INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION MyelosuppressionAdvise patients to contact healthcare provider for new onset fever, or symptoms of infection [see Warnings and Precautions (5.1)]. Constipation and Bowel ObstructionAdvise patients to follow diet rich in fibers, drink fluids to stay well hydrated and use stool softeners to avoid constipation. Contact health care provider for severe constipation, new onset abdominal pain, nausea and vomiting [see Warnings and Precautions (5.3)]. Neurologic ToxicityAdvise patients to contact health care provider for new onset or worsening of numbness, tingling, decrease sensation or muscle weakness [see Warnings and Precautions (5.5)]. Pulmonary ToxicityAdvise patients to contact healthcare provider for new onset or worsening of shortness of breath, cough, wheezing or other new pulmonary symptoms [see Warnings and Precautions (5.6)]. Embryo-Fetal ToxicityAdvise pregnant women of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to use effective contraception during treatment with vinorelbine and for months after the final dose [see Use in Specific Populations (8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with vinorelbine and for months after the final dose [see Use in Specific Population (8.3) and Nonclinical Toxicology (13.1)]. LactationAdvise women not to breastfeed during treatment with vinorelbine and for days after the final dose [see Use in Specific Populations (8.2)]. InfertilityAdvise males of reproductive potential that vinorelbine may impair fertility [see Use in Specific Populations (8.3)]. Manufactured In Romania By:Sindan Pharma SRLBucharest 1, Romania Distributed By: Actavis Pharma, Inc. Parsippany, NJ 07054 USARev. 1/2020. Advise pregnant women of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to use effective contraception during treatment with vinorelbine and for months after the final dose [see Use in Specific Populations (8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with vinorelbine and for months after the final dose [see Use in Specific Population (8.3) and Nonclinical Toxicology (13.1)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS . Lactation: Advise not to breastfeed (8.2). Lactation: Advise not to breastfeed (8.2). 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 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 fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.DataAnimal DataIn mouse embryo-fetal development study, administration of single dose of vinorelbine at dose level of mg/m2 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 days during the period of organogenesis at doses of 5.5 mg/m2 (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. 8.2 Lactation. Risk SummaryThere are no data on the presence of vinorelbine in human milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from vinorelbine, advise women not to breastfeed during treatment with vinorelbine and for days after the final dose.. 8.3 Females and Malesof Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating vinorelbine [see Use in Specific Populations (8.1)]. ContraceptionFemalesVinorelbine can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with vinorelbine and for months after the final dose.MalesVinorelbine may damage spermatozoa [see Nonclinical Toxicology (13.1)]. Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with vinorelbine and for months after the final dose.InfertilityMalesBased on animal findings, vinorelbine may impair fertility in males [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of vinorelbine in pediatric patients have not been established. Results from single-arm study of vinorelbine administered at the dose of 33.75 mg/m2 (for 35 patients) or at the dose of 30 mg/m2 (for 11 patients) every week for weeks followed by weeks of rest were evaluated (courses of weeks). Forty-six patients age to 25 (median 11 years) with recurrent solid malignant tumors, including rhabdomyosarcoma or undifferentiated sarcoma (N=21 patients), neuroblastoma (N= patients) and central nervous system (CNS) tumors (N=21 patients), were enrolled. The most significant grade or hematological adverse reactions were neutropenia (70%) and anemia (33%). The most significant grade or non-hematological adverse reactions were motor (15%) or cranial (13%) neuropathy, hypoxia (13%) and dyspnea (11%). Objective tumor response was observed in out of 21 patients with rhabdomyosarcoma or undifferentiated sarcoma. No objective tumor response was observed in patients with CNS tumors (N=21) or neuroblastoma (N=4). 8.5 Geriatric Use Of the 769 number of patients who received vinorelbine as single agent and in combination with cisplatin in studies 1, and 3, 247 patients were 65 years of age or older. No overall differences in safety, efficacy and pharmacokinetic parameters were observed between these patients and younger patients [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment The influence of hepatic impairment on the pharmacokinetics of vinorelbine has not been evaluated, but the liver plays an important role in the metabolism of vinorelbine. Elevated AST occur in greater than 60% of the patients receiving vinorelbine as single agent (6% Grade to 4). Therefore, exercise caution in patients with hepatic impairment. Reduce the dose of vinorelbine for patients with elevated serum total bilirubin concentrations [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

WARNINGS AND PRECAUTIONS SECTION.

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 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 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 ARDA (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). Hepatic Toxicity: Monitor hepatic function prior to initiation and during treatment (5.2) Severe constipation and bowel obstruction, including necrosis and perforation, occur. Institute 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 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 ARDA (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 single agent and in combination with cisplatin [see Adverse Reactions (6.1 and 6.2)]. Neutropenia is the major dose-limiting toxicity with vinorelbine. Grade to neutropenia occurred in 53% of patients treated with vinorelbine at 30 mg/m2 per week. Dose adjustment due to myelosuppression occurred in 51% of patients (Study 2). In clinical trials with vinorelbine administered at 30 mg/m2 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 and 10 days after dosing with neutropenia count recovery usually occurring within the following 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/mm3. 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 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 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 Reaction (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 or greater neuropathy [see Dosage and Administration (2.2) and Adverse Reaction (6.1)]. 5.6 Pulmonary Toxicity and Respiratory Failure Pulmonary toxicity, including severe acute bronchospasm, interstitial pneumonitis, acute respiratory distress syndrome (ARDS) occur in patients receiving vinorelbine. Interstitial pneumonitis and ARDS included fatalities. The mean time to onset of interstitial pneumonitis and ARDS after vinorelbine administration was one week (range to days) [see Adverse Reactions (6.1)]. Interrupt vinorelbine in patients who develop unexplained dyspnea or have any evidence of pulmonary toxicity. Permanently discontinue vinorelbine for confirmed interstitial pneumonitis or ARDS. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, vinorelbine can cause fetal harm when administered to pregnant woman. 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. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with vinorelbine and for months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with vinorelbine and for months after the final dose [see Use in Specific Populations (8.1, 8.3)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vinorelbine is vinca alkaloid that interferes with microtubule assembly. The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Vinorelbine may also interfere with: 1) amino acid, cyclic AMP and glutathione metabolism, 2) calmodulin-dependent Ca++-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. Vinorelbine inhibited mitotic microtubule formation in intact mouse embryo tectal plates at concentration of uM inducing blockade of cells at metaphase, but produced depolymerization of axonal microtubules at concentration 40 uM, suggesting modest selectivity of vinorelbine for mitotic microtubules.. 12.3 Pharmacokinetics The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m2 administered as 15- to 20-minute constant-rate infusions. Vinorelbine concentrations in plasma decay in triphasic manner. DistributionSteady-state volume of distribution (VSS) values range from 25.4 to 40.1 L/kg. Vinorelbine demonstrated high binding to human platelets and lymphocytes. The free fraction was approximately 0.11 in human plasma over concentration range of 234 to 1169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. Vinorelbine binding was not altered in the presence of cisplatin, fluorouracil, or doxorubicin.EliminationThe terminal phase half-life averages 27.7 to 43.6 hours and the mean plasma clearance ranges from 0.97 to 1.26 L/hr/kg.MetabolismVinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans and has been shown to possess antitumor activity similar to vinorelbine. Therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinorelbine is mediated by hepatic CYP3A.ExcretionAfter intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively. In different study, 10.9% +- 0.7% of 30 mg/m2 intravenous dose was excreted as parent drug in urine.Specific PopulationsAge has no effect on the pharmacokinetics (CL, VSS and t1/2) of vinorelbine.Drug Interaction StudiesThe pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Combination Use with Cisplatin The safety and efficacy of vinorelbine in combination with cisplatin was evaluated in two randomized, multicenter trials.Cisplatin 100 mg/m2Study was randomized, multicenter, open-label trial of vinorelbine plus cisplatin and cisplatin alone for the treatment of stage IV or stage IIIb NSCLC in patients with malignant pleural effusion or multiple lesions in more than one lobe of the ipsilateral lung who had not received prior chemotherapy. total of 432 patients were randomized 1:1 to receive either vinorelbine 25 mg/m2 on Day then every week of each 28-day cycle plus cisplatin 100 mg/m2 administered on Day of each 28-day cycle (N=214) or single agent cisplatin 100 mg/m2 on Day of each 28-day cycle (N=218). Patient demographics and disease characteristics were similar between arms. Of the overall study population, the median age was 64 (range 33 to 84), 66% were male, 80% were White, 92% had stage IV disease and 8% stage IIIB, 53% had adenocarcinoma, 21% squamous cell, 14% large cell histology. The major efficacy outcome measure was overall survival. The efficacy results are presented in Table and Figure 1. Table 7. Efficacy Results (Study 1) Vinorelbine plus Cisplatin Cisplatin (N=214) (N=218) Overall Survival Median Survival in months 7.8 (6.9, 9.6 6.2 (5.4, 7.7) (95% CI) Unstratified log-rank p-value 0.01 Overall Response rate (ORR) Evaluable patients = 206 N=209 ORR (95% CI) 19% (14%, 25%) 8% (5%, 13%) Chi-square test p-value <0.001Figure 1: Overall Survival Vinorelbine /Cisplatin versus Single-Agent CisplatinCisplatin 120 mg/m2Study was randomized, 3-arm, open-label, multicenter trial of vinorelbine plus cisplatin, vindesine plus cisplatin and vinorelbine as single agent for the treatment of patients with stage III or IV NSCLC who had not received prior chemotherapy. The study was conducted in Europe. total of 612 patients were randomized 1:1:1 to receive vinorelbine 30 mg/m2 every week of 6-week cycle plus cisplatin 120 mg/m2 on Day and Day 29, then every weeks thereafter (N=206); and vindesine mg/m2 for weeks, then every other week thereafter plus cisplatin 120 mg/m2 on Days and Day 29, then every weeks thereafter (N=200) or vinorelbine 30 mg/m2 every week of 6-week cycle (N=206). The main efficacy outcome measure was to compare overall survival between vinorelbine plus cisplatin and vindesine plus cisplatin. The other efficacy outcome measure was to compare overall survival in the better of the two combination regimens to that of vinorelbine as single agent. Patient demographics were in general similar between arms: the median age of the overall population was 60 years (range 30 to 75), 90% were male, 78% had WHO performance status of or 1. Tumor characteristics were in general similar with the exception of histologic subtype of NSCLC. Adenocarcinoma was the histologic subtype in 32% of patients in the vinorelbine plus cisplatin arm, 40% of patients in vindesine plus cisplatin arm and 28% of patients on the vinorelbine arm. Ten percent of the patients had stage IIIA disease, 28% stage IIIB and 50% stage IV. Twelve percent of the patients had received prior surgery or radiotherapy. The efficacy results of Study are presented in Table 8.Table 8. Efficacy Results (Study 2) Vinorelbine Vinorelbine plus Vindesine plus (N=206) cisplatin (N=206) cisplatin (N=200) 1n/a not applicable Median survival in months (99.5% CI) 7.2 (5.4, 9.1) 9.2 (7.4, 11.1) 7.4 (6.1, 9.1) Unstratified log-rank n/a1 0.087 p-value 0.05 n/a Overall Response (ORR) N=205 N=203 N=198 Evaluable Patients 14% (10%, 20%) 28% (22%, 35%) 19% (14%, 25%) ORR (95% CI) Chi-square test n/a 0.03 p-value 0.001 n/a. 3c00b60d-figure-02. 14.2 Single Agent The safety and efficacy of vinorelbine as single agent was evaluated in one randomized multi-center trial. Study was randomized, open-label clinical trial of vinorelbine or fluorouracil (FU) plus leucovorin (LV) in patients with Stage IV NSCLC who had not received prior chemotherapy total of 211 patients were randomized 2:1 to receive vinorelbine 30 mg/m2 weekly of an 8-week cycle (N=143) or FU 425 mg/m2 bolus intravenously plus LV 20 mg/m2 bolus intravenously daily for days of 4-weeks cycle (N=68). Patient demographics and disease characteristics were in general similar between arms. In the overall population, the median age was 61 years (range 32 to 83), 74% were male, 88% were White, 46% had adenocarcinoma histology. Fifty percent of the patients had Karnofsky performance status greater than or equal to 90 in the vinorelbine arm compared to 38% in the FU/LV arm. The primary efficacy outcome of the study was overall survival. The median survival time was 30 weeks versus 22 weeks for patients receiving vinorelbine versus FU/LV, respectively (p=0.06). Partial objective responses were observed in 11.1% (95% CI=6.2%, 17.9%) and 3.5% (95% CI=0.4%, 11.9%) of patients who received vinorelbine and FU/LV, respectively.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION . In combination with cisplatin: 25 to 30 mg/m2 as an intravenous injection or infusion once weekly (2.1) Single agent: 30 mg/m2 as intravenously once week (2.1) Adjust dose in patients with decreased neutrophil counts or elevated serum total bilirubin (2.2). In combination with cisplatin: 25 to 30 mg/m2 as an intravenous injection or infusion once weekly (2.1) Single agent: 30 mg/m2 as intravenously once 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/m2The recommended dose of vinorelbine is 25 mg/m2 administered as an intravenous injection or infusion over to 10 minutes on Days 1, 8, 15 and 22 of 28-day cycle in combination with cisplatin 100 mg/m2 on Day only of each 28 day cycle. In Combination with Cisplatin 120 mg/m2The recommended dose of vinorelbine is 30 mg/m2 administered as an intravenous injection or infusion over to 10 minutes once week in combination with cisplatin 120 mg/m2 on Days and 29, then every weeks.Single-Agent The recommended dose of vinorelbine is 30 mg/m2 administered intravenously over to 10 minutes once week.. The recommended dose of vinorelbine is 25 mg/m2 administered as an intravenous injection or infusion over to 10 minutes on Days 1, 8, 15 and 22 of 28-day cycle in combination with cisplatin 100 mg/m2 on Day only of each 28 day cycle. The recommended dose of vinorelbine is 30 mg/m2 administered as an intravenous injection or infusion over to 10 minutes once week in combination with cisplatin 120 mg/m2 on Days and 29, then every weeks.Single-Agent The recommended dose of vinorelbine is 30 mg/m2 administered intravenously over to 10 minutes once week.. 2.2 Dosage Modifications Myelosuppression Hold or decrease the dose of vinorelbine in patients with decreased neutrophil counts according to the following schema [see Warnings and Precautions (5.1)]: Neutrophils on Day of Treatment (cells/mm ) Percentage of Starting Dose of Vinorelbine >= 1,500 100% 1,000 to 1,499 50% 1,000 Do not administer vinorelbine. Repeat neutrophil count in one week. If three consecutive weekly doses are held because neutrophil count is 1,000 cells/mm3, discontinue vinorelbine Note: For patients who experience fever and/or sepsis while neutrophil count is 1,500 cells/mm3 or had consecutive weekly doses held due to neutropenia, subsequent doses of vinorelbine should be: 1,500 75% 1,000 to 1,499 37.5% 1,000 Do not administer vinorelbine. Repeat neutrophil count in one week.Hepatic Impairment/ToxicityReduce vinorelbine 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 <= 2.0 100% 2.1 to 3.0 50% 3.0 25%Concurrent Myelosuppression and Hepatic Impairment/ToxicityIn patients with both myelosuppression and hepatic impairment/toxicity, administer the lower of the doses based on the corresponding starting dose of vinorelbine determined from the above schemas. Neurologic ToxicityDiscontinue vinorelbine for Common Terminology Criteria for Adverse Events (CTCAE) Grade 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 concentration between 0.5 mg/mL and mg/mL. Use one of the following recommended solutions for dilution: 5% Dextrose Injection, USP0.9% Sodium Chloride Injection, USP0.45% Sodium Chloride Injection, USP5% Dextrose and 0.45% Sodium Chloride Injection, USPRingers Injection, USPLactated Ringers Injection, USPStability and Storage Conditions of Diluted SolutionsDiluted vinorelbine injection may be used for up to 24 hours under normal room light when stored in polyvinyl chloride bags at to 30C (41 to 86F). AdministrationAdminister diluted vinorelbine injection over to 10 minutes into the side port of 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 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, vinorelbine injection should not be administered.Management of Suspected ExtravasationIf vinorelbine leakage into surrounding tissue occurs or is suspected, immediately stop administration of vinorelbine and initiate appropriate management measures in accordance with institutional policies [see Warnings and Precautions (5.4)]. 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. Ringers Injection, USP. Lactated Ringers Injection, USP. 2.4 Procedures for Proper Handling and Disposal Vinorelbine is cytotoxic drug. Follow applicable special handling and disposal procedures1 Exercise caution in handling and preparing the solution of vinorelbine injection. The use of gloves is recommended. If the solution of vinorelbine injection contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. Avoid contamination of the eye with vinorelbine injection. If exposure occurs, flush the eyes with water immediately and thoroughly. Discard unused portion.

ADVERSE REACTIONS SECTION.

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)] 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 Actavis at 1-800-432-8534 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 AgentThe data below reflect exposure to vinorelbine as single agent administered at dose of 30 mg/m2 on weekly basis to 365 patients enrolled in controlled studies for metastatic NSCLC and advanced breast cancer. The population included 143 patients with previously untreated metastatic NSCLC (Study 3) who received median of 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 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 and 2. The most common adverse reactions (greater than or equal to 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 (greater than or equal to 5%) Grade or 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 Greater Than 5% of Patients Receiving Vinorelbine +: All Patients NSCLC (N=365)(%) (N= 143)(%) 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. Laboratory Hematologic Neutropenia 2,000 cells/mm3 90 80 500 cells/mm3 36 29 Leukopenia 4,000 cells/mm3 92 81 1,000 cells/mm3 15 12 Thrombocytopenia 100,000 cells/mm3 4 Anemia 11 g/dl 83 77 8 g/dl 1 Hospitalizations due to neutropenic complications 8Table 2: Non-hematologic Adverse Reactions Experienced in Greater Than or Equal to 5% of Patients Receiving Vinorelbine +: All Grades Grades to All Patients(%) NSCLC(%) All Patients(%) NSCLC(%) Grade based on modified criteria from the National Cancer Institute version 1. Incidence of paresthesia plus hypesthesia. +Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy. Laboratory Hepatic AST increased (N=346) 67 54 3 Bilirubin increased 13 7 (N=351) Clinical Nausea 44 34 1 Asthenia 36 27 5 Constipation 35 29 2 Injection site reaction 28 38 5 Injection site pain 16 13 1 Neuropathy peripheral 25 20 <2 Vomiting 20 15 1 Diarrhea 17 13 1 Alopecia 12 12 <=1 Phlebitis 10 <1 Dyspnea 3 2Myelosuppression: In clinical trials, Grade to neutropenia, anemia and thrombocytopenia occurred in 69%, 9% and 1%, respectively of patients receiving single agent vinorelbine. Neutropenia is the major dose-limiting toxicity.Neurotoxicity: Neurotoxicity was most commonly manifested as constipation, paresthesia, hyperesthesia and hyporeflexia. Grade and neuropathy was observed in 1% of the patients receiving single agent vinorelbine.Injection Site Reactions: Injection site reactions, including erythema, pain at injection site and vein discoloration, occurred in approximately one third of patients; 5% were severe. Phlebitis (chemical phlebitis) along the vein proximal to the site of injection was reported in 10% of patients.Cardiovascular Toxicity: Chest pain occurred in 5% of patients; myocardial infarction occurred in less than 0.1% of patients.Pulmonary Toxicity and Respiratory Failure: Dyspnea (shortness of breath) was reported in 3% of patients; it was severe in 2%. Interstitial pulmonary changes were documented.Other: Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in less than 1% of patients.In Combination with CisplatinTable presents the incidence of selected adverse reactions, occurring in greater than or equal to 10% of vinorelbine treated patients reported in randomized trial comparing the combination of vinorelbine 25 mg/m2 administered every week of each 28-day cycle and cisplatin 100 mg/m2 administered on day of each 28-day cycle versus cisplatin alone at the same dose and schedule in patients with previously untreated NSCLC (Study 1). Patients randomized to vinorelbine plus cisplatin received median of cycles of treatment and those randomized to cisplatin alone received median of cycles of treatment. The incidence of Grade and neutropenia was significantly higher in the vinorelbine plus cisplatin arm (82%) compared to the cisplatin alone arm (5%).Thirty-five percent of the eligible patients in the combination arm required treatment discontinuation due to an adverse reaction compared to 19% in the cisplatin alone arm. Four patients in the vinorelbine plus cisplatin arm died of neutropenic sepsis. Seven additional deaths were reported in the combination arm: from cardiac ischemia, cerebrovascular accident, multisystem failure due to an overdose of vinorelbine, and from febrile neutropenia. Table 3: Adverse Reactions Experienced by Greater Than or Equal to 10% of Patients on Vinorelbine plus Cisplatin versus Single-Agent Cisplatin Vinorelbine 25mg/m plus Cisplatin 100 mg/m (N=210) Cisplatin 100 mg/m (N=212) All Grades(%) Grades to 4(%) All Grades(%) Grades to 4(%) Graded according to the standard SWOG criteria version 1. +Categorical toxicity grade not specified Laboratory Hematologic Neutropenia 89 82 26 Anemia 89 24 72 <8 Leukopenia 88 58 31 <1 Thrombocytopenia 29 21 <2 Febrile neutropenia+ N/A 11 N/A Renal Blood creatinine increased 37 28 <5 Clinical Malaise/Fatigue/Lethargy 67 12 49 Vomiting 60 13 60 14 Nausea 58 14 57 12 Decreased appetite 46 37 Constipation 35 16 Alopecia 34 14 Weight decreased 34 21 <1 Fever without infection 20 4 Hearing impaired 18 18 <4 Injection site reaction 17 <1 0 Diarrhea 17 <3 11 <2 Paraesthesia 17 <1 10 <1 Taste alterations 17 15 Peripheral numbness 11 7 <1 Myalgia/Arthralgia 12 <1 <1 Phlebitis/Thrombosis/Embolism 10 <1 <1 Weakness 12 <3 2 Infection 11 <6 <1 <1 Respiratory tract infection 10 <5 3Table presents the incidence of selected adverse reactions, occurring in greater than or equal to 10% of vinorelbine treated patients reported in randomized trial of vinorelbine plus cisplatin, vindesine plus cisplatin and vinorelbine as single agent in patients with stage III or IV NSCLC who had not received prior chemotherapy. total of 604 patients received either vinorelbine 30 mg/m2 every week plus cisplatin 120 mg/m2 on Day and Day 29, then every weeks thereafter (N=207), vindesine mg/m2 for weeks, then every other week thereafter plus cisplatin 120 mg/m2 on Days and Day 29, then every weeks thereafter (N=193) or vinorelbine 30 mg/m2 every week (N=204). Patients randomized to vinorelbine plus cisplatin received median of 15 weeks of treatment, vindesine plus cisplatin 12 weeks and vinorelbine received 13 weeks. Grade and neutropenia was significantly greater in the vinorelbine plus cisplatin arm (78%) compared to vindesine plus cisplatin (48%) and vinorelbine as single agent (53%). Neurotoxicity, including peripheral neuropathy and constipation, was reported in 44% (Grades to 4, 7%) of the patients receiving vinorelbine plus cisplatin, 58% (Grades to 4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grades to 4, 8.5%) of the patients receiving vinorelbine as single agent. Study discontinuation due to an adverse reaction was required in 27, 22 and 10% of the patients randomized to vinorelbine plus cisplatin, vindesine plus cisplatin and cisplatin alone arms, respectively.Table 4: Adverse Reactions Experienced by Greater Than or Equal to 10 of Patients from Comparative Trial of Vinorelbine Plus Cisplatin versus Vindesine Plus Cisplatin versus Single-Agent Vinorelbine Vinorelbine/Cisplatin+ Vindesine/Cisplatin Vinorelbine All Grades(%) Grades to 4(%) All Grades(%) Grades to 4(%) All Grades(%) Grades to 4(%) Grade based on criteria from the World Health Organization (WHO). +N=194 to 207; all patients receiving vinorelbine/cisplatin with laboratory and non-laboratory data. N=173 to 192; all patients receiving vindesine/cisplatin with laboratory and non-laboratory data. N=165 to 201; all patients receiving vinorelbine with laboratory and non-laboratory data. Categorical toxicity grade not specified. Neurotoxicity includes peripheral neuropathy and constipation. Laboratory Hematologic Neutropenia 95 78 79 48 85 53 Leukopenia 94 57 82 27 83 32 Thrombocytopenia 15 10 3.5 0 Renal Blood creatinine 46 N/A 37 N/A 13 N/A increased Clinical Nausea/Vomiting 74 30 72 25 31 Alopecia 51 7.5 56 14 30 Neurotoxicity 44 58 17 44 8.5 Diarrhea 25 1.5 24 12 0.5 Injection site 17 2.5 0 22 reaction Ototoxicity 10 14 1 0. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of vinorelbine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Infections: pneumonia Immune system disorders: anaphylactic reaction, pruritus, urticaria, angioedemaNervous system disorders: loss of deep tendon reflexes, muscular weakness, gait disturbance, headacheEar and labyrinth disorders: vestibular disorder, hearing impairedCardiac disorders: tachycardiaRespiratory disorders: pulmonary edemaVascular disorders: pulmonary embolism, deep vein thrombosis, hypertension, hypotension, flushing, vasodilatationGastrointestinal disorders: mucosal inflammation, dysphagia, pancreatitisSkin disorders: generalized cutaneous reactions (rash), palmar-plantar erythrodysesthesia syndromeMusculoskeletal and connective tissue disorders: jaw pain, myalgia, arthralgiaGeneral disorders and administration site conditions: injection site rash, urticaria, blistering, sloughing of skinInjury, poisoning and procedural complications: radiation recall phenomenon, dermatitis, esophagitisLaboratory abnormalities: electrolyte imbalance including hyponatremiaOther: tumor pain, back pain, abdominal pain.