Vinorelbine: Package Insert and Label Information

VINORELBINE- vinorelbine tartrate injection, solution
Actavis Pharma, Inc.

WARNING: MYELOSUPPRESSION

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

In Combination with Cisplatin 100 mg/m 2

  • The recommended dose of vinorelbine 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/m 2

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

2.2 Dosage Modifications

Myelosuppression

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

Neutrophils on Day of Treatment (cells/mm 3 ) Percentage of Starting Dose of Vinorelbine
≥ 1,500 100%
1,000 to 1,499 50%
< 1,000 Do not administer vinorelbine. Repeat neutrophil count in one week. If three consecutive weekly doses are held because neutrophil count is < 1,000 cells/mm3 , discontinue vinorelbine
Note: For patients who experience fever and/or sepsis while neutrophil count is < 1,500 cells/mm3 or had 2 consecutive weekly doses held due to neutropenia, subsequent doses of vinorelbine should be:
> 1,500 75%
1,000 to 1,499 37.5%
< 1,000 Do not administer vinorelbine.
Repeat neutrophil count in one week.

Hepatic Impairment/Toxicity

Reduce vinorelbine 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)]:

Serum Total Bilirubin Concentration (mg/dl) Percentage of Starting Dose of Vinorelbine
≤ 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 determined from the above schemas.

Neurologic Toxicity

Discontinue vinorelbine 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)].

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 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 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 leakage into surrounding tissue occurs or is suspected, immediately stop administration of vinorelbine and initiate appropriate management measures in accordance with institutional policies [see Warnings and Precautions (5.4)].

2.4 Procedures for Proper Handling and Disposal

Vinorelbine is a cytotoxic drug. Follow applicable special handling and disposal procedures1 .

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.

3 DOSAGE FORMS AND STRENGTHS

Injection: 1 mL (10 mg/mL) and 5 mL (50 mg/ 5 mL) clear colorless to pale yellow solution in single-dose vials:

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Myelosuppression, manifested by neutropenia, anemia and thrombocytopenia, occur in patients receiving 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 to 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 elevated aspartate aminotransferase (AST) and bilirubin occur in patients receiving vinorelbine as a single agent and 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 (8.6)].

5.3 Severe Constipation and Bowel Obstruction

Severe and fatal paralytic ileus, constipation, intestinal obstruction, necrosis, and perforation occur in patients receiving vinorelbine. 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 Reaction (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 CTCAE Grade 2 or greater neuropathy [see Dosage and Administration (2.2) and Adverse Reaction (6.1)].

5.6 Pulmonary Toxicity and Respiratory Failure

Pulmonary toxicity, including severe acute bronchospasm, interstitial pneumonitis, acute respiratory distress syndrome (ARDS) occur in patients receiving 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

Based on findings from animal studies and its mechanism of action, 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.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with vinorelbine and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with vinorelbine and for 3 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

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

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 (greater than or equal to 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 (greater than or equal to 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.

Table 1: Hematologic Adverse Reactions Experienced in Greater Than 5% of Patients Receiving Vinorelbine *†:
All Patients NSCLC
(N=365)(%)

(N= 143)(%)

*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.
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 Greater Than or Equal to 5% of Patients Receiving Vinorelbine *†:
All Grades Grades 3 to 4
All Patients(%) NSCLC(%) All Patients(%) NSCLC(%)
*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.
Laboratory
Hepatic
AST increased (N=346) 67 54 6 3
Bilirubin increased 13 9 7 5
(N=351)
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 to 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 less than 1% of patients.

In Combination with Cisplatin

Table 3 presents the incidence of selected adverse reactions, occurring in greater than or equal to 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 3: Adverse Reactions Experienced by Greater Than or Equal to 10% of Patients on Vinorelbine plus Cisplatin versus Single-Agent Cisplatin*
Vinorelbine 25mg/m 2 plus Cisplatin 100 mg/m 2 (N=210)
Cisplatin 100 mg/m 2 (N=212)
All Grades(%) Grades 3 to 4(%) All Grades(%) Grades 3 to 4(%)
*Graded according to the standard SWOG criteria version 1.
†Categorical toxicity grade not specified
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 greater than or equal to 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 30 mg/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% (Grades 3 to 4, 7%) of the patients receiving vinorelbine plus cisplatin, 58% (Grades 3 to 4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grades 3 to 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.

Table 4: Adverse Reactions Experienced by Greater Than or Equal to 10 % of Patients from a Comparative Trial of Vinorelbine Plus Cisplatin versus Vindesine Plus Cisplatin versus Single-Agent Vinorelbine*
Vinorelbine/Cisplatin† Vindesine/Cisplatin‡ Vinorelbine§
All Grades(%) Grades 3 to 4(%) All Grades(%) Grades 3 to 4(%) All Grades(%) Grades 3 to 4(%)
*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.
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 46 N/A 37 N/A 13 N/A
increased ¦
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 17 2.5 7 0 22 2
reaction
Ototoxicity 10 2 14 1 1 0
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