SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 12 OVERDOSAGE 14 ACTION AND CLINICAL PHARMACOLOGY 15 STORAGE AND STABILITY 16 SPECIAL HANDLING INSTRUCTIONS 16
PHARMACEUTICAL INFORMATION 18 CLINICAL TRIALS 19 DETAILED PHARMACOLOGY 20 TOXICOLOGY 22 REFERENCES 28
PRODUCT MONOGRAPH
Pr
VINORELBINE TARTRATE FOR INJECTION
Vinorelbine tartrate for injection
| Route of Administration | Dosage Form/Strength | Clinically Relevant Nonmedicinal Ingredients |
| Intravenous | Injection / 10 mg Vinorelbine per mL | None For a complete listing see Dosage Forms, Composition and Packaging section |
VINORELBINE TARTRATE FOR INJECTION (vinorelbine tartrate) is indicated for:
treatment of advanced non-small cell lung cancer (NSCLC), as a single agent or in combination.
treatment of patients with metastatic breast cancer who have failed standard first-line chemotherapy for metastatic disease.
treatment of patients with metastatic breast cancer who have relapsed within 6 months of anthracycline-based adjuvant therapy.
Geriatrics (>= 65 years of age):
No overall differences in effectiveness or safety were observed between patients 65 years of age or greater and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (See WARNINGS AND PRECAUTIONS).
Pediatrics:
Safety and effectiveness in children have not been established.
CAUTION:
VINORELBINE TARTRATE FOR INJECTION (vinorelbine tartrate) IS A CYTOTOXIC DRUG AND SHOULD BE USED ONLY BY PHYSICIANS EXPERIENCED WITH CANCER CHEMOTHERAPEUTIC DRUGS. BLOOD COUNTS SHOULD BE TAKEN PRIOR TO EACH DOSE. THE DOSAGE SHOULD BE REDUCED OR THE DRUG DISCONTINUED UPON EVIDENCE OF ABNORMAL, DEPRESSION OF THE BONE MARROW.
This preparation is for intravenous administration only. Intrathecal administration of other vinca alkaloids has resulted in death. Syringes containing this product should be labelled "WARNING - FOR INTRAVENOUS USE ONLY. FATAL if given intrathecally
.
VINORELBINE TARTRATE FOR INJECTION (vinorelbine tartrate) is contraindicated in patients with known hypersensitivity to vinorelbine tartrate. As with other vinca alkaloids, VINORELBINE TARTRATE FOR INJECTION is contraindicated in patients who have drug-induced severe granulocytopenia or severe thrombocytopenia.
Serious WARNINGS and PRECAUTIONS
VINORELBINE TARTRATE FOR INJECTION is for intravenous use only. Vinorelbine tartrate is a moderate vesicant and can produce phlebitis or extravasation injury. Inadequate flushing of the vein after peripheral administration may increase the risk of phlebitis. It is extremely important that the needle be properly positioned in the vein before this product is injected. If leakage into surrounding tissue should occur during intravenous administration of VINORELBINE TARTRATE FOR INJECTION, it may cause severe irritation. The injection should be discontinued immediately, and any remaining portion of the dose should then be introduced into another vein. A low incidence of death (1 %) due to neutropenic sepsis has been reported (see ADVERSE REACTIONS). Bone marrow toxicity, specifically granulocytopenia, is dose-limiting. Complete blood counts with differentials should be performed and results reviewed prior to each dose of VINORELBINE TARTRATE FOR INJECTION. VINORELBINE TARTRATE FOR INJECTION 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). In all instances where the use of VINORELBINE TARTRATE FOR INJECTION (vinorelbine tartrate) is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse events. Most drug-related adverse reactions are reversible. If severe adverse events occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken based on the clinical judgment of the physician. Reinstitution of therapy with VINORELBINE TARTRATE FOR INJECTION should be carried out with caution and alertness as to possible recurrence of toxicity. Patients should be informed that VINORELBINE TARTRATE FOR INJECTION is a vesicant and can produce phlebitis or extravasation injury, and that the major acute toxicities of VINORELBINE TARTRATE FOR INJECTION are related to bone marrow toxicity, specifically granulocytopenia with increased susceptibility to infection, and neuropathy. They should also be advised to report fever or chills immediately. VINORELBINE TARTRATE FOR INJECTION should not be used in pregnancy unless the physician feels the potential benefit justifies the risk of potential harm to the fetus.
Hematologic
VINORELBINE TARTRATE FOR INJECTION 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 previous chemotherapy. 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 prior to each dose of VINORELBINE TARTRATE FOR INJECTION (See ADVERSE REACTIONS, Hematologic).
Hepatic
There is no evidence that the toxicity of vinorelbine tartrate is enhanced in patients with elevated liver enzymes; no data are available for patients with severe baseline cholestasis. However, pharmacologic evidence suggests that the liver plays an important role in the metabolism of vinorelbine tartrate. Although there are no data available from patients with severe liver disease, caution should be exercised when administering vinorelbine tartrate to patients with severe hepatic injury or impairment.
Neurologic
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 TARTRATE FOR INJECTION.
Ophthalmologic
Care must be exercised to avoid contamination of the eye with VINORELBINE TARTRATE FOR INJECTION. Accidental exposure should be treated immediately with a large volume of irrigation solution (water or sodium chloride).
Radiation
Administration of VINORELBINE TARTRATE FOR INJECTION to patients with prior radiation therapy may result in radiation recall reactions (see ADVERSE REACTIONS and DRUG INTERACTIONS).
Respiratory
Acute shortness of breath and severe bronchospasm have been reported infrequently following the administration of vinorelbine tartrate and of other vinca alkaloids. These events have been encountered most commonly when the vinca alkaloid was used in combination with mitomycin and may require aggressive treatment, particularly when there is pre-existing pulmonary dysfunction. Bronchodilators, steroids and/or oxygen have produced symptomatic relief.
Sensitivity
VINORELBINE TARTRATE FOR INJECTION 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 previous chemotherapy. Administration of VINORELBINE TARTRATE FOR INJECTION to patients with prior radiation therapy may result in radiation recall reactions (see ADVERSE REACTIONS and DRUG INTERACTIONS).
: There are no studies in pregnant women. Vinorelbine has been shown to be embryotoxic and/or fetotoxic in animals (see TOXICOLOGY). VINORELBINE TARTRATE FOR INJECTION should not be used in pregnancy.
It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of its potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued in women who are receiving therapy with VINORELBINE TARTRATE FOR INJECTION.
Safety and effectiveness in children have not been established.
: Of the total number of patients in North American clinical studies of intravenous vinorelbine tartrate, approximately one-third were 65 years of age or greater. No overall differences in effectiveness or safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Adverse Drug Reaction Overview
Data in the following tables are based on the experience of 365 patients (143 patients with NSCLC; 222 patients with advanced breast cancer) for whom a complete safety database was available and who were treated with vinorelbine tartrate as a single agent in three North American trials (one NSCLC trial and two advanced breast cancer trials). Patients treated for breast cancer were allowed to have received adjuvant chemotherapy in both trials, and in one, up to two prior regimens for advanced disease. The dosing schedule was 30 mg/m2 intravenous vinorelbine tartrate on a weekly basis.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Table 1
Summary of Adverse Events Occurring in >=5% of 365 Patients Receiving Single-Agent Vinorelbine Tartrate that are Possibly Attributable to the Study Medicationa,b
| Adverse Event | % Incidence All Grades | % Incidence Grade 3 | % Incidence Grade 4 | |||
| ABC n=222 | NSCLC n=143 | ABC n=222 | NSCLC n=143 | ABC n=222 | NSCLC n=143 | |
| General | 21 | 38 | 1 | 5 | 0 | 0 |
| Injection site reaction | ||||||
| Asthenia | 41 | 25 | 8 | 5 | 0 | 0 |
| Pain | 16 | 15 | 3 | 2 | 0 | 0 |
| Pain injection site | 18 | 13 | 3 | 1 | 0 | 0 |
| Fever | 19 | 10 | 1 | 0 | 0 | 0 |
| Pain Abdomen | 12 | 6 | 1 | 1 | 0 | 0 |
| Pain Chest | 8 | 5 | 1 | 2 | 0 | 0 |
| Phlebitis | 5 | 10 | 0 | 1 | 0 | 0 |
| Digestive System | 50 | 33 | 3 | 1 | 0 | 0 |
| Nausea | ||||||
| Constipation | 38 | 28 | 3 | 2 | 0 | 0 |
| Anorexia | 19 | 16 | <1 | 2 | 0 | 0 |
| Stomatitis | 16 | 15 | 0 | 0 | 0 | 0 |
| Vomiting | 23 | 14 | 2 | 1 | 0 | 0 |
| Diarrhea | 20 | 13 | <1 | 1 | 0 | 0 |
| Musculoskeletal System Myasthenia | 9 | 5 | 2 | 1 | <1 | 0 |
| Nervous System | 20 | 11 | 0 | 1 | 0 | 0 |
| Paresthesia | ||||||
| Hypesthesia | 11 | 10 | <1 | 0 | <1 | 0 |
| Respiratory System Dyspnea | 9 | 3 | 1 | 2 | 1 | 0 |
| Skin and Appendages | 12 | 12 | 0 | 1 | 0 | 0 |
| Alopecia | ||||||
| Rash | 5 | 5 | 0 | 0 | 0 | 0 |
ABC=Advanced Breast Cancer NSCLC=Non-Small Cell Lung Cancer
Grade based on modified criteria of the National Cancer Institute
Patients with NSCLC had not received prior chemotherapy. The majority of patients with advanced breast cancer had received prior chemotherapy
Cardiovascular
Chest pain was reported in 5% of NSCLC and 8% of breast cancer 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; however, these have not been shown definitely attributable to vinorelbine tartrate.
Dermatologic
Alopecia was reported in only 12% of patients and was usually mild. Vinorelbine tartrate injection is a moderate vesicant. Injection site reactions, including erythema, pain at injection site, and vein discoloration occurred in approximately one-third of all patients; 2% were severe. Chemical phlebitis along the vein proximal to the site of injection was reported.
Gastrointestinal
Mild or moderate nausea occurred in 32% of NSCLC and 47% of breast cancer patients treated with vinorelbine tartrate. Severe nausea was infrequent (1% and 3% in NSCLC and breast cancer patients respectively). Prophylactic administration of antiemetics was not routine in patients treated with single-agent vinorelbine tartrate. Constipation occurred in approximately 28% of NSCLC and 38% of breast cancer patients, with paralytic ileus occurring in less than 2% of patients. Vomiting, diarrhea, anorexia, and stomatitis were usually mild or moderate and occurred in less than 20% of patients.
Hepatic
Transient elevations of liver enzymes were reported without clinical symptoms.
Neurologic
Mild to moderate peripheral neuropathy manifested by paresthesia and hypesthesia were the most frequently reported neurologic toxicities (10% to 20%, see Table 2). Loss of deep tendon reflexes occurred in less than 5% of patients. The development of severe peripheral neuropathy was unusual.
Pulmonary
Shortness of breath was reported in 3% of NSCLC and 9% of breast cancer patients; and was severe in 2% of each patient population. Interstitial pulmonary changes have been documented in a few patients.
Other
Asthenia occurred in approximately 25% of patients with NSCLC and 41% of patients with breast cancer. It was usually mild or moderate but tended to increase with cumulative dosing. Other toxicities that have been reported in <= 5% of patients include jaw pain, myalgia, arthralgia, headache, dysphagia, and rash. Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in 4% of patients. The treatment of these entities are mainly symptomatic. The treatment of hemorrhagic cystitis is i.v. fluids for forced diuresis and/or irrigation of bladder. For the treatment of SIADH, please refer to the major textbooks of medicine.
Abnormal Hematologic and Clinical Chemistry Findings
Hematologic
Granulocytopenia was the major dose-limiting toxicity with vinorelbine tartrate; it was generally reversible and not cumulative over time. Granulocyte nadirs occurred 7 to 10 days after the dose and usually recovered within the following 7 to 14 days. Granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of NSCLC and 9% of breast cancer patients. Septic deaths occurred in approximately 1% of patients. Grade 3 or 4 anemia occurred in 1% of lung cancer and 14% of breast cancer patients. Blood products were administered to 18% of patients who received vinorelbine tartrate. The incidence of Grade 3 and 4 thrombocytopenia was less than 1%.
Table 2
Hematologic Adverse Events and Clinical Chemistry Elevations in 365 Patients Receiving Single-Agent Vinorelbine Tartrate that are Possibly Attributable to the Study Medicationa,b
| Hematology | ABC (%) | NSCLC (%) |
| Granulocytopenia <2,000 cells/mm 3 | 96 | 80 |
| <500 cells/mm 3 | 41 | 28 |
| Leukopenia <4,000 cells/mm 3 | 99 | 81 |
| <1,000 cells/mm 3 | 16 | 12 |
| Thrombocytopenia <100,000cells/mm 3 | 6 | 4 |
| <50,000 cells/mm 3 | <1 | 1 |
| Anemia <11 g/dL | 87 | 77 |
| <8 g/dL | 14 | 1 |
| Hospitalization due to granulocytopenic complications | 9 | 8 |
| Chemical Chemistry Elevations | % Incidence All Grades | % Incidence Grade 3 | % Incidence Grade 4 | ||||
| ABC | NSCLC | ABC | NSCLC | ABC | NSCLC | ||
| Total Bilirubin NSCLC; ABC: | n=137 n=214 | 14 | 9 | 4 | 3 | 3 | 2 |
| SGOT NSCLC: ABC: | n=133 n=213 | 74 | 54 | 7 | 2 | <1 | 1 |
ABC = Advanced Breast Cancer NSCLC = Non-Small Cell Lung Cancer
Grade based on modified criteria of the National Cancer Institute
Patients with NSCLC had not received prior chemotherapy. The majority of patients with advanced breast cancer had received prior chemotherapy.
Observed During Clinical Practice
:
In a randomized study in NSCLC patients, 206 patients received treatment with vinorelbine tartrate plus cisplatin and 206 patients received single-agent vinorelbine tartrate. The incidence of severe nausea and vomiting was 30% for vinorelbine tartrate/cisplatin compared to <2% for single-agent vinorelbine tartrate. Cisplatin did not appear to increase the incidence of neurotoxicity observed with single-agent vinorelbine tartrate. However, myelosuppression, specifically Grade 3 and 4 granulocytopenia, was greater with the combination of vinorelbine tartrate/cisplatin (79%) than with single-agent vinorelbine tartrate (53%). The incidence of fever and infection may be increased with the combination.
Post-Market Adverse Drug Reactions:
In addition to adverse events reported from clinical trials, the following events have been identified during post marketing use of vinorelbine tartrate. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to combination of their seriousness, frequency of reporting, or potential causal connection to vinorelbine tartrate or a combination of these factors.
Body as a Whole:
Systemic allergic reactions reported as anaphylaxis, pruritis, urticaria and angioedema, flushing and radiation recall events such as dermatitis and esophagitis (see WARNINGS AND PRECAUTIONS) have been reported.
Cardiovascular:
Hypertension, hypotension, vasodilation, tachycardia, and pulmonary edema have been reported.
Gastrointestinal
: Dysphagia and mucositis have been reported.
Hematologic:
Thromboembolic events including pulmonary embolus and deep venous thrombosis have been reported primarily in seriously ill and debilitated patients with known predisposing risk factors for these events.
Musculoskeletal
: Headache has been reported with and without other musculoskeletal aches and pains.
Neurologic:
Peripheral neurotoxicities such as, but not limited to, muscle weakness and disturbance of gait have been observed in patients with and without prior symptoms. Vestibular and auditory deficits have been observed with vinorelbine tartrate, usually when used in combination with cisplatin. There may be increased potential for neurotoxicity in patients with pre-existing neuropathy, regardless of etiology, who receive vinorelbine tartrate. Patients who receive vinorelbine tartrate and paclitaxel, either concomitantly or sequentially, should be monitored for signs and symptoms of neuropathy (see WARNINGS AND PRECAUTIONS).
Pulmonary
: Pneumonia has been reported.
Vinorelbine can produce acute and subacute pulmonary reactions. The acute reaction usually resembles an allergic event and may respond to bronchodilators. Subacute pulmonary reactions occur shortly after drug administration and may be characterized by cough, dyspnea, hypoxemia, and interstitial infiltration. Subacute pulmonary reactions may respond to corticosteroid therapy.
Skin:
Injection site reactions, including localised rash and urticaria, blister formation and skin sloughing have been observed in clinical practice. Some of these reactions may be delayed in appearance.
Other
: Pain in tumour-containing tissue, back pain and abdominal pain have been reported. Electrolyte abnormalities including hyponatremia consistent with the syndrome of inappropriate ADH secretion, have been reported in seriously ill and debilitated patients.
Combination Use
: Patients with prior exposure to paclitaxel and who have demonstrated neuropathy should be monitored closely for new or worsening neuropathy. Patients who have experienced neuropathy with previous drug regimens should be monitored for symptoms of neuropathy while receiving VINORELBINE TARTRATE FOR INJECTION.VINORELBINE TARTRATE FOR INJECTION may result in radiosensitizing effects with prior or concomitant radiation therapy (see WARNINGS AND PRECAUTIONS).
Drug-Drug Interactions
Acute pulmonary reactions have been reported with vinorelbine tartrate and other vinca alkaloids used in conjunction with mitomycin (see WARNINGS AND PRECAUTIONS, General). VINORELBINE TARTRATE FOR INJECTION should be administered with caution in combination with mitomycin. Although the pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of toxicities, specifically granulocytopenia, high frequency hearing loss and tinnitus, with the combination of vinorelbine tartrate and cisplatin are higher than with single-agent vinorelbine tartrate. Patients who receive vinorelbine tartrate and paclitaxel, either concomitantly or sequentially, should be monitored for signs and symptoms of neuropathy. Administration of VINORELBINE TARTRATE FOR INJECTION to patients with prior or concomitant radiation therapy may result in radiosensitizing effects.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Dosing Considerations
The usual initial dose of VINORELBINE TARTRATE FOR INJECTION (vinorelbine tartrate) 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 tartrate was given weekly until progression or dose-limiting toxicity. No dose adjustments are required for renal insufficiency. If moderate or severe neurotoxicity develops, VINORELBINE TARTRATE FOR INJECTION should be discontinued. The dosage should be adjusted according to hematologic toxicity or hepatic insufficiency. Dose Modifications for Hematologic Toxicity: Granulocyte counts should be >= 1000 cells/mm3 prior to the administration of VINORELBINE TARTRATE FOR INJECTION. In the referenced North American trial, in which hematologic adverse events were observed, the following dose adjustment scheme was employed and should be followed in patients receiving VINORELBINE TARTRATE FOR INJECTION.
| Granulocytes (cells/mm 3 ) On days of Treatment | Dose of VINORELBINE TARTRATE FOR INJECTION (mg/m 2 ) |
| >= 1500 | 30 |
| 1000 to 1499 | 15 |
| <1000 | Do not administer. Repeat granulocyte count in 1 week. If granulocyte count is <1000 cells/mm 3 for >3 weeks, discontinue VINORELBINE TARTRATE FOR INJECTION. |
| Note: For patients who, during treatment with VINORELBINE TARTRATE FOR INJECTION, have experienced fever and/or sepsis while granulocytopenic or required a delay in dosing of up to 3 weeks due to granulocytopenia, the dose of VINOREL,BINE TARTRATE INJECTION should be: 22.5 mg/m 2 for granulocytes >= 1500 cells/m 3 11.25 mg/m 2 for granulocytes 1000 to 1499cells/m 3 | |
VINORELBINE TARTRATE FOR INJECTION should be administered with caution to patients with hepatic insufficiency. In patients who develop hyperbilirubinemia during treatment with VINORELBINE TARTRATE FOR INJECTION, the dose should be adjusted for total bilirubin.
Administration
VINORELBINE TARTRATE FOR INJECTION must be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any VINORELBINE TARTRATE FOR INJECTION is injected. Leakage into surrounding tissue during intravenous administration of VINORELBINE TARTRATE FOR INJECTION 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. The application of moderate heat to the area of leakage in the form of warm compress applied for 15 to 20 minutes at least four times per day for the first 24 to 48 hours in addition to rest and elevation of the affected site for 48 -72 hours has been reported to help disperse drug and minimize discomfort associated with the extravasation of other vinca alkaloids. As with other toxic compounds, caution should be exercised in handling and preparing the solution of VINORELBINE TARTRATE FOR INJECTION. Skin reactions may occur with accidental exposure. The use of gloves is recommended. If the solution of VINORELBINE TARTRATE FOR INJECTION 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 TARTRATE FOR INJECTION, the eye should be washed with water immediately and thoroughly.
: VINORELBINE TARTRATE FOR INJECTION must be diluted in either a syringe or I.V. bag using one of the recommended solutions. The diluted VINORELBINE TARTRATE FOR INJECTION should be administered over 6 to 10 minutes into the side port of a free-flowing I.V. followed by flushing with at least 75 to 125 mL of one of the solutions. For diluents that may be used, see below.
: The calculated dose of VINORELBINE TARTRATE FOR INJECTION should be diluted to a concentration between 1.5 and 3.0 mg/mL.
: The calculated dose of VINORELBINE TARTRATE FOR INJECTION should be diluted to a concentration between 0.5 and 2.0 mg/mL.
Syringe: VINORELBINE TARTRATE FOR INJECTION diluted to a concentration between 1.5 and 3.0 mg/mL may be used for up to 24 hours when stored in polypropylene syringes at 5o to 30degC. The following solutions may be used for dilution: 5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP I.V. Bag: VINORELBINE TARTRATE FOR INJECTION diluted to a concentration between 0.5 and 2.0 mg/mL may be used for up to 24 hours when stored in polyvinylchloride bags at 5o to 30degC. 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 Potassium chloride injection solutions are found to be compatible with vinorelbine tartrate. As with all the parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, discoloration and leakage prior to administration, whenever solution and container permit. Any unused portion should be discarded.
The primary anticipated complications of overdosage would consist of bone marrow suppression and peripheral neurotoxicity. There is no known antidote for VINORELBINE TARTRATE FOR INJECTION overdosage. Overdoses involving quantities up to ten times the recommended dose (30 mg/m2) have been reported. The toxicities described were consistent with those listed in the Adverse Reactions section including paralytic ileus, stomatitis, and esophagitis. Bone marrow aplasia, sepsis, and paresis have also been reported. Fatalities have occurred following overdose of vinorelbine tartrate. If overdosage occurs, general supportive measures together with appropriate blood transfusions, growth factors and antibiotics should be instituted as deemed necessary by the physician.
Mechanism of Action
Vinorelbine tartrate is a novel vinca alkaloid which interferes with microtubule assembly. Vinca alkaloids are structurally similar compounds comprising two multiringed units, vindoline and catharanthine. Vinorelbine is a vinca alkaloid in which the catharanthine unit is the site of structural modification. This structural change imparts unique pharmacologic properties which may translate into clinical benefits for patients with various malignancies. The antitumour activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Vinorelbine may also interfere with amino acid, cyclic AMP, and glutathione metabolism; calmodulin-dependent Ca++-transport ATPase activity; cellular respiration; and nucleic acid and lipid biosynthesis.
Pharmacokinetics
Following intravenous administration, vinorelbine concentration in plasma decays in a triphasic manner. The initial rapid decline represents distribution of drug to peripheral compartments and metabolism of the drug. The prolonged terminal phase is due to relatively slow efflux of vinorelbine from peripheral compartments. The terminal phase half-life averaged 27.7 to 43.6 hours; the mean plasma clearances ranged from 0.97 to 1.26 L/hr/kg; and steady state volume of distribution (Vss) values ranged from 25.4 to 40.1 L/kg. The disposition of radiolabelled vinorelbine has been studied in a limited number of patients. Approximately 18% of the administered dose was recovered in the urine and 46% in the feces. Incomplete recovery in humans is consistent with results in animals. A separate study of the urinary excretion of vinorelbine showed that 10.9% +-0.7% of a 30 mg/m2 intravenous dose was excreted unchanged in the urine. One metabolite of vinorelbine, deacetylvinorelbine, has been shown to possess antitumour activity. This metabolite has been detected but not quantified in human plasma. The effects of renal or hepatic dysfunction on the disposition of vinorelbine have not been assessed. The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin with vinorelbine (see Drug Interactions).
Special Populations and Conditions
Pharmacokinetics of common name have not been studied in the pediatric population.
Pharmacokinetics of common name have not been studied in the geriatric population.
Differences in pharmacokinetics based on gender have not been established.
Differences in pharmacokinetics based on race have not been established.
Differences in pharmacokinetics based on hepatic function have not been established.
Differences in pharmacokinetics based on renal function have not been established.
Differences in pharmacokinetics based on genetic polymorphism have not been established.
Stability and Storage Recommendations
Store VINORELBINE TARTRATE FOR INJECTION vials under refrigeration (2degC to 8degC) in the original package. Protect from light and freezing. Single use vials. Discard unused portion. VINORELBINE TARTRATE FOR INJECTION is initially clear and colourless to pale yellow, but may develop a slightly darker yellow to light amber colour in time. This does not indicate a change which should preclude its use. 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 TARTRATE FOR INJECTION should not be administered.
Since vinorelbine tartrate is a cytostatic agent, established procedures specific to the handling and use of such agents must be followed.
VINORELBINE TARTRATE FOR INJECTION is supplied in clear glass vials as a solution of 10 mg/mL vinorelbine base in 1 mL, and 5 mL single-dose vials.
VINORELBINE TARTRATE FOR INJECTION consists of an aqueous solution of vinorelbine tartrate, equivalent to 10 mg vinorelbine base per millilitre of solution. No other preservatives or other additives are present. VINORELBINE TARTRATE FOR INJECTION is a clear colorless to pale yellow solution in Water for Injection.