DRUGS & SUPPLEMENTS

Vinorelbine

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Vinorelbine uses


WARNING: MYELOSUPPRESSION

  • Severe myelosuppression resulting in serious infection, septic shock, hospitalization and death may occur .
  • Decrease the dose or withhold Vinorelbine in accord with recommended dose modifications .

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 Vinorelbine in accord with recommended dose modifications ( 2.2 ).

1 INDICATIONS AND USAGE

Vinorelbine injection, USP is indicated:

  • In combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)
  • As a single agent, for the treatment of patients with metastatic NSCLC

Vinorelbine injection, USP 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)
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2 DOSAGE AND ADMINISTRATION

  • In combination with cisplatin: 25 to 30 mg/m2 as a single intravenous injection weekly
  • 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)

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 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/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 Dose Modifications

Hematologic Toxicity

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

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 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:

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 Hematologic Toxicity and Hepatic Impairment

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

Neurologic Toxicity

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

2.3 Preparation and Administration

Preparation of Vinorelbine Injection, USP

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

Syringe

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

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

Intravenous Bag

Dilute to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution:

  • 5% Dextrose Injection, USP
  • 0.9% Sodium Chloride Injection, USP
  • 0.45% Sodium Chloride Injection, USP
  • 5% Dextrose and 0.45% Sodium Chloride Injection, USP
  • Ringer's Injection, USP
  • Lactated Ringer's Injection, USP

Stability

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

Administration

Administer diluted Vinorelbine Injection, USP over 6 to 10 minutes into the side port of a free-flowing intravenous line followed by flushing with at least 75 to 125 mL of one of the solutions.

Vinorelbine Injection, USP must only be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any Vinorelbine is injected.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If particulate matter is seen, Vinorelbine Injection, USP should not be administered.

Management of Suspected Extravasation

  • If Vinorelbine leakage into surrounding tissue occurs or is suspected, immediately stop administration of Vinorelbine and initiate appropriate management measures in accordance with institutional policies.

2.4 Procedures for Proper Handling and Disposal

Handle and dispose Vinorelbine Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs1.

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

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

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3 DOSAGE FORMS AND STRENGTHS

Vinorelbine Injection, USP

Clear colorless to pale yellow solution in single use vials:

1 mL (10 mg/1 mL)

5 mL (50 mg/5 mL)

  • Injection: single use vials of 10 mg/1 mL and 50 mg/5 mL (3)

4 CONTRAINDICATIONS

None

None

5 WARNINGS AND PRECAUTIONS

  • Hepatic toxicity: monitor liver function during treatment
  • 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 Vinorelbine 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 Vinorelbine. Monitor patients respiratory disorders: dyspnea and bronchospasm Interrupt Vinorelbine 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).

5.1 Myelosuppression

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

Monitor complete blood counts prior to each dose of Vinorelbine. Do not administer Vinorelbine to patients with neutrophil counts less than 1,000 cells/mm3. Adjustments in the dosage of Vinorelbine should be based on neutrophil counts obtained on the day of treatment.

5.2 Hepatic Toxicity

Drug-induced liver injury manifest by elevations of aspartate aminotransferase and bilirubin can occur in patients receiving Vinorelbine alone or in combination with cytotoxic agents. Assess hepatic function prior to initiation of Vinorelbine and periodically during treatment. Reduce the dose of Vinorelbine for patients who develop elevations in total bilirubin greater than 2 times upper limit of normal.

5.3 Severe Constipation and Bowel Obstruction

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

5.4 Extravasation and Tissue Injury

Extravasation of Vinorelbine can result in severe irritation, local tissue necrosis and/or thrombophlebitis. If signs or symptoms of extravasation occur, immediately stop administration of Vinorelbine and institute recommended management procedures.

5.5 Neurologic Toxicity

Sensory and motor neuropathies, including severe neuropathies, occur in patients receiving Vinorelbine. Monitor patients for new or worsening signs and symptoms of neuropathy such as paresthesia, hyperesthesia, hyporeflexia and muscle weakness while receiving Vinorelbine. Discontinue Vinorelbine for NCI CTCAE Grade 2 or greater neuropathy

5.6 Pulmonary Toxicity and Respiratory Failure

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

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

5.7 Embryo-Fetal Toxicity

Vinorelbine can cause fetal harm when administered to a pregnant woman. In animal reproduction studies in mice and rabbits, embryo and fetal toxicity were observed with administration of Vinorelbine at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during therapy with Vinorelbine.

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6 ADVERSE REACTIONS

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

  • Myelosuppression
  • Pulmonary Toxicity and Respiratory Failure
  • Constipation and Bowel Obstruction
  • Extravasation Tissue Injury
  • Neurologic Toxicity
  • Hepatic Toxicity

Most common adverse reactions (incidence greater than or equal to 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 Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial 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 previously untreated metastatic NSCLC patients (Study 3) who received a median of 8 doses of Vinorelbine. The patients were aged 32 to 79 (median 61 years), 71% were male, 91% Caucasian, 48% had adenocarcinoma histology. The data also reflect exposure to Vinorelbine in 222 patients with previously treated advanced breast cancer who received a median of 10 doses of Vinorelbine. Vinorelbine is not indicated for the treatment of breast cancer.

Selected adverse reactions reported in these studies are provided in Tables 1 and 2. The most common adverse reactions (greater than or equal to 20%) of single agent Vinorelbine were leukopenia, neutropenia, anemia, Aspartate aminotransferase (AST) elevation, nausea, vomiting, constipation, asthenia, injection site reaction, and peripheral neuropathy. The most common (greater than or equal to 5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, anemia, increased total bilirubin, AST elevation, injection site reaction and asthenia. Approximately 49% of NSCLC patients treated with Vinorelbine experienced at least one dose reduction due to an adverse reaction. Thirteen percent of patients discontinued Vinorelbine due to adverse reactions. The most frequent adverse reactions leading to Vinorelbine discontinuation were asthenia, dyspnea, nausea, constipation, anorexia, myasthenia and fever.

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%
Anaemia < 11 g/dl 83% 77%
< 8 g/dl 9% 1%
Hospitalizations due to neutropenic complications 9% 8%
All grades Grades 3+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 3-4 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, hypersthesia, 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. Thirty-Five percent of the eligible patients in the combination arm required treatment discontinuation due to an adverse reaction compared to 19% in the cisplatin alone arm. The incidence of Grade 3 and 4 neutropenia was significantly higher in the Vinorelbine plus cisplatin arm (82%) compared to the cisplatin alone arm (5%). Four patients in the Vinorelbine plus cisplatin arm died of neutropenic sepsis. Seven additional deaths were reported in the combination arm: 2 from cardiac ischemia, 1 cerebrovascular accident, 1 multisystem failure due to an overdose of Vinorelbine, and 3 from febrile neutropenia.

Vinorelbine 25mg/m 2 plus Cisplatin 100mg/m 2 (n=210)
Cisplatin 100 mg/m 2 (n=212)
All Grades Grades 3+4 All Grades Grades 3+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 alone in patients with stage III or IV NSCLC who had not received prior chemotherapy. A total of 604 patients received either Vinorelbine 30 mg/m2 every week plus cisplatin 120 mg/m2 on Day 1 and Day 29, then every 6 weeks thereafter (N=207), vindesine 3 mg/m2 for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m2 on Days 1 and Day 29, then every 6 weeks thereafter (N=193) or Vinorelbine 30mg/m2 every week (N=204).

Patients randomized to Vinorelbine plus cisplatin received a median of 15 weeks of treatment, vindesine plus cisplatin 12 weeks and Vinorelbine received 13 weeks. Study discontinuation due to an adverse reaction was required in 27, 22 and 10% of the patients randomized to Vinorelbine plus cisplatin, vindesine plus cisplatin and cisplatin alone arms, respectively. Grade 3 and 4 neutropenia was significantly greater in the Vinorelbine plus cisplatin arm (78%) compared to vindesine plus cisplatin (48%) and Vinorelbine alone (53%). Neurotoxicity, including peripheral neuropathy and constipation was reported in 44% (Grades 3-4, 7%) of the patients receiving Vinorelbine plus cisplatin, 58% (Grades 3-4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grades 3-4, 8.5%) of the patients receiving Vinorelbine alone.

Vinorelbine /Cisplatin† Vindesine/Cisplatin‡ Vinorelbine §
All Grades Grades 3+4 All Grades Grades 3+4 All Grades Grades 3+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%

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Vinorelbine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and infestations: pneumonia

Immune system disorders: anaphylactic reaction, pruritus, urticaria, angioedema

Nervous system disorders: loss of deep tendon reflexes, muscular weakness, gait disturbance, headache

Ear and labyrinth disorders: vestibular disorder, hearing impaired

Cardiac disorders: tachycardia

Respiratory disorders: pulmonary edema

Vascular disorders: pulmonary embolism, deep vein thrombosis, hypertension, hypotension, flushing, vasodilatation

Gastrointestinal disorders: mucosal inflammation, dysphagia, pancreatitis

Skin disorders: generalized cutaneous reactions (rash)

Musculoskeletal and connective tissue disorders: jaw pain, myalgia, arthralgia

General disorders and administration site conditions: injection site rash, urticaria, blistering, sloughing of skin

Injury, poisoning and procedural complications: radiation recall phenomenon, dermatitis, esophagitis

Laboratory abnormalities: electrolyte imbalance including hyponatremia

Other: tumor pain, back pain, abdominal pain

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7 DRUG INTERACTIONS

  • Inhibitors of CYP3A4: increased severity of adverse reactions

7.1 CYP3A Inhibitors

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

8 USE IN SPECIFIC POPULATIONS

  • Nursing Mothers: discontinue drug or nursing taking into consideration importance of drug to mother

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category D

Risk Summary

Vinorelbine can cause fetal harm when administered to a pregnant woman. In animal reproduction studies in mice and rabbits, embryo and fetal toxicity were observed with administration of Vinorelbine at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data

In a mouse embryofetal development study, administration of a single dose of Vinorelbine at a dose level of 9 mg/m2 or greater (approximately 0.33 times the recommended human dose based on body surface area) was embryotoxic and fetotoxic. Vinorelbine was embryotoxic and fetotoxic to pregnant rabbits when administered every 6 days during the period of organogenesis at doses of 5.5 mg/m2 (approximately 0.18 times the recommended human dose based on body surface area) or greater. At doses that did not cause maternal toxicity in either species, Vinorelbine administration resulted in reduced fetal weight and delayed ossification.

8.3 Nursing Mothers

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

8.4 Pediatric Use

The safety and effectiveness of Vinorelbine in pediatric patients have not been established. Results from a single-arm study of Vinorelbine administered at the dose of 33.75 mg/m2 or at the dose of 30mg/m2 (for 11 patients) every week during 6 weeks followed by 2 weeks of rest was evaluated (courses of 8 weeks). Forty-six patients age 1 to 25 (median 11 years) with recurrent solid malignant tumors, including rhabdomyosarcoma or undifferentiated sarcoma (N=21 patients), neuroblastoma (N= 4 patients), and central nervous system (CNS) tumors (N=21 patients) were enrolled. The most significant grade 3 or 4 hematological adverse reactions were neutropenia (70%) and anemia (33%). The most significant grade 3 or 4 non-hematological toxicity adverse reactions were motor (15%) or cranial (13%) neuropathy, hypoxia (13%) and dyspnea (11%). Objective tumor response was observed in 2 out of 21 patients with rhabdomyosarcoma or undifferentiated sarcoma. No objective tumor response was observed in patients with CNS tumors (N=21) or neuroblastoma (N=4).

8.5 Geriatric Use

Of the 769 number of patients who received Vinorelbine alone and Vinorelbine in combination with Cisplatin in studies 1, 2 and 3, 247 patients were 65 years of age or older. No overall differences in safety, efficacy and pharmacokinetic parameters were observed between these patients and younger patients..

8.6 Hepatic Impairment

The influence of hepatic impairment on the pharmacokinetics of Vinorelbine has not been evaluated, but the liver plays an important role in the metabolism of Vinorelbine. Elevations of aspartate aminotransferase occur in greater than 60% of the patients receiving Vinorelbine alone. Therefore, exercise caution in patients with hepatic impairment. Reduce the dose of Vinorelbine for patients with bilirubin elevation.

8.7 Females and Males of Reproductive Potential

Contraception

Females

Vinorelbine can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception during therapy with Vinorelbine.

Males

Vinorelbine may damage spermatozoa. Males with female sexual partners of reproductive potential should use highly effective contraception during and for 3 months after therapy with Vinorelbine.

Fertility

Males

Based on animal findings, Vinorelbine may cause decreased fertility in males

10 OVERDOSAGE

There is no known antidote for overdoses of Vinorelbine. Overdoses involving quantities up to 10 times the recommended dose (30 mg/m2) have been reported. The toxicities described were consistent with those listed in the ADVERSE REACTIONS section including paralytic ileus, stomatitis, and esophagitis. Bone marrow aplasia, sepsis, and paresis have also been reported. Fatalities have occurred following overdose of Vinorelbine. If overdosage occurs, general supportive measures together with appropriate blood transfusions, growth factors, and antibiotics should be instituted as deemed necessary by the physician.

11 DESCRIPTION

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

Cisplatin 120 mg/m 2

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

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

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

Vinorelbine Alone Vinorelbine plus Vindesine plus
(N=206) cisplatin (N=206) cisplatin (N=200)
1n/a = not applicable
Median survival in months (99.5% CI) 7.2 (5.4 to 9.1) 9.2 (7.4 to 11.1) 7.4 (6.1 to 9.1)
Unstratified log-rank n/a1 0.087
p-value 0.05 n/a
Overall Response
(ORR) N=205 N=203 N=198
Evaluable Patients 14% (10%, 20%) 28% (22%, 35%) 19% (14%, 25%)
ORR (95% CI)
Chi-square test n/a 0.03
p-value < 0.001 n/a
3c00b60d-figure-02

14.2 Single Agent

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

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

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

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

15 REFERENCES

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Vinorelbine Injection, USP is a clear, colorless to pale yellow solution in Water for Injection, containing 10 mg Vinorelbine per mL. Vinorelbine Injection, USP is available in single-use, clear glass vials with elastomeric stoppers and red (10 mg/1 mL) and green (50 mg/5 mL) caps, individually packaged in a carton in the following vial sizes:

NDC Vinorelbine Injection, USP Package Factor
45963-607-55 10 mg/1 mL Single-Use Vial 1 vial per carton
45963-607-56 50 mg/5 mL Single-Use Vial 1 vial per carton

Storage Conditions

Store the vials under refrigeration at 2° to 8°C (36° to 46°F) in the carton.

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

Protect from light.

DO NOT FREEZE.

The container closure is not made with natural rubber latex.

Sterile, Nonpyrogenic, Preservative-free.

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

17 PATIENT COUNSELING INFORMATION

Inform patients of the following:

  • Myelosuppression

    Advise patients to contact a healthcare provider for new onset fever, or symptoms of infection

  • 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

  • Neurologic toxicity

    Advise patients to contact a health care provider for new onset or worsening of numbness, tingling, decrease sensation or muscle weakness

  • 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

  • Females and Males of Reproductive Potential
    • Vinorelbine Injection, USP can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use highly effective contraception during treatment with Vinorelbine Injection, USP, and to contact their healthcare provider if they become pregnant, or if pregnancy is suspected.
    • Vinorelbine Injection, USP may damage sperm. Advise males to use highly effective contraception during and for 3 months after therapy.
    • Vinorelbine Injection, USP, may cause decreased fertility in males.

Made in Italy

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Revised – May 2015

Vinorelbine pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Vinorelbine available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.

Price
Injectable; Injection; Vinorelbine Tartrate 10 mg / ml
Navelbine 50 mg/5 ml vial42.0 USD
Vinorelbine 50 mg/5 ml vial27.6 USD

Vinorelbine destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Vinorelbine Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Vinorelbine pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."VINORELBINE INJECTION, SOLUTION [ACTAVIS PHARMA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."NAVELBINE (VINORELBINE TARTRATE) INJECTION [PIERRE FABRE PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "vinorelbine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Vinorelbine?

Depending on the reaction of the Vinorelbine after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Vinorelbine not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Vinorelbine addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Vinorelbine, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Vinorelbine consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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