Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Vinorelbine is a 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 a concentration of 2 μM inducing a blockade of cells at metaphase, but produced depolymerization of axonal microtubules at a concentration 40 μM, suggesting a modest selectivity of vinorelbine for mitotic microtubules. 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 a triphasic manner. The 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. Distribution Steady-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 a 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, 5-fluorouracil, or doxorubicin. Metabolism Vinorelbine 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 cytochrome P450 isoenzymes in the CYP3A subfamily. Excretion After intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively. In a different study, 10.9% ± 0.7% of a 30-mg/m² intravenous dose was excreted as parent drug in urine. Specific Populations Elderly: Age has no effect on the pharmacokinetics (CL, V SS and t1/2 ) of vinorelbine. Drug Interactions The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin. Clinical Studies Combination Use With Cisplatin The safety and efficacy of NAVELBINE in combination with cisplatin was evaluated in two randomized, multicenter trials. Cisplatin 100mg/m² Study 1 was a randomized, multicenter, open-label trial of NAVELBINE plus cisplatin and cisplatin alone for the treatment of stage IV or stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe of the ipsilateral lung who had not received prior chemotherapy. A total of 432 patients were randomized 1:1 to receive either NAVELBINE 25 mg/m² on Day 1 then every week of each 28-day cycle with cisplatin 100 mg/m² administered on Day 1 of each 28-day cycle (N=214) or cisplatin 100 mg/m² on Day 1 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 33-84), 66% were male, 80% were Caucasian, 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 7 and Figure 1. Table 7: Efficacy Results (Study 1) NAVELBINE plus Cisplatin (N=214) Cisplatin Alone (N=218) Overall Survival Median Survival in months (95% CI) 7.8 (6.9, 9.6 ) 6.2 (5.4, 7.7) Unstratified log-rank p-value 0.01 Overall Response rate (ORR) Evaluable patients ORR (95% CI) N = 206 19% (14%, 25%) N=209 8% (5%, 13% ) Chi-square test p-value < 0.001 Figure 1 : Overall Survival NAVELBINE/Cisplatin versus Single-Agent Ciplatin Cisplatin 120mg/m² Study 2 was a randomized, 3-arm, open-label, multicenter trial of NAVELBINE plus cisplatin, vindesine plus cisplatin and NAVELBINE alone for the treatment of patients with stage III or IV NSCLC who had not received prior chemotherapy. The study was conducted in Europe. A total of 612 patients were randomized 1:1:1 to receive NAVELBINE 30 mg/m² every week of a 6week cycle plus cisplatin 120 mg/m² on Day 1 and Day 29, then every 6 weeks thereafter (N=206); and vindesine 3 mg/m² for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m² on Days 1 and Day 29, then every 6 weeks thereafter (N=200) or NAVELBINE 30mg/m² every week of a 6-week cycle (N=206). The main efficacy outcome measure was to compare overall survival between NAVELBINE 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 NAVELBINE alone. 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 0 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 NAVELBINE plus cisplatin arm, 40% of patients in vindesine plus cisplatin arm and 28% of patients on the NAVELBINE alone 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 2 are presented in Table 8. Table 8: Efficacy Results (Study 2) NAVELBINE Alone (N=206) NAVELBINE plus cisplatin (N=206) Vindesine plus cisplatin (N=200) 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 p-value n/a1 0.087 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 p-value n/a 0.03 < 0.001 n/a 1n/a = not applicable Single Agent The safety and efficacy of NAVELBINE as a single agent was evaluated in one randomized multi-center trial. Study 3 was a randomized, open-label clinical trial of NAVELBINE or 5-Fluorouracil (5-FU) plus leucovorin (LV) in patients with Stage IV NSCLC who had not received prior chemotherapy A total of 211 patients were randomized 2:1 to receive NAVELBINE 30 mg/m² weekly of a 8-week cycle (N=143) or 5-FU 425 mg/m² bolus intravenously plus LV 20 mg/m² bolus intravenously daily for 5 days of a 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 -83), 74% were male, 88% were Caucasian, 46% had adenocarcinoma histology. Fifty percent of the patients had Karnofsky performance status ≥ 90 in the NAVELBINE arm compared to 38% in the 5-FU and 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 NAVELBINE versus 5-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 NAVELBINE and 5-FU/LV, respectively.

Find Lowest Prices on NAVELBINE® (vinorelbine tartrate) for Intravenous Injection WARNING MYELOSUPPRESSION Severe myelosuppression resulting in serious infection, septic shock, hospitalization and death may occur [see WARNINGS AND PRECAUTIONS]. Decrease the dose or withhold NAVELBINE in accord with recommended dose modifications [see DOSAGE AND ADMINISTRATION]. DESCRIPTION NAVELBINE (vinorelbine tartrate) is a semi-synthetic vinca alkaloid for intravenous injection. Chemically, vinorelbine tartrate is 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R(R*,R*)-2, 3-dihydroxybutanedioate (1:2)(tartrate)] and has the following structure: C45H54N4O82C4H6O6 M.W. 1079.12. NAVELBINE Injection is a sterile nonpyrogeinc aqueous solution. Each milliliter of solution contains 10 mg vinorelbine tartrate in Water for Injection. The pH of NAVELBINE Injection is approximately 3.5.

INDICATIONS NAVELBINE is indicated: In combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) As a single agent, for the treatment of patients with metastatic NSCLC DOSAGE AND ADMINISTRATION Recommended Dose In Combination with Cisplatin 100 mg/m² The recommended dose of NAVELBINE is 25 mg/m² administered as an intravenous injection or infusion over 6 to 10 minutes on days 1, 8, 15 and 21 of a 28 day cycle in combination with cisplatin 100 mg/m² on day 1 only of each 28 day cycle. In Combination with Cisplatin 120 mg/m² The recommended dose of NAVELBINE is 30 mg/m² administered as an intravenous injection or infusion over 6 to 10 minutes once a week in combination with cisplatin 120 mg/m² on days 1 and 29, then every 6 weeks. Single-Agent The recommended dose of NAVELBINE is 30 mg/m² administered intravenously over 6 to 10 minutes once a week. Dose Modifications Hematologic Toxicity [see WARNINGS AND PRECAUTIONS] Hold or decrease the dose of NAVELBINE in patients with decreased neutrophil counts using the following schema. Neutrophils on Day of Treatment (Cells/mm³) Percentage of Starting Dose of NAVELBINE ≥ 1,500 100% 1,000 to 1,499 50% < 1,000 Do not administer NAVELBINE. Repeat neutrophil count in one week. If three consecutive weekly doses are held because Neutrophil count is < 1,000 cells/mm³, discontinue NAVELBINE Note : For patients who experience fever and/or sepsis while neutrophil count is < 1,500 or had 2 consecutive weekly doses held due to neutropenia, subsequent doses of NAVELBINE should be: > 1,500 75% 1,000 to 1,499 37.5% < 1,000 Do not administer NAVELBINE. Repeat neutrophil count in one week. Hepatic Impairment/Toxicity [see WARNINGS AND PRECAUTIONS and Use In Specific Populations] Reduce NAVELBINE dose in patients with elevated serum total bilirubin concentration according to the following schema: Serum total bilirubin concentration (mg/dl) Percentage of Starting Dose of NAVELBINE ≤ 2.0 100% 2.1 to 3.0 50% > 3.0 25% Concurrent Hematologic Toxicity and Hepatic Impairment In patients with both hematologic toxicity and hepatic impairment, administer the lower of the doses based on the corresponding starting dose of NAVELBINE determined from the above schemas. Neurologic Toxicity [see WARNINGS AND PRECAUTIONS] Discontinue NAVELBINE for NCI CTCAE Grade 2 or higher peripheral neuropathy or autonomic neuropathy causing constipation. Preparation And Administration Preparation of NAVELBINE Dilute NAVELBINE in either a syringe or intravenous bag using one of the recommended solutions. Syringe Dilute to a concentration between 1.5 and 3 mg/mL. The following solutions may be used for dilution: 5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP Intravenous Bag Dilute to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution: 5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP 0.45% Sodium Chloride Injection, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP Ringer's Injection, USP Lactated Ringer's Injection, USP Stability Diluted NAVELBINE may be used for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5° to 30°C (41° to 86°F). Administration Administer diluted NAVELBINE over 6 to 10 minutes into the side port of a free-flowing intravenous line followed by flushing with at least 75 to 125 mL of one of the solutions. NAVELBINE must only be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any NAVELBINE 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, NAVELBINE should not be administered. Management of Suspected Extravasation If NAVELBINE leakage into surrounding tissue occurs or is suspected, immediately stop administration of NAVELBINE and initiate appropriate management measures in accordance with institutional policies. [see WARNINGS AND PRECAUTIONS] Procedures For Proper Handling And Disposal Handle and dispose NAVELBINE consistent with recommendations for the handling and disposal of hazardous drugs2 . Exercise caution in handling and preparing the solution of NAVELBINE. The use of gloves is recommended. If the solution of NAVELBINE contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. Avoid contamination of the eye with NAVELBINE. If exposure occurs, flush the eyes with water immediately and thoroughly. HOW SUPPLIED Dosage Forms And Strengths NAVELBINE Injection Clear colorless to pale yellow solution in single use vials: 1 mL (10 mg/ 1 mL) 5 mL (50 mg/ 5 mL) Storage And Handling NAVELBINE Injection is a clear, colorless to pale yellow aqueous solution available in single-dose vials with royal blue caps, individually packaged in a carton as: 10 mg/1 mL (NDC 64370-532-01). 50 mg/5 mL (NDC 64370-532-02). Store the vials at 2° to 8°C (36° to 46°F) in the carton. Protect from light. DO NOT FREEZE. Unopened vials of NAVELBINE are stable at 25°C (77°F) for up to 72 hours. NAVELBINE is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 REFERENCES 1. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html Manufactured by: Pierre Fabre Médicament 45 place Abel Gance -92100 Boulogne –FRANCE. Distributed by: Pierre Fabre Pharmaceuticals, Inc. Parsippany, NJ 07054. Revised: 03/2014

OVERDOSE There is no known antidote for overdoses of NAVELBINE. Overdoses involving quantities up to 10 times the recommended dose (30 mg/m²) have been reported. The toxicities 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 NAVELBINE. If overdosage occurs, general supportive measures together with appropriate blood transfusions, growth factors, and antibiotics should be instituted as deemed necessary by the physician. CONTRAINDICATIONS None

SIDE EFFECTS The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the label: Myelosuppression [see WARNINGS AND PRECAUTIONS] Pulmonary Toxicity and Respiratory Failure [see WARNINGS AND PRECAUTIONS] Constipation and Bowel Obstruction [see WARNINGS AND PRECAUTIONS] Extravasation Tissue Injury [see WARNINGS AND PRECAUTIONS] Neurologic Toxicity [see WARNINGS AND PRECAUTIONS] Hepatic Toxicity [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. Single Agent The data below reflect exposure to NAVELBINE as a single agent administered at a dose of 30 mg/m² on a weekly basis to 365 patients enrolled in 3 controlled studies for metastatic NSCLC and advanced breast cancer. The population included 143 previously untreated metastatic NSCLC patients (Study 3) who received a median of 8 doses of NAVELBINE. The patients were aged 32 to 79 (median 61 years), 71% were male, 91% Caucasian, 48% had adenocarcinoma histology. The data also reflect exposure to NAVELBINE in 222 patients with previously treated advanced breast cancer who received a median of 10 doses of NAVELBINE. NAVELBINE is not indicated for the treatment of breast cancer. Selected adverse reactions reported in these studies are provided in Tables 1 and 2. The most common adverse reactions ( ≥ 20%) of single agent NAVELBINE were leukopenia, neutropenia, anemia, Aspartate aminotransferase (AST) elevation, nausea, vomiting, constipation, asthenia, injection site reaction, and peripheral neuropathy. The most common ( ≥ 5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, anemia, increased total bilirubin, AST elevation, injection site reaction and asthenia. Approximately 49% of NSCLC patients treated with Navelbine experienced at least one dose reduction due to an adverse reaction. Thirteen percent of patients discontinued NAVELBINE due to adverse reactions. The most frequent adverse reactions leading to NAVELBINE discontinuation were asthenia, dyspnea, nausea, constipation, anorexia, myasthenia and fever. Table 1: Hematologic Adverse Reactions Experienced in > 5% of Patients Receiving NAVELBINE*† All patients (n=365) NSCLC (n= 143) 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 5% 4% Anaemia < 11 g/dl 83% 77% < 8 g/dl 9% 1% Hospitalizations due to neutropenic complications 9% 8% *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. Table 2: Non-hematologic Adverse Reactions Experienced in ≥ 5% of Patients Receiving NAVELBINE*† All grades Grades 3+4 All Patients NSCLC All Patients NSCLC Laboratory Hepatic AST increased (n=346) 67% 54% 6% 3% bilirubin increased (n=351) 13% 9% 7% 5% Clinical Nausea 44% 34% 2% 1% Asthenia 36% 27% 7% 5% Constipation 35% 29% 3% 2% Injection site reaction 28% 38% 2% 5% Injection site pain 16% 13% 2% 1% Neuropathy peripheral} 25% 20% < 2% 1% Vomiting 20% 15% 2% 1% Diarrhea 17% 13% 1% 1% Alopecia 12% 12%

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Myelosuppression Myelosuppression manifested by neutropenia, anemia and thrombocytopenia occur with NAVELBINE® as a single agent and in combination with cisplatin [see ADVERSE REACTIONS]. Neutropenia is the major dose-limiting toxicity with NAVELBINE. Grade 3-4 neutropenia occurred in 53% of patients treated with NAVELBINE at 30 mg/m² per week. Dose adjustment due to myelosuppression occurred in 51% of patients (Study 2). In clinical trials with NAVELBINE 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 7 and 10 days after dosing with neutropenia count recovery usually occurring within the following 7 to 14 days. Monitor complete blood counts prior to each dose of NAVELBINE. Do not administer NAVELBINE to patients with neutrophil counts < 1,000 cells/mm³. Adjustments in the dosage of NAVELBINE should be based on neutrophil counts obtained on the day of treatment [see DOSAGE AND ADMINISTRATION]. Hepatic Toxicity Drug-induced liver injury manifest by elevations of aspartate aminotransferase and bilirubin can occur in patients receiving NAVELBINE alone or in combination with cytotoxic agents. Assess hepatic function prior to initiation of NAVELBINE and periodically during treatment. Reduce the dose of NAVELBINE for patients who develop elevations in total bilirubin > 2 times upper limit of normal [see DOSAGE AND ADMINISTRATION and Use In Specific Populations]. Severe Constipation And Bowel Obstruction Severe and fatal paralytic ileus, constipation, intestinal obstruction, necrosis, and perforation occur with NAVELBINE administration. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction and/or paralytic ileus, considering adequate dietary fiber intake, hydration, and routine use of stool softeners. Extravasation And Tissue Injury Extravasation of NAVELBINE can result in severe irritation, local tissue necrosis and/or thrombophlebitis. If signs or symptoms of extravasation occur, immediately stop administration of NAVELBINE and institute recommended management procedures. [see DOSAGE AND ADMINISTRATION  and ADVERSE REACTION] Neurologic Toxicity Sensory and motor neuropathies, including severe neuropathies, occur in patients receiving NAVELBINE. Monitor patients for new or worsening signs and symptoms of neuropathy such as paresthesia, hyperesthesia, hyporeflexia and muscle weakness while receiving NAVELBINE. Discontinue NAVELBINE for NCI CTCAE Grade 2 or greater neuropathy [see DOSAGE AND ADMINISTRATION and ADVERSE REACTION] Pulmonary Toxicity And Respiratory Failure Pulmonary toxicity, including severe acute bronchospasm, interstitial pneumonitis, acute respiratory distress syndrome (ARDS) occurs with use of NAVELBINE. Interstitial pneumonitis and ARDS included fatalities. The mean time to onset of interstitial pneumonitis and ARDS after vinorelbine administration was one week (range 3 to 8 days) [see ADVERSE REACTIONS]. Interrupt NAVELBINE in patients who develop unexplained dyspnea, or have any evidence of pulmonary toxicity. Permanently discontinue NAVELBINE for confirmed interstitial pneumonitis or ARDS. Embryo-Fetal Toxicity NAVELBINE can cause fetal harm when administered to a 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during therapy with NAVELBINE [see Use In Specific Populations]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility The carcinogenic potential of NAVELBINE 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 a 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 a statistically significant extent when administered to rats on either a 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. Use In Specific Population Pregnancy Pregnancy Category D Risk Summary NAVELBINE can cause fetal harm when administered to a 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data In a mouse embryofetal development study, administration of a single dose of vinorelbine at a dose level of 9 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 6 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. Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from vinorelbine, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of NAVELBINE in pediatric patients have not been established. Results from a single-arm study of NAVELBINE administered at the dose of 33.75 mg/m² (for 35 patients) or at the dose of 30mg/m² (for 11 patients) every week during 6 weeks followed by 2 weeks of rest was evaluated (courses of 8 weeks). Forty-six patients age 1 to 25 (median 11 years) with recurrent solid malignant tumors, including rhabdomyosarcoma or undifferentiated sarcoma (N=21 patients), neuroblastoma (N= 4 patients), and central nervous system (CNS) tumors (N=21 patients) were enrolled. The most significant grade 3 or 4 hematological adverse reactions were neutropenia (70%) and anemia (33%). The most significant grade 3 or 4 nonhematological toxicity adverse reactions were motor (15%) or cranial (13%) neuropathy, hypoxia (13%) and dyspnea (11%). Objective tumor response was observed in 2 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). Geriatric Use Of the 769 number of patients who received NAVELBINE alone and NAVELBINE in combination with Cisplatin in studies 1, 2 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]. Hepatic Impairment The influence of hepatic impairment on the pharmacokinetics of NAVELBINE has not been evaluated, but the liver plays an important role in the metabolism of NAVELBINE. Elevations of aspartate aminotransferase occur in > 60% of the patients receiving NAVELBINE alone (6% Grade 3-4). Therefore, exercise caution in patients with hepatic impairment. Reduce the dose of NAVELBINE for patients with bilirubin elevation [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Females And Males Of Reproductive Potential Contraception Females NAVELBINE can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations]. Advise female patients of reproductive potential to use highly effective contraception during therapy with NAVELBINE. Males NAVELBINE may damage spermatozoa [see Nonclinical Toxicology]. Males with female sexual partners of reproductive potential should use highly effective contraception during and for 3 months after therapy with NAVELBINE. Fertility Males Based on animal findings, NAVELBINE may cause decreased fertility in males [see Nonclinical Toxicology]