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A - Drug Name

vinBLAStine

 
B - Mechanism of Action and Pharmacokinetics

Similar to other vinca alkaloids, vinblastine binds to the microtubular proteins of the mitotic spindle, leading to depolymerization of the microtubule and mitotic arrest at metaphase or cell death.  It also has complex effects on nucleic acid and protein synthesis in high concentrations.  Vinblastine has some immunosuppressant effects. The vinca alkaloids are considered to be cell cycle phase-specific (M and S phases).



Distribution

Rapid and extensive binding to tissues and to formed elements of peripheral blood.  Distributes to the liver.

PPB 99%
Cross blood brain barrier? poorly
Metabolism

Extensively metabolized in the liver

Active metabolites

Yes

Inactive metabolites Yes
Elimination

Slowly excreted in urine and feces (via bile).

Urine < 1% unchanged
Feces 95%
Half-life 25 hours (terminal)
 
C - Indications and Status
Health Canada Approvals:

  • Frequently responsive:
    • Hodgkin disease
    • Lymphocytic lymphoma
    • Histolytic lymphoma
    • Mycosis fungoides
    • Testicular cancer
    • Kaposi's sarcoma
    • Letterer-Siwe disease (histiocytosis-X)
  • Less frequently responsive:
    • Choriocarcinoma resistant to other chemotherapy
    • Breast cancer (unresponsive to endocrine surgery and hormonal therapy)


Other Uses:

  • Bladder cancer
  • Non-small cell lung cancer
  • Desmoid tumour
  • CNS cancer 
 
D - Adverse Effects

Emetogenic Potential:  

Minimal

Extravasation Potential:   Vesicant

The incidences for the adverse effects are based on product monographs where available.  Adverse events from other trial data or severe / post-marketing events may also be included.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Auditory Hearing impaired (rare) E
Cardiovascular Arterial thromboembolism (in combination with cisplatin and bleomycin) E
ECG changes (transient; rare) E
Hypertension (≤10%) I  E
Dermatological Alopecia (>10%) (usually incomplete; re-growth in some cases while on treatment) E
Photosensitivity (≤10%) E
Rash (≤10%) E
Gastrointestinal Abdominal pain (>10%) E
Anorexia (>10%) E
Constipation (>10%) (may be severe) E
Diarrhea (≤10%) E
Mucositis (>10%) E
Nausea, vomiting (>10%) I
General Fatigue (≤10%) E
Pain (in tumour-containing tissue, rare) I
Hematological Immunosuppression E
Myelosuppression ± infection, bleeding (>10%) E
Hypersensitivity Hypersensitivity (rare) I
Injection site Phlebitis (≤10%) I  E
Metabolic / Endocrine Hyperuricemia (≤10%) (during periods of active cell lysis) I
SIADH (rare) E
Musculoskeletal Musculoskeletal pain (≤10%) (including jaw pain, may be severe) E
Nervous System Depression (≤10%) E
Dysgeusia (>10%) E
Headache (≤10%) E
Paresthesia (20%) (autonomic, loss of deep tendon reflex, cranial neuropathy - rare) E
Seizure (≤10%) E
Respiratory Bronchospasm / pneumonitis (or shortness of breath, especially in combination with mitomycin; ≤10%) I
Vascular Peripheral ischemia (≤10%) (Raynauds; in combination with cisplatin and bleomycin) D


* "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)

Myelosuppression and neurotoxicity are the main dose-limiting effects of vinblastine.

Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g. some leukemias and lymphomas), can be minimized with allopurinol and hydration.  In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.

Neurotoxicity with the vinca alkaloids is qualitatively similar but quantitatively different (vincristine> vinblastine>vinorelbine). Symptoms tend to be worse with prolonged exposure. Neurotoxicity may manifest as numbness, paresthesia, mental depression, loss of deep tendon reflex, headache, malaise, dizziness, seizures or psychosis. Cranial nerve neuropathy may lead to vocal cord paresis or paralysis, oculomotor nerve dysfunction, hearing impairment and facial nerve palsies.  Vocal cord effects or facial nerve palsies tend to be bilateral and reversible when treatment with vinblastine is discontinued.  High doses (> 20 mg) may be associated with autonomic neuropathy, which manifests as constipation, abdominal pain, urinary retention and paralytic ileus. 

Severe jaw pain or parotid gland pain can occur within a few hours of the first dose of vinblastine. This is not an indication to stop or modify the dose; treat with analgesics.

 
E - Dosing

Refer to protocol by which patient is being treated. 

Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy. Do not re-treat with vinblastine until marrow recovery has occurred.

 



Adults:

Intravenous: 6 mg/m² Every 1 week
(range 3.7-18.5 mg/m2; usual weekly dose: 5.5 – 7.4 mg/m2; maximum weekly dose: 18.5 mg/m2)
Intravenous: 6 mg/m² on days 1 and 15; every 4 weeks (ABVD)

Intravenous: 0.11 mg/kg days 1 and 2; every 3 weeks (VEIP)

Intravenous: 3 mg/m² day 2 Every 14 days (MVAC(HD))

Dosage with Toxicity:

Modify according to protocol by which patient is being treated.

Suggested:

Worst Toxicity / Counts in Previous Cycle (x 109/L)
Dose (% previous dose)*

Febrile neutropenia, grade 4 ANC for ≥ 5-7 days or thrombocytopenic bleeding

Grade 3  related organ / non-hematologic
Hold, then 75%*

Grade 4  related organ / non-hematologic

Discontinue

*Do not retreat until ANC ≥ 1-1.5 x 109L, platelets ≥ 100 x 109L and toxicity ≤ grade 2



Dosage with Hepatic Impairment:

Bilirubin %  Usual dose
>1 - 2.5 x ULN 50%
> 2.5 x ULN 25%


Dosage with Renal Impairment:

No adjustment required.



Dosage in the elderly:

Toxicity may be increased; used with caution.



Children:

Refer to protocol being used.



 
F - Administration Guidelines

FOR INTRAVENOUS USE ONLY.
Intrathecal administration of other vinca alkaloids has resulted in death. Containers with this product should be labelled:
WARNING – FOR INTRAVENOUS USE ONLY.  FATAL if given intrathecally.



  • Direct IV push is not recommended to reduce the risk of inadvertently administering vinca alkaloids via intrathecal route.
  • Mix in 50 mL minibag (NS or D5W).
  • Dilutions in large volumes (≥ 100mL) and infusions over ≥30-60 minutes are not recommended, since these can increase the risk of vein irritation and extravasation.
  • If any signs or symptoms of extravasation occur, the injection or infusion should be immediately terminated and restarted in another vein. Any known or suspected extravasation should be managed promptly according to local guidelines.
  • Store unopened vials at 2 to 8ºC; protect from light.
 
G - Special Precautions
Contraindications:

  • Patients who have hypersensitivity to vinblastine or its formulation
  • Patients with severe myelosuppression or infection
  • Intrathecal vinblastine administration is absolutely contraindicated.

Other Warnings/Precautions:

  • Myelosuppressive effects are more marked in patients with bone marrow infiltration, cachexia or skin ulcers
  • Use with caution in hepatic impairment due to an increased risk of neurotoxicity.
  • Use with caution in patients with ischemic heart disease and in combination with neurotoxic drugs.
  • Do not give vinblastine more frequently than once every 7 days.
  • Standard doses of vinblastine given for prolonged periods (e.g. daily for 7 days) may result in permanent or fatal neurologic toxicity and should not be used.


Other Drug Properties:

  • Carcinogenicity: Yes

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

    Vinblastine is contraindicated in pregnancy. Adequate contraception should be used by both sexes during vinblastine treatment and for at least 6 months after the last dose (general recommendation).

  • Breastfeeding:

    Breast feeding is not recommended due to the potential secretion of vinblastine into breast milk.

  • Fertility effects: Yes

    Aspermia and amenorrhea have been reported. Recovery of menses is variable.

 
H - Interactions

Vinblastine is metabolized by CYP3A4 and is a potent CYP3A4 inhibitor.

AGENT EFFECT MECHANISM MANAGEMENT
Mitomycin Acute bronchospasm has occurred minutes to hours after administration. Reaction may occur up to 2 weeks after mitomycin. Unknown Caution; discontinue vinblastine if this occurs
Phenytoin ↓ serum concentration of phenytoin Possibly ↓ absorption or increased metabolism of phenytoin Monitor serum levels of phenytoin and adjust dose as needed
CYP3A4 inhibitors (i.e. ketoconazole, voriconazole, clarithromycin, erythromycin, ritonavir, fruit or juice from grapefruit, Seville oranges, starfruit or pomegranate ) ↑ risk of neurotoxicity inhibition of vinblastine metabolism Avoid concomitant use
CYP3A4 substrates (i.e., aprepitant, tolterodine) ↑ toxicity of CYP3A4 substrates ↓ metabolism of CYP3A4 substrates Avoid if possible. If must use, monitor or adjust dose.
CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) ↓ vinblastine effect ↑ metabolism of vinblastine Caution
Bleomycin +/- cisplatin Raynaud's phenomenon, nephrotoxicity, neurotoxicity, MI, CVA reported Unknown Caution
Ototoxic drugs (i.e., cisplatin, aminoglycosides) ↑ ototoxicity (reported with other vinca alkaloids) Additive Caution
 
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 before each dose

Liver function tests

Baseline and before each cycle

Clinical assessment for neurotoxicity, infection, bleeding, GI, local toxicity (i.e. extravasation), hypersensitivity, hyperuricemia

At each visit

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



 
K - References

Vinblastine sulfate:  ASHP's Interactive Handbook on Injectable Drugs. Accessed April 16, 2020.

Bouffet E, Jakacki R, Goldman S, et al. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol 2012; 30(12):1358-63.

CPhA Monograph:  Vinblastine.  Canadian Pharmacists Association, October 2017.

ISMP 2018-2019 Targeted Medication Safety Best Practices for Hospitals.  (From http://www.ismp.org/tools/bestpractices)

Johnson IS, Armstrong JG, Gorman M, et al.  The vinca alkaloids:  a new class of oncolytic agents. Cancer Research 1963;23:1390-427.

Lafay-Cousin L, Holm S, Qaddoumi I, et al. Weekly vinblastine in pediatric low-grade glioma patients with carboplatin allergic reaction. Cancer 2005;103:2636-42.

McEvoy GK, editor. AHFS Drug Information 2011. Bethesda: American Society of Health-System Pharmacists, p. 1263-5.

Prescribing information:  Vinblastine. Bedford Laboratories (US)., December 2001.

Product Monograph: Vinblastine. Pfizer Canada, April 2019.

Scripture CD, Figg WD. Drug interactions in cancer therapy. Nature Reviews Cancer 2006;6:546-58.

Summary of Product Characteristics:  Vinblastine.  Hospira UK Ltd., October 2018.

Vinblastine:  BC Cancer Agency Cancer Drug Manual, February 2015.

Zidan J, Robenstein W, Abzah A, et al. Treatment of Kaposi's Sarcoma with Vinblastine in Patients with Disseminated Dermal Disease. IMAJ 2001;3:251-3.

 


April 2020 Updated adverse effects, dosing, warnings/precautions, administration, interactions and monitoring sections

 
L - Disclaimer

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

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

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