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NAVELBINE(vinorelbine tartrate)injection

2012-12-22 10:04:24  作者:新特药房  来源:互联网  浏览次数:227  文字大小:【】【】【
简介: 部分中文诺维本处方资料(仅供参考) 分类名称 一级分类:抗肿瘤药物 二级分类:抗肿瘤植物药 三级分类: 药品英文名 Vinorelbine 药品别名 异长春花碱、长春瑞宾双酒石酸盐、去甲长春花碱、盖港、 ...

部分中文诺维本处方资料(仅供参考)
药品英文名
Vinorelbine 
药品别名
异长春花碱、长春瑞宾双酒石酸盐、去甲长春花碱、盖港、诺维本、Navelbine、NVB、Ditartrate
药物剂型
注射剂:10mg(1ml),50mg(5ml)。
药理作用
与前述的长春花生物碱相似,本品的作用系通过阻滞微管蛋白聚合形成微管和诱导微管解聚,使细胞停止于细胞分裂中期,系抗有丝分裂的细胞周期特异性药物。动物实验表明NVB对多种肿瘤有抑制作用,具有广谱的抗肿瘤活性。
药动学
仅静脉给药,组织吸收迅速,且在组织中的浓度明显高于VDS和VCR,在肺内浓度差别最大,分别高于VDS和VCR3.4和14.8倍,而在脂肪组织中、胃肠道组织中仅有微小差别。半衰期长,平均为40h。NVB的代谢主要发生在细胞外,大多由粪便排出,且持续3~5周。
适应证
1.非小细胞肺癌:是目前单药治疗最有效的药物之一,单药有效率高达30%。
2.乳腺癌:是较为有效的药物之一,与其他有效药物联合治疗,总有效率超过60%,完全缓解率达20%左右。
3.晚期卵巢癌:用于治疗强烈化疗后复发或进展的晚期卵巢癌,耐受性较好。
4.其他:如恶性淋巴瘤、头颈部癌、小细胞肺癌、食管癌等。剂量与用法:静脉给药:25~30mg/m2(低于20mg/m2时疗效下降或无效)溶于生理盐水10~20ml,静脉注射,或以生理盐水125~150ml稀释,快速静脉滴入(15~20min),每周1次,2次为1个疗程。
禁忌证
在进行包括肝脏的放疗时禁用本品。
注意事项
1.本品局部刺激性强,注射时应特别注意,药物注射完毕时应沿原静脉输入大量生理盐水,以减轻局部血管的刺激性。必要时先给予深静脉置管。
2.使用时避免药物溅到皮肤或眼球内,一旦发生这种情况应立即进行冲洗。
不良反应
1.骨髓抑制:为其主要剂量限制毒性。主要是白细胞减少,尤其是粒细胞减少,3、4度白细胞下降占11%~15%。可有贫血,血小板下降少见。
2.胃肠道反应:恶心、呕吐等,均较轻。
3.神经毒性:较VCR轻,有感觉异常、便秘,偶有腱反射消失,有致麻痹性肠梗阻的报道。
4.呼吸道毒性:本品可引起呼吸困难和气管痉挛,常于注药后数min或几小时内发生。
5.局部刺激:与其他长春花生物碱类药物相同,具有很强的局部刺激性,常用剂量(30mg/m2)时,注射部位静脉炎发生率为18%。
6.其他:脱发、转氨酶升高、下颌痛等。
用法用量
25~30mg/m2,静脉注射,每周1次,2次为1个疗程。
生产单位:
皮尔·法伯药物研制公司Laboratories Pierre Fabre

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NAVELBINE safely and effectively.  See full prescribing information for NAVELBINE.
NAVELBINE® (vinorelbine tartrate) injection, for intravenous use
Initial U.S. Approval: 1994
WARNING: MYELOSUPPRESSION See full prescribing information for complete boxed warning.
Severe myelosuppression resulting in serious infection, septic shock, and death may occur (5.1). 
Decrease the dose or withhold NAVELBINE in accord with recommended dose modifications (2.2).
INDICATIONS AND USAGE
NAVELBINE 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) (1)
As a single agent for first-line treatment of patients with metastatic NSCLC (1)
DOSAGE AND ADMINISTRATION
In combination with cisplatin: 25 to 30 mg/m2 as a single intravenous injection weekly (2.1)
Single agent: 30 mg/m2 as a single intravenous injection weekly (2.1)
Adjust the dose in patients with decreased  neutrophil counts or elevated serum total bilirubin (2.2)
DOSAGE FORMS AND STRENGTHS
Injection: single use vials of 10 mg/1 mL and 50 mg/5 mL (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS
Hepatic toxicity: monitor liver function during treatment (5.2)
Severe constipation and bowel obstruction including necrosis and perforation can occur. Institute a prophylactic bowel regimen to mitigate potential constipation. Monitor for abdominal pain and severe constipation (5.3)
Extravasation can result in severe tissue injury, necrosis and/or thrombophlebitis. Immediately stop NAVELBINE and institute recommended management procedures (5.4)
Neurologic toxicity: severe sensory and motor neuropathies can occur. Monitor patients for new or worsening signs and symptoms of neuropathy (5.5)
Pulmonary toxicity and respiratory failure can occur with use of NAVELBINE. Monitor patients respiratory disorders: dyspnea and  bronchospasm Interrupt NAVELBINE in patients who develop unexplained dyspnea (5.6)
Embryo-fetal toxicity: can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus (5.7, 8.1)
ADVERSE REACTIONS
Most common adverse reactions (incidence ≥ 20%) are neutropenia, anemia, liver enzyme elevation, nausea, vomiting, asthenia, constipation, injection site reaction, and peripheral neuropathy (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Pierre Fabre Pharmaceuticals at 1- 855-PFPHARM (1-855-737-4276) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Inhibitors of CYP3A4: increased severity of adverse reactions (7.1)
USE IN SPECIFIC POPULATIONS
Nursing Mothers: discontinue drug or nursing taking into consideration importance of drug to mother (8.3)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 5/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
NAVELBINE 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 Dose
In Combination with Cisplatin 100 mg/m2
The recommended dose of NAVELBINE 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 NAVELBINE 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 NAVELBINE is 30 mg/m2 administered intravenously over 6 to 10 minutes once a week.
2.2 Dose Modifications
Hematologic Toxicity
[see Warnings and Precautions (5.1)]
Hold or decrease the dose of NAVELBINE in patients with decreased neutrophil counts using the following schema. 

Neutrophils on Day of Treatment (Cells/mm3)

Percentage of Starting Dose of NAVELBINE

≥ 1,500

100%

1,000 to 1,499

50%

< 1,000

Do not administer NAVELBINE.

Repeat neutrophil count in one week. 

If three consecutive weekly doses are held because  

Neutrophil count is < 1,000 cells/mm3, discontinue NAVELBINE

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 NAVELBINE should be:

> 1,500

75%

1,000 to 1,499

37.5%

< 1,000

                    Do not administer NAVELBINE. Repeat neutrophil count in one week.

Hepatic Impairment/Toxicity
[see Warnings and Precautions (5.2) and Use in Specific Populations(8.6)]
Reduce NAVELBINE 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 NAVELBINE    

< 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 NAVELBINE determined from the above schemas.
Neurologic Toxicity
[see Warnings and Precautions (5.5)]
Discontinue NAVELBINE for NCI CTCAE Grade 2 or higher peripheral neuropathy or autonomic neuropathy causing constipation.
2.3 Preparation and Administration
Preparation of NAVELBINE
Dilute NAVELBINE in either a syringe or intravenous bag using one of the recommended solutions.
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 NAVELBINE 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 NAVELBINE 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.
NAVELBINE must only be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any NAVELBINE 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, NAVELBINE should not be administered.
Management of Suspected Extravasation
If NAVELBINE leakage into surrounding tissue occurs or is suspected, immediately stop administration of NAVELBINE and initiate appropriate management measures in accordance with institutional policies [see Warnings and Precautions (5.4)].
2.4 Procedures for Proper Handling and Disposal
Handle and dispose NAVELBINE consistent with recommendations for the handling and disposal of hazardous drugs1.
Exercise caution in handling and preparing the solution of NAVELBINE. The use of gloves is recommended. If the solution of NAVELBINE contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.
Avoid contamination of the eye with NAVELBINE. If exposure occurs, flush the eyes with water immediately and thoroughly.
3  DOSAGE FORMS AND STRENGTHS
NAVELBINE Injection
Clear colorless to pale yellow solution in single use vials:
1 mL(10 mg/ 1 mL)
5 mL(50 mg/ 5 mL)
4   CONTRAINDICATIONS
None
5  WARNINGS AND PRECAUTIONS
5.1 Myelosuppression
Myelosuppression manifested by neutropenia, anemia and thrombocytopenia occur with NAVELBINE® 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 NAVELBINE.  Grade 3-4 neutropenia occurred in 53% of patients treated with NAVELBINE at 30 mg/m2 per week. Dose adjustment due to myelosuppression occurred in 51% of patients (Study 2). In clinical trials with NAVELBINE 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 NAVELBINE. Do not administer NAVELBINE to patients with neutrophil counts <1,000 cells/mm3.  Adjustments in the dosage of NAVELBINE 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 NAVELBINE alone or in combination with cytotoxic agents. Assess hepatic function prior to initiation of NAVELBINE and periodically during treatment.  Reduce the dose of NAVELBINE 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 NAVELBINE 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 NAVELBINE can result in severe irritation, local tissue necrosis and/or thrombophlebitis. If signs or symptoms of extravasation occur, immediately stop administration of NAVELBINE 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 NAVELBINE. Monitor patients for new or worsening signs and symptoms of neuropathy such as paresthesia, hyperesthesia, hyporeflexia and muscle weakness while receiving NAVELBINE.  Discontinue NAVELBINE for NCI 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) occurs with use of NAVELBINE.  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 NAVELBINE in patients who develop unexplained dyspnea, or have any evidence of pulmonary toxicity. Permanently discontinue NAVELBINE for confirmed interstitial pneumonitis or ARDS.
5.7 Embryo-Fetal Toxicity
NAVELBINE 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 NAVELBINE [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.
Single Agent
The data below reflect exposure to NAVELBINE 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 NAVELBINE. 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 NAVELBINE in 222 patients with previously treated advanced breast cancer who received a median of 10 doses of NAVELBINE.  NAVELBINE 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 NAVELBINE 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 Navelbine experienced at least one dose reduction due to an adverse reaction. Thirteen percent of patients discontinued NAVELBINE due to adverse reactions. The most frequent adverse reactions leading to NAVELBINE discontinuation were asthenia, dyspnea, nausea, constipation, anorexia, myasthenia and fever.
Table 1: Hematologic Adverse Reactions Experienced in > 5% of Patients Receiving NAVELBINE*†:

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%
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.
Table 2: Non-hematologic Adverse Reactions Experienced in > 5% of Patients Receiving NAVELBINE*†:

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%
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.
Incidence of paresthesia plus hypesthesia.
Myelosuppression: In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 69%, 9% and 1%, respectively of patients receiving single-agent NAVELBINE.  Neutropenia is the major dose-limiting toxicity.
Neurotoxicity: neurotoxicity was most commonly manifested as constipation, paresthesia, hypersthesia, and hyporeflexia.  Grade 3 and 4 neuropathy was observed in 1% of the patients receiving single-agent NAVELBINE.                
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 NAVELBINE treated patients reported in a randomized trial comparing the combination of NAVELBINE 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 NAVELBINE 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 NAVELBINE plus cisplatin arm (82%) compared to the cisplatin alone arm (5%).  Four patients in the NAVELBINE 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 NAVELBINE, and 3 from febrile neutropenia.
Table 3: Adverse Reactions Experienced by > 10% of Patients on NAVELBINE plus Cisplatin versus Single-Agent Cisplatin*

NAVELBINE 25mg/m2 plus Cisplatin 100mg/m2 
Cisplatin 100 mg/m2 (N=212)  (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 apetite

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%

Graded according to the standard SWOG criteria version 1.
Categorical toxicity grade not specified
Table 4 presents the incidence of selected adverse reactions, occurring in ≥ 10% of NAVELBINE treated patients reported in a randomized trial of NAVELBINE plus cisplatin, vindesine plus cisplatin and NAVELBINE alone in patients with stage III or IV NSCLC who had not received prior chemotherapy.  A total of 604 patients received either NAVELBINE 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 NAVELBINE 30mg/m2 every week (N=204).
Patients randomized to NAVELBINE plus cisplatin received a median of 15 weeks of treatment, vindesine plus cisplatin 12 weeks and NAVELBINE received 13 weeks.  Study discontinuation due to an adverse reaction was required in 27, 22 and 10% of the patients randomized to NAVELBINE plus cisplatin, vindesine plus cisplatin and cisplatin alone arms, respectively.  Grade 3 and 4 neutropenia was significantly greater in the NAVELBINE plus cisplatin arm (78%) compared to vindesine plus cisplatin (48%) and NAVELBINE alone (53%).  Neurotoxicity, including peripheral neuropathy and constipation was reported in 44% (Grades 3-4, 7%) of the patients receiving NAVELBINE 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 NAVELBINE alone.
Table 4: Adverse Reactions Experienced by > 10 % of Patients from a Comparative Trial of NAVELBINE Plus Cisplatin versus Vindesine Plus Cisplatin versus Single-Agent NAVELBINE*

NAVELBINE/Cisplatin   Vindesine/Cisplatin     NAVELBINE§
 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%
Grade based on criteria from the World Health Organization (WHO).
n=194 to 207; all patients receiving NAVELBINE/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 NAVELBINE with laboratory and non-laboratory data.
Categorical toxicity grade not specified.
Neurotoxicity includes peripheral neuropathy and constipation.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of NAVELBINE. 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  DRUG INTERACTIONS
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 NAVELBINE with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of adverse reactions. 
8  USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D
Risk Summary
NAVELBINE 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.
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 NAVELBINE in pediatric patients have not been established. Results from a single-arm study of NAVELBINE 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 NAVELBINE alone and NAVELBINE 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 NAVELBINE has not been evaluated, but the liver plays an important role in the metabolism of NAVELBINE. Elevations of aspartate aminotransferase occur in > 60% of the patients receiving NAVELBINE alone (6% Grade 3-4). Therefore, exercise caution in patients with hepatic impairment. Reduce the dose of NAVELBINE for patients with bilirubin elevation [see Dosage and Administration (2.2)  and Warnings and Precautions (5.2)].
8.7 Females and Males of Reproductive Potential
Contraception
Females
NAVELBINE 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 NAVELBINE.
Males
NAVELBINE 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 NAVELBINE.
Fertility
Males
Based on animal findings, NAVELBINE may cause decreased fertility in males [see Nonclinical Toxicology (13.1)].
10  OVERDOSAGE
There is no known antidote for overdoses of NAVELBINE. 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 NAVELBINE. 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
NAVELBINE (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
NAVELBINE Injection is a sterile nonpyrogeinc aqueous solution. Each milliliter of solution contains vinorelbine tartrate equivalent to 10 mg vinorelbine in Water for Injection. The pH of NAVELBINE Injection is approximately 3.5.
12  CLINICAL PHARMACOLOGY
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.
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, 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, VSS and t1/2) of vinorelbine.
Drug Interactions
The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin.
13  NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of NAVELBINE 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  CLINICAL STUDIES
14.1 Combination Use with Cisplatin
The safety and efficacy of NAVELBINE in combination with cisplatin was evaluated in two randomized, multicenter trials.
Cisplatin 100mg/m2
Study 1 was a randomized, multicenter, open-label trial of NAVELBINE 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 NAVELBINE 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)

NAVELBINE plus Cisplatin           Cisplatin Alone        
   (N=214)  (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

Cisplatin 120mg/m2
Study 2 was a randomized, 3-arm, open-label, multicenter trial of NAVELBINE plus cisplatin, vindesine plus cisplatin and NAVELBINE 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 NAVELBINE 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 NAVELBINE 30mg/m2 every week of a 6-week cycle (N=206). The main efficacy outcome measure was to compare overall survival between NAVELBINE 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 NAVELBINE 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 NAVELBINE plus cisplatin arm, 40% of patients in vindesine plus cisplatin arm and 28% of patients on the NAVELBINE 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)

NAVELBINE Alone      NAVELBINE plus     Vindesine plus   
   (N=206)  cisplatin (N=206)    cisplatin (N=200) 
 Median survival in  7.2 (5.4-9.1)  9.2 (7.4-11.1)  7.4 (6.1-9.1)
 months (99.5% CI)      
 Unstratified log-rank  n/a1  0.087
 p-value  0.05  n/a
 
 Overall Response (ORR)      
 Evaluable Patients  N=205  N=203  N=198
 ORR  (95% CI)  14% (10%, 20%)  28% (22%, 35%)  19% (14%, 25% )
     
 Chi-square test  p-value  n/a  0.03
 < 0.001  n/a
1n/a = not applicable
14.2 Single Agent
The safety and efficacy of NAVELBINE as a single agent was evaluated in one randomized multi-center trial.
Study 3 was a randomized, open-label clinical trial of NAVELBINE 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 NAVELBINE 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 NAVELBINE 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 NAVELBINE 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 NAVELBINE and 5-FU/LV, respectively.
15  REFERENCES
1.  OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
16  HOW SUPPLIED/STORAGE AND HANDLING
NAVELBINE Injection is a clear, colorless to pale yellow aqueous solution available in single-dose vials with royal blue caps, individually packaged in a carton as:
10 mg/1 mL (NDC 64370-532-01).
50 mg/5 mL (NDC 64370-532-02).
Store the vials at 2° to 8°C (36° to 46°F) in the carton. Protect from light. DO NOT FREEZE. Unopened vials of NAVELBINE are stable at 25°C (77°F) for up to 72 hours.
NAVELBINE is a cytotoxic drug. Follow applicable special handling and disposal procedures.1


-----------------------------------------
产地国家: 美国
原产地英文商品名:
NAVELBINE 50mg/5ml/Vial 5vials/box
原产地英文药品名:
VINORELBINE TARTRATE
中文参考商品译名:
诺维本 50毫克/5毫升/瓶 5瓶/盒
中文参考药品译名:
酒石酸长春瑞滨
生产厂家中文参考译名:
皮尔·法伯药物研制公司
生产厂家英文名:
PIERRE FABRE
----------------------------------------
产地国家: 美国
原产地英文商品名:
NAVELBINE 10mg/Vial
原产地英文药品名:
VINORELBINE TARTRATE
中文参考商品译名:
诺维本 10毫克/瓶/盒
中文参考药品译名:
酒石酸长春瑞滨
生产厂家中文参考译名:
皮尔·法伯药物研制公司
生产厂家英文名:
PIERRE FABRE
---------------------------------------
产地国家: 美国
原产地英文商品名:
NAVELBINE 10mg/Vial 10vials/box
原产地英文药品名:
VINORELBINE TARTRATE
中文参考商品译名:
诺维本 10毫克/瓶 10瓶/盒
中文参考药品译名:
酒石酸长春瑞滨
生产厂家中文参考译名:
皮尔·法伯药物研制公司
生产厂家英文名:
PIERRE FABRE

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