Navelbine
Injection
Generic
Name: vinorelbine tartrate
Dosage Form: injection
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 NAVELBINE in accord with recommended dose
modifications [see Dosage
and Administration (2.2)].
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
SLIDESHOW
Immune Checkpoint Inhibitors: Boosting the Cancer Battle
DOSAGE AND ADMINISTRATION
Recommended
Dose
In Combination with Cisplatin 100 mg/m2
The recommended dose of NAVELBINE is 25 mg/m2administered
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. 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.
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, USP0.9% 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, USP0.9% Sodium Chloride Injection, USP0.45% Sodium Chloride Injection, USP5% Dextrose and 0.45% Sodium Chloride Injection,
USPRinger's Injection, USPLactated 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)]. 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.
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)
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
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)].
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)].
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.
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)].
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)].
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.
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)].
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)]
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/m2administered 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.
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
DRUG INTERACTIONS
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.
USE IN SPECIFIC POPULATIONS
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.
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.
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).
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)].
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)].
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)].
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.
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.
CLINICAL PHARMACOLOGY
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.
Pharmacokinetics
The pharmacokinetics of vinorelbine
were studied in 49 patients who received doses of 30 mg/m2administered 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.
NONCLINICAL TOXICOLOGY
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.
CLINICAL STUDIES
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
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.
REFERENCES
1. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
· 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
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
o NAVELBINE can cause fetal harm when administered to a pregnant
woman. Advise females of reproductive potential to use highly effective
contraception during treatment with NAVELBINE, 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)].
o NAVELBINE may damage sperm. Advise males to use highly
effective contraception during and for 3 months after therapy [see Use in
Specific Population (8.7) and Nonclinical
Toxicology (13.1)].
o NAVELBINE, may cause decreased fertility in males [see Nonclinical
Toxicology (13.1)].
45 place Abel Gance - 92100
Boulogne - FRANCE
Distributed by:
Pierre Fabre Pharmaceuticals,
Inc.
Parsippany, NJ 07054
Made in France
PRINCIPAL DISPLAY PANEL
- 10 mg Vial Label
NDC 64370-532-01
1 mL Single-Use Vial
NAVELBINE®
(VINORELBINE
TARTRATE)
INJECTION
equivalent to 10 mg/mL vinorelbine
Rx
only
Sterile, nonpyrogenic.
FOR I.V. USE ONLY.
MUST BE DILUTED.
Store at 2o to 8oC (36o to 46oF).
Protect from light.
DO NOT FREEZE.
Mfd. for Pierre Fabre
Pharmaceuticals, Inc.
Parsippany, NJ 07054
1-855-PFPHARM (737-4276)
Made in France
(01)00364370532012
Lot:
Exp:
PRINCIPAL DISPLAY PANEL
- 50 mg Vial Label
NDC 64370-532-02
5 mL Single-Use Vial
NAVELBINE®
(VINORELBINE
TARTRATE)
INJECTION
equivalent to 50 mg/5 mL (10 mg/mL) vinorelbine
Sterile, nonpyrogenic.
FOR I.V. USE ONLY.
MUST BE DILUTED.
Store at 2o to 8oC (36o to 46o F).
Protect from light. DO NOT
FREEZE
Mfd. for Pierre Fabre
Pharmaceuticals, Inc.
Parsippany, NJ 07054
1-855-PFPHARM (737-4276)
Made in France
Rx only
(01)003643705320129
Lot:
Exp:
|
NAVELBINE vinorelbine tartrate
injection
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:64370-532
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
VINORELBINE TARTRATE (VINORELBINE)
|
VINORELBINE
|
10 mg
in 1 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
WATER
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:64370-532-01
|
1 VIAL,
SINGLE-USE in 1 CARTON
|
|
|
1
|
|
1 mL in 1 VIAL,
SINGLE-USE
|
|
|
2
|
NDC:64370-532-02
|
1 VIAL,
SINGLE-USE in 1 CARTON
|
|
|
2
|
|
5 mL in 1 VIAL,
SINGLE-USE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA020388
|
11/15/2005
|
|
|
|
Labeler - Pierre Fabre Pharmaceuticals, Inc. (968997101)
|
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Pierre Fabre
Médicament
|
|
267116254
|
ANALYSIS(64370-532),
API MANUFACTURE(64370-532)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Pierre Fabre
Médicament Production
|
|
504638276
|
ANALYSIS(64370-532),
MANUFACTURE(64370-532)
|
|
|
|
|
|
|
|
Revised:
05/2014
Pierre Fabre
Pharmaceuticals, Inc.
