NAVELBINE

Vinorelbine is an anti-mitotic chemotherapy drug that is used in the treatment of several types of malignancies, including breast cancer and non-small cell lung cancer (NSCLC) 5.

It was initially approved in the

USA in 1990's for the treatment of NSCLC 13.

It is a third-generation vinca alkaloid.

The introduction of third-generation drugs (vinorelbine, gemcitabine, taxanes) in platinum combination improved survival of patients with advanced NSCLC, with very similar results from the various drugs.

Treatment toxicities are considerable in the combination treatment setting 2.

A study was done on the clearance rate of vinorelbine on individuals with various single polymorphonuclear mutations.

It was found that there was 4.3-fold variation in vinorelbine clearance across the cohort, suggesting a strong influence of genetics on the clearance of this drug 7.

Vinorelbine tartrate is indicated for adults in the treatment of advanced non-small cell lung cancer (NSCLC), as a single therapy or in combination with other chemotherapeutic drugs 5.

Used in relapsed or refractory

Hodgkin lymphoma, in combination with other chemotherapy agents 14.

For the treatment of desmoid tumor or aggressive fibromatosis, in combination with methotrexate 14.

For the treatment of recurrent or metastatic squamous cell head and neck cancer 14.

For the treatment of recurrent ovarian cancer 14.

For the treatment of metastatic breast cancer, in patients previously treated with anthracyline and/or taxane therapy 14.

For the treatment of

HER2-positive, trastuzumab-resistant, advanced breast cancer in patients previously treated with a taxane, in combination with trastuzumab and everolimus 14.

Vinorelbine is a semi-synthetic vinca-alkaloid with a wide spectrum of anti-tumor activity.

The vinca-alkaloids are considered spindle poisons.

They work by interfering with the polymerization of tubulin, a protein responsible for building the microtubule system which appears during cell division in proliferating cancer cells 11.

Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours 5.

Vinorelbine is highly bound to platelets and lymphocytes and is also bound to alpha 1-acid glycoprotein, albumin, and lipoproteins 4.

The volume of distribution is large, indicating extensive extravascular distribution 4.

The steady-state volume of distribution values range from 25.4-40.1 L/kg, according to one study 7.

Widely distributed, with highest amounts found in elimination organs such as liver and kidneys, minimal in heart and brain 7.

Vinorelbine undergoes substantial hepatic elimination in 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 9, 10.

Vinorelbine is metabolized into two other minor metabolites, 20'-hydroxyvinorelbine and vinorelbine 6'-oxide 10.

Therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine.

The metabolism of vinorelbine is mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily 8, 4.

As the liver provides the main route for metabolism of the drug, patients with hepatic impairment may demonstrate increased toxicity with standard dosing, however, there are no available data on this.

Likewise, the contribution of cytochrome P450 enzyme action to vinorelbine metabolism has potential implications in patients receiving other drugs metabolized by this route 11.

Hover over products below to view reaction partners Vinorelbine 4-0-deacetyl Vinorelbine.

Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans 5.

Urinary excretion of unchanged drug accounts for less than 20% of an intravenous dose, with fecal elimination accounting for an additional 30% to 60% 4.

After intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively 7.

The terminal phase half-life averaged 27.7-43.6 hours; the mean plasma clearances ranged from 0.97-1.26 L/hr/kg 4.

The plasma clearance of vinorelbine is high, approaching the same as hepatic blood flow in humans, and its volume of distribution is large, indicating extensive extravascular distribution.

In comparison to vinblastine or vincristine 4.

The clearance was found to be in the range of 0.29-1./26 L/ per kg in 4 clinical trials of patients receiving 30 mg/m2 of vinorelbine 12.

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Due to the wide array of adverse effects of this drug, the toxicity of is categorized into organ systems 5.

Granulocytopenia was the primary dose-limiting toxicity with vinorelbine tartrate therapy; it is generally reversible and not cumulative.

In one study, granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of NSCLC and 9% of breast cancer patients 5.

Infectious (septic) deaths occurred in about 1% of patients.

Grade 3 or 4 anemia occurred in about 1% of lung cancer and approximately 14% of breast cancer patients.

Blood transfusions were administered to 18% of patients who received vinorelbine tartrate therapy.

The incidence of

Grade and 4 thrombocytopenia was found to be less than 1% 5.

Mild to moderate peripheral neuropathy may occur.

Symptoms of paresthesia and hypesthesia are reported as the most commonly reported neurologic toxicities of this drug.

The loss of deep tendon reflexes (DTR) occurs in less than 5% of patients, according to one study.

The development of severe peripheral neuropathy is rare 5.

Alopecia has been reported in only about 12% of patients and is usually reported as mild.

Vinorelbine tartrate is a moderate vesicant, leading to injection site reactions.

Symptoms include erythema, pain at the injection site and vein discoloration occurred in about 1/3 of all patients.

Chemical phlebitis along the vein, near the site of injection, has been reported 5.

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 5.

Mild or moderate nausea symptoms occurred in 32% of NSCLC and 47% of breast cancer patients treated with vinorelbine tartrate.

Severe nausea was occurred infrequently (1% and 3% in NSCLC and breast cancer patients, respectively).

Prophylactic administration of anti-emetics was not routine in patients treated with single-agent vinorelbine tartrate.

Constipation occurred in about 28% of NSCLC and 38% of breast cancer patients.

The paralytic ileus incidence of less than 2% of patients.

Vomiting, diarrhea, anorexia and stomatitis were found to be mild or moderate and occurred in less than 20% of study patients 5.

Transient elevations of liver enzymes were reported without clinical symptoms.

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 8.

Muscle weakness (asthenia) occurred in about 25% of patients with NSCLC and 41% of patients with breast cancer.

It was usually mild or moderate but showed a linear increase with cumulative doses 8.

Several other toxicities reported in approximately 5% of patients include jaw pain, myalgia, arthralgia, headache, dysphagia, and skin rash.

Hemorrhagic cystitis (bladder inflammation with blood in urine) and the syndrome of inappropriate ADH secretion were both reported in less than 1% of patients.

The treatment of these entities are mainly symptomatic 8.

The carcinogenic potential of

Vinorelbine has not been adequately studied.

Vinorelbine has been demonstrated to affect chromosome number and likely the chromosome structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice were observed) 8.

In combination with cisplatin: 25 to 30 mg/m as an intravenous injection or infusion once weekly Single agent: 30 mg/m as intravenously once a week Adjust dose in patients with decreased neutrophil counts or elevated serum total bilirubin 2.1 Recommended Dosage In Combination with Cisplatin 100 mg/m The recommended dosage of Vinorelbine Injection is 25 mg/m 2 administered as an intravenous injection or infusion over to 10 minutes on Days and 22 of a 28-day cycle in combination with cisplatin 100 mg/m on Day 1 only of each 28-day cycle.

In Combination with

Cisplatin 120 mg/m The recommended dosage of Vinorelbine Injection is 30 mg/m 2 administered as an intravenous injection or infusion over to 10 minutes once a week in combination with cisplatin 120 mg/m on Days and 29, then every 6 weeks.

Single Agent The recommended dosage of Vinorelbine Injection is 30 mg/m 2 administered intravenously over to 10 minutes once a week. 2.2 Dosage Modifications Myelosuppression Hold or decrease the dose of Vinorelbine Injection in patients with decreased neutrophil counts according to the following schema: Neutrophils on Day of Treatment (cells/mm 3 ) Percentage of Starting Dose of Vinorelbine Injection ≥ 1,500 100% 1,000 to 1,499 50% < 1,000 Do not administer Vinorelbine Injection.

Repeat neutrophil count in one week.

If three consecutive weekly doses are held because neutrophil count is < 1,000 cells/mm 3, discontinue Vinorelbine Injection Note: For patients who experience fever and/or sepsis while neutrophil count is < 1,500 cells/mm 3 or had 2 consecutive weekly doses held due to neutropenia, subsequent doses of Vinorelbine Injection should be: > 1,500 75% 1,000 to 1,499 37.5% < 1,000 Do not administer Vinorelbine Injection.

Impairment/Toxicity Reduce Vinorelbine Injection dose in patients with elevated serum total bilirubin concentration according to the following schema: Serum Total Bilirubin Concentration (mg/dl) Percentage of Starting Dose of Vinorelbine Injection ≤ 2.0 100% 2.1 to 3.0 50% > 3.0 25% Concurrent Myelosuppression and Hepatic Impairment/Toxicity In patients with both myelosuppression and hepatic impairment/toxicity, administer the lower of the doses based on the corresponding starting dose of Vinorelbine Injection determined from the above schemas.

Neurologic Toxicity Discontinue Vinorelbine Injection for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or higher peripheral neuropathy or autonomic neuropathy causing constipation. 2.3 Preparation and Administration Preparation Dilute Vinorelbine Injection in an intravenous bag to a concentration between 0.5 mg/mL and 2 mg/mL.

Use one of the following recommended solutions 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 Stability and Storage Conditions of Diluted Solutions Diluted Vinorelbine Injection may be used for up to 24 hours under normal room light when stored in polyvinyl chloride bags at 5° to 30°C (41° to 86°F).

Administration Administer diluted Vinorelbine

Injection over to 10 minutes into the side port of a free-flowing intravenous line followed by flushing with at least to 125 mL of one of the solutions.

Injection must only be administered intravenously.

It is extremely important that the intravenous needle or catheter be properly positioned before any Vinorelbine Injection is injected.

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 Injection should not be administered.

Management of Suspected Extravasation If Vinorelbine

Injection leakage into surrounding tissue occurs or is suspected, immediately stop administration of Vinorelbine Injection and initiate appropriate management measures in accordance with institutional policies. 2.4 Procedures for Proper Handling and Disposal Vinorelbine Injection is a cytotoxic drug.

Follow applicable special handling and disposal procedures 1.

Exercise caution in handling and preparing the solution of Vinorelbine Injection.

The use of gloves is recommended.

If the solution of Vinorelbine

Injection contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Avoid contamination of the eye with Vinorelbine Injection.

If exposure occurs, flush the eyes with water immediately and thoroughly.

Discard unused portion.

Injection, USP is supplied as follows: Vinorelbine Injection, USP NDC (10 mg per mL) Package Factor 25021-204-01 10 mg per mL Single-Dose Vial 1 vial per carton 25021-204-05 50 mg per 5 mL Single-Dose Vial 1 vial per carton Vinorelbine Injection, USP is a clear, colorless to pale yellow aqueous solution.

Store refrigerated between 2° and 8°C (36° and 46°F).

Do not freeze.

Protect from light.

Retain in carton until time of use.

Discard unused portion.

Unopened vials of Vinorelbine

Injection, USP are stable at 25°C (77°F) for up to 72 hours.

Store diluted solutions of Vinorelbine

Injection, USP at 5° to 30°C (41° to 86°F) .

Injection, USP is a cytotoxic drug.

Follow applicable special handling and disposal procedures.

The container closure is not made with natural rubber latex.

Store refrigerated between 2° and 8°C (36° and 46°F).

Do not freeze.

Protect from light.

Retain in carton until time of use.

Discard unused portion.

Unopened vials of Vinorelbine

Injection, USP are stable at 25°C (77°F) for up to 72 hours.

Store diluted solutions of Vinorelbine

Injection, USP at 5° to 30°C (41° to 86°F) .

Injection, USP is a cytotoxic drug.

Follow applicable special handling and disposal procedures.

The container closure is not made with natural rubber latex.

Based on findings from animal studies and its mechanism of action, vinorelbine can cause fetal harm when administered to a pregnant woman.

Available human data are insufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies in mice and rabbits, embryo and fetal toxicity were observed with administration of vinorelbine at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively.

Advise pregnant women of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and to 20%, respectively.

In a mouse embryo-fetal development study, administration of a single dose of vinorelbine at a dose level of 9 mg/m 2 or greater (approximately 0.33 times the recommended human dose based on body surface area) was embryotoxic and fetotoxic.

Vinorelbine was embryotoxic and fetotoxic to pregnant rabbits when administered every 6 days during the period of organogenesis at doses of 5.5 mg/m 2 (approximately 0.18 times the recommended human dose based on body surface area) or greater.

At doses that did not cause maternal toxicity in either species, vinorelbine administration resulted in reduced fetal weight and delayed ossification.

The safety and effectiveness of vinorelbine in pediatric patients have not been established.

Results from a single-arm study of vinorelbine administered at the dose of 33.75 mg/m 2 (for 35 patients) or at the dose of 30 mg/m 2 (for 11 patients) every week for 6 weeks followed by 2 weeks of rest were evaluated (courses of 8 weeks).

Forty-six patients age to 25 (median 11 years) with recurrent solid malignant tumors, including rhabdomyosarcoma or undifferentiated sarcoma (N=21 patients), neuroblastoma (N= 4 patients) and central nervous system (CNS) tumors (N=21 patients), were enrolled.

The most significant grade 3 or 4 hematological adverse reactions were neutropenia (70%) and anemia (33%).

The most significant grade 3 or 4 non-hematological adverse reactions were motor (15%) or cranial (13%) neuropathy, hypoxia (13%) and dyspnea (11%).

Objective tumor response was observed in 2 out of 21 patients with rhabdomyosarcoma or undifferentiated sarcoma.

No objective tumor response was observed in patients with CNS tumors (N=21) or neuroblastoma (N=4).

Of the 769 number of patients who received vinorelbine as a single agent and in combination with cisplatin in studies and 3, 247 patients were 65 years of age or older.

No overall differences in safety, efficacy and pharmacokinetic parameters were observed between these patients and younger patients.