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vinorelbine

( Vin-ORE-ell-been )
Funding:
New Drug Funding Program
  • Vinorelbine - Non-Small Cell Lung Cancer (NSCLC)
  • Vinorelbine - Adjuvant Treatment of Completely Resected Stage II or IIIa Non-Small Cell Lung Cancer
  • Vinorelbine - Metastatic Breast Cancer
Other Name(s): Navelbine® (multiple brands available)
Appearance: Clear, colourless to pale yellow solution mixed into larger volume of fluids
A - Drug Name

vinorelbine

COMMON TRADE NAME(S):   Navelbine® (multiple brands available)

 
B - Mechanism of Action and Pharmacokinetics

Vinorelbine, a semi-synthetic vinca alkaloid, exerts its anti-tumour activity by binding to tubulin and inhibiting microtubule assembly, thereby preventing cell mitosis and causing cell death. It is cell cycle phase-specific. 



Distribution

Initial rapid decline in plasma concentration after IV administration due to distribution to peripheral compartments and metabolism. Widely distributed, with highest amounts found in elimination organs such as liver and kidneys, minimal in heart and brain.

Cross blood brain barrier? minimal
PPB 80-90%
Metabolism

Largely metabolized via hepatobiliary system (P450, CYP3A4)

Active metabolites yes, deacetylvinorelbine
Inactive metabolites

yes

Elimination

Mainly eliminated by the liver, with approximately 46% of dose being recovered in the feces.

Urine 18 %
Half-life 27.7 - 43.6 hours (terminal)
 
C - Indications and Status
Health Canada Approvals:

  • Advanced non-small cell lung cancer (single agent or in combination)
  • Metastatic breast cancer after failure of standard first-line chemotherapy or after relapse within 6 months of anthracycline-based adjuvant therapy


Other Uses:

Refer to ST-QBP regimens for details:

  • Ovarian cancer
  • Vulva cancer
  • Head and neck cancer
  • Desmoid tumour
  • Hodgkin lymphoma 
 
D - Adverse Effects

Emetogenic Potential:  

Minimal

Extravasation Potential:   Vesicant

The following adverse events were observed in single-agent treatment (30mg/m2) in advanced breast cancer patients. Some severe, life-threatening or post-marketing events in other studies are also listed.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Auditory Hearing impaired (rare; when used with cisplatin) E
Cardiovascular Venous thromboembolism (rare) E
Dermatological Alopecia (12%) (usually mild) E
Radiation recall reaction (rare) E
Rash (<5%) E
Gastrointestinal Anorexia (19%) E
Constipation (38%) (may be severe) E
Diarrhea (20%) E
Mucositis (16%) E
Nausea, vomiting (50%) I
General Fatigue (41%) E
Pain (16%) (including chest, abdomen and tumour) I  E
Hematological Myelosuppression ± infection, bleeding (41% grade 4 neutropenia) E
Hepatobiliary ↑ LFTs (7% grade 3 or 4) E
Hypersensitivity Hypersensitivity (rare) I
Injection site Injection site reaction (21%) I
Metabolic / Endocrine ↑ antidiuretic hormone (<1%) E
Musculoskeletal Muscle weakness (9%) E
Nervous System Headache (<5%) E
Neuropathy (20%) (sensory; motor and autonomic less common) E
Respiratory Bronchospasm (3%) (especially with mitomycin) I
Dyspnea (9%) E
Pneumonitis (rare) E
Urinary Hemorrhagic Cystitis (<1%) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for vinorelbine include nausea, vomiting, fatigue, constipation, injection site reaction, diarrhea, neuropathy, anorexia, mucositis, pain and alopecia.

Granulocytopenia is the major dose-limiting toxicity and results in febrile neutropenia or infections in 8-9% of patients, and is fatal in 1% of patients. It is generally reversible and is not cumulative.

Chest Pain, sometimes accompanied by changes in electrocardiograms, occurs mostly in those with a previous history of cardiovascular disease or the presence of a bulky tumour within the chest. 

Neurotoxicity is generally mild to moderate and reversible on drug discontinuation. Patients with a prior history or pre-existing neuropathy may be at risk.  Severe neurotoxicity is seen in less than 1% of patients.  Cisplatin does not appear to increase neurotoxicity observed with single agent vinorelbine.  Cases of ileus have been reported. 

 

Fatigue, usually mild or moderate, tends to increase with cumulative dosing.

 
Elevated liver enzymes were usually transient and asymptomatic. 
 

Injection site reactions, such as pain, erythema, or vein discolouration are common, but severe in only 2% of patients. Long infusion times (i.e. more than 20 minutes) may increase the risk of phlebitis and injection site reactions.  One study has shown that the incidence of phlebitis can be reduced by infusing dexamethasone IV immediately following the administration of vinorelbine.

 
Back pain has been reported if infusion duration of vinorelbine is too short (i.e. less than 6 minutes).
 

Acute shortness of breath and severe bronchospasm have been reported, more commonly when vinorelbine or other vinca alkaloids are combined with mitomycin, and may be acute or subacute.  Aggressive treatment of symptoms with bronchodilators, steroids and /or oxygen may be required, especially in patients with pre-existing pulmonary dysfunction.  

 
E - Dosing

Refer to protocol by which patient is being treated.



Adults:

Intravenous:

  • Continuous:  30 mg/m2 given weekly
  • Q 3 weekly:  30 mg/m2 given on days 1 and 8
  • Q 4 weekly:  30 mg/m2 given on days 1, 8 and 15
 
 
 
 

Dosage with Toxicity:

Worst toxicity in previous cycle

Dose (% previous dose)

Febrile neutropenia

Thrombocytopenic bleeding

ANC < 0.5 and/or grade 4 thrombocytopenia for ≥ 5 to 7 days

Grade 2 peripheral neuropathy
Discontinue
Grade 3 peripheral neuropathy
Discontinue

Grade 3 related organ/ non-hematological toxicity

75 %*

Grade 4 related organ/ non-hematological toxicity, OR delay > 3 weeks

Discontinue

*Do not start new cycle until platelets ≥ 100 x 109/L, neutrophils ≥ 1.5 x 109/L, hemoglobin > 80 g/L and major toxicity has recovered to ≤ grade 2 (may consider administering if neutrophils 1-1.5 x 109/L at 50% of planned dose).

 

Dose on Day 8, 15 of cycle

Toxicity on Day 8, 15 of cycle

 

Non–hematologic 
(related organ)

 

Hematologic

Day 8 (or 15)
(% day 1 dose)

ANC 
(x 109/L)

 

Platelets 
(x 109/L)

≤ grade 2

and

≥ 1.5

and

≥ 100

100%

≤ grade 2

and

1-1.49

and/or

≥ 100

50%

Grade 3 or 4 related organ

or

< 1

or

<100

Omit



Dosage with Hepatic Impairment:

As vinorelbine undergoes hepatobiliary metabolism and excretion, administer with caution in hepatic insufficiency. Consider adjusting doses with hyperbilirubinemia.
       

(Continued on next page)

Suggested adjustments for increases in total bilirubin:

Total Bilirubin (micromol/L)

% Usual dose

< 1.5 x ULN

100%

1.5 to 2 x ULN

50%

> 2 x ULN

25%

 



Dosage with Renal Impairment:

No adjustment required



Dosage in the elderly:

No dosage adjustments are required for increased age



Children:

Safety and efficacy not established



 
F - Administration Guidelines

FOR INTRAVENOUS USE ONLY.

Intrathecal administration of other vinca alkaloids has resulted in death. Syringes containing this product should be labeled “WARNING – FOR INTRAVENOUS USE ONLY. FATAL if given intrathecally.”  

  • Mix in 50mL minibag (D5W, NS) to a final concentration 0.5 - 2mg/mL; infuse over 6-10 minutes through free-flowing IV.
  • Or may push (at final concentration of 1.5 – 3mg/mL) through sidearm of free-flowing IV (D5W, NS); inject over 6-10 minutes. 
  • After administration is completed, the manufacturer recommends flushing IV line with at least 75 to 125mL of D5W or NS.
  • Flushing the line before and after administration of vinorelbine may reduce injection site reactions and phlebitis risk.
  • Discontinue the injection if extravasation occurs and the remaining dose should be given into another vein.  Warm compresses applied for 15 to 20 minutes 4 times per day for 1-2 days and elevation of affected area for 2-3 days may help disperse the drug and minimize discomfort.
  • Refrigerate unopened vials (2-8°C); protect from light and do not freeze.


 
G - Special Precautions
Contraindications:

  • Patients with known hypersensitivity to vinorelbine
  • Patients who have drug-induced severe myelosuppression
  • Intrathecal administration is absolutely contraindicated

Other Warnings/Precautions:

  • Use with extreme caution in patients with compromised marrow reserve
  • May result in radiosensitizing effects with prior or concomitant radiation therapy
  • Patients with pre-existing neuropathy or prior treatment with other neurotoxic drugs may have increased potential for neurotoxicity


Other Drug Properties:

  • Carcinogenicity: Unknown

Pregnancy and Lactation:
  • Mutagenicity: Yes
  • Embryotoxicity: Yes
  • Fetotoxicity: Yes

    Vinorelbine is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.

  • Excretion into breast milk: Probable

    Breastfeeding is not recommended.

  • Fertility effects: Probable
 
H - Interactions

AGENT EFFECT MECHANISM MANAGEMENT
Mitomycin Acute bronchospasm has occurred minutes to hours after administration. Reaction may occur up to 2 weeks after mitomycin. Unknown Avoid combination.
Paclitaxel /other neurotoxic / ototoxic compounds Neuropathy Additive spindle toxicity (speculated) Monitor closely, consider dose adjustment
Cisplatin ↑ ototoxicity / vestibular effects and myelosuppression Additive effects Monitor closely
CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) ↑ neurotoxicity and other toxicity inhibits vinorelbine metabolism use with caution; consider vinorelbine dose adjustment when used with azole antifungals
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline and at each dose

Liver function tests

Baseline and before each cycle

Clinical toxicity assessment for signs of neurotoxicity, local toxicity, bleeding, infection, hypersensitivity, thromboembolism, lung or GI toxicity, radiation recall

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



Suggested Clinical Monitoring

Monitor Type Monitor Frequency

Local site toxicity ratings, if incidence of phlebitis

At each visit
 
J - Supplementary Public Funding

New Drug Funding Program (

NDFP Website

)
  • Vinorelbine - Non-Small Cell Lung Cancer (NSCLC)
  • Vinorelbine - Adjuvant Treatment of Completely Resected Stage II or IIIa Non-Small Cell Lung Cancer
  • Vinorelbine - Metastatic Breast Cancer

 
K - References

Floyd J, Mirza I, Sachs B, et al. Hepatotoxicity of Chemotherapy. Semin Oncol 2006;33:50-67.

Ginopoulous P, Matronikolis NS, Karana A et .al: Use of dexamethasone in the management of phlebitis caused by intravenous of vinorelbine (Navelbine). Medical Science Research 1998;26:397-8.

Gregory RK, Smith IE. Vinorelbine – a clinical review. British J Cancer 2000;82(12):1907-13.

Marty M, Fumoleau P, Adenis A, et al. Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors. Annals of Oncology 2001;12:1643-9.

McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1269-75.

Mouchard-Delmas C, Gourdier B, Vistelle R, et al. Modification of the blood-brain barrier permeability by vinorelbine: effect of intracarotid infusion compared with intravenous infusion. Anticancer Drugs 1996;7(2):213-9.

Product Monograph: Navelbine® (vinorelbine). Pierre Fabre Pharma Canada, Inc., December 19, 2005.

Product Monograph: Vinorelbine Injection. Pharmaceutical Partners of Canada Inc., March 12, 2015.

Superfin D, Iannucci AA, Davies AM.  Commentary: Oncologic drugs in patients with organ dysfunction: a summary. Oncologist 2007;12(9):1070-83.


 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

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