NAVELBINE - vinorelbine tartrate injection
Pierre Fabre M�dicament
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 - FOR IV USE ONLY. FATAL if given intrathecally."
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) 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 is a white to yellow or light brown amorphous powder with the molecular formula C45 H54 N4 O8 �2C4 H6 O6 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. 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) calmodulin-dependent 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 �M), inducing a blockade of cells at metaphase. Vincristine produced depolymerization of axonal microtubules at 5 �M, but vinblastine and vinorelbine did not have this effect until concentrations of 30 �M and 40 �M, respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules.
INDICATIONS AND USAGE
NAVELBINE is indicated as a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unresectable, advanced non-small cell lung cancer (NSCLC). In patients with Stage IV NSCLC, NAVELBINE is indicated as a single agent or in combination with cisplatin. In Stage III NSCLC, NAVELBINE is indicated in combination with cisplatin
CONTRAINDICATIONS
Administration of NAVELBINE is contraindicated in patients with pretreatment granulocyte counts <1,000 cells/mm3 (see WARNINGS).
WARNINGS
NAVELBINE should be administered in carefully adjusted doses by or under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Patients treated with NAVELBINE should be frequently monitored for myelosuppression both during and after therapy. Granulocytopenia is dose-limiting. Granulocyte nadirs occur between 7 and 10 days after dosing with granulocyte count recovery usually within the following 7 to 14 days. Complete blood counts with differentials should be performed and results reviewed prior to administering each dose of NAVELBINE. NAVELBINE should not be administered to patients with granulocyte counts <1,000 cells/mm3. Patients developing severe granulocytopenia should be monitored carefully for evidence of infection and/or fever. See DOSAGE AND ADMINISTRATION for recommended dose adjustments for granulocytopenia. Acute shortness of breath and severe bronchospasm have been reported infrequently, following the administration of NAVELBINE and other vinca alkaloids, most commonly when the vinca alkaloid was used in combination with mitomycin. These adverse events may require treatment with supplemental oxygen, bronchodilators, and/or corticosteroids, particularly when there is pre-existing pulmonary dysfunction. Reported cases of interstitial pulmonary changes and acute respiratory distress syndrome (ARDS), most of which were fatal, occurred in patients treated with single-agent NAVELBINE. The mean time to onset of these symptoms after vinorelbine administration was 1 week (range 3 to 8 days). Patients with alterations in their baseline pulmonary symptoms or with new onset of dyspnea, cough, hypoxia, or other symptoms should be evaluated promptly.
NAVELBINE has been reported to cause severe constipation (e.g., Grade 3-4), paralytic ileus, intestinal obstruction, necrosis, and/or perforation. Some events have been fatal.
DOSAGE AND ADMINISTRATION
Single-Agent NAVELBINE
The usual initial dose of single-agent NAVELBINE is 30 mg/m2 administered weekly. The recommended method of administration is an intravenous injection over 6 to 10 minutes. In controlled trials, single-agent NAVELBINE was given weekly until progression or dose-limiting toxicity.
NAVELBINE in Combination with Cisplatin
NAVELBINE may be administered weekly at a dose of 25 mg/m2 in combination with cisplatin given every 4 weeks at a dose of 100 mg/m2.
Blood counts should be checked weekly to determine whether dose reductions of vinorelbine and/or cisplatin are necessary. In the SWOG study, most patients required a 50% dose reduction of NAVELBINE at day 15 of each cycle and a 50% dose reduction of cisplatin by cycle 3.
NAVELBINE may also be administered weekly at a dose of 30 mg/m2 in combination with cisplatin, given on days 1 and 29, then every 6 weeks with cisplatin at a dose of 120 mg/m2.
Dose Modifications for NAVELBINE
The dosage should be adjusted according to hematologic toxicity or hepatic insufficiency, whichever results in the lower dose for the corresponding starling dose of NAVELBINE
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.
