PRESCRIBING INFORMATION NAVELBINEÆ (vinorelbine tartrate) Injection WARNING NAVELBINE (vinorelbine tartrate) Injection should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. This product is for intravenous (IV) use only. Intrathecal administration of other vinca alkaloids has resulted in death. Syringes containing this product should be labeled "WARNING ñ FOR IV USE ONLY. FATAL if given intrathecally.î Severe granulocytopenia resulting in increased susceptibility to infection may occur. Granulocyte counts should be ≥1,000 cells/mm3 prior to the administration of NAVELBINE. The dosage should be adjusted according to complete blood counts with differentials obtained on the day of treatment. Caution - It is extremely important that the intravenous needle or catheter be properly positioned before NAVELBINE is injected. Administration of NAVELBINE may result in extravasation causing local tissue necrosis and/or thrombophlebitis (see DOSAGE AND ADMINISTRATION: Administration Precautions). DESCRIPTION NAVELBINE (vinorelbine tartrate) Injection is for intravenous administration. Each vial contains vinorelbine tartrate equivalent to 10 mg (1-mL vial) or 50 mg (5-mL vial) vinorelbine in Water for Injection. No preservatives or other additives are present. The aqueous solution is sterile and nonpyrogenic. Vinorelbine tartrate is a semi-synthetic vinca alkaloid with antitumor activity. The chemical name is 3′,4′-didehydro-4′-deoxy-C ′-norvincaleukoblastine [R-(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)]. Vinorelbine tartrate has the following structure: Vinorelbine tartrate is a white to yellow or light brown amorphous powder with the molecular formula C45H54N4O8·2C4H6O6 and molecular weight of 1079.12. The aqueous solubility is >1,000 mg/mL in distilled water. The pH of NAVELBINE Injection is approximately 3.5. CLINICAL PHARMACOLOGY Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline and catharanthine. NAVELBINEÆ (vinorelbine tartrate) Injection 2 Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for vinorelbine. The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, vinorelbine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulindependent Ca++-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. In intact tectal plates from mouse embryos, vinorelbine, vincristine, and vinblastine inhibited mitotic microtubule formation at the same concentration (2 µM), inducing a blockade of cells at metaphase. Vincristine produced depolymerization of axonal microtubules at 5 µM, but vinblastine and vinorelbine did not have this effect until concentrations of 30 µM and 40 µM, respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules. Pharmacokinetics: The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m2 in 4 clinical trials. Doses were administered by 15- to 20-minute constant-rate infusions. Following intravenous administration, vinorelbine concentration in plasma decays in a triphasic manner. The initial rapid decline primarily represents distribution of drug to peripheral compartments followed by metabolism and excretion of the drug during subsequent phases. The prolonged terminal phase is due to relatively slow efflux of vinorelbine from peripheral compartments. 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. 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 pooled human plasma over a concentration range of 234 to 1,169 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. Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans. 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 NAVELBINE (30 mg/m2 ) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes (see PRECAUTIONS). The effects of renal or hepatic dysfunction on the disposition of vinorelbine have not been assessed, but based on experience with other anticancer vinca alkaloids, dose adjustments are recommended for patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION). The disposition of radiolabeled vinorelbine given intravenously was studied in a limited number of patients. Approximately 18% and 46% of the administered dose was recovered in the urine and in the feces, respectively. Incomplete recovery in humans is consistent with results in animals where recovery is incomplete, even after prolonged sampling times. A separate study of the urinary excretion of vinorelbine using specific chromatographic analytical methodology showed that 10.9% ± 0.7% of a 30-mg/m2 intravenous dose was excreted unchanged in the urine. The influence of age on the pharmacokinetics of vinorelbine was examined using data from 44 cancer patients (average age, 56.7 ± 7.8 years; range, 41 to 74 years; with 12 patients ≥60 years and 6 patients ≥65 years) in 3 studies. CL (the mean plasma clearance), t1/2 (the terminal phase NAVELBINEÆ (vinorelbine tartrate) Injection 3 half-life), and VZ (the volume of distribution during terminal phase) were independent of age. A separate pharmacokinetic study was conducted in 10 elderly patients with metastatic breast cancer (age range, 66 to 81 years; 3 patients >75 years; normal liver function tests) receiving vinorelbine 30 mg/m2 intravenously. CL, Vss, and t1/2 were similar to those reported for younger adult patients in previous studies. No relationship between age, systemic exposure (AUC0-∞), and hematological toxicity was observed. The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin with NAVELBINE (see PRECAUTIONS: Drug Interactions). Clinical Trials: Data from 1 randomized clinical study (211 evaluable patients) with single-agent NAVELBINE and 2 randomized clinical trials (1,044 patients) using NAVELBINE combined with cisplatin support the use of NAVELBINE in patients with advanced nonsmall cell lung cancer (NSCLC). Single-Agent NAVELBINE: Single-agent NAVELBINE was studied in a North American, randomized clinical trial in which patients with Stage IV NSCLC, no prior chemotherapy, and Karnofsky Performance Status ≥70 were treated with NAVELBINE (30 mg/m2 ) weekly or 5-fluorouracil (5-FU) (425 mg/m2 IV bolus) plus leucovorin (LV) (20 mg/m2 IV bolus) daily for 5 days every 4 weeks. A total of 211 patients were randomized at a 2:1 ratio to NAVELBINE (143) or 5-FU/LV (68). NAVELBINE showed improved survival time compared to 5-FU/LV. In an intent-to-treat analysis, the median survival time was 30 weeks versus 22 weeks for patients receiving NAVELBINE versus 5-FU/LV, respectively (P = 0.06). The 1-year survival rates were 24% (±4% SE) for NAVELBINE and 16% (±5% SE) for the 5-FU/LV group, using the Kaplan-Meier product-limit estimates. The median survival time with 5-FU/LV was similar to or slightly better than that usually observed in untreated patients with advanced NSCLC, suggesting that the difference was not related to some unknown detrimental effect of 5-FU/LV therapy. The response rates (all partial responses) for NAVELBINE and 5-FU/LV were 12% and 3%, respectively. NAVELBINE in Combination with Cisplatin: NAVELBINE plus Cisplatin versus Single-Agent Cisplatin: A Phase III open-label, randomized study was conducted which compared NAVELBINE (25 mg/m2 /week) plus cisplatin (100 mg/m2 every 4 weeks) to single-agent cisplatin (100 mg/m2 every 4 weeks) in patients with Stage IV or Stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe who were not previously treated with chemotherapy. Patients included in the study had a performance status of 0 or 1, and 34% had received prior surgery and/or radiotherapy. Characteristics of the 432 randomized patients are provided in Table 1. Two hundred and twelve patients received NAVELBINE plus cisplatin and 210 received single-agent cisplatin. The primary objective of this trial was to compare survival between the 2 treatment groups. Survival (Figure 1) for patients receiving NAVELBINE plus cisplatin was significantly better compared to the patients who received single-agent cisplatin. The results of this trial are summarized in Table 1. NAVELBINE plus Cisplatin versus Vindesine plus Cisplatin versus SingleAgent NAVELBINE: In a large European clinical trial, 612 patients with Stage III or IV NSCLC, no prior chemotherapy, and WHO Performance Status of 0, 1, or 2 were randomized to treatment with single-agent NAVELBINE (30 mg/m2 /week), NAVELBINE (30 mg/m2 /week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks), and vindesine (3 mg/m2 /week for 7 weeks, then every other week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks). Patient characteristics are provided in Table 1. Survival was longer in patients treated with NAVELBINE NAVELBINEÆ (vinorelbine tartrate) Injection 4 plus cisplatin compared to those treated with vindesine plus cisplatin (Figure 2). Study results are summarized in Table 1. Dose-Ranging Study: A dose-ranging study of NAVELBINE (20, 25, or 30 mg/m2 /week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks) in 32 patients with NSCLC demonstrated a median survival of 10.2 months. There were no responses at the lowest dose level; the response rate was 33% in the 21 patients treated at the 2 highest dose levels. Table 1. Randomized Clinical Trials of NAVELBINE in Combination with Cisplatin in NSCLC NAVELBINE/Cisplatin vs. Single-Agent Cisplatin NAVELBINE/Cisplatin vs. Vindesine/Cisplatin vs. Single-Agent NAVELBINE NAVELBINE/ Cisplatin Cisplatin NAVELBINE/ Cisplatin Vindesine/ Cisplatin NAVELBINE Demographics Number of patients 214 218 206 200 206 Number of males 146 141 182 179 188 Number of females 68 77 24 21 18 Median age (years) Range (years) 63 33-84 64 37-81 59 32-75 59 31-75 60 30-74 Stage of disease Stage IIIA NA NA 11% 11% 10% Stage IIIB 8% 8% 28% 25% 32% Stage IV 92% 92% 50% 55% 47% Local recurrence NA NA 2% 3% 3% Metastatic after surgery NA NA 9% 8% 9% Histology Adenocarcinoma 54% 52% 32% 40% 28% Squamous 19% 22% 56% 50% 56% Large cell 14% 14% 13% 11% 16% Unspecified 13% 13% NA NA NA Results Median survival (months) 7.8 6.2 9.2*Ü 7.4 7.2 P value P = 0.01 *P = 0.09 vs. vindesine/cisplatin Ü = 0.05 vs. single-agent NAVELBINE 12-Month survival rate 38% 22% 35% 27% 30% Overall response 19% 8% 28%á ß 19% 14% P value P < 0.001 á P = 0.03 vs. vindesine/cisplatin ßP<0.001 vs="" single-agent="" navelbine="" vinorelbine="" tartrate="" injection="" 5="" figure="" 1="" overall="" survival="" cisplatin="" versus="" 2="" vindesine="" indications="" and="" usage="" 6="" is="" indicated="" as="" a="" single="" agent="" or="" in="" combination="" with="" for="" the="" first-line="" treatment="" of="" ambulatory="" patients="" unresectable="" advanced="" nonsmall="" cell="" lung="" cancer="" nsclc="" stage="" iv="" iii="" contraindications="" administration="" contraindicated="" pretreatment="" granulocyte="" counts="" 000="" cells="" mm3="" see="" warnings="" should="" be="" administered="" carefully="" adjusted="" doses="" by="" under="" supervision="" physician="" experienced="" use="" chemotherapeutic="" agents="" treated="" frequently="" monitored="" myelosuppression="" both="" during="" after="" therapy="" granulocytopenia="" dose-limiting="" nadirs="" occur="" between="" 7="" 10="" days="" dosing="" count="" recovery="" usually="" within="" following="" to="" 14="" complete="" blood="" differentials="" performed="" results="" reviewed="" prior="" administering="" each="" dose="" not="" developing="" severe="" evidence="" infection="" fever="" dosage="" recommended="" adjustments="" acute="" shortness="" breath="" bronchospasm="" have="" been="" reported="" infrequently="" other="" vinca="" alkaloids="" most="" commonly="" when="" alkaloid="" was="" used="" mitomycin="" these="" adverse="" events="" may="" require="" supplemental="" oxygen="" bronchodilators="" corticosteroids="" particularly="" there="" pre-existing="" pulmonary="" dysfunction="" cases="" interstitial="" changes="" respiratory="" distress="" syndrome="" ards="" which="" were="" fatal="" occurred="" mean="" time="" onset="" symptoms="" week="" range="" 3="" 8="" alterations="" their="" baseline="" new="" dyspnea="" cough="" hypoxia="" evaluated="" promptly="" has="" cause="" constipation="" e="" g="" grade="" 3-4="" paralytic="" ileus="" intestinal="" obstruction="" necrosis="" perforation="" some="" pregnancy:="" pregnancy="" category="" d="" fetal="" harm="" if="" pregnant="" woman="" shown="" embryo-="" fetotoxic="" mice="" rabbits="" at="" 9="" mg="" m2="" respectively="" one="" third="" sixth="" human="" nonmaternotoxic="" weight="" reduced="" ossification="" delayed="" are="" no="" studies="" women="" patient="" becomes="" while="" receiving="" this="" drug="" apprised="" potential="" hazard="" fetus="" childbearing="" advised="" avoid="" becoming="" precautions="" general:="" drug-related="" reversible="" discontinued="" appropriate="" corrective="" measures="" taken="" reinstitution="" carried="" out="" caution="" alertness="" possible="" recurrence="" toxicity="" extreme="" whose="" bone="" marrow="" reserve="" compromised="" irradiation="" chemotherapy="" function="" recovering="" from="" effects="" previous="" radiation="" result="" recall="" reactions="" interactions="" history="" neuropathy="" regardless="" etiology="" worsening="" signs="" care="" must="" contamination="" eye="" concentrations="" clinically="" irritation="" accidental="" exposure="" another="" occurs="" immediately="" thoroughly="" flushed="" water="" information="" patients:="" informed="" that="" major="" toxicities="" related="" specifically="" increased="" susceptibility="" they="" report="" chills="" contact="" experience="" abdominal="" pain="" laboratory="" tests:="" since="" clinical="" depression="" white="" it="" imperative="" obtained="" on="" day="" reactions:="" hematologic="" hepatic:="" enhanced="" elevated="" liver="" enzymes="" data="" available="" cholestasis="" but="" plays="" an="" important="" role="" metabolism="" because="" disease="" limited="" exercised="" hepatic="" injury="" impairment="" interactions:="" anticancer="" conjunction="" although="" pharmacokinetics="" influenced="" concurrent="" incidence="" significantly="" higher="" than="" who="" receive="" paclitaxel="" either="" concomitantly="" sequentially="" concomitant="" radiosensitizing="" concurrently="" taking="" drugs="" known="" inhibit="" cytochrome="" p450="" isoenzymes="" cyp3a="" subfamily="" inhibitor="" metabolic="" pathway="" earlier="" severity="" side="" carcinogenesis="" mutagenesis="" fertility:="" carcinogenic="" studied="" affect="" chromosome="" number="" possibly="" structure="" vivo="" polyploidy="" chinese="" hamsters="" positive="" micronucleus="" test="" mutagenic="" ames="" gave="" inconclusive="" mouse="" lymphoma="" tk="" locus="" assay="" significance="" short-term="" risk="" unknown="" did="" fertility="" statistically="" significant="" extent="" rats="" once-weekly="" approximately="" alternate-day="" schedule="" 4="" seventh="" mating="" however="" biweekly="" 13="" 26="" weeks="" rat="" fifteenth="" fourth="" resulted="" decreased="" spermatogenesis="" prostate="" seminal="" vesicle="" secretion="" section="" nursing="" mothers:="" whether="" excreted="" milk="" many="" serious="" infants="" pediatric="" use:="" safety="" effectiveness="" established="" single-arm="" study="" 46="" recurrent="" solid="" malignant="" tumors="" including="" rhabdomyosarcoma="" undifferentiated="" sarcoma="" neuroblastoma="" cns="" similar="" those="" adults="" showed="" meaningful="" activity="" geriatric="" total="" north="" american="" 65="" years="" age="" greater="" differences="" observed="" younger="" adult="" identified="" responses="" elderly="" sensitivity="" older="" individuals="" cannot="" ruled="" pharmacology="" pattern="" summarized="" tables="" 2-4="" navelbine:="" table="" based="" 365="" 143="" 222="" breast="" 30="" weekly="" basis="" summary="" event="" all="" n="346)" 90="" 80="" 500="" 36="" 29="" leukopenia="" 92="" 81="" 15="" 12="" thrombocytopenia="" 100="" 50="" anemia="" 11="" dl="" 83="" 77="" hospitalizations="" due="" granulocytopenic="" complications="" grades="" chemistry="" elevations="" bilirubin="" sgot="" 67="" 54="" general="" asthenia="" 27="" 0="" site="" 28="" 38="" 16="" phlebitis="" digestive="" nausea="" 44="" 34="" vomiting="" 20="" 35="" diarrhea="" 17="" peripheral="" 25="" alopecia="" none="" modified="" criteria="" national="" institute="" had="" received="" majority="" remaining="" paresthesia="" plus="" hypesthesia="" hematologic:="" required="" insufficiency="" generally="" cumulative="" over="" sepsis="" septic="" deaths="" prophylactic="" growth="" factors="" routinely="" medically="" necessary="" 24="" hours="" cytotoxic="" period="" before="" whole="" packed="" red="" 18="" neurologic:="" loss="" deep="" tendon="" reflexes="" less="" development="" infrequent="" skin:="" like="" moderate="" vesicant="" erythema="" vein="" discoloration="" chemical="" along="" proximal="" gastrointestinal:="" antiemetics="" routine="" low="" serotonin="" antagonists="" transient="" without="" cardiovascular:="" chest="" reports="" cardiovascular="" tumor="" rare="" myocardial="" infarction="" pulmonary:="" documented="" other:="" fatigue="" mild="" tended="" increase="" include="" jaw="" myalgia="" arthralgia="" rash="" hemorrhagic="" cystitis="" inappropriate="" adh="" cisplatin:="" :="" predominant="" 82="" compared="" arm="" four="" died="" granulocytopenia-related="" colony-stimulating="" factor="" g-csf="" filgrastim="" permitted="" mandated="" first="" course="" developed="" neutropenic="" cycles="" beginning="" completion="" started="" mcg="" kg="" per="" continued="" until="">1,000 cells/mm3 on 2 successive determinations. G-CSF was not administered on the day of treatment. Grade 3 and 4 anemia occurred more frequently in the combination arm compared to control, 24% vs. 8%, respectively. Thrombocytopenia occurred in 6% of patients treated with NAVELBINE plus cisplatin compared to 2% of patients treated with cisplatin. The incidence of severe non-hematologic toxicity was similar among the patients in both treatment groups. Patients receiving NAVELBINE plus cisplatin compared to single-agent cisplatin experienced more Grade 3 and/or 4 peripheral numbness (2% vs. <1%), phlebitis/thrombosis/embolism (3% vs. <1%), and infection (6% vs. <1%). Grade 3-4 constipation and/or ileus occurred in 3% of patients treated with combination therapy and in 1% of patients treated with cisplatin. Seven deaths were reported on the combination arm; 2 were related to cardiac ischemia, 1 massive cerebrovascular accident, 1 multisystem failure due to an overdose of NAVELBINE, and 3 from febrile neutropenia. One death, secondary to respiratory infection unrelated to granulocytopenia, occurred with single-agent cisplatin. NAVELBINE plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent NAVELBINE (Table 4): Myelosuppression, specifically Grade 3 and 4 granulocytopenia, was significantly greater with the combination of NAVELBINE plus cisplatin (79%) than with either single-agent NAVELBINE (53%) or vindesine plus cisplatin (48%), P<0.0001. hospitalization="" due="" to="" documented="" sepsis="" occurred="" in="" 4="" of="" patients="" treated="" with="" navelbine="" plus="" cisplatin="" 2="" vindesine="" and="" single-agent="" grade="" 3="" thrombocytopenia="" was="" infrequent="" receiving="" combination="" chemotherapy="" no="" events="" were="" reported="" the="" incidence="" or="" nausea="" vomiting="" alopecia="" renal="" toxicity="" more="" frequently="" cisplatin-containing="" combinations="" compared="" severe="" local="" reactions="" containing="" none="" observed="" arm="" neurotoxicity="" significantly="" frequent="" 17="" 7="" 9="" p="" 0="" 005="" did="" not="" appear="" increase="" vinorelbine="" tartrate="" injection="" 12="" table="" selected="selected" adverse="" from="" a="" comparative="" trial="" versus="" 25="" mg="" m2="" 100="" n="165" event="" all="" grades="" bone="" marrow="" granulocytopenia="" anemia="" leukopenia="" 89="" 88="" 29="" 22="" 21="" 39="" 60="" 19="" 1="" 26="" 72="" 31="" febrile="" neutropenia="" 11="" hepatic="" elevated="" transaminase="" creatinine="" 37="" 28="" non-laboratory="" malaise="" fatigue="" lethargy="" anorexia="" constipation="" weight="" loss="" fever="" without="" infection="" hearing="" site="" diarrhea="" paresthesias="" taste="" alterations="" peripheral="" numbness="" myalgia="" arthralgia="" phlebitis="" thrombosis="" embolism="" weakness="" dizziness="" vertigo="" respiratory="" 67="" 58="" 46="" 35="" 34="" 20="" 18="" 10="" 14="" 5="" 6="" 49="" 57="" 16="" 15="" 8="" graded="" according="" standard="" swog="" criteria="" 13="" 95="" 94="" 40="" 79="" 82="" 24="" 85="" 83="" bilirubin="" ototoxicity="" 74="" 51="" 44="" 27="" 56="" 30="" based="" on="" world="" health="" organization="" who="" 207="" laboratory="" data="" 192="" 201="" categorical="" specified="" includes="" neuropathy="" during="" clinical="" practice:="" addition="" trials="" following="" have="" been="" identified="" post-approval="" use="" because="" they="" are="" voluntarily="" population="" unknown="" size="" estimates="" frequency="" cannot="" be="" made="" these="" chosen="" for="" inclusion="" their="" seriousness="" reporting="" potential="" causal="" connection="" body="" as="" whole:="" systemic="" allergic="" anaphylaxis="" pruritus="" urticaria="" angioedema="" flushing="" radiation="" recall="" such="" dermatitis="" esophagitis="" see="" precautions="" hematologic:="" thromboembolic="" including="" pulmonary="" embolus="" deep="" venous="" primarily="" seriously="" ill="" debilitated="" known="" predisposing="" risk="" factors="" neurologic:="" neurotoxicities="" but="" limited="" muscle="" disturbance="" gait="" prior="" symptoms="" there="" may="" increased="" pre-existing="" regardless="" etiology="" receive="" vestibular="" auditory="" deficits="" usually="" when="" used="" skin:="" localized="" rash="" blister="" formation="" skin="" sloughing="" practice="" some="" delayed="" appearance="" gastrointestinal:="" dysphagia="" mucositis="" pancreatitis="" cardiovascular:="" hypertension="" hypotension="" vasodilation="" tachycardia="" edema="" pulmonary:="" pneumonia="" has="" musculoskeletal:="" headache="" other="" musculoskeletal="" aches="" pains="" other:="" pain="" tumor-containing="" tissue="" back="" abdominal="" electrolyte="" abnormalities="" hyponatremia="" syndrome="" inappropriate="" adh="" secretion="" use:="" exposure="" paclitaxel="" demonstrated="" should="" monitored="" closely="" new="" worsening="" experienced="" previous="" drug="" regimens="" while="" result="" radiosensitizing="" effects="" concomitant="" therapy="" overdosage="" is="" antidote="" overdoses="" involving="" quantities="" up="" times="" recommended="" dose="" toxicities="" described="" consistent="" those="" listed="" section="" paralytic="" ileus="" stomatitis="" aplasia="" paresis="" also="" fatalities="" overdose="" if="" occurs="" general="" supportive="" measures="" together="" appropriate="" blood="" transfusions="" growth="" antibiotics="" instituted="" deemed="" necessary="" by="" physician="" dosage="" administration="" navelbine:="" usual="" initial="" administered="" weekly="" method="" an="" intravenous="" over="" minutes="" controlled="" given="" until="" progression="" dose-limiting="" cisplatin:="" at="" every="" weeks="" counts="" checked="checked" determine="" whether="" reductions="" study="" most="" required="" 50="" reduction="" day="" each="" cycle="" days="" then="" 120="" modifications="" adjusted="" hematologic="" insufficiency="" whichever="" results="" lower="" corresponding="" starting="" toxicity:="" granulocyte="" 000="" cells="" mm3="" adjustments="" obtained="" treatment="" granulocytes="" percentage="" 500="" 499="" do="" administer="" repeat="" count="" week="" consecutive="" doses="" held="" discontinue="" note:="" granulocytopenic="" had="" subsequent="" be:="" 75="" above="" insufficiency:="" caution="" develop="" hyperbilirubinemia="" total="" modification="" dl="">3.0 25% Dose Modifications for Concurrent Hematologic Toxicity and Hepatic Insufficiency: In patients with both hematologic toxicity and hepatic insufficiency, the lower of the doses based on the corresponding starting dose of NAVELBINE determined from Table 5 and Table 6 should be administered. Dose Modifications for Renal Insufficiency: No dose adjustments for NAVELBINE are required for renal insufficiency. Appropriate dose reductions for cisplatin should be made when NAVELBINE is used in combination. Dose Modifications for Neurotoxicity: If Grade ≥2 neurotoxicity develops, NAVELBINE should be discontinued. Administration Precautions: Caution - NAVELBINE must be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any NAVELBINEÆ (vinorelbine tartrate) Injection 16 NAVELBINE is injected. Leakage into surrounding tissue during intravenous administration of NAVELBINE may cause considerable irritation, local tissue necrosis, and/or thrombophlebitis. If extravasation occurs, the injection should be discontinued immediately, and any remaining portion of the dose should then be introduced into another vein. Since there are no established guidelines for the treatment of extravasation injuries with NAVELBINE, institutional guidelines may be used. The ONS Chemotherapy Guidelines provide additional recommendations for the prevention of extravasation injuries. 1 As with other toxic compounds, caution should be exercised in handling and preparing the solution of NAVELBINE. Skin reactions may occur with accidental exposure. 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. Severe irritation of the eye has been reported with accidental contamination of the eye with another vinca alkaloid. If this happens with NAVELBINE, the eye should be flushed with water immediately and thoroughly. Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published.2-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. NAVELBINE Injection is a clear, colorless to pale yellow solution. 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. Preparation for Administration: NAVELBINE Injection must be diluted in either a syringe or IV bag using one of the recommended solutions. The diluted NAVELBINE should be administered over 6 to 10 minutes into the side port of a free-flowing IV closest to the IV bag followed by flushing with at least 75 to 125 mL of one of the solutions. 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). Syringe: The calculated dose of NAVELBINE should be diluted to a concentration between 1.5 and 3.0 mg/mL. The following solutions may be used for dilution: 5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP IV Bag: The calculated dose of NAVELBINE should be diluted 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: Unopened vials of NAVELBINE are stable until the date indicated on the package when stored under refrigeration at 2° to 8°C (36° to 46°F) and protected from light in the carton. Unopened vials of NAVELBINE are stable at temperatures up to 25°C (77°F) for up to 72 hours. This product should not be frozen. HOW SUPPLIED NAVELBINEÆ (vinorelbine tartrate) Injection 17 NAVELBINE Injection is a clear, colorless to pale yellow solution in Water for Injection, containing 10 mg vinorelbine per mL. NAVELBINE Injection is available in single-use, clear glass vials with elastomeric stoppers and royal blue caps, individually packaged in a carton in the following vial sizes: 10 mg/1 mL Single-Use Vial, Carton of 1 (NDC 0173-0656-01). 50 mg/5 mL Single-Use Vial, Carton of 1 (NDC 0173-0656-44). Store the vials under refrigeration at 2° to 8°C (36° to 46°F) in the carton. Protect from light. DO NOT FREEZE. REFERENCES 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41. 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, National Institutes of Health; 1983. US Dept of Health and Human Services, Public Health Service publication NIH 83-2621. 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591. 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428. 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263. 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685. Manufactured by Pierre Fabre MÈdicament Production 64320 Idron FRANCE for GlaxoSmithKline Research Triangle Park, NC 27709 Under license of Pierre Fabre MÈdicament - Centre National de la Recherche Scientifique-France ©2002, GlaxoSmithKline. All rights reserved. November 2002 RL-1157