Navelbine® (Vinorelbine)

Vinorelbine - Navelbine®

Usual Diluents

Dilution Data

Administration Precautions1:  Caution – vinorelbine must be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any vinorelbine is injected. Leakage into surrounding tissue during intravenous administration of vinorelbine 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.
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Preparation for Administration1
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Vinorelbine Tartrate Injection must be diluted in either a syringe or IV bag using one of the recommended solutions. The diluted vinorelbine 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 vinorelbine 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 vinorelbine 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
0.9% Sodium Chloride Injection

IV Bag: The calculated dose of vinorelbine should be diluted to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution:
5% Dextrose Injection
0.9% Sodium Chloride Injection
0.45% Sodium Chloride Injection
5% Dextrose and 0.45% Sodium Chloride Injection
Ringer's Injection
Lactated Ringer's Injection

Stability1:  Unopened vials of vinorelbine 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 vinorelbine are stable at temperatures up to 25°C (77°F) for up to 72 hours. This product should not be frozen.
Store the vials under refrigeration at 2° to 8°C (36° to 46°F) in the carton. Protect from light. DO NOT FREEZE.

DESCRIPTION
Vinorelbine Injection USP 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.

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 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.

INDICATIONS AND USAGE
Vinorelbine is indicated as a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unresectable, advanced nonsmall cell lung cancer (NSCLC). In patients with Stage IV NSCLC, vinorelbine is indicated as a single agent or in combination with cisplatin. In Stage III NSCLC, vinorelbine is indicated in combination with cisplatin.

CONTRAINDICATIONS
Administration of vinorelbine is contraindicated in patients with pretreatment granulocyte counts <1000 cells/mm3 (see WARNINGS).

WARNINGS
Vinorelbine 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 vinorelbine 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 vinorelbine. Vinorelbine should not be administered to patients with granulocyte counts <1000 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 vinorelbine 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 vinorelbine. 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.

Vinorelbine 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.

Pregnancy
Vinorelbine may cause fetal harm if administered to a pregnant woman. A single dose of vinorelbine has been shown to be embryo- and/or fetotoxic in mice and rabbits at doses of 9 mg/m2 and 5.5 mg/m2, respectively (one third and one sixth the human dose). At nonmaternotoxic doses, fetal weight was reduced and ossification was delayed. There are no studies in pregnant women. If vinorelbine is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with vinorelbine.

DOSAGE AND ADMINISTRATION

Single-Agent Vinorelbine
The usual initial dose of single-agent vinorelbine 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 vinorelbine was given weekly until progression or dose-limiting toxicity.

Vinorelbine in Combination with Cisplatin
Vinorelbine 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 vinorelbine at day 15 of each cycle and a 50% dose reduction of cisplatin by cycle 3.

Vinorelbine 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 at a dose of 120 mg/m2.

Dose Modifications for Vinorelbine
The dosage should be adjusted according to hematologic toxicity or hepatic insufficiency, whichever results in the lower dose for the corresponding starting dose of vinorelbine (see Table 5).

Dose Modifications for Hematologic Toxicity
Granulocyte counts should be ≥1000 cells/mm3 prior to administration of vinorelbine. Adjustments in the dosage of vinorelbine should be based on granulocyte counts obtained on the day of treatment according to Table 5.

Dose Modifications for Hepatic Insufficiency
Vinorelbine should be administered with caution to patients with hepatic insufficiency. In patients who develop hyperbilirubinemia during treatment with vinorelbine, the dose should be adjusted for total bilirubin according to Table 6.

Dose Modification 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 vinorelbine determined from Table 5 and Table 6 should be administered.

Dose Modifications for Renal Insufficiency
No dose adjustments for vinorelbine are required for renal insufficiency. Appropriate dose reductions for cisplatin should be made when vinorelbine is used in combination.

Dose Modifications for Neurotoxicity: If Grade ≥2 neurotoxicity develops, vinorelbine should be discontinued.

Administration Precautions
Caution – vinorelbine must be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any vinorelbine is injected. Leakage into surrounding tissue during intravenous administration of vinorelbine 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 vinorelbine, 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 vinorelbine. Skin reactions may occur with accidental exposure. The use of gloves is recommended. If the solution of vinorelbine 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 vinorelbine, 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.

Preparation for Administration
Vinorelbine Tartrate Injection must be diluted in either a syringe or IV bag using one of the recommended solutions. The diluted vinorelbine 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 vinorelbine 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 vinorelbine 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
0.9% Sodium Chloride Injection

IV Bag: The calculated dose of vinorelbine should be diluted to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution:
5% Dextrose Injection
0.9% Sodium Chloride Injection
0.45% Sodium Chloride Injection
5% Dextrose and 0.45% Sodium Chloride Injection
Ringer's Injection
Lactated Ringer's Injection

Stability
Unopened vials of vinorelbine 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 vinorelbine are stable at temperatures up to 25°C (77°F) for up to 72 hours. This product should not be frozen.

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 should not be administered.

HOW SUPPLIED
Vinorelbine Injection USP is a clear, colorless to pale yellow solution in water for injection, containing 10 mg vinorelbine per mL. Vinorelbine Injection USP 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-Dose Vial, individually-boxed NDC 55390-069-01
50 mg/5 mL Single-Dose Vial, individually-boxed NDC 55390-070-01

Store the vials under refrigeration at 2° to 8°C (36° to 46°F) in the carton. Protect from light. DO NOT FREEZE.

Manufactured by: Manufactured for:
Ben Venue Laboratories, Inc. Bedford laboratories™

Handling: ONS Clinical Practice Committe. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society: 1999:32-41. 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. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics JAMA. 1985;253: 1590-1591. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commision on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1: 426-428. 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. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.