Revised: 01 Mar 2008
SYNONYM(S): VBL,1 Vincaleukoblastine Sulfate,2 VLB2
COMMON TRADE NAME(S): Vinblastine Sulfate Injection
CLASSIFICATION: mitotic inhibitor,1 cytotoxic3
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
MECHANISM OF ACTION:
Vinblastine is the salt of a naturally-occurring vinca alkaloid obtained from the flowering herb periwinkle.1,2 Vinca alkaloids act by preventing the polymerization of tubulin to form microtubules, as well as inducing depolymerization of formed tubules.1 Vinblastine may also interfere with nucleic acid and protein synthesis by blocking glutamic acid utilization.1,2,4 Vinca alkaloids are cell cycle phase-specific for M phase and S phase.4,5 Vinblastine exerts some immunosuppressive activity.1,2,5 Cross-resistance with vincristine has been reported.1
PHARMACOKINETICS:
|
Oral Absorption |
not given orally due to incomplete and variable absorption |
|
Distribution |
extensive binding to tissue and formed peripheral blood elements6 |
|
cross blood brain barrier? |
poorly; not in therapeutic concentrations |
|
volume of distribution4 |
27.3 L/kg |
|
plasma protein binding4 |
99% |
|
Metabolism |
primarily hepatic, involves the CYP3A hepatic enzyme system2 |
|
active metabolite |
desacetylvinblastine |
|
inactive metabolite(s)5 |
yes |
|
Excretion |
primarily bilary/fecal, some renal excretion7 |
|
urine4 |
yes, <1% as unchanged drug |
|
feces4 |
95%, via bile2 |
|
terminal half life7 |
25 h |
|
clearance6 |
0.74 L/hr/kg |
Adapted from standard reference1 unless specified otherwise.
USES:
|
Primary uses: |
Other uses: |
|
Fibromatosis8 |
Bladder cancer2 |
|
Germ cell tumour2,9 |
*Breast cancer |
|
*Kaposi’s sarcoma |
*Choriocarcinoma |
|
Lung cancer, non-small cell2,10 |
*Histiocytosis X |
|
*Lymphoma, Hodgkin’s |
Melanoma2 |
|
*Lymphoma, non-Hodgkin’s |
|
|
*Mycosis fungoides |
|
|
*Testicular cancer |
|
|
Ureter, transitional cell cancer11,12 |
|
*Health Canada approved indication
SPECIAL PRECAUTIONS:
Inadvertent administration of vinblastine by the intrathecal (IT) route is nearly always fatal and is a medical emergency.2 All vinblastine doses dispensed should be labelled with an auxiliary label and a medication label, both stating “WARNING: FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES”.13
Use with caution in patients with preexisting pulmonary dysfunction, ischemic cardiovascular disease, and in patients receiving other potentially ototoxic medications such as platinum-containing antineoplastics.2,5
Elderly patients with cachexia or skin ulcers may develop a more profound leukopenia; avoid vinblastine use.1
Carcinogenicity: Vinblastine is potentially carcinogenic.5,6
Mutagenicity: Vinblastine is potentially mutagenic5; vinblastine is not mutagenic in Ames test.6 No information found regarding clastogenicity in mammalian in vitro and in vivo chromosome tests.
Fertility: Aspermia has been reported.1 Animal studies have demonstrated degenerative changes in germ cells.1 In humans, vinblastine-related oligospermia is typically temporary (6-24 months); recovery of normal spermatogenesis can be expected.14
Pregnancy: FDA Pregnancy Category D.4 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Use of vinblastine for selected patients with coincident Hodgkin’s lymphoma and pregnancy has been reported without evidence of fetal toxicity.14
Breastfeeding is not recommended due to the potential secretion into breast milk.2,4
SIDE EFFECTS:
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.14,15 When placebo-controlled trials are available, adverse events are included if the incidence is >5% higher in the treatment group.
ORGAN SITE |
SIDE EFFECT |
|
Clinically important side effects are in bold, italics |
|
auditory/hearing |
hearing impairment; related to eighth cranial nerve damage, may be partial or total, temporary or permanent2; see paragraph following the Side Effects table |
|
blood/bone marrow/
febrile neutropenia |
myelosuppression (>10%)5 |
|
anemia2; typically not significant |
|
leukopenia; dose-related, nadir days 4-10 with recovery within another 7-14 days, with high-dose therapy recovery may take >21 days 2 |
|
thrombocytopenia (1-5%)7; typically mild and transient, but significant platelet count depression may occur in patients who have bone marrow infiltrated with disease or who have received prior radiation therapy or chemotherapy |
|
cardiovascular (general) |
angina pectoris,2 myocardial infarction,2 coronary ischemia2 |
|
hypertension (1-10%)4,5 |
|
constitutional symptoms |
fatigue (1-10%)5 |
|
fever2 |
|
dermatology/skin |
extravasation hazard: vesicant16 |
|
alopecia2 (>10%)4,5; including loss of body hair; typically incomplete, re-growth may occur during treatment |
|
photosensitivity2 (1-10%)4,5 |
|
rash/dermatitis (1-10%)4,5 |
|
endocrine |
SIADH4 (<1%)5; typically with high-dose17,18 |
|
gastrointestinal |
emetogenic potential: rare19 |
|
anorexia |
|
constipation (1-10%)4; related to autonomic neuropathy,5,20 see paragraph following the Side Effects table |
|
diarrhea (1-10%)5 |
|
ileus (1-10%)4,5; related to autonomic neuropathy,20 see paragraph following the Side Effects table |
|
mucositis (1-10%)4 |
|
nausea and vomiting (1-10%)4; typically mild,4 usually lasts2 < 24 h |
|
hemorrhage |
bleeding from old rectal ulcers2 |
|
hemorrhagic enterocolitis (<1%)4,5 |
|
rectal bleeding (<1%)5,7 |
|
metabolic/laboratory |
hyperuricemia2 (1-10%)4,5 |
|
musculoskeletal |
cramps14 |
|
weakness |
|
neurology |
depression (1-10%)4,5 |
|
paresthesias (20%),21 neurotoxicity (<1%);4 see paragraph following the Side Effects table |
|
pain |
abdominal pain (1-10%)4; related to autonomic neuropathy20 |
|
face, jaw and/or parotid gland pain; see paragraph following the Side Effects table |
|
headache (1-10%)4,5 |
|
muscle pain |
|
pain at the tumour site (1-5%)7; immediate or delayed, may be severe |
|
pulmonary |
acute shortness of breath and bronchospasm (1-10%)5; see paragraph following the Side Effects table |
|
renal/genitourinary |
urinary retention4 (1-10%)4,5; related to autonomic neuropathy,5 see paragraph following the Side Effects table |
|
sexual/reproductive function |
aspermia, oligospermia14; reversible, typical duration 6-24 months14 |
|
syndromes |
tumour lysis syndrome2 |
|
vascular |
Raynaud’s phenomenon (1-10%)4,5; reported in patients receiving vinblastine and bleomycin +/- cisplatin2 |
Adapted from standard reference1 unless specified otherwise.
Neurotoxicity (<1%)4 The vinca alkaloids can cause central and peripheral, including autonomic, neurotoxicity. Risk of neurotoxicity may be increased with high-dose or prolonged therapy.2,5,21 Neurotoxicity may occur days to weeks after starting treatment,5 with recovery typically occurring weeks to months after stopping therapy.22 Neurologic effects are typically much less common and severe than with vincristine.2,5,6,21 Mild paresthesia (20%)21 is the most frequently reported neurologic toxicity and is usually reversible on discontinuation of vinblastine. Other neurologic toxicities may include numbness, neuritis, muscle cramps,14 loss of deep tendon reflexes, headache, malaise, weakness, dizziness, seizures, depression, psychoses, severe face and jaw pain, severe immediate or delayed pain at the tumour site, bone pain, vocal cord paralysis, ocular toxicities including ptosis, and dysfunction of the autonomic system.1,2,22 High doses (>20 mg) can cause autonomic neuropathy including urinary retention, orthostatic hypotension, and constipation.5 Patients receiving vinblastine should receive opioid analgesics with caution due to the risk of additive autonomic neuropathy which may result in severe constipation.14 An appropriate bowel routine to prevent or treat constipation should be initiated prior to starting vinblastine treatment.15
Severe jaw or parotid gland pain can occur within a few hours of the first dose of vinblastine. This is not an indication to stop treatment or modify the dose; treat with analgesics.5
Ototoxicity due to eighth cranial nerve damage manifests as dizziness, nystagmus, vertigo, and hearing impairment. Hearing impairment may be partial or total, temporary or permanent.2 Use vinblastine with caution in patients receiving other potentially ototoxic medications such as platinum-containing antineoplastics.2,5
Acute shortness of breath and bronchospasm (1-10%)5 has occurred with vinca alkaloids and is more frequent with concomitant mitomycin.2,5 Symptoms may occur minutes to hours after vinblastine injection2,5 or up to 2 weeks after a mitomycin dose.2 Symptoms may be characterized by cough, dyspnea, hypoxemia, and interstitial infiltration.17 Aggressive treatment may be required.2,5 Progressive dyspnea has occurred; do not readminister vinblastine.2,5 Patients with preexisting pulmonary dysfunction may have increased risk of respiratory toxicity with vinblastine.5
Tumour lysis syndrome may result from cell lysis by cytotoxic chemotherapy and may lead to electrolyte disturbances or acute renal failure.23 It is most likely with highly proliferative tumours of massive burden, such as leukemias, high-grade lymphomas, and myeloproliferative diseases. The risk may be increased in patients with preexisting renal dysfunction, especially ureteral obstruction. Suggested prophylactic measures for high-risk patients24:
- aggressive hydration
- allopurinol
- if possible, discontinuation of drugs that cause hyperuricemia (e.g., thiazide diuretics) or acidic urine (e.g., salicylates)
- monitoring of electrolytes, calcium, phosphate, renal function, LDH, and uric acid
- electrolyte replacement as required
- alkalinization of urine, if the uric acid level is elevated, use sodium bicarbonate IV or PO titrated to maintain urine pH > 7
INTERACTIONS:
AGENT |
EFFECT |
MECHANISM |
MANAGEMENT |
|
azole antifungal agents 2,25 (e.g., itraconozole, ketoconazole, voriconazole) |
increased toxic effect of vinblastine
|
possible inhibition of vinblastine metabolism (CYP 3A4) |
avoid combination; if used concomitantly, decrease dose of vinblastine and monitor for toxicity |
|
carbamazepine25
|
decreased therapeutic effect of vinblastine |
possible increase in vinblastine metabolism (CYP 3A4) |
avoid combination if possible |
|
erythromycin2,25
|
increased toxic effect of vinblastine
|
possible inhibition of vinblastine metabolism (CYP 3A4) |
avoid combination; if used concomitantly decrease dose of vinblastine and monitor for toxicity |
|
mitomycin2,5 |
acute shortness of breath and severe bronchospasm have occurred following use of vinblastine in patients who had received mitomycin simultaneously or within 2 weeks |
unknown |
avoid combination if possible; use with caution |
|
phenytoin25
|
decreased therapeutic effect of phenytoin |
decreased absorption and/or increased metabolism of phenytoin |
monitor phenytoin serum levels |
Vinblastine is a potent CYP 3A4 inhibitor; therefore, vinblastine may increase the levels/effects of drugs or herbs that are CYP3A4 substrates.2
Vinblastine is a major CYP3A4 substrate; therefore, drugs or herbs that are CYP3A4 inducers may decrease the levels/effects of vinblastine. Likewise, drugs or herbs that are CYP3A4 inhibitors may increase the levels/effects of vinblastine.2
SUPPLY AND STORAGE:
Injection: Mayne Pharma (Canada) Inc, supplies vinblastine as single use 10 mg/10 mL vials. Store in the refrigerator and protect from light.1
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
SOLUTION PREPARATION AND COMPATIBILITY:
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
Compatibility: consult detailed reference
PARENTERAL ADMINISTRATION:
|
BCCA administration guideline noted in bold, italics |
|
Subcutaneous |
not used due to corrosive nature2,5 |
|
Intramuscular |
not used due to corrosive nature5 |
|
Direct intravenous1 |
preferred method due to need for frequent monitoring for signs of extravasation, directly into a vein or into tubing of running IV over >1 minute; see Prevention and Management of Extravasation of Chemotherapy |
|
*Intermittent infusion |
over 5-15 minutes4,20 Infusions over >30-60 minutes are not recommended due to corrosive nature2; however, infusions of 3-8 h have been used.2 |
|
*Continuous infusion |
not recommended due to corrosive nature2; has been used4,6,20 |
|
Intraperitoneal |
not used due to corrosive nature26 |
|
Intrapleural |
not used due to corrosive nature26 |
|
Intrathecal |
ABSOLUTELY CONTRAINDICATED; INTRATHECAL INJECTION CAN BE FATAL1 |
|
Intra-arterial |
investigational, has been used27 |
|
Intravesical |
no information found |
|
Intralesional |
investigational, has been used17,28 |
DOSAGE GUIDELINES:
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults:
|
|
|
BCCA usual dose noted in bold, italics |
|
|
Cycle Length: |
|
|
*Intravenous: |
1-4 weeks1,8,29: |
6 mg/m2 (range 3.7-18.5 mg/m2) IV for one dose on day 1
(total dose per cycle 6 mg/m2 [range 3.7-18.5 mg/m2])
|
|
|
2 weeks30: |
6-10 mg IV for one dose on day 1
(total dose per cycle 6-10 mg)
|
|
|
3 weeks9: |
0.11 mg/kg IV once daily for 2 consecutive days starting on day 1
(total dose per cycle 0.22 mg/kg)
|
|
|
4 weeks31: |
6 mg/m2 IV for one dose on days 1 and 15
(total dose per cycle 12 mg/m2)
|
|
|
4 weeks11: |
4 mg/m2 IV for one dose on days 1 and 8
(total dose per cycle 8 mg/m2)
|
|
|
4 weeks12: |
3 mg/m2 IV for one dose on days 2, 15, and 22
(total dose per cycle 9 mg/m2)
|
|
|
n/a10: |
5 mg/m2 IV for one dose on days 1, 8, 15, 22, and 29
(total dose 25 mg/m2)
|
|
*maximum weekly dose2: 18.5 mg/m2 |
|
|
|
|
|
Concurrent radiation: |
investigational, has been used32 |
|
Dosage in myelosuppression: |
modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression" |
|
|
|
|
|
Dosage in renal failure: |
no adjustment required17,33 |
|
|
|
|
|
Dosage in hepatic failure5: |
adjustment required; suggested dose adjustment: |
|
Serum bilirubin (micromol/L) |
Dose |
|
25-50 |
50% |
|
>50 |
25% |
|
|
|
|
|
|
Dosage in dialysis: |
not removed by hemodialysis4 |
|
|
|
|
Children:
|
|
Cycle Length: |
|
†Intravenous: |
1-2 weeks1,34,35: |
2.5-6 mg/m2 (range 2.5-12.5 mg/m2) IV for one dose on day 1
(total dose per cycle 2.5-6 mg/m2 [range 2.5-12.5 mg/m2])
|
|
|
7-10 days34: |
0.4 mg/kg IV for one dose on day 1
(total dose per cycle 0.4 mg/kg)
|
|
|
3 weeks34: |
0.2 mg/kg IV once daily for 2 consecutive days starting on day 1
(total dose per cycle 0.2 mg/kg)
|
|
†maximum weekly dose34: 12.5 mg/m2 |
References:
1. Mayne Pharma (Canada) Inc. Vinblastine sulfate injection product monograph. Montreal, Quebec; 10 August 2003.
2. McEvoy GK, editor. AHFS 2007 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc. p. 1225-8.
3. National Institute for Occupational Safety and Health (NIOSH). Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. Cincinnati, Ohio: NIOSH - Publications Dissemination; September 2004. p. 31-40.
4. Anonymous. Vinblastine. In: Rose BD, editor. UpToDate. Waltham, Massachusetts: UpToDate 15.1; 2007.
5. Repchinsky C, editor. Vinblastine, CPhA monograph, Compendium of Pharmaceuticals and Specialties. Ottawa, Ontario: Canadian Pharmacists Association; 2006.
6. Chabner BA, Longo DL. Cancer Chemotherapy and Biotherapy. 4th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2006. p. 240-53.
7. USPDI® Drug Information for the Health Care Professional (database on the Internet). Vinblastine (Systemic). Thompson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 18 May 2007.
8. BC Cancer Agency Sarcoma Tumour Group. (SAMV) BCCA Protocol Summary for Palliative Therapy for Aggressive Fibromatosis Using Weekly or Alternate Week Methotrexate and Vinblastine Intravenously. Vancouver, British Columbia: BC Cancer Agency; 1 April 2007.
9. BC Cancer Agency Genitourinary Tumour Group. (GUVEIP) BCCA Protocol Summary for Consolidation/Salvage Treatment for Germ Cell Cancer Using Vinblastine, Cisplatin, Ifosfamide and Mesna. Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
10. BC Cancer Agency Lung Tumour Group. (LUCMT-1) BCCA Protocol Summary for Combined Chemotherapy and Radiation Treatment for Stage 3 Non-Small Cell Lung Cancer. Vancouver, British Columbia: BC Cancer Agency; 1 January 2005.
11. BC Cancer Agency Genitourinary Tumour Group. (GUBCV) BCCA Protocol Summary for Therapy for Transitional Cell Cancers Using Carboplatin-Vinblastine. Vancouver, British Columbia: BC Cancer Agency; 16 January 2007.
12. BC Cancer Agency Genitourinary Tumour Group. (GUMVAC) BCCA Protocol Summary for Therapy for Transitional Cell Cancer of the Urothelium using Methotrexate, Vinblastine, Doxorubicin, and Cisplatin. Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
13. BCCA Provincial Systemic Therapy Program. Policy V-40: Labeling of Vinca Alkaloid Preparations. Vancouver, British Columbia: BC Cancer Agency; 1 February 2008.
14. Joseph Connors, MD. BC Cancer Agency Lymphoma Tumour Group. Personal communication. Vancouver, British Columbia;28 June 2007.
15. Nevin Murray, MD. BC Cancer Agency Genitourinary Tumour Group. Personal communication. Vancouver, British Columbia;20 July 2007.
16. B.C. Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and management of extravasation of chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 September 2006.
17. DRUGDEX® Evaluations (database on the Internet). Vinblastine. Thomson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 18 May 2007.
18. MARTINDALE- The Complete Drug Reference (database on the Internet). Vinblastine Sulfate. Thomson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 18 May 2007.
19. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005.
20. Solimando DA, Jr. Cancer chemotherapy update: Updates of vinblastine and vincristine. Hosp Pharm 1997;32(4):475-82.
21. Wen PW, Plotkin SR. Neurologic complications of cancer chemotherapy. In: Rose BD, editor. UpToDate®. Waltham, Massachusetts: UpToDate 15.1; 8 December 2006.
22. Parentin F, Liberali T, Perissutti P, et al. Unilateral palpebral ptosis associated with vinblastine therapy. Neuro-ophthalmol 2005;29(3):133-5.
23. DeVita VT, Hellman S, Rosenberg SA. Cancer Principles & Practice of Oncology. 6th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2001. p. 2640.
24. Leukemia/Bone Marrow Transplant Program of British Columbia. Leukemia/BMT Manual. 4th ed. Vancouver, British Columbia: Vancouver Hospital and Health Sciences Centre / BC Cancer Agency; 2003. p. 27.
25. Drug Interaction Facts (database on the Internet). Vinblastine. Facts and Comparisons 4.0, 2007. Available from http://online.factsandcomparisons.com. Accessed 18 May 2007.
26. Trissel L. Handbook on injectable drugs. 13th ed. Bethesda, Maryland: American Society of Health-System Pharmacists; 2005. p. 1469-74.
27. Melichar B, Dvorak J, Jandik P, et al. Intraarterial chemotherapy of malignant melanoma metastatic to the liver. Hepatogastroenterology 2001;48(42):1711-5.
28. Dezube BJ, Groopman JE. AIDS-related Kaposi's sarcoma: Clinical features and treatment. In: Rose BD, editor. UpToDate®. Waltham, Massachusetts: UpToDate 15.1; 8 January 2007.
29. BC Cancer Agency Lymphoma Tumour Group. (LYPALL) BCCA Protocol Summary for Lymphoma Palliative Chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
30. BC Cancer Agency Kaposi's Sarcoma Tumour Group. (KSVB) BCCA Protocol Summary for Palliative Treatment for Kaposi's Sarcoma using Vinblastine Alternating with Vincristine. Vancouver, British Columbia: BC Cancer Agency; 1 September 2002.
31. B.C. Cancer Agency Lymphoma Tumour Group. (LYABVD) BCCA Protocol Summary for Treatment of Hodgkin's Disaese with Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine. Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
32. Kragelj B, Jereb B, Kragelj L, et al. Concurrent vinblastine and radiation therapy in bladder cancer. Cancer 1992;70(12):2885-90.
33. Aronoff GR, Berns JS, Brier ME, et al. Drug Prescribing in Renal Failure: Dosing guidelines for adults. 4th ed. Philadelphia, Pennsylvania: American College of Physicians; 1999. p. 74.
34. Anonymous. Vinblastine: pediatric drug information. In: Rose BD, editor. UpToDate. Waltham, Massachusetts: UpToDate 15.1; 2007.
35. Pizzo P, Poplack D. Principles and Practice of Pediatric Oncology. 5th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2006. p. 302.