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 Sagent Pharmaceuticals, Inc. 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 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 (>= 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 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 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/mm3 9080< 500 cells/mm3 3629 Leukopenia< 4,000 cells/mm3 9281< 1,000 cells/mm3 1512 Thrombocytopenia< 100,000 cells/mm3 54 Anemia< 11 g/dl8377< g/dl91 Hospitalizations due to neutropenic complications98Table 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 GradesGrade 3-4All Patients(%)NSCLC(%)All Patients(%)NSCLC(%)Laboratory Hepatic AST increased (N=346)675463 Bilirubin increased (N=351)13975Clinical Nausea443421 Asthenia362775 Constipation352932 Injection site reaction283825 Injection site pain161321 Neuropathy peripheral 2520<21 Vomiting201521 Diarrhea171311 Alopecia1212<=11 Phlebitis710<11 Dyspnea7332Myelosuppression: In clinical trials, Grade 3-4 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 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 <1% of patients.. In Combination with CisplatinTable presents the incidence of selected adverse reactions, occurring in >=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>= 10% of Patients on Vinorelbine plus Cisplatin versus Single Agent Cisplatin Graded according to the standard SWOG criteria version 1.+Categorical toxicity grade not specifiedVinorelbine 25mg/m2plusCisplatin 100 mg/m2(N=212)Cisplatin 100 mg/m2(N=210)All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)LaboratoryHematologicNeutropenia8982265Anemia892472<8Leukopenia885831<1Thrombocytopenia29521<2Febrile neutropenia+ N/A11N/A0RenalBlood creatinine increased37428<5ClinicalMalaise/Fatigue/Lethargy6712498Vomiting60136014Nausea58145712Decreased appetite460370Constipation353161Alopecia340140Weight decreased34121<1Fever without infection20240Hearing impaired18418<4Injection site reaction17<110Diarrhea17<311<2Paraesthesia17<110<1Taste alterations170150Peripheral numbness1127<1Myalgia/Arthralgia12<13<1Phlebitis/Thrombosis/Embolism103<1<1Weakness12<372Infection11<6<1<1Respiratory tract infection10<533Table presents the incidence of selected adverse reactions, occurring in >=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 30mg/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% (Grade 3-4, 7%) of the patients receiving vinorelbine plus cisplatin, 58% (Grade 3-4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grade 3-4, 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>= 10 of Patients from Comparative Trial of Vinorelbine Plus Cisplatin versus Vindesine Plus Cisplatin versus Single Agent Vinorelbine 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.Vinorelbine/Cisplatin+Vindesine/CisplatinVinorelbineAll Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Laboratory Hematologic Neutropenia957879488553 Leukopenia945782278332 Thrombocytopenia154103.530 Renal Blood creatinine increased 46N/A37N/A13N/AClinical Nausea/Vomiting74307225312 Alopecia517.55614302 Neurotoxicity 4475817448.5 Diarrhea251.5241120.5 Injection site reaction172.570222 Ototoxicity10214110. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval 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: pneumoniaImmune 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.

BOXED WARNING SECTION.

WARNING: MYELOSUPPRESSION. Severe myelosuppression resulting in serious infection, septic shock, hospitalization and death can occur[see Warnings and Precautions (5.1)].Decrease the dose or withhold vinorelbine in accord with recommended dose modifications[see Dosage and Administration (2.2)].. Severe myelosuppression resulting in serious infection, septic shock, hospitalization and death can occur[see Warnings and Precautions (5.1)].. Decrease the dose or withhold vinorelbine in accord with recommended dose modifications[see Dosage and Administration (2.2)].. WARNING: MYELOSUPPRESSIONSee full prescribing information for complete boxed warning.Severe myelosuppression resulting in serious infection, septic shock, and death can occur (5.1).Decrease the dose or withhold vinorelbine in accord with recommended dose modifications (2.2).. Severe myelosuppression resulting in serious infection, septic shock, and death can occur (5.1).. Decrease the dose or withhold vinorelbine in accord with recommended dose modifications (2.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. The carcinogenic potential of vinorelbine has not been studied. Vinorelbine has been shown to affect chromosome number and possibly structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and positive micronucleus test in mice). It was not mutagenic in the Ames test and gave inconclusive results in the mouse lymphoma TK Locus assay.Vinorelbine did not affect fertility to statistically significant extent when administered to rats on either once-weekly (9 mg/m2, approximately one third the human dose) or alternate-day schedule (4.2 mg/m2, approximately 0.14 times the human recommended dose) prior to and during mating. In male rats, administration of vinorelbine twice weekly for 13 or 26 weeks at dose levels of 2.1 and 7.2 mg/m2 (approximately 0.07 and 0.24 times the recommended human dose), respectively, resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.

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 100mg/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(N=214)Cisplatin(N=218)Overall SurvivalMedian Survival in months(95% CI)7.8(6.9, 9.6)6.2(5.4, 7.7)Unstratified log-rank p-value0.01Overall Response rate (ORR)Evaluable patientsORR (95% CI)N=20619% (14%, 25%)N=2098% (5%, 13%)Chi-square test p-value<0.001Figure 1: Overall Survival Vinorelbine Cisplatin versus Single Agent Cisplatin. Figure 1. Cisplatin 120mg/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 30mg/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)1n/a not applicableVinorelbine (N=206)Vinorelbine pluscisplatin(N=206)Vindesine pluscisplatin(N=200)Median survival inmonths (99.5% CI)7.2(5.4, 9.1)9.2(7.4, 11.1)7.4(6.1, 9.1)Unstratified log-rankp-valuen/a1 0.0870.05n/aOverall Response (ORR)Evaluable PatientsORR(95% CI)N=20514%(10%, 20%)N=20328%(22%, 35%)N=19819%(14%, 25%)Chi-square test p-valuen/a0.03< 0.001n/a. 14.2 Single Agent. The safety and efficacy of vinorelbine as single agent was evaluated in one randomized multicenter 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 >= 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None. None.

DESCRIPTION SECTION.

11 DESCRIPTION. Vinorelbine Injection, USP contains vinorelbine, semi-synthetic vinca alkaloid. The molecular formula for vinorelbine tartrate is C45H54N4O8o2C4H6O6. It has molecular weight of 1079.11. The structural formula is as follows:Vinorelbine tartrate is white to light yellow amorphous powder. It is easily soluble in water, very soluble in methanol and practically insoluble in hexane.Vinorelbine Injection, USP is sterile nonpyrogenic aqueous solution for intravenous use. Each milliliter of solution contains 10 mg vinorelbine (equivalent to 13.85 mg vinorelbine tartrate) in Water for Injection, USP. The pH of Vinorelbine Injection, USP is approximately 3.5.. Structural Formula.

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 dosage of Vinorelbine Injection 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 dosage of Vinorelbine Injection 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/m2 The recommended dosage of Vinorelbine Injection 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.. The recommended dosage of Vinorelbine Injection 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 AgentThe recommended dosage of Vinorelbine Injection is 30 mg/m2 administered intravenously over to 10 minutes once week.. The recommended dosage of Vinorelbine Injection is 30 mg/m2 administered intravenously over to 10 minutes once week.. 2.2 Dosage Modifications. MyelosuppressionHold 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/mm3)Percentage of Starting Dose of Vinorelbine Injection>= 1,500100%1,000 to 1,49950%< 1,000Do not administer Vinorelbine Injection.Repeat neutrophil count in one week.If three consecutive weekly doses are held becauseneutrophil count is 1,000 cells/mm3, discontinue Vinorelbine InjectionNote: 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 Injection should be:> 1,50075%1,000 to 1,49937.5%< 1,000Do not administer Vinorelbine Injection. Repeat neutrophil count in one week.. Hepatic Impairment/ToxicityReduce 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 ofVinorelbine Injection<= 2.0100%2.1 to 3.050%> 3.025%. 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 Injection determined from the above schemas.. Neurologic ToxicityDiscontinue Vinorelbine Injection 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. PreparationDilute 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, USP. 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. Stability 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 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, Vinorelbine Injection should not be administered.. Management of Suspected ExtravasationIf Vinorelbine Injection leakage into surrounding tissue occurs or is suspected, immediately stop administration of Vinorelbine Injection and initiate appropriate management measures in accordance with institutional policies [see Warnings and Precautions (5.4)]. If Vinorelbine Injection leakage into surrounding tissue occurs or is suspected, immediately stop administration of Vinorelbine Injection and initiate appropriate management measures in accordance with institutional policies [see Warnings and Precautions (5.4)]. 2.4 Procedures for Proper Handling and Disposal. Vinorelbine Injection 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Vinorelbine Injection, USP: mL (10 mg per mL) and mL (50 mg per mL) clear colorless to pale yellow solution in single-dose vial.. Vinorelbine Injection: 10 mg per mL and 50 mg per mL in single-dose vial (3). Vinorelbine Injection: 10 mg per mL and 50 mg per mL in single-dose vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Inhibitors of CYP3A4: May cause earlier onset and/or increased severity of adverse reactions (7.1). 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 CYP3A inhibitor may cause an earlier onset and/or an increased severity of adverse reactions.

GERIATRIC USE SECTION.

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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Vinorelbine Injection, USP is supplied as follows:Vinorelbine Injection, USPNDC(10 mg per mL)Package Factor25021-204-0110 mg per mL Single-Dose Vial1 vial per carton25021-204-0550 mg per mL Single-Dose Vial1 vial per cartonVinorelbine Injection, USP is clear, colorless to pale yellow aqueous solution.. Storage Conditions Store refrigerated between and 8C (36 and 46F).Do not freeze. Protect from light. Retain in carton until time of use.Discard unused portion.Unopened vials of Vinorelbine Injection, USP are stable at 25C (77F) for up to 72 hours. Store diluted solutions of Vinorelbine Injection, USP at to 30C (41 to 86F) [see Dosage and Administration (2.3)].Vinorelbine Injection, USP is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.

INDICATIONS & USAGE SECTION.

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 single agent for the treatment of patients with metastatic NSCLC. In combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). As single agent for the treatment of patients with metastatic NSCLC. Vinorelbine Injection is 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 single agent for first-line treatment of patients with metastatic NSCLC (1). In combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) (1). As single agent for first-line treatment of patients with metastatic NSCLC (1).

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 Injection 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 Injection and for months after the final dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. 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 Injection 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 Injection and for months after the final dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. LactationAdvise women not to breastfeed during treatment with Vinorelbine Injection and for days after the final dose [see Use in Specific Populations (8.2)]. InfertilityAdvise males of reproductive potential that Vinorelbine Injection may impair fertility [see Use in Specific Populations (8.3)]. SAGENT(R) Mfd. for SAGENT PharmaceuticalsSchaumburg, IL 60195 (USA)Made in China(C)2020 Sagent Pharmaceuticals, Inc.Revised: April 2020SAGENT Pharmaceuticals(R).

LACTATION SECTION.

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.

MECHANISM OF ACTION SECTION.

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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. The carcinogenic potential of vinorelbine has not been studied. Vinorelbine has been shown to affect chromosome number and possibly structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and positive micronucleus test in mice). It was not mutagenic in the Ames test and gave inconclusive results in the mouse lymphoma TK Locus assay.Vinorelbine did not affect fertility to statistically significant extent when administered to rats on either once-weekly (9 mg/m2, approximately one third the human dose) or alternate-day schedule (4.2 mg/m2, approximately 0.14 times the human recommended dose) prior to and during mating. In male rats, administration of vinorelbine twice weekly for 13 or 26 weeks at dose levels of 2.1 and 7.2 mg/m2 (approximately 0.07 and 0.24 times the recommended human dose), respectively, resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no known antidote for overdoses of vinorelbine. Overdoses involving quantities up to 10 times the recommended dose (30 mg/m2) have been reported. The adverse reactions described were consistent with those listed in the ADVERSE REACTIONS section, including paralytic ileus, stomatitis and esophagitis. Bone marrow aplasia, sepsis and paresis have also been reported. Fatalities have occurred following overdose of vinorelbine. If overdosage occurs, general supportive measures together with appropriate blood transfusions, growth factors and antibiotics should be instituted as deemed necessary by the physician.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial LabelNDC 25021-204-01VINORELBINE INJECTION, USP10 mg per mLRx only1 mL Single-Dose VialMust Be DilutedFor Intravenous Use OnlyCaution: Cytotoxic Agent. PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial Label.

PEDIATRIC USE SECTION.

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).

PHARMACOKINETICS SECTION.

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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased 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.. Data. Animal 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.

REFERENCES SECTION.

15 REFERENCES. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. In Combination with Cisplatin 100 mg/m2The recommended dosage of Vinorelbine Injection 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 dosage of Vinorelbine Injection 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/m2 The recommended dosage of Vinorelbine Injection 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.. The recommended dosage of Vinorelbine Injection 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 AgentThe recommended dosage of Vinorelbine Injection is 30 mg/m2 administered intravenously over to 10 minutes once week.. The recommended dosage of Vinorelbine Injection is 30 mg/m2 administered intravenously over to 10 minutes once week.

STORAGE AND HANDLING SECTION.

Storage Conditions Store refrigerated between and 8C (36 and 46F).Do not freeze. Protect from light. Retain in carton until time of use.Discard unused portion.Unopened vials of Vinorelbine Injection, USP are stable at 25C (77F) for up to 72 hours. Store diluted solutions of Vinorelbine Injection, USP at to 30C (41 to 86F) [see Dosage and Administration (2.3)].Vinorelbine Injection, USP is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.

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 SummaryBased 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.. Data. Animal 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 Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating vinorelbine [see Use in Specific Populations (8.1)]. Contraception. FemalesVinorelbine 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.. Infertility. MalesBased 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 occurs in >60% of the patients receiving vinorelbine as single agent (6% Grade 3-4). 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 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). 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 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 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/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>= 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 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 or greater neuropathy [see Dosage and Administration (2.2) and Adverse Reactions (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)].