Vinorelbine Drug Information

• Vinorelbine Injection is indicated: In combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) As a single agent for the treatment of patients with metastatic NSCLC Vinorelbine Injection is a vinca alkaloid indicated: In combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) As a single agent for first-line treatment of patients with metastatic NSCLC

Dosage Modifications Myelosuppression Hold or decrease the dose of Vinorelbine Injection in patients with decreased neutrophil counts according to the following schema: Hepatic Impairment/Toxicity Reduce Vinorelbine Injection dose in patients with elevated serum total bilirubin concentration according to the following schema: 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.

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 6 to 10 minutes into the side port of a free-flowing intravenous line followed by flushing with at least 75 to 125 mL of one of the solutions.

Vinorelbine 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.

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.

Clinical Trials Experience

Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial and may not reflect the rates actually observed in clinical practice. Single Agent The data below reflect exposure to vinorelbine as a single agent administered at a dose of 30 mg/m 2 on a weekly basis to 365 patients enrolled in 3 controlled studies for metastatic NSCLC and advanced breast cancer. The population included 143 patients with previously untreated metastatic NSCLC (Study 3) who received a median of 8 doses of vinorelbine.

The data also reflect exposure to vinorelbine in 222 patients with previously treated advanced breast cancer who received a median of 10 doses of vinorelbine. Vinorelbine is not indicated for the treatment of breast cancer. Selected adverse reactions reported in these studies are provided in Tables 1 and 2.

The most common adverse reactions (≥ 20%) of single agent vinorelbine were leukopenia, neutropenia, anemia, increased aspartate aminotransferase (AST), nausea, vomiting, constipation, asthenia, injection site reaction and peripheral neuropathy. The most common (≥ 5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, anemia, increased total bilirubin, increased AST, injection site reaction and asthenia. Approximately 49% of patients with NSCLC who were treated with vinorelbine experienced at least one dose reduction due to an adverse reaction.

Thirteen percent of patients discontinued vinorelbine due to adverse reactions. The most frequent adverse reactions leading to vinorelbine discontinuation were asthenia, dyspnea, nausea, constipation, anorexia, myasthenia and fever. Neutropenia is the major dose-limiting toxicity.

Neurotoxicity: Neurotoxicity was most commonly manifested as constipation, paresthesia, hyperesthesia and hyporeflexia. Grade 3 and 4 neuropathy was observed in 1% of the patients receiving single agent vinorelbine. Injection Site Reactions: Injection site reactions, including erythema, pain at injection site and vein discoloration, occurred in approximately one third of patients; 5% were severe.

Phlebitis (chemical phlebitis) along the vein proximal to the site of injection was reported in 10% of patients. Cardiovascular Toxicity: Chest pain occurred in 5% of patients; myocardial infarction occurred in ˂0.1% of patients. Pulmonary Toxicity and Respiratory Failure: Dyspnea (shortness of breath) was reported in 3% of patients; it was severe in 2%.

Interstitial pulmonary changes were documented. Other: Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in <1% of patients. In Combination with Cisplatin Table 3 presents the incidence of selected adverse reactions, occurring in ≥10% of vinorelbine treated patients reported in a randomized trial comparing the combination of vinorelbine 25 mg/m 2 administered every week of each 28-day cycle and cisplatin 100 mg/m 2 administered on day 1 of each 28-day cycle versus cisplatin alone at the same dose and schedule in patients with previously untreated NSCLC (Study 1).

Patients randomized to vinorelbine plus cisplatin received a median of 3 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. Thirty-five percent of the eligible patients in the combination arm required treatment discontinuation due to an adverse reaction compared to 19% in the cisplatin alone arm. Four patients in the vinorelbine plus cisplatin arm died of neutropenic sepsis.

Table 3: Adverse Reactions Experienced by ≥ 10% of Patients on Vinorelbine plus Cisplatin versus Single Agent Cisplatin 3 3 Table 4 presents the incidence of selected adverse reactions, occurring in ≥10% of vinorelbine treated patients reported in a randomized trial of vinorelbine plus cisplatin, vindesine plus cisplatin and vinorelbine as a single agent in patients with stage III or IV NSCLC who had not received prior chemotherapy. Patients randomized to vinorelbine plus cisplatin received a median of 15 weeks of treatment, vindesine plus cisplatin 12 weeks and vinorelbine received 13 weeks. Study discontinuation due to an adverse reaction was required in 27, 22 and 10% of the patients randomized to vinorelbine plus cisplatin, vindesine plus cisplatin and cisplatin alone arms, respectively.

Table 4: Adverse Reactions Experienced by ≥ 10 % of Patients from a Comparative Trial of Vinorelbine Plus Cisplatin versus Vindesine Plus Cisplatin versus Single Agent Vinorelbine Postmarketing Experience The following adverse reactions have been identified during postapproval use of vinorelbine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections: pneumonia Immune system disorders: anaphylactic reaction, pruritus, urticaria, angioedema Nervous system disorders: loss of deep tendon reflexes, muscular weakness, gait disturbance, headache Ear and labyrinth disorders: vestibular disorder, hearing impaired Cardiac disorders: tachycardia Respiratory disorders: pulmonary edema Vascular disorders: pulmonary embolism, deep vein thrombosis, hypertension, hypotension, flushing, vasodilatation Gastrointestinal disorders: mucosal inflammation, dysphagia, pancreatitis Skin disorders: generalized cutaneous reactions (rash), palmar-plantar erythrodysesthesia syndrome Musculoskeletal and connective tissue disorders: jaw pain, myalgia, arthralgia General disorders and administration site conditions: injection site rash, urticaria, blistering, sloughing of skin Injury, poisoning and procedural complications: radiation recall phenomenon, dermatitis, esophagitis Laboratory abnormalities: electrolyte imbalance including hyponatremia Other: tumor pain, back pain, abdominal pain

CYP3A Inhibitors

Exercise caution in patients concurrently taking drugs known to inhibit CYP3A. Concurrent administration of vinorelbine with a CYP3A inhibitor may cause an earlier onset and/or an increased severity of adverse reactions.

Pregnancy Risk Summary 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 (see Data ).

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 respectively. Data Animal Data 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.

Pediatric Use The safety and effectiveness of vinorelbine in pediatric patients have not been established. Forty-six patients age 1 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. 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).

There is no known antidote for overdoses of vinorelbine. Overdoses involving quantities up to 10 times the recommended dose (30 mg/m 2 ) have been reported. The adverse reactions 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. If overdosage occurs, general supportive measures together with appropriate blood transfusions, growth factors and antibiotics should be instituted as deemed necessary by the physician.