FDA Label for Vinorelbine

Warning: Myelosuppression

• Severe myelosuppression resulting in serious infection, septic shock, hospitalization and death may occur [see Warnings and Precautions (5.1)].
• Decrease the dose or withhold Vinorelbine in accord with recommended dose modifications [see Dosage and Administration (2.2)].

1 Indications And Usage

Vinorelbine Injection, USP 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

Other

In Combination with Cisplatin 100 mg/m²

• The recommended dose of Vinorelbine Injection, USP is 25 mg/m² administered as an intravenous injection or infusion over 6 to 10 minutes on days 1, 8, 15 and 21 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 dose of Vinorelbine Injection, USP 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 dose of Vinorelbine Injection, USP is 30 mg/m² administered intravenously over 6 to 10 minutes once a week.

Hematologic Toxicity

[see Warnings and Precautions (5.1)]

Hold or decrease the dose of Vinorelbine Injection, USP in patients with decreased neutrophil counts using the following schema.

Neutrophils on Day of Treatment (Cells/mm3)	Percentage of Starting Dose of Vinorelbine Injection, USP
≥ 1,500	100%
1,000 to 1,499	50%
< 1,000	Do not administer Vinorelbine Injection, USP. Repeat neutrophil count in one week. If three consecutive weekly doses are held because Neutrophil count is < 1,000 cells/mm3, discontinue Vinorelbine Injection, USP
Note : For patients who experience fever and/or sepsis while neutrophil count is < 1,500 or had 2 consecutive weekly doses held due to neutropenia, subsequent doses of Vinorelbine Injection, USP should be:
> 1,500	75%
1,000 to 1,499	37.5%
< 1,000	Do not administer Vinorelbine Injection, USP. Repeat neutrophil count in one week.

Hepatic Impairment/Toxicity

[see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)]

Reduce Vinorelbine Injection, USP 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, USP
≤ 2.0	100%
2.1 to 3.0	50%
> 3.0	25%

Concurrent Hematologic Toxicity and Hepatic Impairment

In patients with both hematologic toxicity and hepatic impairment, administer the lower of the doses based on the corresponding starting dose of Vinorelbine Injection, USP determined from the above schemas.

Neurologic Toxicity

[see Warnings and Precautions (5.5)]

Discontinue Vinorelbine Injection, USP for NCI CTCAE Grade 2 or higher peripheral neuropathy or autonomic neuropathy causing constipation.

Syringe

Dilute to a concentration between 1.5 and 3 mg/mL. The following solutions may be used for dilution:

• 5% Dextrose Injection, USP
• 0.9% Sodium Chloride Injection, USP

Intravenous Bag

Dilute to a concentration between 0.5 and 2 mg/mL. 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

Stability

Diluted Vinorelbine Injection, USP may be used for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5° to 30°C (41° to 86°F).

Administration

Administer diluted Vinorelbine Injection, USP 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, USP must only be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any Vinorelbine Injection, USP 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, USP should not be administered.

Management of Suspected Extravasation

• If Vinorelbine Injection, USP leakage into surrounding tissue occurs or is suspected, immediately stop administration of Vinorelbine Injection, USP 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 previously untreated metastatic NSCLC patients (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% Caucasian, 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, Aspartate aminotransferase (AST) elevation, 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, AST elevation, injection site reaction and asthenia. Approximately 49% of NSCLC patients 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.

Table 1: Hematologic Adverse Reactions Experienced in > 5% of Patients Receiving Vinorelbine*†:

*Grade based on modified criteria from the National Cancer Institute version 1.
†Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy.
		All patients (n=365)	NSCLC (n=143)
Laboratory       Hematologic
Neutropenia	< 2,000 cells/mm3	90%	80%
	< 500 cells/mm3	36%	29%
Leukopenia	< 4,000 cells/mm3	92%	81%
	< 1,000 cells/mm3	15%	12%
Thrombocytopenia	< 100,000 cells/mm3	5%	4%
Anemia	< 11 g/dl	83%	77%
	< 8 g/dl	9%	1%
Hospitalizations due to neutropenic complications		9%	8%

Table 2: Non-hematologic Adverse Reactions Experienced in ≥ 5% of Patients Receiving Vinorelbine*†:

*Grade based on modified criteria from the National Cancer Institute version 1.
‡ Incidence of paresthesia plus hypesthesia.
†Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy.
	All grades		Grades 3+4
	All Patients	NSCLC	All Patients	NSCLC
Laboratory
Hepatic
AST increased (n=346)	67%	54%	6%	3%
bilirubin increased (n=351)	13%	9%	7%	5%
Clinical
Nausea	44%	34%	2%	1%
Asthenia	36%	27%	7%	5%
Constipation	35%	29%	3%	2%
Injection site reaction	28%	38%	2%	5%
Injection site pain	16%	13%	2%	1%
Neuropathy peripheral‡	25%	20%	<2%	1%
Vomiting	20%	15%	2%	1%
Diarrhea	17%	13%	1%	1%
Alopecia	12%	12%	≤1%	1%
Phlebitis	7%	10%	<1%	1%
Dyspnea	7%	3%	3%	2%

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 less than 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. 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. 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%). 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 3: Adverse Reactions Experienced by ≥ 10% of Patients on Vinorelbine plus Cisplatin versus Single-Agent Cisplatin*

*Graded according to the standard SWOG criteria version 1.
*Categorical toxicity grade not specified
	Vinorelbine 25mg/m2 plus Cisplatin 100 mg/m2 (n=212)		Cisplatin 100mg/m2 (n=210)
	All Grades	Grades 3+4	All Grades	Grades 3+4
Laboratory    Hematologic
Neutropenia	89%	82%	26%	5%
Anemia	89%	24%	72%	<8%
Leukopenia	88%	58%	31%	<1%
Thrombocytopenia	29%	5%	21%	<2%
Febrile neutropenia	N/A*	11%	N/A*	0%
Renal
Blood creatinine increased	37%	4%	28%	<5%
Clinical
Malaise/Fatigue/Lethargy	67%	12%	49%	8%
Vomiting	60%	13%	60%	14%
Nausea	58%	14%	57%	12%
Decreased appetite	46%	0%	37%	0%
Constipation	35%	3%	16%	1%
Alopecia	34%	0%	14%	0%
Weight decreased	34%	1%	21%	<1%
Fever without infection	20%	2%	4%	0%
Hearing impaired	18%	4%	18%	<4%
Injection site reaction	17%	<1%	1%	0%
Diarrhea	17%	<3%	11%	<2%
Paraesthesia	17%	<1%	10%	<1%
Taste alterations	17%	0%	15%	0%
Peripheral numbness	11%	2%	7%	<1%
Myalgia/Arthralgia	12%	<1%	3%	<1%
Phlebitis/Thrombosis/Embolism	10%	3%	<1%	<1%
Weakness	12%	<3%	7%	2%
Infection	11%	<6%	<1%	<1%
Respiratory tract infection	10%	<5%	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 alone 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. 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. Grade 3 and 4 neutropenia was significantly greater in the Vinorelbine plus cisplatin arm (78%) compared to vindesine plus cisplatin (48%) and Vinorelbine alone (53%). Neurotoxicity, including peripheral neuropathy and constipation was reported in 44% (Grades 3-4, 7%) of the patients receiving Vinorelbine plus cisplatin, 58% (Grades 3-4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grades 3-4, 8.5%) of the patients receiving Vinorelbine alone.

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*

* Grade based on criteria from the World Health Organization (WHO).
† n=194 to 207; all patients receiving Vinorelbine/cisplatin with laboratory and non-laboratory data.
‡ n=173 to 192; all patients receiving vindesine/cisplatin with laboratory and non-laboratory data.
§ n=165 to 201; all patients receiving Vinorelbine with laboratory and non-laboratory data.
¦ Categorical toxicity grade not specified.
¶ Neurotoxicity includes peripheral neuropathy and constipation.
	Vinorelbine/Cisplatin†		Vindesine/Cisplatin†		Vinorelbine§
	All Grades	Grades 3+4	All Grades	Grades 3+4	All Grades	Grades 3+4
Laboratory
Hematologic
Neutropenia	95%	78%	79%	48%	85%	53%
Leukopenia	94%	57%	82%	27%	83%	32%
Thrombocytopenia	15%	4%	10%	3.5%	3%	0%
Renal
Blood creatinine increased ¦	46%	N/A	37%	N/A	13%	N/A
Clinical
Nausea/Vomiting	74%	30%	72%	25%	31%	2%
Alopecia	51%	7.5%	56%	14%	30%	2%
Neurotoxicity¶	44%	7%	58%	17%	44%	8.5%
Diarrhea	25%	1.5%	24%	1%	12%	0.5%
Injection site reaction	17%	2.5%	7%	0%	22%	2%
Ototoxicity	10%	2%	14%	1%	1%	0%

Risk Summary

Vinorelbine can cause fetal harm when administered to a pregnant woman. 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data

In a mouse embryofetal development study, administration of a single dose of vinorelbine at a dose level of 9 mg/m² 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/m² (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.

Contraception

Females

Vinorelbine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use highly effective contraception during therapy with Vinorelbine.

Males

Vinorelbine may damage spermatozoa [see Nonclinical Toxicology (13.1)]. Males with female sexual partners of reproductive potential should use highly effective contraception during and for 3 months after therapy with Vinorelbine.

Fertility

Males

Based on animal findings, Vinorelbine may cause decreased fertility in males [see Nonclinical Toxicology (13.1)].

Distribution

Steady-state volume of distribution (V_SS) 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, 5-fluorouracil, or doxorubicin.

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 cytochrome P450 isoenzymes in the CYP3A subfamily.

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

Elderly: Age has no effect on the pharmacokinetics (CL, V_SS and t_1/2) of vinorelbine.

Drug Interactions

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 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 with cisplatin 100 mg/m² administered on Day 1 of each 28-day cycle (N=214) or 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 33-84), 66% were male, 80% were Caucasian, 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.

Table 7. Efficacy Results (Study 1)

	Vinorelbine plus Cisplatin (N=214)	Cisplatin Alone (N=218)
Overall Survival
Median Survival in months (95% CI)	7.8 (6.9, 9.6 )	6.2 (5.4, 7.7)
Unstratified log-rank p-value	0.01
Overall Response rate (ORR)
Evaluable patients ORR (95% CI)	N = 206 19% (14%, 25%)	N=209 8% (5%, 13%)
Chi-square test p-value	<0.001

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 alone 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 alone.

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 alone 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.

Table 8. Efficacy Results (Study 2)

1n/a = not applicable
	Vinorelbine Alone (N=206)	Vinorelbine plus cisplatin (N=206)	Vindesine plus cisplatin (N=200)
Median survival in months (99.5% CI)	7.2 (5.4-9.1)	9.2 (7.4-11.1)	7.4 (6.1-9.1)
Unstratified log-rank p-value	n/a1	0.087
	0.05		n/a
Overall Response (ORR) Evaluable Patients ORR (95% CI)	N=205 14% (10%, 20%)	N=203 28% (22%, 35%)	N=198 19% (14%, 25%)
Chi-square test p-value	n/a	0.03
	< 0.001		n/a

2.3 Preparation And Administration

Preparation of Vinorelbine Injection, USP

Dilute Vinorelbine Injection, USP in either a syringe or intravenous bag using one of the recommended solutions.

2.4 Procedures For Proper Handling And Disposal

Handle and dispose Vinorelbine Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs.¹

Exercise caution in handling and preparing the solution of Vinorelbine Injection, USP. The use of gloves is recommended. If the solution of Vinorelbine Injection, USP contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Avoid contamination of the eye with Vinorelbine Injection, USP. If exposure occurs, flush the eyes with water immediately and thoroughly.

3 Dosage Forms And Strengths

Vinorelbine Injection, USP

Clear colorless to pale yellow solution in single-use vials:

1 mL (10 mg per 1 mL)

5 mL (50 mg per 5 mL)

4 Contraindications

None

5.1 Myelosuppression

Myelosuppression manifested by neutropenia, anemia and thrombocytopenia occur with Vinorelbine as a single agent and in combination with cisplatin [see Adverse Reactions (6.1 and 6.2)]. Neutropenia is the major dose-limiting toxicity with Vinorelbine. Grade 3-4 neutropenia occurred in 53% of patients treated with Vinorelbine at 30 mg/m² per week. Dose adjustment due to myelosuppression occurred in 51% of patients (Study 2). In clinical trials with Vinorelbine administered at 30 mg/m² per week, neutropenia resulted in hospitalizations for pyrexia and/or sepsis in 8% of patients. Death due to sepsis occurred in 1% of patients. Neutropenia nadirs occur between 7 and 10 days after dosing with neutropenia count recovery usually occurring within the following 7 to 14 days.

Monitor complete blood counts prior to each dose of Vinorelbine. Do not administer Vinorelbine to patients with neutrophil counts <1,000 cells/mm³. Adjustments in the dosage of Vinorelbine should be based on neutrophil counts obtained on the day of treatment [see Dosage and Administration (2.2)].

5.2 Hepatic Toxicity

Drug-induced liver injury manifest by elevations of aspartate aminotransferase and bilirubin can occur in patients receiving Vinorelbine alone or in combination with cytotoxic agents. Assess hepatic function prior to initiation of Vinorelbine and periodically during treatment.  Reduce the dose of Vinorelbine for patients who develop elevations in total bilirubin ≥ 2 times upper limit of normal [see Dosage and Administration (2.2) and Use in Specific Populations (8.5)].

5.3 Severe Constipation And Bowel Obstruction

Severe and fatal paralytic ileus, constipation, intestinal obstruction, necrosis, and perforation occur with Vinorelbine administration. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction and/or paralytic ileus, considering adequate dietary fiber intake, hydration, and routine use of stool softeners.

5.4 Extravasation And Tissue Injury

Extravasation of Vinorelbine can result in severe irritation, local tissue necrosis and/or thrombophlebitis. If signs or symptoms of extravasation occur, immediately stop administration of Vinorelbine and institute recommended management procedures [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

5.5 Neurologic Toxicity

Sensory and motor neuropathies, including severe neuropathies, occur in patients receiving Vinorelbine. Monitor patients for new or worsening signs and symptoms of neuropathy such as paresthesia, hyperesthesia, hyporeflexia and muscle weakness while receiving Vinorelbine. Discontinue Vinorelbine for NCI CTCAE Grade 2 or greater neuropathy [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

5.6 Pulmonary Toxicity And Respiratory Failure

Pulmonary toxicity, including severe acute bronchospasm, interstitial pneumonitis, acute respiratory distress syndrome (ARDS) occurs with use of Vinorelbine. Interstitial pneumonitis and ARDS included fatalities. The mean time to onset of interstitial pneumonitis and ARDS after vinorelbine administration was one week (range 3 to 8 days) [see Adverse Reactions (6.1)].

Interrupt Vinorelbine in patients who develop unexplained dyspnea, or have any evidence of pulmonary toxicity. Permanently discontinue Vinorelbine for confirmed interstitial pneumonitis or ARDS.

5.7 Embryo-Fetal Toxicity

Vinorelbine can cause fetal harm when administered to a pregnant woman. 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during therapy with Vinorelbine [see Use in Specific Populations (8.1, 8.7)].

6 Adverse Reactions

The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the label:

• Myelosuppression [see Warnings and Precautions (5.1)]
• Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.2)]
• Constipation and Bowel Obstruction [see Warnings and Precautions (5.3)]
• Extravasation Tissue Injury [see Warnings and Precautions (5.4)]
• Neurologic Toxicity [see Warnings and Precautions (5.5)]
• Hepatic Toxicity [see Warnings and Precautions (5.6)]

6.1 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval 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 and infestations: 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)

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

7.1 Cyp3a Inhibitors

Exercise caution in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. Concurrent administration of Vinorelbine with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of adverse reactions.

Teratogenic Effects

Teratogenic Effects: Pregnancy Category D

8.3 Nursing Mothers

It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from vinorelbine, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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/m² (for 35 patients) or at the dose of 30mg/m² (for 11 patients) every week during 6 weeks followed by 2 weeks of rest was evaluated (courses of 8 weeks). 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. 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 toxicity 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).

8.5 Geriatric Use

Of the 769 number of patients who received Vinorelbine alone and Vinorelbine in combination with Cisplatin in studies 1, 2 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 [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

The influence of hepatic impairment on the pharmacokinetics of Vinorelbine has not been evaluated, but the liver plays an important role in the metabolism of Vinorelbine. Elevations of aspartate aminotransferase occur in > 60% of the patients receiving Vinorelbine alone (6% Grade 3-4). Therefore, exercise caution in patients with hepatic impairment. Reduce the dose of Vinorelbine for patients with bilirubin elevation [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

10 Overdosage

There is no known antidote for overdoses of Vinorelbine. Overdoses involving quantities up to 10 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. If overdosage occurs, general supportive measures together with appropriate blood transfusions, growth factors, and antibiotics should be instituted as deemed necessary by the physician.

11 Description

Vinorelbine (vinorelbine tartrate) is a semi-synthetic vinca alkaloid for intravenous injection. Chemically, vinorelbine tartrate is 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2, 3-dihydroxybutanedioate (1:2)(tartrate)] and has the following structure:

C₄₅H₅₄N₄O₈•2C₄H₆O₆

M.W. 1079.12

Vinorelbine Injection, USP is a sterile nonpyrogenic aqueous solution. Each milliliter of solution contains 10 mg vinorelbine tartrate in Water for Injection. The pH of Vinorelbine Injection, USP is approximately 3.5.

12.1 Mechanism Of Action

Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The antitumor 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: 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. Vinorelbine inhibited mitotic microtubule formation in intact mouse embryo tectal plates at a concentration of 2 μM inducing a blockade of cells at metaphase, but produced depolymerization of axonal microtubules at a concentration 40 μM, suggesting a modest selectivity of vinorelbine for mitotic microtubules.

12.3 Pharmacokinetics

The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m² administered as 15- to 20-minute constant-rate infusions. Vinorelbine concentrations in plasma decay in a triphasic manner. 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.

13.1 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.

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 0.14 times the human recommended dose) prior to and during mating. In male rats, administration of vinorelbine twice weekly for 13 or 26 weeks at dose levels of 2.1 and 7.2 mg/m² (approximately 0.07 and 0.24 times the recommended human dose), respectively, resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.

14.1 Combination Use With Cisplatin

The safety and efficacy of Vinorelbine in combination with cisplatin was evaluated in two randomized, multicenter trials.

14.2 Single Agent

The safety and efficacy of Vinorelbine as a single agent was evaluated in one randomized multi-center trial.

Study 3 was a randomized, open-label clinical trial of Vinorelbine or 5-Fluorouracil (5-FU) plus leucovorin (LV) in patients with Stage IV NSCLC who had not received prior chemotherapy A total of 211 patients were randomized 2:1 to receive Vinorelbine 30 mg/m² weekly of a 8-week cycle (N=143) or 5-FU 425 mg/m² bolus intravenously plus LV 20 mg/m² bolus intravenously daily for 5 days of a 4-weeks cycle (N=68).

Patient demographics and disease characteristics were in general similar between arms. In the overall population, the median age was 61 years (range 32 - 83), 74% were male, 88% were Caucasian, 46% had adenocarcinoma histology. Fifty percent of the patients had Karnofsky performance status ≥ 90 in the Vinorelbine arm compared to 38% in the 5-FU and LV arm.

The primary efficacy outcome of the study was overall survival. The median survival time was 30 weeks versus 22 weeks for patients receiving Vinorelbine versus 5-FU/LV, respectively (P=0.06). Partial objective responses were observed in 11.1% (95% CI=6.2%, 17.9%) and 3.5% (95% CI=0.4%, 11.9%) of patients who received Vinorelbine and 5-FU/LV, respectively.

15 References

• OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 How Supplied/Storage And Handling

Vinorelbine Injection, USP is supplied as follows:

Vinorelbine Injection, USP is a clear, colorless to pale yellow aqueous solution.

Storage And Handling

Storage Conditions

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

Do not freeze.

Protect from light. Retain in carton until time of use.

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

Vinorelbine Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.

17 Patient Counseling Information

Inform patients of the following:

• Myelosuppression
  Advise patients to contact a healthcare provider for new onset fever, or symptoms of infection [see Warnings and Precautions (5.1)].
• Constipation and bowel obstruction
  Advise patients to follow a diet rich in fibers, drink fluids to stay well hydrated and use stool softeners to avoid constipation. Contact a health care provider for severe constipation, new onset abdominal pain, nausea and vomiting [see Warnings and Precautions (5.3)].
• Neurologic toxicity
  Advise patients to contact a health care provider for new onset or worsening of numbness, tingling, decrease sensation or muscle weakness [see Warnings and Precautions (5.5)].
• Pulmonary Toxicity
  Advise patients to contact a healthcare provider for new onset or worsening of shortness of breath, cough, wheezing or other new pulmonary symptoms [see Warnings and Precautions (5.6)].
• Females and Males of Reproductive Potential
  • Vinorelbine can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use highly effective contraception during treatment with Vinorelbine, and to contact their healthcare provider if they become pregnant, or if pregnancy is suspected [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)].
  • Vinorelbine may damage sperm. Advise males to use highly effective contraception during and for 3 months after therapy [see Use in Specific Populations (8.7) and Nonclinical Toxicology (13.1)].
  • Vinorelbine, may cause decreased fertility in males [see Nonclinical Toxicology (13.1)].

  SAGENT™

  Mfd. for SAGENT Pharmaceuticals
  Schaumburg, IL 60195 (USA)
  Made in China
  ©2014 Sagent Pharmaceuticals, Inc.

  Revised: May 2014

  
  

Package Label.Principal Display Panel

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-204-01

Vinorelbine Injection, USP

10 mg per mL

Rx only

1 mL Single-Use Vial

Must Be Diluted

For Intravenous Use Only

Caution: Cytotoxic Agent