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vinorelbine
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.
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% |
Largely metabolized via hepatobiliary system (P450, CYP3A4)
| Active metabolites | yes, deacetylvinorelbine |
| Inactive metabolites |
yes |
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) |
- 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
Emetogenic Potential:
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.
** 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.
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.
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.
Refer to protocol by which patient is being treated.
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
|
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 |
|
Hematologic |
Day 8 (or 15) |
||
|
ANC |
|
Platelets |
|||
|
≤ 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 |
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% |
No adjustment required
No dosage adjustments are required for increased age
Safety and efficacy not established
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.
- Patients with known hypersensitivity to vinorelbine
- Patients who have drug-induced severe myelosuppression
- Intrathecal administration is absolutely contraindicated
- 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
-
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
| 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 |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| 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
| Monitor Type | Monitor Frequency |
|---|---|
Local site toxicity ratings, if incidence of phlebitis |
At each visit |
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.
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