Dosage Form: injection
Vinorelbine
Tartrate
Injection
Package Insert
Rx ONLY
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 ≥1000 cells/mm3 prior to the administration of Vinorelbine. 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 Vinorelbine tartrate is injected. Administration of Vinorelbine tartrate injection may result in extravasation causing local tissue necrosis and/or thrombophlebitis. (SeeDOSAGE AND ADMINISTRATION: Administration Precautions.)
Vinorelbine Description
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 >1000 mg/mL in distilled water. The pH of Vinorelbine Tartrate Injection is approximately 3.5.
Vinorelbine - 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.
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/h per 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 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.
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 Vinorelbine (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. (SeePRECAUTIONS.) 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. (SeeDOSAGE 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 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 Vinorelbine tartrate injection. (SeePRECAUTIONS: Drug Interactions.)
Clinical Trials
Data from 1 randomized clinical study (211 evaluable patients) with single-agent Vinorelbine and 2 randomized clinical trials (1044 patients) using Vinorelbine combined with cisplatin support the use of Vinorelbine tartrate injection in patients with advanced nonsmall cell lung cancer (NSCLC).
Single-Agent Vinorelbine
Single-agent Vinorelbine 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 Vinorelbine (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 Vinorelbine (143) or 5-FU/LV (68). Vinorelbine 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 Vinorelbine versus 5-FU/LV, respectively (P = 0.06). The 1-year survival rates were 24% (±4% SE) for Vinorelbine 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 Vinorelbine and 5-FU/LV were 12% and 3%, respectively.
Vinorelbine in Combination with Cisplatin: Vinorelbine plus Cisplatin versus Single-Agent Cisplatin
A Phase III open-label, randomized study was conducted which compared Vinorelbine (25 mg/m2 per 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 Vinorelbine 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 Vinorelbine plus cisplatin was significantly better compared to the patients who received single-agent cisplatin. The results of this trial are summarized inTable 1.
Vinorelbine plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine
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 Vinorelbine (30 mg/m2 per week), Vinorelbine (30 mg/m2 per week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks), and vindesine (3 mg/m2 per 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 inTable 1. Survival was longer in patients treated with Vinorelbine plus cisplatin compared to those treated with vindesine plus cisplatin (Figure 2). Study results are summarized inTable 1.
Dose-Ranging Study
A dose-ranging study of Vinorelbine (20, 25, or 30 mg/m2 per 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.
| Vinorelbine/Cisplatin vs. Single-Agent Cisplatin | Vinorelbine/Cisplatin vs. Vindesine/Cisplatin vs. Single-Agent Vinorelbine | ||||
| Vinorelbine/ Cisplatin | Cisplatin | Vinorelbine/ Cisplatin | Vindesine/ Cisplatin | Vinorelbine | |
| |||||
| 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) | 63 | 64 | 59 | 59 | 60 |
| Range (years) | 33–84 | 37–81 | 32–75 | 31–75 | 30–74 |
| Stage of disease | |||||
| Stage IIIA | N/A | N/A | 11% | 11% | 10% |
| Stage IIIB | 8% | 8% | 28% | 25% | 32% |
| Stage IV | 92% | 92% | 50% | 55% | 47% |
| Local recurrence | N/A | N/A | 2% | 3% | 3% |
| Metastatic after surgery | N/A | N/A | 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% | N/A | N/A | N/A |
| Results Median survival (months) | 7.8 | 6.2 | 9.2*† | 7.4 | 7.2 |
| P value | P = 0.01 | ||||
| 12-Month survival rate | 38% | 22% | 35% | 27% | 30% |
| Overall response | 19% | 8% | 28%ठ| 19% | 14% |
| P value | P < 0.001 | ||||
Indications and Usage for Vinorelbine
Vinorelbine tartrate injection 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 tartrate injection is contraindicated in patients with pretreatment granulocyte counts <1000 cells/mm3. (SeeWARNINGS.)
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. SeeDOSAGE AND ADMINISTRATIONfor 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
Pregnancy Category D
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.
Precautions
General
Most drug-related adverse events of Vinorelbine are reversible. If severe adverse events occur, Vinorelbine should be reduced in dosage or discontinued and appropriate corrective measures taken. Reinstitution of therapy with Vinorelbine should be carried out with caution and alertness as to possible recurrence of toxicity.
Vinorelbine should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from the effects of previous chemotherapy. (SeeDOSAGE AND ADMINISTRATION.)
Administration of Vinorelbine to patients with prior radiation therapy may result in radiation recall reactions. (SeeADVERSE REACTIONSandDrug Interactions.)
Patients with a prior history or pre-existing neuropathy, regardless of etiology, should be monitored for new or worsening signs and symptoms of neuropathy while receiving Vinorelbine.
Care must be taken to avoid contamination of the eye with concentrations of Vinorelbine used clinically. Severe irritation of the eye has been reported with accidental exposure to another vinca alkaloid. If exposure occurs, the eye should immediately be thoroughly flushed with water.
Information for Patients
Patients should be informed that the major acute toxicities of Vinorelbine are related to bone marrow toxicity, specifically granulocytopenia with increased susceptibility to infection. They should be advised to report fever or chills immediately. Women of childbearing potential should be advised to avoid becoming pregnant during treatment. Patients should be advised to contact their physician if they experience increased shortness of breath, cough, or other new pulmonary symptoms, or if they experience symptoms of abdominal pain or constipation.
Laboratory Tests
Since dose-limiting clinical toxicity is the result of depression of the white blood cell count, it is imperative that complete blood counts with differentials be obtained and reviewed on the day of treatment prior to each dose of Vinorelbine. (SeeADVERSE REACTIONS: Hematologic.)
Hepatic
There is no evidence that the toxicity of Vinorelbine is enhanced in patients with elevated liver enzymes. No data are available for patients with severe baseline cholestasis, but the liver plays an important role in the metabolism of Vinorelbine. Because clinical experience in patients with severe liver disease is limited, caution should be exercised when administering Vinorelbine to patients with severe hepatic injury or impairment. (SeeDOSAGE AND ADMINISTRATION.)
Drug Interactions
Acute pulmonary reactions have been reported with Vinorelbine and other anticancer vinca alkaloids used in conjunction with mitomycin. Although the pharmacokinetics of Vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of granulocytopenia with Vinorelbine used in combination with cisplatin is significantly higher than with single-agent Vinorelbine. Patients who receive Vinorelbine and paclitaxel, either concomitantly or sequentially, should be monitored for signs and symptoms of neuropathy. Administration of Vinorelbine to patients with prior or concomitant radiation therapy may result in radiosensitizing effects.
Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of Vinorelbine tartrate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of Vinorelbine 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. The significance of these or other short-term test results for human risk is unknown. 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 one seventh the human dose) prior to and during mating. However, biweekly administration for 13 or 26 weeks in the rat at 2.1 and 7.2 mg/m2 (approximately one fifteenth and one fourth the human dose) resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.
Pregnancy
Pregnancy Category D
SeeWARNINGSsection.
Nursing Mothers
It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Vinorelbine, it is recommended that nursing be discontinued in women who are receiving therapy with Vinorelbine.
Pediatric Use
Safety and effectiveness of Vinorelbine tartrate injection in pediatric patients have not been established. Data from a single arm study in 46 patients with recurrent solid malignant tumors, including rhabdomyosarcoma/undifferentiated sarcoma, neuroblastoma, and CNS tumors, at doses similar to those used in adults showed no meaningful clinical activity. Toxicities were similar to those reported in adult patients
Geriatric Use
Of the total number of patients in North American clinical studies of IV Vinorelbine, approximately one third were 65 years of age or greater. No overall differences in effectiveness or safety were observed between these patients and younger adult patients. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.
The pharmacokinetics of Vinorelbine in elderly and younger adult patients are similar. (See CLINICAL PHARMACOLOGY.)
Adverse Reactions
The pattern of adverse reactions is similar whether Vinorelbine is used as a single agent or in combination. Adverse reactions from studies with single-agent and combination use of Vinorelbine are summarized in Tables 2–4.
Single-Agent Vinorelbine
Data in the following table are based on the experience of 365 patients (143 patients with NSCLC; 222 patients with advanced breast cancer) treated with IV Vinorelbine as a single agent in 3 clinical studies. The dosing schedule in each study was 30 mg/m2 Vinorelbine on a weekly basis.
| Adverse Event | All Patients (n = 365) | NSCLC (n = 143) | ||||
| ||||||
| Bone Marrow | ||||||
| Granulocytopenia | <2000 cells/mm3 | 90% | 80% | |||
| <500 cells/mm3 | 36% | 29% | ||||
| Leukopenia | <4000 cells/mm3 | 92% | 81% | |||
| <1000 cells/mm3 | 15% | 12% | ||||
| Thrombocytopenia | <100,000 cells/mm3 | 5% | 4% | |||
| <50,000 cells/mm3 | 1% | 1% | ||||
| Anemia | <11 g/dL | 83% | 77% | |||
| <8 g/dL | 9% | 1% | ||||
| Hospitalizations due to granulocytopenic complications | 9% | 8% | ||||
| Adverse Event | All Grades | Grade 3 | Grade 4 | |||
| All Patients | NSCLC | All Patients | NSCLC | All Patients | NSCLC | |
| Clinical Chemistry Elevations | ||||||
| Total Bilirubin (n = 351) | 13% | 9% | 4% | 3% | 3% | 2% |
| SGOT (n = 346) | 67% | 54% | 5% | 2% | 1% | 1% |
| General | ||||||
| Asthenia | 36% | 27% | 7% | 5% | 0% | 0% |
| Injection Site Reactions | 28% | 38% | 2% | 5% | 0% | 0% |
| Injection Site Pain | 16% | 13% | 2% | 1% | 0% | 0% |
| Phlebitis | 7% | 10% | <1% | 1% | 0% | 0% |
| Digestive | ||||||
| Nausea | 44% | 34% | 2% | 1% | 0% | 0% |
| Vomiting | 20% | 15% | 2% | 1% | 0% | 0% |
| Constipation | 35% | 29% | 3% | 2% | 0% | 0% |
| Diarrhea | 17% | 13% | 1% | 1% | 0% | 0% |
| Peripheral Neuropathy‡ | 25% | 20% | 1% | 1% | <1% | 0% |
| Dyspnea | 7% | 3% | 2% | 2% | 1% | 0% |
| Alopecia | 12% | 12% | ≤1% | 1% | 0% | 0% |
Granulocytopenia is the major dose-limiting toxicity with Vinorelbine. Dose adjustments are required for hematologic toxicity and hepatic insufficiency. (SeeDOSAGE AND ADMINISTRATION.) Granulocytopenia was generally reversible and not cumulative over time. Granulocyte nadirs occurred 7 to 10 days after the dose, with granulocyte recovery usually within the following 7 to 14 days. Granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of patients. Septic deaths occurred in approximately 1% of patients. Prophylactic hematologic growth factors have not been routinely used with Vinorelbine. If medically necessary, growth factors may be administered at recommended doses no earlier than 24 hours after the administration of cytotoxic chemotherapy. Growth factors should not be administered in the period 24 hours before the administration of chemotherapy.
Whole blood and/or packed red blood cells were administered to 18% of patients who received Vinorelbine.
Neurologic
Loss of deep tendon reflexes occurred in less than 5% of patients. The development of severe peripheral neuropathy was infrequent (1%) and generally reversible.
Skin
Like other anticancer vinca alkaloids, Vinorelbine is a moderate vesicant. Injection site reactions, including erythema, pain at injection site, and vein discoloration, occurred in approximately one third of patients; 5% were severe. Chemical phlebitis along the vein proximal to the site of injection was reported in 10% of patients.
Gastrointestinal
Prophylactic administration of antiemetics was not routine in patients treated with single-agent Vinorelbine. Due to the low incidence of severe nausea and vomiting with single-agent Vinorelbine, the use of serotonin antagonists is generally not required.
Hepatic
Transient elevations of liver enzymes were reported without clinical symptoms.
Cardiovascular
Chest pain was reported in 5% of patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest. There have been rare reports of myocardial infarction.
Pulmonary
Shortness of breath was reported in 3% of patients; it was severe in 2%. (SeeWARNINGS.) Interstitial pulmonary chan
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