Vinorelbine (Navelbine ) is a semisynthetic vinca alkaloid which binds to tubulin and inhibits microtubule formation.

It is used as a first-line treatment (in combination with cisplatin) of locally advanced or metastatic non-small cell lung cancer (NSCLC)

It is also the single-agent treatment of metastatic NSCLC.

• Off Label Usage of Vinorelbine in Adults:

  • Metastatic Breast cancer

  • Persistent or recurrent cervical cancer

  • Relapsed or refractory Hodgkin lymphoma,

  • Malignant pleural mesothelioma

  • Relapsed Ovarian cancer

  • Recurrent Salivary gland cancer

  • Refractory Small cell lung cancer

  • Advanced soft tissue sarcoma

Vinorelbine Dose in Adults

Off label Dosage in the treatment of metastatic Breast cancer:

• 25 mg/m² intravenous once weekly (as a single agent) until disease progression or unacceptable toxicity
• An alternative is 30 mg/m² once weekly (as a single agent)
• After 13 weeks, Dosing interval can be changed to every 14 days (for patient convenience)
• It is continued until either the disease progress or the patient develops unacceptable toxicity.
• Another option is to give 25 mg/m² every 7 days (in combination with trastuzumab) until disease progression or unacceptable toxicity
• Another alternative dosage is 30 or 35 mg/m² days 1 and 8 every 21 days (in combination with trastuzumab) until disease progression or unacceptable toxicity.

Off label dosage in the treatment of Cervical cancer:

• 30 mg/m² intravenous on days 1 and 8 of a 2-week treatment cycle

Off label dosage in the treatment of relapsed or refractory Hodgkin lymphoma:

• GVD regimen:
  • It is given 15 mg/m² (post-transplant patients)
  • It can also be given as 20 mg/m² (transplant-naïve patients) on days 1 and 8 of a 21-day cycle (in combination with gemcitabine and doxorubicin liposomal) for 2 to 6 cycles
• IGEV regimen:
  • It is given 20 mg/m² on day 1 of a 2-week cycle (in combination with ifosfamide, mesna, gemcitabine, and prednisolone) for 4 cycles

Off label dosage in the treatment of malignant pleural mesothelioma :

• It is given 30 mg/m² (maximum dose: 60 mg) every 7 days per 6-week treatment cycle
• It is continued until disease progression
• It is also be given 30 mg/m² (maximum dose: 60 mg) every 7 days for 6 weeks, off 2 weeks, then repeat the cycle

Dosage in the treatment of Non-small cell lung cancer (NSCLC):

Metastatic (single-agent therapy):

• It is given 30 mg/m² once a week

Locally advanced or metastatic (in combination with cisplatin):

• It is given 25 mg/m² on days 1, 8, 15, and 22 of a 28-day cycle or 30 mg/m² once a week

Advanced NSCLC (off-label dosing):

• It is given 25 to 30 mg/m² days 1, 8, and 15 every 28 days (in combination with gemcitabine) for 6 cycles or until disease progression or unacceptable toxicity occurs

Off label dosage in the treatment of relapsed Ovarian cancer:

• It is given  25 mg/m² intravenous every 7 days
• It is also be given  30 mg/m² days 1 and 8 of a 21-day treatment cycle until disease progression or unacceptable toxicity occurs

Off label dosage in the treatment of recurrent Salivary gland cancer:

• It is given 25 mg/m² intravenous on days 1 and 8 of a 21-day cycle (in combination with cisplatin) for a minimum of 3 cycles and for up to 6 cycles

Off label dosage in the treatment of refractory Small cell lung cancer:

• It is given 25 or 30 mg/m² intravenous every 7 days until disease progression or unacceptable toxicity.

Off label dosage in the treatment of advanced Soft tissue sarcoma:

• It is given 25 mg/m² intravenous on days 1 and 8 of a 21-day treatment cycle (in combination with gemcitabine) until disease progression or unacceptable toxicity occurs

Vinorelbine Dose in Childrens

Dose in the treatment of refractory or recurrent Hodgkin’s lymphoma: 

• Children ≥10 years and Adolescents:
  • It is given  25 mg/m² IV once weekly on days 1 and 8 of a 3-week cycle in combination with gemcitabine

Dose in the treatment of refractory, or recurrent acute Leukemias (ALL, AML):

• Infants:
  • It is given as 67 mg/kg once weekly on days 0, 7, 14 of a 2-week cycle in combination with topotecan, clofarabine, and thiotepa (TVTC regimen)
• Children and Adolescents:
  • It is given  20 mg/m² once weekly on days 0, 7, and 14 of a 2-week cycle in combination with topotecan, clofarabine, and thiotepa (TVTC regimen)

Dose in the treatment of refractory or recurrent solid tumors:

• Children and Adolescents:
  • Monotherapy:
    • It is given 30 mg/m once weekly for weeks 1-6 of an 8-week cycle for 10 courses
    • It may be reduced  to 27 mg/m for Grade 3 or 4 hematologic toxicity in patients who show an objective response or who have had treatment delay beyond 63 days (week 9) from the previous course
  • Combination therapy:
    • It is given  25 mg/m² once weekly for 3 weeks on days 1, 8, and 15 of each 4-week cycle in combination with cyclophosphamide
  • Dosing adjustment for toxicity:
    • The presented dosing adjustments are based on the dosage given in adult patients. Refer to a specific protocol for management in pediatric patients if available.

• In patients with hematologic toxicity and hepatic impairment at the same time, give the lower of the doses determined from the adjustment recommendations.
  • Granulocyte counts should be more than 1000 cells/mm³ before the administration of vinorelbine.
  • Adjustments in the dose should be made on granulocyte counts obtained on the day of treatment as follows:
    • Granulocytes more than 1500 cells/mm³ on day of treatment:
      • Give 100% of starting dose
    • Granulocytes 1000-1499 cells/mm³ on day of treatment:
      • Give 50% of starting dose
    • Granulocytes <1000 cells/mm on day of treatment:
      • Do not give. Repeat granulocyte count in 1 week; if 3 consecutive doses are not given because granulocyte count is <1000 cells/mm³, stop vinorelbine.
    • For patients who, during treatment, have experienced fever and/or sepsis while granulocytopenia or had 2 consecutive weekly dose not given due to granulocytopenia, subsequent doses of vinorelbine should be:
      • 75% of the starting dose for granulocytes more than 1500 cells/mm³
      • 50% of the starting dose for granulocytes 1000-1499 cells/mm³
    • Neurotoxicity ≥grade 2:
      • Stop treatment
    • Severe adverse events:
      • Reduce dose or stop treatment

Vinorelbine pregnancy Risk Factor: D

• Vinorelbine may cause harm to the fetus if given to pregnant women.
• Before treatment can be initiated for females with reproductive potential, it is important to verify their pregnancy status.
• For effective contraception, pregnant women of reproductive potential must be advised that they are able to use it during vinorelbine treatment as well as for six months afterward.
• Effective contraception should be used by males who have female partners with reproductive potential during treatment and for three months after the last vinorelbine dosage.
• Vinorelbine may damage the spermatozoa, which can lead to decreased fertility in male patients.

Vinorelbine can be used during lactation

• Breastfeeding is not recommended during treatment or for the first 9 days following the last vinorelbine dose.

Vinorelbine (Navelbine) dose in Renal disease: 

There are no dosage adjustments given in the manufacturer's labeling.

Hemodialysis:

• Initially reduce dose to 20 mg/m² once a week
• Then administer either after dialysis (on dialysis days) or on nondialysis days

Vinorelbine (Navelbine) dose in Liver disease: 

• Patients with concomitant hematologic toxicities and hepatic impairment should be given the lowest dose as per the adjustment recommendations.
• Patients with hepatic impairment should be cautious.
• Patients who become hyperbilirubinmic after treatment with vinorelbine should adjust their dose for total bilirubin, as follows:
  • Serum bilirubin lower than 2 mg/dL
    • Take 100% of the dose
  • Serum bilirubin, 2.1 to 3.0 mg/dL
    • Half the dose should be given
  • More than 3 mg/dL serum bilirubin:
    • 25% of the dose should be given
  • Patients with advanced liver metastases (more that 75% of the liver volume) (breast Cancer):
    • Half the dose should be given

Common Side Effects of Vinorelbine Include:

• Central Nervous System:
  • Neurotoxicity
  • Peripheral Neuropathy
• Dermatologic:
  • Alopecia
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Constipation
  • Diarrhea
• Hematologic & Oncologic:
  • Neutropenia
  • Leukopenia
  • Anemia
• Hepatic:
  • Increased Serum Aspartate Aminotransferase
• Local:
  • Injection Site Reaction
  • Pain At Injection Site
• Neuromuscular & Skeletal:
  • Asthenia
• Renal:
  • Increased Serum Creatinine

Less Common Side Effects of Vinorelbine Include:

• Cardiovascular:
  • Localized phlebitis
  • chest pain
• Central nervous system:
  • Neuropathy
• Hematologic & oncologic:
  • Febrile neutropenia
  • thrombocytopenia
• Hepatic:
  • Increased serum bilirubin
• Infection:
  • Sepsis
• Otic:
  • Ototoxicity
• Respiratory:
  • Dyspnea

Frequency not defined:

• Gastrointestinal:
  • Intestinal Necrosis
  • Intestinal Obstruction
  • Intestinal Perforation
  • Paralytic Ileus
• Hematologic & Oncologic:
  • Bone Marrow Depression
• Hepatic:
  • Hepatotoxicity
• Respiratory:
  • Interstitial Pulmonary Disease
  • Pulmonary Toxicity (Including Acute Respiratory Distress Syndrome
  • Interstitial Pneumonitis
  • Severe Acute Bronchospasm)

Contraindication to Vinorelbine Include:

• The manufacturer's labeling does not list any contraindications.

Warnings and precautions

• Suppression of bone marrow: [US Boxed Warning]
  • Septic shock, death, or severe myelosuppression can result in serious infections, hospitalizations, and even death.
  • It could require treatment interruption, dose reduction and/or discontinuation.
  • Vinorelbine can cause anemia, neutropenia, and thrombocytopenia. It can be used alone or in combination with other chemotherapy.
  • Neutropenia, which is the most severe dose-limiting toxicity (grades 3 and 4 neutropenia have often been observed).
  • Neutropenia can lead to hospitalization for fever and/or sepsis.
  • The neutrophil nadir is reached between 7-10 days after administration. Recovery occurs within 7-14 days.
  • Before each dose, monitor your complete blood count.
  • Based on blood counts taken on the day of therapy, adjust the dose.
  • If ANC is less than 1000/mm, do not administer.
• Extravasation
  • Before infusion, use Vesicant to ensure the proper position of the needle or catheter.
  • Avoid excessive use.
  • Extravasation can lead to tissue necrosis or thrombophlebitis.
• Gastrointestinal toxicities:
  • Vinorelbine may cause severe and fatal paralytic and fatal ileus, necrosis and intestinal obstruction. Perforation can also occur.
  • To reduce constipation, bowel obstruction, and paralytic ileus, you can start a prophylactic stool regimen.
  • Oral vinorelbine has moderate antiemetic properties
  • To prevent nausea/vomiting, antiemetics can be used
  • IV vinorelbine is very low in emetic potential
• Hepatotoxicity
  • Patients receiving vinorelbine can experience a drug-induced increase in transaminases or bilirubin elevations. This could be either as a single-agent treatment or in combination chemotherapy.
  • Before treatment begins, monitor liver function and continue to do so throughout treatment.
  • Patients with total bilirubin levels >2 times the ULN should be advised to reduce their doses.
  • Vinorelbine elimination occurs predominantly through the liver; patients with impaired hepatic function should be cautious and dose reductions advised.
• Neuropathy
  • Patients who receive vinorelbine may develop motor and sensory neuropathies.
  • Monitor for signs and symptoms of muscle weakness or neuropathy. This includes paresthesia, hyperesthesia, hyporeflexia, and hyperesthesia.
  • Vinorelbine should be stopped if you have >= grade 2 neuropathy.
• Toxicity in the lungs:
  • Vinorelbine can cause pulmonary toxicity. This includes severe acute bronchospasm and interstitial pneumonitis.
  • The median time it took for interstitial pneumonia and ARDS to develop was 7 days. This ranged from 3 to 8 days.
  • Patients who have unexplained dyspnea, or any evidence of pulmonary toxicities should be treated with vinorelbine.
  • Stop vinorelbine permanently if you have been diagnosed with interstitial pneumonitis (ARDS) or confirmed interstitial pneumonia.

Monitor:

• CBC with differential and platelet count (before each dose, and after treatment),
• Liver function tests;
• Confirm pregnancy status in females of reproductive potential prior to treatment initiation.
• Monitor for new-onset pulmonary symptoms (or worsening from baseline);
• monitor for new or worsening symptoms neuropathy.
• monitor for signs and symptoms of constipation and ileus
• monitor infusion site regularly

How to administer Vinorelbine?

For intravenous use only. It may be fatal if given by other routes.

• Give over 6 - 10 minutes
• Follow the infusion with at least 75 to 125 mL of a compatible solution to lessen the incidence of phlebitis and inflammation.
• It is a vesicant, ensure proper needle or catheter position before administration.
• Avoid extravasation.

Extravasation management:

• If extravasation happens, stop infusion immediately and disconnect (leave cannula/needle in place)
• Aspirate the extravasated solution gently
• Do NOT flush the line
• Start hyaluronidase antidote
• remove needle/cannula
• apply dry warm compresses for 20 minutes 4 times a day for 1 - 2 days
• elevation of extremity should be done
• The remaining portion of the vinorelbine dose should be given through a separate vein.

Hyaluronidase:

• If needle/cannula still in place, give 1 to 6 mL hyaluronidase (150 units/mL) into the existing IV line
• the usual dose is 1 mL hyaluronidase for each 1 mL of the extravasated drug.
• If needle/cannula is removed then inject 1 to 6 mL (150 units/mL) subcutaneously in a clockwise manner using 1 mL for each 1 mL of drug extravasated
• It can also be administered 1 mL (150 units/mL) as 5 separate 0.2 mL injections (using a 25-gauge needle) subcutaneously into the extravasation site

Mechanism of action of Vinorelbine:

• It is semisynthetic vinca, an alkaloid that binds to tubulin.
• It stops the formation of the mitotic spindle and arrests the cell in metaphase
• Vinorelbine has a specific use for the M- and S phases.
• Vinorelbine may also cause interference with protein synthesis and nucleic acids by blocking glutamic acid usage.
• Distribution: It binds extensively to human platelets and lymphocytes (80% to 91%)

Protein binding:

• 80% - 91%

Metabolism:

• Extensively via hepatic, via CYP3A4, to two metabolites, deacetylvinorelbine (active) and vinorelbine N-oxide

Half-life elimination: Triphasic:

• Children and Adolescents 2 - 17 years of age: 16.5 ± 9.7 hours
• Adults: Terminal: ~28 to 44 hours

Excretion:

• Fecal route (~46%)
• urine (~18%, 10% to 12% as unchanged drug)

International Brands of Vinorelbine:

• Eberelbin
• Filcrin
• Navelbin
• Navelbine
• Navildez
• Viessia
• Vilne
• Vinbine
• Vinelbine
• Vinorel
• Vinorelsin
• Vinorgen
• Vinotec
• Vinotel
• Zinavin

Vinorelbine Brands in Pakistan: