Vindesine (Systemic)



USAN:
Vindesine
VA CLASSIFICATION
Primary: AN900

Commonly used brand name(s): Eldisine®.

Other commonly used names are
desacetyl vinblastine amide sulfate and vincaleukoblastine.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.



Category:


Antineoplastic —

Indications

Accepted

Leukemia, acute lymphocytic (treatment)—Vindesine is indicated for the treatment of acute lymphocytic leukemia of childhood that is resistant to vincristine.{01}

Carcinoma, lung, non-oat cell (treatment)—Vindesine is indicated for the treatment of non-oat cell lung cancer.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Vindesine is a vinca alkaloid.{01} It is a synthetic derivative of vinblastine.{02}
Molecular weight—
    851.9{01}

Solubility
    Vindesine is freely soluble in water and methyl alcohol and practically insoluble in cyclohexane.{02}


pH
    The pH of a 0.5% solution of vindesine is 3.5 to 5.5.{02}

Mechanism of action/Effect:

Vindesine causes the arrest of cells in metaphase mitosis.{01} It is three times more potent than vincristine and nearly 10 times more potent than vinblastine in causing mitotic arrest in in vitro studies at doses designed to arrest from 10 to 15% of the cells in mitosis.{01} Vindesine and vincristine are approximately equipotent at dose levels that arrest 40 to 50% of the cells in mitosis.{01} Unlike vinblastine, vindesine produces very few postmetaphase cells.{01} Vindesine has demonstrated activity in patients who have relapsed while receiving multiple-agent treatment that included vincristine.{01}

Distribution:

Volume of distribution (Vol D)—8 L/kg.{03}

Biotransformation:

Hepatic; extensive.{02}


Half-life:

Elimination—24 hours.{01}

Elimination:
    Biliary—Primary route of excretion.{01}{02}
    Renal—13% excreted in the urine.{04}


Precautions to Consider

Carcinogenicity/Mutagenicity

Vindesine is neither carcinogenic nor mutagenic according to standard tests that are used to determine these potentials.{01}

Pregnancy/Reproduction
Fertility—
Toxic doses of vindesine given to male and female rats have not affected fertility.{01} There is no evidence as to whether this drug may adversely affect fertility in either men or women.

Pregnancy—
Safe use of vindesine in pregnancy has not been established. Studies have not been done in humans.

Benefit-to-risk ratio must be considered before using vindesine in pregnant women.{01} It usually is recommended that use of antineoplastics, especially combination chemotherapy, be avoided during pregnancy whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.

Other hazards to the fetus include adverse reactions seen in adults.

In general, use of contraception is recommended during cytotoxic drug therapy.

Studies in rats have indicated that vindesine is embryotoxic and possibly teratogenic.{01} In rabbit studies, doses which produced maternal toxicity were embryotoxic but not teratogenic.{01}

Breast-feeding

It not known whether vindesine is distributed into breast milk.{01}

Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended during chemotherapy because of the potential risks to the infant (adverse effects, mutagenicity, carcinogenicity).

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of vindesine in children.

Vindesine doses greater than 4 mg per square meter of body surface area should only be used by physicians skilled in treating children with leukemia.{01}

It is important to strictly adhere to the recommended dosage schedule.{01} The use of small amounts of vindesine daily for long periods for the treatment of children with acute lymphocytic leukemia is not advised, even though the resulting weekly dosage may be similar to the recommended dosage.{01} Little or no therapeutic benefit has been demonstrated when such regimens are used, and the incidence of adverse reactions is increased.{01}


Geriatrics


No information is available on the relationship of age to the effects of vindesine in geriatric patients.


Dental

The bone marrow depressant effects of vindesine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of vindesine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of vindesine, if necessary, should be based on blood counts )


» Bone marrow depressants, other (see Appendix II) or
» Radiation therapy    (additive bone marrow depression, including severe dermatitis and/or mucositis, may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


Mitomycin-C    (acute shortness of breath and severe bronchospasm have frequently been reported with combination therapy including vinca alkaloids; the reaction may occur within minutes or several hours after the vinca alkaloid is injected{01})


» Neurotoxic medications (see Appendix II)    (neurologic toxicity may occur early in treatment and may be more severe if used concomitantly with other drugs having a neurotoxic potential{01})


» Phenytoin    (increased seizure activity due to reduced blood concentrations have been reported following concomitant administration with other vinca alkaloids [vincristine, vinblastine]. The dosage adjustment of phenytoin should be based on serial blood concentration monitoring{01})


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by vindesine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by vindesine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the vindesine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Charcot-Marie-Tooth syndrome, demyelinating form    (may cause neuropathy)


» Granulocytopenia, severe, drug-induced
» Thrombocytopenia, severe, drug-induced    (will worsen and increase the risk of infection)


» Infection, pre-existing    (use of vindesine is contraindicated unless infection is resolved prior to start of treatment)


Risk-benefit should be considered when the following medical problems exist
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe, generalized disease)


Hepatic function impairment{01}    (initial dosage should be lowered followed by an increase based on clinical response)


Neuromuscular disease, pre-existing{01}    (dosage may need to be adjusted)


Note: Caution also should be used in patients who have had previous cytotoxic drug therapy or radiation therapy.



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Hematocrit or hemoglobin and
» Leukocyte count, total and differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently; white blood cell count nadir may be expected to occur three to six days after administration and recovery 7 to 10 days after administration{01})


» Hepatic function    (recommended prior to initiation of therapy and at periodic intervals during treatment; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Leukopenia{01} (black, tarry stools; chest pain; chills; cough; fever ; painful or difficult urination; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands)—dose-limiting and resolves 7 to 10 days after administration{01}

Incidence less frequent or rare
    
Cortical blindness{01}
    
neurotoxicity{01} (blurred or double vision; convulsions; difficulty in walking ; drooping eyelids; headache; jaw pain; numbness or tingling in fingers and toes; pain in fingers and toes; weakness)
    
thrombocytopenia{01} (shortness of breath; unusual bleeding or bruising; unusual tiredness or weakness)— more likely to occur if patient has had prior radiation or chemotherapy

{01}

Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare
    
Anorexia{01} (loss of appetite; weight loss )
    
constipation
    
diarrhea{01} ( increase in bowel movements; loose stools; soft stools)
    
malaise{01} (general feeling of discomfort or illness)
    
musculoskeletal pain{01} (muscle or bone pain)
    
nausea and vomiting
    
skin rash{01}



Those not indicating need for medical attention
Incidence less frequent or rare
    
Alopecia{01} (hair loss; thinning of hair )





Overdose
For specific information on the agents used in the management of vindesine toxicity or overdose, see:    • Diuretics, Loop (Systemic) monograph.
   • Phenobarbital in Barbiturates (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Syndrome of inappropriate antidiuretic hormone (SIADH){01} (agitation; confusion; decreased urine output; depression; dizziness; headache; hostility; irritability; lethargy; muscle twitching; nausea; rapid weight gain; seizures; stupor; swelling of face, ankles, or hands; unusual tiredness or weakness)


Treatment of overdose
Restrict fluid intake and perhaps administer a loop diuretic.{01}

Administer anticonvulsant doses of phenobarbital.{01}See the package insert or phenobarbital for specific dosing guidelines for use of this product.

Administer cathartics to prevent ileus.{01}

Monitor the cardiovascular system and determine daily blood counts to guide transfusion requirements.{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Vindesine (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Benefit-to-risk ratio must be considered because of embryotoxic, fetotoxic, and carcinogenic potential; advisability of using contraception; informing physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of potential serious adverse effects
Other medications, especially blood dyscrasia–causing medications, bone marrow depressants, neurotoxic medications, live virus vaccines, phenytoin, or radiation therapy
Other medical problems, especially Charcot-Marie-Tooth syndrome (demyelinating form), drug-induced granulocytopenia (severe), drug-induced thrombocytopenia (severe), existing or recent chickenpox or herpes zoster infection, or pre-existing infection

Proper use of this medication
Possible nausea and vomiting; importance of continuing medication despite stomach upset

Checking with physician about using laxative if constipation and stomach pain occur

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by the physician, especially blood counts and liver function tests

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine, or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
» Possibility of local tissue injury and scarring if infiltration of intravenous solution occurs; telling doctor or nurse right away about redness, pain, or swelling at injection site


Side/adverse effects
Signs of potential side effects, especially cortical blindness, leukopenia, neurotoxicity, and thrombocytopenia


General Dosing Information
Vindesine may be administered by intravenous push or injected into the tubing of a running intravenous infusion, over a 1- to 3-minute period. Do not administer vindesine intrathecally, because death of the patient will occur.{01}

If vindesine is accidentally administered intrathecally, the following treatment is recommended and should be started immediately{01}:   #149; Remove as much spinal fluid as is safely possible through the lumbar access.{01}
   #149; Insert a catheter into a lateral cerebral ventricle in order to flush the subarachnoid space from above, with removal occurring through a lumbar access.{01}
   #149; Flush through the cerebral catheter with lactated Ringer's solution at a rate of 150 mL/hour. Replace lactated Ringer's with fresh frozen plasma when it becomes available.{01}
   #149; Infuse 25 mL of fresh frozen plasma diluted in 1 liter of lactated Ringer's at a rate of 75 mL/hour. Adjust the rate of infusion to maintain a protein concentration in the spinal fluid of 150 mg/dL.{01}
   #149; Administer 10 grams of glutamic acid intravenously over 24 hours followed by 500 mg 3 times a day orally for one month or until neurological dysfunction stabilizes. The role of glutamic acid is not clear and may not be essential.{01}

Note: The above treatment has been used to successfully arrest progressive paralysis in a single patient accidentally given vincristine intrathecally. The use of this treatment has not been reported following accidental intrathecal vindesine administration.{01}



Patients receiving vindesine should be under supervision of a physician experienced in cancer chemotherapy.

It is very important that the largest accessible vein be chosen, and that the needle is properly positioned in the vein, before injecting vindesine. Extravasation may cause considerable irritation. If extravasation occurs, discontinue the injection immediately and reintroduce any remaining drug into another vein. Local injection of hyaluronidase and the application of moderate heat to the site of extravasation is recommended to help disperse the drug and minimize discomfort and the possibility of cellulitis.{01}

After injection, the extremity should be elevated for a few minutes so that the site is above the heart to reduce intravenous pressure to a minimum in order to prevent post-injection leakage.{01}

Avoid contamination of the eye with vindesine as severe irritation and/or corneal ulceration may result. The contaminated eye should be washed immediately with water or saline.{01}

Patients with significant hepatic disease should receive an initial dosage lower than that recommended, followed by increases based on clinical response.{01}

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastic agents may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves, goggles, gowns, and masks.
   • Pregnant personnel should not come in contact with antineoplastic medication containers or mixing supplies.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampules, and unused medication.
   • Use of proper technique in handling spills, including the use of dilute sodium hypochlorite solution (1% active chlorine) and water, and proper disposal of waste.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Parenteral Dosage Forms

VINDESINE INJECTION

Usual Adult Dose
Leukemia, acute lymphocytic (treatment) or
Carcinoma, lung, non-oat cell (treatment)
Intravenous infusion (over 1 to 3 minutes), 3 milligrams per square meter of body surface area, given at 7 to 10 day intervals, repeated for eight cycles.{01}


Note: In adult patients with leukemia, upward adjustment of the dosage may be necessary to achieve the desired effect. Lower doses may be needed in those whose bone marrow is depressed due to other previous treatment. Patients with decreased marrow function caused by disease will require full doses in attempting to restore marrow function. Avoid sustained white blood cell counts of less than 2500/mm3 during vindesine therapy.{01}


Usual Pediatric Dose
Leukemia, acute lymphocytic (treatment)
Intravenous infusion (over 1 to 3 minutes), 4 milligrams per square meter of body surface area, given at 7 to 10 day intervals and repeated for 8 cycles.{01}

Alternatively, a regimen of 2 milligrams per square meter of body surface area may be used for two consecutive days, followed by a 5 to 7 day rest without medication. This course is then repeated for 8 cycles.{01}


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


5 mg (5 mL vials) (Rx) [Eldisine® ( mannitol 25 mg)]{01}

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F).{01}

Preparation of dosage form:
Reconstitute the contents of the vial with 5 mL of Bacteriostatic Sodium Chloride Injection, USP to provide a solution of 1 mg/mL.{01}.

Stability:
The solution is stable for 24 hours at room temperature and 14 days under refrigeration (2 and 8 °C; 36 and 46 °F).{01}

Do not mix solutions of other medications in the same vessel with vindesine.{01}


Caution:
When dispensed, the container or the syringe holding the individual dose prepared for administration to the patient must be labeled with the statement: “ELDISINE FOR INTRAVENOUS USE ONLY”.{01}



Revised: 05/25/2000



References
  1. Product Information: Eldisine®, vindesine sulfate. Eli Lilly Canada, Toronto, Ontario (PI revised 12/1992) reviewed 4/2000.
  1. Parfitt K (ed): Martindale: The Complete Drug Reference, 32nd ed. The Pharmaceutical Press, London, England, 1999; p. 577.
  1. Dyke RW & Nelson RL: Phase I anti-cancer agents: vindesine (desacetyl vinblastine amide sulfate). Cancer Treat Rev 1977; 4:135-142.
  1. Dorr RT & Von Hoff DD (eds): Cancer Chemotherapy Handbook, 2nd ed. Appleton & Lange, Norwalk, CT, 1994; p. 957–966.
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