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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Vinorelbine may be confused with vinBLAStine
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Vinorelbine is intended for I. V. use only: Inadvertent intrathecal administration of other vinca alkaloids has resulted in death. Syringes containing vinorelbine should be labeled “For I.V. use only. Fatal if given intrathecally.”
Pronunciation
(vi NOR el been)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of nonsmall cell lung cancer (NSCLC)
Use: Unlabeled/Investigational
Treatment of breast cancer, cervical cancer, and ovarian cancer
Pregnancy Risk Factor
D
Pregnancy Considerations
Animal studies have demonstrated embryotoxicity, fetotoxicity, decreased fetal weight, and delayed ossification. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should avoid becoming pregnant during vinorelbine treatment.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.
Contraindications
Pretreatment granulocyte counts <1000/mm3
Warnings/Precautions
Boxed warnings:
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Experienced physician: See “Other warnings/precautions” below.
• Extravasation: See “Other warnings/precautions” below.
• NOT for intrathecal use: See “Other warnings/precautions” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal; avoid eye contamination (exposure may cause severe irritation).
Concerns related to adverse effects:
• Bone marrow suppression: [U.S. Boxed Warning]: Severe granulocytopenia may occur with treatment; granulocytopenia is a dose-limiting toxicity; granulocyte counts should be ?1000/mm3 prior to treatment initiation; monitor closely for infections and/or fever; may require dosage adjustment. Use with caution in patients with compromised marrow reserve due to prior chemotherapy therapy or prior radiation therapy.
• Gastrointestinal effects: May cause severe constipation (grade 3-4), paralytic ileus, intestinal obstruction, necrosis, and/or perforation.
• Neuropathy: May cause new onset or worsening of pre-existing neuropathy; use with caution in patients with neuropathy.
• Pulmonary toxicity: Fatal cases of interstitial pulmonary changes and ARDS have been reported with single-agent therapy. Promptly evaluate changes in baseline pulmonary symptoms or any new-onset pulmonary symptoms.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage modification required.
• Neurotoxicity: Use with caution in patients with neurotoxicity; dosage modification required.
• Radiation therapy: May have radiosensitizing effects with prior or concurrent radiation therapy; radiation recall reactions may occur in patients who have received prior radiation therapy.
Concurrent drug therapy issues:
• Cisplatin: The incidence of granulocytopenia is significantly higher when given in combination with cisplatin when compared to single-agent vinorelbine.
• Mitomycin C: Acute shortness of breath and severe bronchospasm have been reported rarely; usually associated with concurrent administration of mitomycin.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
• Extravasation: [U.S. Boxed Warning]: Avoid extravasation; infiltration may cause irritation, thrombophlebitis and/or local tissue necrosis.
• NOT for intrathecal use: [U.S. Boxed Warning]: Intrathecal administration may result in death. For I.V. use only.
Adverse Reactions
Note: Reported with single-agent therapy.
>10%:
Central nervous system: Fatigue (27%)
Dermatologic: Alopecia (12% to 30%)
Gastrointestinal: Nausea (31% to 44%; grade 3: 1% to 2%), constipation (35%; grade 3: 3%), vomiting (20% to 31%; grade 3: 1% to 2%), diarrhea (12% to 17%)
Hematologic: Leukopenia (83% to 92%; grade 4: 6% to 15%), granulocytopenia (90%; grade 4: 36%; nadir: 7-10 days; recovery 14-21 days; dose-limiting), neutropenia (85%; grade 4: 28%), anemia (83%; grades 3/4: 9%)
Hepatic: AST increased (67%; grade 3: 5%; grade 4: 1%), total bilirubin increased (5% to 13%; grade 3: 4%; grade 4: 3%)
Local: Injection site reaction (22% to 28%; includes erythema, vein discoloration), injection site pain (16%)
Neuromuscular & skeletal: Weakness (36%), peripheral neuropathy (25%; grade 3: 1%; grade 4: <1%)
Renal: Creatinine increased (13%)
1% to 10%:
Cardiovascular: Chest pain (5%)
Dermatologic: Rash (<5%)
Gastrointestinal: Paralytic ileus (1%)
Hematologic: Neutropenic fever/sepsis (8%; grade 4: 4%), thrombocytopenia (3% to 5%; grades 3/4: 1%)
Local: Phlebitis (7% to 10%)
Neuromuscular & skeletal: Loss of deep tendon reflexes (<5%), myalgia (<5%), arthralgia (<5%), jaw pain (<5%)
Otic: Ototoxicity (?1%)
Respiratory: Dyspnea (7%)
<1%, postmarketing, and/or case reports: Abdominal pain, allergic reactions, anaphylaxis, angioedema, back pain, DVT, dysphagia, esophagitis, flushing, gait instability, headache, hemorrhagic cystitis, hyper-/hypotension, hyponatremia, intestinal necrosis, intestinal obstruction, intestinal perforation, interstitial pulmonary changes, local rash, local urticaria, MI (rare), mucositis, muscle weakness, pancreatitis, paralytic ileus, pneumonia, pruritus, pulmonary edema, pulmonary embolus, radiation recall (dermatitis, esophagitis), skin blistering, syndrome of inappropriate ADH secretion, tachycardia, thromboembolic events, tumor pain, urticaria, vasodilation
Metabolism/Transport Effects
Substrate of CYP2D6 (minor), 3A4 (major); Inhibits CYP2D6 (weak), 3A4 (weak)
Drug Interactions
CISplatin: May enhance the adverse/toxic effect of Vinorelbine. Specifically, the combination may be associated with a higher risk of granulocytopenia. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Macrolide Antibiotics: May increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Macrolides may also increase the distribution of Vinca Alkaloids into certain cells and/or tissues. Management: Consider an alternative to using a macrolide antibiotic when possible in order to avoid the potential for increased vinca alkaloid toxicity. Exceptions: Azithromycin. Risk D: Consider therapy modification
Mitomycin: Antineoplastic Agents (Vinca Alkaloids) may enhance the adverse/toxic effect of Mitomycin. Specifically, the risk of pulmonary toxicity may be increased. Risk C: Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Paclitaxel: May enhance the neurotoxic effect of Vinorelbine. Risk C: Monitor therapy
Paclitaxel (Protein Bound): May enhance the neurotoxic effect of Vinorelbine. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Posaconazole: May enhance the adverse/toxic effect of Antineoplastic Agents (Vinca Alkaloids). Posaconazole may increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Risk D: Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Voriconazole: May enhance the adverse/toxic effect of Antineoplastic Agents (Vinca Alkaloids). Voriconazole may increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid St John's wort (may decrease vinorelbine levels).
Storage
Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Intact vials are stable at room temperature of 25°C (77°F) for up to 72 hours. Dilutions in D5W or NS are stable for 24 hours at room temperature.
Reconstitution
Dilute in D5W or NS to a final concentration of 1.5-3 mg/mL (for syringe) or 0.5-2 mg/mL (for I.V. bag).
Compatibility
Stable in D51/2NS, D5W, LR, NS, 1/2NS.
Y-site administration: Compatible: Amikacin, aztreonam, bleomycin, bumetanide, buprenorphine, butorphanol, calcium gluconate, carboplatin, carmustine, cefotaxime, ceftazidime, ceftizoxime, chlorpromazine, cimetidine, cisplatin, clindamycin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, dexamethasone sodium phosphate, diphenhydramine, doxorubicin, doxorubicin liposome, doxycycline, droperidol, enalaprilat, etoposide, famotidine, filgrastim, floxuridine, fluconazole, fludarabine, gatifloxacin, gemcitabine, gentamicin, granisetron, haloperidol, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydromorphone, hydroxyzine, idarubicin, ifosfamide, imipenem/cilastatin, lorazepam, mannitol, mechlorethamine, melphalan, meperidine, mesna, methotrexate, metoclopramide, metronidazole, minocycline, mitoxantrone, morphine, nalbuphine, netilmicin, ondansetron, plicamycin, streptozocin, teniposide, ticarcillin, ticarcillin/clavulanate, tobramycin, vancomycin, vinblastine, vincristine, zidovudine. Incompatible: Acyclovir, allopurinol, aminophylline, amphotericin B, amphotericin B cholesteryl sulfate complex, ampicillin, cefazolin, cefoperazone, cefotetan, ceftriaxone, cefuroxime, co-trimoxazole, fluorouracil, furosemide, ganciclovir, methylprednisolone sodium succinate, mitomycin, piperacillin, sodium bicarbonate, thiotepa. Variable (consult detailed reference): Heparin.
Mechanism of Action
Semisynthetic vinca alkaloid which binds to tubulin and inhibits microtubule formation, therefore, arresting the cell at metaphase by disrupting the formation of the mitotic spindle; it is specific for the M and S phases. Vinorelbine may also interfere with nucleic acid and protein synthesis by blocking glutamic acid utilization.
Pharmacodynamics/Kinetics
Absorption: Unreliable; must be given I.V.
Distribution: Vd: 25-40 L/kg; binds extensively to human platelets and lymphocytes (80% to 91%)
Protein binding: 80% to 91%
Metabolism: Extensively hepatic, via CYP3A4, to two metabolites, deacetylvinorelbine (active) and vinorelbine N-oxide
Bioavailability: Oral (not approved in the U. S.): 26% to 45%
Half-life elimination: Triphasic: Terminal: 28-44 hours
Excretion: Feces (46%); urine (18%, 10% to 12% as unchanged drug)
Clearance: Plasma: Mean: 0.97-1.26 L/hour/kg
Dosage
Details concerning dosing in combination regimens should also be consulted.
I.V.: Adults:
NSCLC:
Single-agent therapy: 30 mg/m2/dose every 7 days
Combination therapy with cisplatin: 25-30 mg/m2/dose every 7 days (in combination with cisplatin)
Breast cancer (unlabeled use): 25 mg/m2/dose every 7 days
Cervical cancer (unlabeled use): 30 mg/m2/dose days 1 and 8 of a 21-day treatment cycle
Ovarian cancer (unlabeled use): 25 mg/m2/dose every 7 days or 30 mg/m2/dose days 1 and 8 of a 21-day treatment cycle
Dosage adjustment in hematological toxicity: Granulocyte counts should be ?1000 cells/mm3 prior to the administration of vinorelbine. Adjustments in the dosage of vinorelbine should be based on granulocyte counts obtained on the day of treatment as follows:
Granulocytes ?1500 cells/mm3 on day of treatment: Administer 100% of starting dose
Granulocytes 1000-1499 cells/mm3 on day of treatment: Administer 50% of starting dose
Granulocytes <1000 cells/mm3 on day of treatment: Do not administer. Repeat granulocyte count in one week; if 3 consecutive doses are held because granulocyte count is <1000 cells/mm3, discontinue vinorelbine.
For patients who, during treatment, have experienced fever and/or sepsis while granulocytopenic or had 2 consecutive weekly doses held due to granulocytopenia, subsequent doses of vinorelbine should be:
75% of starting dose for granulocytes ?1500 cells/mm3
37.5% of starting dose for granulocytes 1000-1499 cells/mm3
Dosage adjustment for neurotoxicity: Neurotoxicity ?grade 2: Discontinue treatment
Dosage adjustment in renal impairment: No adjustment is necessary.
Dosing adjustment in hepatic impairment: The FDA-approved labeling guidelines are as follows: Vinorelbine should be administered with caution in patients with hepatic insufficiency. In patients who develop hyperbilirubinemia during treatment with vinorelbine, the dose should be adjusted for total bilirubin as follows:
Serum bilirubin ?2 mg/dL: Administer 100% of dose
Serum bilirubin 2.1-3 mg/dL: Administer 50% of dose
Serum bilirubin >3 mg/dL: Administer 25% of dose
Dosing adjustment in patients with concurrent hematologic toxicity and hepatic impairment: Administer the lower of the doses determined from the adjustment recommendations.
Dosage: Combination Regimens
Breast cancer:
Paclitaxel-Vinorelbine
VD
Vinorelbine-FEC
Vinorelbine-Trastuzumab
Vinorelbine-Trastuzumab-FEC
Cervical cancer: Cisplatin-Vinorelbine
Leukemia, acute lymphocytic: TVTG
Leukemia, acute myeloid: TVTG
Lung cancer (nonsmall cell):
Cetuximab-Cisplatin-Vinorelbine
Gemcitabine-Vinorelbine
Vinorelbine-Cisplatin
Vinorelbine-Gemcitabine
Lymphoma, Hodgkin's: Gemcitabine-Vinorelbine-Doxorubicin (Liposomal)
Prostate cancer: Estramustine + Vinorelbine
Administration: I.V.
FATAL IF GIVEN INTRATHECALLY. Administer as a direct intravenous push or rapid bolus, over 6-10 minutes (up to 30 minutes). Longer infusions may increase the risk of pain and phlebitis. Intravenous doses should be followed by at least 75-125 mL of saline or D5W to reduce the incidence of phlebitis and inflammation. Assure proper needle or catheter position prior to administration.
Administration: I.V. Detail
Do not administer in an extremity with poor circulation or repeatedly into the same vein.
pH: 3.5 (injection)
Monitoring Parameters
CBC with differential and platelet count, hepatic function tests; monitor for new-onset pulmonary symptoms (or worsening from baseline); monitor for neuropathy
Patient Education
Do not take any new medication during therapy unless approved by prescriber. This medication can only be administered by infusion; report immediately any redness, swelling, burning, or pain at infusion site. Maintain adequate hydration unless instructed to restrict fluid intake, and nutrition (small, frequent meals will help). You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations unless approved by prescriber). May cause hair loss (will grow back after therapy); nausea or vomiting (request antiemetic); photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight); feelings of weakness or lethargy (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or mouth sores (use soft toothbrush, waxed dental floss and frequent oral care). Report persistent constipation or abdominal pain; numbness or tingling in fingers or toes (use care to prevent injury); weakness, numbness, or pain in muscles or extremities; signs of infection (eg, fever, chills, sore throat, burning urination, fatigue); unusual bleeding (eg, tarry stools, easy bruising, blood in stool, urine, or mouth); unresolved mouth sores; skin rash or itching; or respiratory difficulty. Pregnancy/breast-feeding precautions: Do not get pregnant (females) or cause a pregnancy (males) during this therapy. Consult prescriber for appropriate contraceptive measures. Do not breast-feed.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness
Mental Health: Effects on Psychiatric Treatment
Bone marrow suppression is common; avoid clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Assess potential for interactions with other pharmacological agents and herbal products patient may be taking. Premedication with antiemetic is advisable. May cause severe constipation, paralytic ileus, intestinal obstruction, necrosis, and/or perforation; prophylactic bowel management regimen may be advisable. See Administration for infusion specifics. Infusion site must be monitored closely to prevent extravasation (may cause tissue damage and necrosis). Assess results of laboratory tests regularly. Evaluate therapeutic effectiveness and adverse reactions prior to each infusion and throughout therapy. Teach patient possible side effects/appropriate interventions and adverse symptoms to report.
Oncology: Emetic Potential
Very low (<10%)
Oncology: Vesicant
Yes. See Management of Drug Extravasations.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [preservative free]: 10 mg/mL (1 mL, 5 mL)
Navelbine®: 10 mg/mL (1 mL, 5 mL)
References
Bajetta E, Di Leo A, Biganzoli L, et al, “Phase II Study of Vinorelbine in Patients With Pretreated Advanced Ovarian Cancer: Activity in Platinum-Resistant Disease,” J Clin Oncol, 1996, 14(9):2546-51.
Budman DR, “Vinorelbine (Navelbine®): A Third-Generation Vinca Alkaloid,” Cancer Invest, 1997, 15(5);475-90.
Johnson SA, Harper P, Hortobagyi GN, et al, “Vinorelbine: An Overview,” Cancer Treat Rev, 1996, 22(2):127-42.
Jones SF and Burris HA 3d, “Vinorelbine: A New Antineoplastic Drug for the Treatment of Nonsmall Cell Lung Cancer,” Ann Pharmacother, 1996, 30(5):501-6.
LeVeque D and Jehl F, “Clinical Pharmacokinetics of Vinorelbine,” Clin Pharmacokinet, 1996, 31(3):184-97.
Muggia FM, Blessing JA, Method M, et al, “Evaluation of Vinorelbine in Persistent or Recurrent Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study,” Gynecol Oncol, 2004, 92(2):639-43.
Muggia FM, Blessing JA, Waggoner S, et al, “Evaluation of Vinorelbine in Persistent or Recurrent Nonsquamous Carcinoma of the Cervix: A Gynecologic Oncology Group Study,” Gynecol Oncol, 2005, 96(1):108-11.
Rothenberg ML, Liu PY, Wilczynski s, et al, “Phase II Trial of Vinorelbine for Relapsed Ovarian Cancer: A Southwest Oncology Group Study,” Gynecol Oncol, 2004, 95(3):506-12.
Toso C and Lindley C, “Vinorelbine: A Novel Vinca Alkaloid,” Am J Health Syst Pharm, 1995, 52(12):1287-304.
Zelek L, Barthier S, Riofrio M, et al, “Weekly Vinorelbine is an Effective Palliative Regimen After Failure With Anthracyclines and Taxanes in Metastatic Breast Carcinoma,” Cancer, 2001, 92(9):2267-72.
International Brand Names
Lexi-Comp.com
Last full review/revision September 2009
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