In Combination with Cisplatin 100 mg/m2

• The recommended dosage of Vinorelbine Injection is 25 mg/m2 administered as an intravenous injection or infusion over 6 to 10 minutes on Days 1, 8, 15 and 22 of a 28-day cycle in combination with cisplatin 100 mg/m2 on Day 1 only of each 28-day cycle.

In Combination with Cisplatin 120 mg/m2

• The recommended dosage of Vinorelbine Injection is 30 mg/m2 administered as an intravenous injection or infusion over 6 to 10 minutes once a week in combination with cisplatin 120 mg/m2 on Days 1 and 29, then every 6 weeks.

Single Agent

• The recommended dosage of Vinorelbine Injection is 30 mg/m2 administered intravenously over 6 to 10 minutes once a week.

Myelosuppression

Hold or decrease the dose of Vinorelbine Injection in patients with decreased neutrophil counts according to the following schema [see Warnings and Precautions (5.1)]:

Hepatic Impairment/Toxicity

Reduce Vinorelbine Injection dose in patients with elevated serum total bilirubin concentration according to the following schema [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)]:

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 [see Warnings and Precautions (5.5)].

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 [see Warnings and Precautions (5.4)].

Single Agent

The data below reflect exposure to vinorelbine as a single agent administered at a dose of 30 mg/m2 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 patients were aged 32 to 79 (median 61 years), 71% were male, 91% White, 48% had adenocarcinoma histology. 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.

Myelosuppression: In clinical trials, Grade 3-4 neutropenia, anemia and thrombocytopenia occurred in 69%, 9% and 1%, respectively of patients receiving single agent vinorelbine. 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/m2 administered every week of each 28-day cycle and cisplatin 100 mg/m2 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. The incidence of Grade 3 and 4 neutropenia was significantly higher in the vinorelbine plus cisplatin arm (82%) compared to the cisplatin alone arm (5%).

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. Seven additional deaths were reported in the combination arm: 2 from cardiac ischemia, 1 cerebrovascular accident, 1 multisystem failure due to an overdose of vinorelbine and 3 from febrile neutropenia.

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. A total of 604 patients received either vinorelbine 30 mg/m2 every week plus cisplatin 120 mg/m2 on Day 1 and Day 29, then every 6 weeks thereafter (N=207), vindesine 3 mg/m2 for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m2 on Days 1 and Day 29, then every 6 weeks thereafter (N=193) or vinorelbine 30mg/m2 every week (N=204).

Patients randomized to vinorelbine plus cisplatin received a median of 15 weeks of treatment, vindesine plus cisplatin 12 weeks and vinorelbine received 13 weeks. Grade 3 and 4 neutropenia was significantly greater in the vinorelbine plus cisplatin arm (78%) compared to vindesine plus cisplatin (48%) and vinorelbine as a single agent (53%). Neurotoxicity, including peripheral neuropathy and constipation, was reported in 44% (Grade 3-4, 7%) of the patients receiving vinorelbine plus cisplatin, 58% (Grade 3-4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grade 3-4, 8.5%) of the patients receiving vinorelbine as a single agent.

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.

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], 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 2 to 4% and 15 to 20%, respectively.

Data

Risk Summary

There are no data on the presence of vinorelbine in human milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from vinorelbine, advise women not to breastfeed during treatment with vinorelbine and for 9 days after the final dose.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating vinorelbine [see Use in Specific Populations (8.1)].

Contraception

Females

Vinorelbine can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with vinorelbine and for 6 months after the final dose.

Males

Vinorelbine may damage spermatozoa [see Nonclinical Toxicology (13.1)]. Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with vinorelbine and for 3 months after the final dose.

Infertility

Males

Based on animal findings, vinorelbine may impair fertility in males [see Nonclinical Toxicology (13.1)].

Distribution

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 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, fluorouracil, or doxorubicin.

Elimination

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/hr/kg.

Metabolism

Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces. 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 vinorelbine is mediated by hepatic CYP3A.

Excretion

After intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively. In a different study, 10.9% ± 0.7% of a 30 mg/m2 intravenous dose was excreted as parent drug in urine.

Specific Populations

Age has no effect on the pharmacokinetics (CL, VSS and t1/2) of vinorelbine.

Drug Interaction Studies

The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin.

Cisplatin 100mg/m2

Study 1 was a randomized, multicenter, open-label trial of vinorelbine plus cisplatin and cisplatin alone for the treatment of stage IV or stage IIIb NSCLC in patients with malignant pleural effusion or multiple lesions in more than one lobe of the ipsilateral lung who had not received prior chemotherapy. A total of 432 patients were randomized 1:1 to receive either vinorelbine 25 mg/m2 on Day 1 then every week of each 28-day cycle plus cisplatin 100 mg/m2 administered on Day 1 of each 28-day cycle (N=214) or single agent cisplatin 100 mg/m2 on Day 1 of each 28-day cycle (N=218).

Patient demographics and disease characteristics were similar between arms. Of the overall study population, the median age was 64 (range 33 to 84), 66% were male, 80% were White, 92% had stage IV disease and 8% stage IIIB, 53% had adenocarcinoma, 21% squamous cell, 14% large cell histology. The major efficacy outcome measure was overall survival. The efficacy results are presented in Table 7 and Figure 1.

Figure 1: Overall Survival Vinorelbine / Cisplatin versus Single Agent Cisplatin

Cisplatin 120mg/m2

Study 2 was a randomized, 3-arm, open-label, multicenter trial of vinorelbine plus cisplatin, vindesine plus cisplatin and vinorelbine as a single agent for the treatment of patients with stage III or IV NSCLC who had not received prior chemotherapy. The study was conducted in Europe. A total of 612 patients were randomized 1:1:1 to receive vinorelbine 30 mg/m2 every week of a 6-week cycle plus cisplatin 120 mg/m2 on Day 1 and Day 29, then every 6 weeks thereafter (N=206); and vindesine 3 mg/m2 for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m2 on Days 1 and Day 29, then every 6 weeks thereafter (N=200) or vinorelbine 30mg/m2 every week of a 6-week cycle (N=206). The main efficacy outcome measure was to compare overall survival between vinorelbine plus cisplatin and vindesine plus cisplatin. The other efficacy outcome measure was to compare overall survival in the better of the two combination regimens to that of vinorelbine as a single agent.

Patient demographics were in general similar between arms: the median age of the overall population was 60 years (range 30 to 75), 90% were male, 78% had WHO performance status of 0 or 1. Tumor characteristics were in general similar with the exception of histologic subtype of NSCLC. Adenocarcinoma was the histologic subtype in 32% of patients in the vinorelbine plus cisplatin arm, 40% of patients in vindesine plus cisplatin arm and 28% of patients on the vinorelbine arm. Ten percent of the patients had stage IIIA disease, 28% stage IIIB and 50% stage IV. Twelve percent of the patients had received prior surgery or radiotherapy.

The efficacy results of Study 2 are presented in Table 8.