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vinCRIStine

( Vin-KRIST-een )
Other Name(s): Oncovin® (multiple brands available)
Appearance: clear, colourless solution; may be mixed into larger bags for injection
A - Drug Name

vinCRIStine

SYNONYM(S):   LCR; leurocristine; VCR

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

 
B - Mechanism of Action and Pharmacokinetics

The vinca alkaloids have become clinically useful since the discovery of their antitumour properties in 1959. Vincristine binds reversibly to spindle proteins in S phase. Inhibition of RNA synthesis has also been noted. Vincristine has been shown to arrest cells in metaphase.



Absorption
Not absorbed orally
Distribution

Rapid and extensive reversible tissue binding

Cross blood brain barrier? Minimal
PPB 75 %
Metabolism

Metabolized in liver by the CYP 3A4 family of P450 isoenzymes

Active metabolites no information found
Inactive metabolites no information found
Elimination

Disposition described by a three-compartment model; 30% of the dose is excreted into bile and feces.

Urine 10-20%
Half-life

T ½ α : 5 min

T ½ ß : 2.3 hours

T ½ (gamma) : 85 hours

 
C - Indications and Status
Health Canada Approvals:

  • Acute leukemias (acute lymphoblastic leukemia, acute myeloid leukemia)
  • Breast cancer
  • Sarcomas (soft tissue, bony tissue, specialized structures)
  • Hodgkin's disease
  • Non-Hodgkin's lymphoma
  • Small cell lung cancer
  • Cervical Cancer
  • Colorectal cancer
  • Wilm's tumour
  • Melanoma


Other Uses:

  • Other hematological cancers (chronic lymphocytic leukemia, myeloma)
  • Gastrointestinal cancers (gastroesophageal, hepatobiliary, pancreatic, neuroendocrine tumours)
  • Genitourinary cancers (adrenal, prostate)
  • Gynecological cancers (endometrial, ovarian, GTD)
  • Thymoma
  • Brain tumours
 
D - Adverse Effects

Emetogenic Potential:  

Minimal

Extravasation Potential:   Vesicant

 

 

ORGAN SITE SIDE EFFECT* (%) ONSET**
Auditory Hearing impaired (rare) E
Cardiovascular Hypertension (rare, autonomic) E
Hypotension (rare, autonomic) E
Dermatological Alopecia (up to 50%) E
Rash (occasional) I  E
Gastrointestinal Abdominal pain E
Anorexia, weight loss E
Constipation (neuropathy) E
Diarrhea E
GI perforation E
Mucositis E
Nausea, vomiting (mild) I
Hematological Myelosuppression (mild) E
Hypersensitivity Hypersensitivity (rare) I
Injection site Phlebitis (chemical) I  E
Metabolic / Endocrine SIADH (rare, central neurotoxicity) E
Tumor lysis syndrome I
Musculoskeletal Musculoskeletal pain (may be severe) E
Neoplastic Secondary malignancy (in combination) D
Nervous System Autonomic neuropathy (paralytic ileus) E
Cranial neuropathy (rare; diplopia, transient blindness, optic atrophy) E
Headache E
Insomnia (rare) E
Peripheral neuropathy (common) I  E  D
Seizure (rare) I
Vertigo (rare) E
Reproductive and breast disorders Infertility E
Respiratory Bronchospasm (acute, rare) I
Urinary Urinary retention (autonomic neuropathy; may be severe) 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 adverse effects are alopecia and neurotoxicity. Myelosuppression is minimal.

Hyperuricemia during periods of active cell lysis can be minimized with allopurinol and hydration. However, fluid restriction may be required for a patient showing signs of SIADH. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids.

The tissue necrosis that happens with extravasation may happen days to weeks after the treatment. Patents must be observed for delayed reactions and prior injection sites carefully inspected.
 
Neurotoxicity with the vinca alkaloids is dose-limiting, qualitatively similar but quantitatively different (vincristine >vinblastine>vinorelbine).  It is dose- and exposure-related, with increased toxicity in prolonged infusion.  Previous neurotoxicity or neurological disorders may result in decreased tolerance and increased sensitivity. Neurotoxicity is generally reversible, but recovery may be slow.
 

The most frequent manifestation of nervous system toxicity is peripheral neuropathy; the earliest indication of which is the depression of the Achilles reflex.  Later loss of other deep tendon reflexes occurs and is accompanied by peripheral paresthesias, pain and tingling. If therapy is prolonged or high doses are administered, wrist and foot drop, ataxia, a slapping gait and difficulty in walking may occur. Young children may refuse to walk due to extremity pain. 

 

Cranial nerve neuropathy may lead to vocal cord paresis or paralysis (hoarseness, weak voice), ocular motor nerve dysfunction (ptosis, strabismus), bilateral facial nerve palsies, or jaw pain. Severe jaw pain can occur within a few hours of the first dose of vincristine. Cranial nerve toxicities tend to be bilateral and reversible when treatment with vincristine is discontinued.

Autonomic neuropathy is manifested as constipation (which can be severe), abdominal pain, urinary retention and paralytic ileus.  Laxatives or stool softeners should be given routinely to prevent constipation. These symptoms resolve with time and may not occur with subsequent treatment. Urinary retention may occur in older patients with obstructive uropathy. If bladder atony occurs, vincristine should be held until symptoms resolve.

 
E - Dosing

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. SPECIAL LABELLING IS REQUIRED. (see Administration Guidelines)



Adults:

Intravenous:  1.4 mg/m2 weekly
Intravenous:  1 to 1.4 mg/m2 q2-3 weeks (maximum dose of 2 mg used in some regimens)

Dose capping
Due to concerns of neurotoxicity, the ASCO guideline recommends vincristine to be capped at a maximum dose of 2 mg when used as part of the CHOP and CVP regimens. It would be prudent to question any dose of vincristine >3 mg or more frequent administration than once a week.


Dosage with Toxicity:

Toxicity / Worst counts in cycle
Action*

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

Hold; No dose adjustment required
Neurotoxicity
  • Areflexia only
  • Abnormal buttoning, writing
  • Moderate motor neuropathy (± cranial)
  • Severe motor neuropathy
 
  • 100%
  • 67%
  • Hold until recovery then reduce dose by 50% 
  • Omit
Respiratory symptoms (e.g. bronchospasm, pneumonitis)
Discontinue
Grade 3 other related non-hematological/organ toxicity
Hold
Grade 4 other related non-hematological/organ toxicity
Discontinue

*Do not re-treat unless ANC 1.5 x 109L (or defined by protocol), platelets ≥ 100 x 109L and other toxicities have recovered to ≤ grade 2 or indicated in table above.



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:

Older patients may have more neurotoxicity.



Children:

Refer to regimen being used.  Infants are especially susceptible to neurotoxicity and doses should be based on body weight rather than surface area. Doses may be gradually increased as tolerated.  Infants are also more susceptible to ileus, SIADH and hematological toxicities from vincristine.



 
F - Administration Guidelines

FOR INTRAVENOUS USE ONLY.  Vincristine is lethal if given intrathecally. No successful antidotes have been described.  Syringes containing this product should be labelled “WARNING – FOR INTRAVENOUS USE ONLY.  FATAL if given by other routes.” 
  • Direct IV push not recommended, due to risk of inadvertent intrathecal administration.
  • For intermittent IV use, may mix in small volume minibag (ie. 50mL NS or D5W for adults).
  • Infuse IV via gravity. Infusion pumps should not be used peripherally, since they deliver infusions at higher pressures and may continue to infuse when extravasation occurs.
  • During the infusion, suggest nurse to remain present with the patient to observe the IV site for extravasation.


 
G - Special Precautions
Other:

Contraindicated in patients with the demyelinating form of Charcot-Marie-Tooth Syndrome, childhood polio or with hypersensitivity to vinca alkaloids. Intrathecal administration is absolutely contraindicated. Vincristine should not be given to patients who are receiving radiation that includes liver portals. Use with caution with other neuromuscular disorders, neurotoxic/ototoxic drugs, in leukopenia, complicating infection, or and in patients with Guillain-Barre Syndrome.

Vincristine is potentially fetotoxic, teratogenic, and potentially carcinogenic.  It should not be used in pregnancy. Adequate contraception should be used by both sexes during vincristine treatment and for at least 6 months after the last dose. Breast feeding is not recommended since it is unknown whether vincristine or its metabolites are secreted in milk.  Fertility may be affected.

 
H - Interactions

AGENT EFFECT MECHANISM MANAGEMENT
Asparaginase ↑ neuropathy; disturbances of erythropoiesis asparaginase may ↓ hepatic clearance of vincristine give vincristine 12-24 hours before asparaginase
Digoxin, ciprofloxacin ↓ effect of digoxin, ciprofloxacin ↓ absorption Caution; monitor.
Mitomycin Acute bronchopasm has reported to occur minutes to hours after administration with vinca alkaloids Unknown Caution
nifedipine ↑ half-life of vincristine possibly decreased excretion of vincristine Avoid combination; monitor closely if given concurrently
phenytoin ↓ serum concentrations of phenytoin ↓ absorption or increased metabolism monitor serum levels of phenytoin and adjust dose prn
verapamil ↑ vincristine toxicity ↓ protein binding Avoid combination; monitor closely if given concurrently
CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) ↓ vincristine effect ↑ metabolism Caution
Potent CYP 3A4 inhibitors (erythromycin, INH, itraconazole) ↑ vincristine toxicity, especially neurotoxicity ↓ metabolism Caution
Ototoxic drugs (e.g. cisplatin, aminoglycosides) ↑ ototoxicity risk Additive; hearing impairment (8th cranial nerve damage) have been described in patients receiving vinca alkaloids Use with extreme 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
Liver function tests; baseline and regular At each visit
CBC and electrolytes; baseline and regular

Clinical assessment of neurotoxicity, local toxicity, tumour lysis syndrome

At each visit

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



 
K - References

Chemotherapy FAQ:  Does ONS have recommendations regarding the administration of vincristine by minibag or IV Push?  Oncology Nursing Society.  Accessed January 30, 2009.

Eisenberg S. Prevent inadvertent administration of intrathecal vincristine. ONS Connect 2009; (Jan): 22.

Gilbar PJ, Carrington CV.  The incidence of extravasation of vinca alkaloids supplied in syringes or mini-bags. J Oncol Pharm Practice 2006; 12: 113-8.

Griggs JJ, Mangu PB, Anderson H, et al.  Appropriate chemotherapy dosing for obese adult patients with cancer:  American Society of Clinical Oncology clinical practice guideline.  April 2, 2012.

Han JY, Choi BG, Song DH, et al. Vinorelbine-associated myelopathy in a patient who previously received paclitaxel: a case report. Med Oncol. 2001; 18(1): 95-7.

McEvoy GK, editor. AHFS Drug Information 2011. Bethesda: American Society of Health-System Pharmacists, p. 1266-9.

Preventing vincristine administration errors.  The Joint Commission, Issue 34, July 14, 2005.

Product Monograph:  Vincristine Sulfate Injection.  Novopharm Limited.  March 16, 2012.

Product Monograph: Vincasar PFS® (Vincristine sulfate), Sicor Pharmaceuticals (US), 2003.

Schulmeister L.   Preventing vincristine administration errors: does evidence support minibag infusions? Clinical Journal of Oncology Nursing 2006; 10(2):271-3. 

Systemic therapy update: Vincristine prepared in minibag and administered by infusion. British Columbia Cancer Agency (BCCA), December 2007.

Vincristine Monograph. Compendium of Pharmaceuticals and Specialties. Canadian Pharmacists Association, March 2009.

World Health Organization. Information Exchange System: Alert No. 115 (QSM/MC/IEA.115). Geneva, Switzerland: World Health Organization; 18 July 2007.


November 2017 republished to enable search by "cancer type" filter

 
L - Disclaimer

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