatin 120 mg/m 2 The recommended dosage of Vinorelbine Injection is 30 mg/m 2 administered as an intravenous injection or infusion over 6 to 10 minutes once a week in combination with cisplatin 120 mg/m 2 on Days 1 and 29, then every 6 weeks. Single Agent The recommended dosage of Vinorelbine Injection is 30 mg/m 2 administered intravenously over 6 to 10 minutes once a week. 2.2 Dosage Modifications Myelosuppression Hold or decrease the dose of Vinorelbine Injection in patients with decreased neutrophil counts according to the following schema [see Warnings and Precautions ( 5.1 )]: Neutrophils on Day of Treatment (cells/mm 3 ) Percentage of Starting Dose of Vinorelbine Injection ≥ 1,500 100% 1,000 to 1,499 50% < 1,000 Do not administer Vinorelbine Injection. Repeat neutrophil count in one week. If three consecutive weekly doses are held because neutrophil count is < 1,000 cells/mm 3 , discontinue Vinorelbine Injection Note: For patients who experience fever and/or sepsis while neutrophil count is < 1,500 cells/mm 3 or had 2 consecutive weekly doses held due to neutropenia, subsequent doses of Vinorelbine Injection should be: > 1,500 75% 1,000 to 1,499 37.5% < 1,000 Do not administer Vinorelbine Injection. Repeat neutrophil count in one week. Hepatic Impairment/Toxicity Reduce Vinorelbine Injection dose in patients with elevated serum total bilirubin concentration according to the following schema [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 )] : Serum Total Bilirubin Concentration (mg/dl) Percentage of Starting Dose of Vinorelbine Injection ≤ 2.0 100% 2.1 to 3.0 50% > 3.0 25% Concurrent Myelosuppression and Hepatic Impairment/Toxicity In patients with both myelosuppression and hepatic impairment/toxicity, administer the lower of the doses based on the corresponding starting dose of Vinorelbine Injection determined from the above schemas. Neurologic Toxicity Discontinue Vinorelbine Injection for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or higher peripheral neuropathy or autonomic neuropathy causing constipation [see Warnings and Precautions ( 5.5 )]. 2.3 Preparation and Administration Preparation Dilute Vinorelbine Injection in an intravenous bag to a concentration between 0.5 mg/mL and 2 mg/mL. Use one of the following recommended solutions for dilution: 5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP 0.45% Sodium Chloride Injection, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP Ringer's Injection, USP Lactated Ringer's Injection, USP Stability and Storage Conditions of Diluted Solutions Diluted Vinorelbine Injection may be used for up to 24 hours under normal room light when stored in polyvinyl chloride bags at 5° to 30°C (41° to 86°F). Administration Administer diluted Vinorelbine Injection over 6 to 10 minutes into the side port of a free-flowing intravenous line followed by flushing with at least 75 to 125 mL of one of the solutions. Vinorelbine Injection must only be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any Vinorelbine Injection is injected. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If particulate matter is seen, Vinor…

5 WARNINGS AND PRECAUTIONS Hepatic Toxicity: Monitor hepatic function prior to initiation and during treatment ( 5.2 ) Severe constipation and bowel obstruction, including necrosis and perforation, occur. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction and/or paralytic ileus ( 5.3 ) Extravasation can result in severe tissue injury, local tissue necrosis and/or thrombophlebitis. Immediately stop vinorelbine and institute recommended management procedures ( 5.4 ) Neurologic Toxicity: Severe sensory and motor neuropathies occur. Monitor patients for new or worsening signs and symptoms of neuropathy. Discontinue for Grade 2 or greater neuropathy ( 5.5 ) Pulmonary toxicity and respiratory failure occur. Interrupt vinorelbine in patients who develop unexplained dyspnea or have any evidence of pulmonary toxicity. Permanently discontinue for confirmed interstitial pneumonitis or ARDS ( 5.6 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus and to use effective contraception ( 5.7 , 8.1 , 8.3 ) 5.1 Myelosuppression Myelosuppression, manifested by neutropenia, anemia and thrombocytopenia, occur in patients receiving vinorelbine as a single agent and in combination with cisplatin [see Adverse Reactions ( 6.1 , 6.2 )] . Neutropenia is the major dose-limiting toxicity with vinorelbine. Grade 3-4 neutropenia occurred in 53% of patients treated with vinorelbine at 30 mg/m 2 per week. Dose adjustment due to myelosuppression occurred in 51% of patients (Study 2). In clinical trials with vinorelbine administered at 30 mg/m 2 per week, neutropenia resulted in hospitalizations for pyrexia and/or sepsis in 8% of patients. Death due to sepsis occurred in 1% of patients. Neutropenia nadirs occur between 7 and 10 days after dosing with neutropenia count recovery usually occurring within the following 7 to 14 days. Monitor complete blood counts prior to each dose of vinorelbine. Do not administer vinorelbine to patients with neutrophil counts <1,000 cells/mm 3 . Adjustments in the dosage of vinorelbine should be based on neutrophil counts obtained on the day of treatment [see Dosage and Administration ( 2.2 )]. 5.2 Hepatic Toxicity Drug-induced liver injury manifest by elevated aspartate aminotransferase (AST) and bilirubin occur in patients receiving vinorelbine as a single agent and in combination with cytotoxic agents. Assess hepatic function prior to initiation of vinorelbine and periodically during treatment. Reduce the dose of vinorelbine for patients who develop elevations in total bilirubin ≥ 2 times upper limit of normal [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )]. 5.3 Severe Constipation and Bowel Obstruction Severe and fatal paralytic ileus, constipation, intestinal obstruction, necrosis, and perforation occur in patients receiving vinorelbine. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction and/or paralytic ileus, considering adequate dietary fiber intake, hydration and routine use of stool softeners. 5.4 Extravasation and Tissue Injury Extravasation of vinorelbine can result in severe irritation, local tissue necrosis and/or thrombophlebitis. If signs or symptoms of extravasation occur, immediately stop administration of vinorelbine and institute recommended management procedures [see Dosage and Administration ( 2.2 ) and Adverse Reactions ( 6.1 )]. 5.5 Neurologic Toxicity Sensory and motor neuropathies, including severe neuropathies, occur in patients receiving vinorelbine. Monitor patients for new or worsening signs and symptoms of neuropathy, such as paresthesia, hyperesthesia, hyporeflexia and muscle weakness while receiving vinorelbine. Discontinue vinorelbine for CTCAE Grade 2 or greater neuropathy [see Dosage and Administration ( 2.2 ) and Adverse Reactions ( 6.1 )]. 5.6 Pulmonary Toxicity and Respiratory Failure Pulmonary toxicity, includin…

4 CONTRAINDICATIONS None None

7 DRUG INTERACTIONS Inhibitors of CYP3A4: May cause earlier onset and/or increased severity of adverse reactions ( 7.1 ) 7.1 CYP3A Inhibitors Exercise caution in patients concurrently taking drugs known to inhibit CYP3A. Concurrent administration of vinorelbine with a CYP3A inhibitor may cause an earlier onset and/or an increased severity of adverse reactions.

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , vinorelbine can cause fetal harm when administered to a pregnant woman. Available human data are insufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies in mice and rabbits, embryo and fetal toxicity were observed with administration of vinorelbine at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively (see Data ) . Advise pregnant women 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 are 2 to 4% and 15 to 20%, respectively. Data Animal Data In a mouse embryo-fetal development study, administration of a single dose of vinorelbine at a dose level of 9 mg/m 2 or greater (approximately 0.33 times the recommended human dose based on body surface area) was embryotoxic and fetotoxic. Vinorelbine was embryotoxic and fetotoxic to pregnant rabbits when administered every 6 days during the period of organogenesis at doses of 5.5 mg/m 2 (approximately 0.18 times the recommended human dose based on body surface area) or greater. At doses that did not cause maternal toxicity in either species, vinorelbine administration resulted in reduced fetal weight and delayed ossification.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions ( 5.1 )] Hepatic Toxicity [see Warnings and Precautions ( 5.2 )] Severe Constipation and Bowel Obstruction [see Warnings and Precautions ( 5.3 )] Extravasation and Tissue Injury [see Warnings and Precautions ( 5.4 )] Neurologic Toxicity [see Warnings and Precautions ( 5.5 )] Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions ( 5.6 )] Most common adverse reactions (incidence ≥ 20%) are leukopenia, neutropenia, anemia, increased aspartate aminotransferase, nausea, vomiting, constipation, asthenia, injection site reaction and peripheral neuropathy ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial and may not reflect the rates actually observed in clinical practice. Single Agent The data below reflect exposure to vinorelbine as a single agent administered at a dose of 30 mg/m 2 on a weekly basis to 365 patients enrolled in 3 controlled studies for metastatic NSCLC and advanced breast cancer. The population included 143 patients with previously untreated metastatic NSCLC (Study 3) who received a median of 8 doses of vinorelbine. The patients were aged 32 to 79 (median 61 years), 71% were male, 91% White, 48% had adenocarcinoma histology. The data also reflect exposure to vinorelbine in 222 patients with previously treated advanced breast cancer who received a median of 10 doses of vinorelbine. Vinorelbine is not indicated for the treatment of breast cancer. Selected adverse reactions reported in these studies are provided in Tables 1 and 2 . The most common adverse reactions (≥ 20%) of single agent vinorelbine were leukopenia, neutropenia, anemia, increased aspartate aminotransferase (AST), nausea, vomiting, constipation, asthenia, injection site reaction and peripheral neuropathy. The most common (≥ 5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, anemia, increased total bilirubin, increased AST, injection site reaction and asthenia. Approximately 49% of patients with NSCLC who were treated with vinorelbine experienced at least one dose reduction due to an adverse reaction. Thirteen percent of patients discontinued vinorelbine due to adverse reactions. The most frequent adverse reactions leading to vinorelbine discontinuation were asthenia, dyspnea, nausea, constipation, anorexia, myasthenia and fever. Table 1: Hematologic Adverse Reactions Experienced in > 5% of Patients Receiving Vinorelbine *† : * Grade based on modified criteria from the National Cancer Institute version 1. † Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy. All Patients (N=365) (%) NSCLC (N=143) (%) Laboratory Hematologic Neutropenia < 2,000 cells/mm 3 90 80 < 500 cells/mm 3 36 29 Leukopenia < 4,000 cells/mm 3 92 81 < 1,000 cells/mm 3 15 12 Thrombocytopenia < 100,000 cells/mm 3 5 4 Anemia < 11 g/dl 83 77 < 8 g/dl 9 1 Hospitalizations due to neutropenic complications 9 8 Table 2: Non-hematologic Adverse Reactions Experienced in ≥ 5% of Patients Receiving Vinorelbine *† : * Grade based on modified criteria from the National Cancer Institute version 1. † Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy. ‡ Incidence of paresthesia plus hypesthesia. All Grades Grade 3-4 All Patients (%) NSCLC (%) All Patients (%) NSCLC (%) Laboratory Hepatic AST increased (N=346) 67 54 6 3 Bilirubin increased (N=351) 13 9 7 5 Clinical Nausea 44 34 2 1 Asthenia 36 27 7 5 Cons…