RxMed: Pharmaceutical Information – ELDISINE

ELDISINE® INJECTION

Lilly

Vindesine Sulfate

Antineoplastic

Action And Clinical Pharmacology: The mode of action of vindesine is not completely understood. Like the other vinca alkaloids, vinblastine sulfate (Velbe) and vincristine sulfate (Oncovin), vindesine causes arrest of cells in metaphase mitosis. In addition, in vitro investigation has demonstrated that vindesine prevents invasion of normal tissue by malignant cells. Comparative studies with these 3 alkaloids, however, demonstrate differences in their effect at the molecular level. Vindesine has been shown to be 3 times more potent than vincristine and nearly 10 times more potent than vinblastine in effecting mitotic arrest in tissue culture studies designed to arrest from 10% to 15% of the cells in mitosis. At dose levels that arrest 40% to 50% of the cells in mitosis, vindesine and vincristine are approximately equipotent, and both have 3 times the potency of vinblastine. In addition, qualitative differences are noted among the 3 alkaloids. At the lower dose, vinblastine produced a predominance of postmetaphase cells in which the midbody and chromosomes were strikingly apparent. In contrast, cells exposed to vincristine displayed a ball-type metaphase with compact chromosomes within a shrunken spindle.

Unlike vinblastine, vindesine produced very few postmetaphase cells. The spindles in cells exposed to vindesine were swollen with dispersed chromosomes, in distinct contrast to the closely packed chromosomes seen with vincristine.

Vindesine has displayed oncolytic activity in patients who have relapsed while on multiple-agent treatment that included vincristine.

In laboratory animals and man, the biliary system is the major route of excretion of vindesine.

Hematologic Effects: Clinically, temporary leukopenia is an expected effect of vindesine and the level of the leukocyte count is an important guide to therapy with this drug. In general, the larger the dose employed, the more profound and longer-lasting the leukopenia will be. Following administration of vindesine, the nadir in white-blood-cell count may be expected to occur 3 to 6 days after the day of drug therapy. Recovery of the white blood count usually occurs 7 to 10 days after a dose.

Although the thrombocyte count ordinarily is not significantly lowered by therapy with vindesine, patients whose bone marrow has recently been impaired by prior therapy with radiation or with other oncolytic drugs may show thrombocytopenia (fewer than 200 000 platelets/mm. Thrombocytopenia is not common when a bolus dose is administered once a week to patients with normal marrow function.

Elevation of platelet count has occurred even when vindesine has produced granulocytopenia.

The pharmacokinetics of vindesine have been studied in patients with advanced cancer. Following a rapid i.v. dose, the kinetics of vindesine were described by a triphasic serum-decay curve. Serum half-lives were 2 minutes, 50 minutes, and 24 hours. The volume of the central compartment approximated the plasma volume in all patients studied. Distribution occurred quickly into a superficial tissue compartment in fairly rapid equilibrium with that in the plasma compartment and also into a deep-tissue compartment with slower redistribution to the central compartment.

Indications And Clinical Uses: For the treatment of: acute lymphocytic leukemia of childhood which is resistant to vincristine and non-oat-cell lung cancer.

Contra-Indications: Patients who have drug-induced severe granulocytopenia or severe thrombocytopenia and in those who have serious bacterial infection. Infections must be brought under control prior to initiation of therapy with vindesine. Patients with the demyelinating form of Charcot-Marie-Tooth syndrome. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Caution: Vindesine is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs. Blood counts should be taken once or twice weekly. Discontinue or reduce the dosage upon evidence of abnormal depression of the bone marrow.

This preparation is for i.v. use only. It should be administered by individuals experienced in the administration of vindesine. The intrathecal administration of vindesine has resulted in death. Syringes containing this product should be labeled “Warning – For I.V. Use Only”.

Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labeled “Do not remove covering until moment of injection. Fatal if given intrathecally. For i.v. use only.”

The following treatment successfully arrested progressive paralysis in a single patient mistakenly given the related vinca alkaloid, vincristine, intrathecally. If vindesine is mistakenly administered intrathecally, this treatment is recommended and should be initiated immediately after the intrathecal injection. 1. Remove as much spinal fluid as can be safely done through the lumbar access. 2. Insert a catheter in a lateral cerebral ventricle for the purpose of flushing the subarachnoid space from above with removal through a lumbar access. 3. Initiate flushing through the cerebral catheter with lactated Ringer’s solution infused at the rate of 150 mL/hour. 4. As soon as fresh frozen plasma becomes available, infuse the fresh frozen plasma, 25 mL, diluted in 1 L of Lactated Ringer’s solution through the cerebral ventricular catheter at the rate of 75 mL/hour with removal through the lumbar access. The rate of infusion should be adjusted to maintain a protein level in the spinal fluid of 150 mg/dL. Repeat this procedure using a second litre of diluted fresh frozen plasma. 5. Administer 10 g of glutamic acid i.v. over 24 hours followed by 500 mg 3 times daily by mouth for 1 month or until neurological dysfunction stabilizes. The role of glutamic acid in this treatment is not certain and may not be essential.

Pregnancy and Lactation: Safety for use during pregnancy or lactation has not been established.

Reproduction studies indicated that at toxic levels vindesine was embryotoxic and possibly teratogenic in rats. The benefit-to-risk ratio must be carefully considered before vindesine is used in pregnant or lactating patients. It is not known whether vindesine crosses the placental barrier or is excreted in breast milk.

Doses greater than 4 mg/mshould be used only by those skilled in treating children with leukemia.

Precautions: Strict adherence to the recommended dosage is advised. In preliminary assessments, neurotoxicity induced by vindesine is generally less severe and progressive in nature than the effects observed with vincristine. Individual patient variation has been observed with respect to severity of adverse reactions, including neurotoxicity, granulocytopenia, alopecia, and decrease in bowel motility. Prophylactic measures should be taken to prevent constipation that may result from a decrease in bowel motility.

There have been instances in which neurotoxicity has made it necessary to reduce the dosage or temporarily discontinue the use of vindesine.

Particular attention should be given to dosage and neurologic side effects if vindesine is administered to patients with preexisting neuromuscular disease and also when other drugs with neurotoxic potential are being used.

Since the biliary system is the major route of excretion of vindesine, patients with significant hepatic disease should receive an initial dosage that is lower than that recommended, followed by increases based on clinical response (see Dosage).

Extreme care should be exercised to prevent injection of vindesine outside the vein. Extravasation during i.v. injection will cause cellulitis and phlebitis. If the amount of extravasation is great enough, sloughing will occur. Healing of such wounds may require several weeks and may be attended by severe pain. The discomfort may persist after healing of the ulcer.

Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids. These reactions have been encountered most frequently when the vinca alkaloid was used in combination with mitomycin-C. The onset may be within minutes or several hours after the vinca is injected.

Care must be taken to avoid contamination of the eye with concentrations of vindesine used clinically. If accidental contamination occurs, severe irritation and/or corneal ulceration may result. The eye should be washed immediately and thoroughly with water or saline.

Neurologic toxicity may appear early in the course of treatment and may be more severe if vindesine is used concomitantly with other drugs having a neurologic potential.

Carcinogenic potential of vindesine has not been detected in the standard tests.

Drug Interactions: The simultaneous oral or i.v. administration of phenytoin and antineoplastic chemotherapy combinations that include vincristine and vinblastine has been reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Dosage adjustment should be based on serial blood level monitoring. The contribution of vincristine and vinblastine to this interaction is not certain. The interaction may result from reduced absorption of phenytoin or an increase in the rate of its metabolism and elimination.

Adverse Reactions: Prior to the use of the drug, patients and/or their parents/guardian should be advised of the possibility of untoward symptoms.

In general, the incidence of adverse effects attending the use of vindesine appears to be related to the size of the dose employed. Leukopenia, the most common adverse reaction, is usually the dose-limiting factor. Neurotoxicity and alopecia of varying degree occur.

When alopecia occurs, it may not be total, and hair usually regrows while maintenance therapy continues. Thrombocytopenia has not commonly been observed with the dosage schedule of 1 bolus injection/week, but it has been reported with other dosage schedules and in patients with pre-existing compromised bone-marrow function.

The following adverse reactions have been reported: Gastrointestinal: Constipation, abdominal pain, ileus, nausea, vomiting, vesiculation of the mouth, diarrhea, and anorexia. (Nausea and vomiting usually may be controlled by antiemetic agents.)

Neurologic: Numbness and tingling of digits, (paresthesias), loss of deep-tendon reflexes, jaw pain, mental depression, convulsions, peripheral neuritis, and headache. Cortical blindness has been reported in patients treated with multiple-agent chemotherapy that has included vindesine. The contribution of vindesine to this reaction is uncertain.

Hematologic: Granulocytopenia and thrombocytopenia.

Miscellaneous: Generalized musculoskeletal pain, epilation, chills and fever, malaise, macular skin rash, and pain in tumor site.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Side effects, following the use of vindesine are dose related. Therefore, following administration of an overdose, patients can be expected to experience side effects in an exaggerated fashion. Supportive care should include the following: 1. Prevention of side effects resulting from the syndrome of inappropriate secretion of antidiuretic hormone (this would include restriction of fluid intake and perhaps the administration of a diuretic affecting the function of the loop of Henle and the distal tubule); 2. administration of anticonvulsant doses of phenobarbital; 3. use of cathartics to prevent ileus; 4. monitoring the cardiovascular system; and 5. determining daily blood counts for guidance in transfusion requirements.

Dosage And Administration: This preparation is for i.v. use only. It should be administered by individuals experienced in the administration of vindesine. The intrathecal administration of vindesine has resulted in death. Syringes containing this product should be labeled “Warning – For I.V. Use Only”.

Extreme care must be used in calculating and administering the dose of vindesine, since overdosage may have a very serious or fatal outcome.

Since the biliary system is the major route of excretion, patients with significant hepatic disease should receive an initial dosage that is lower than that recommended below, followed by increases based on clinical response.

The drug is administered i.v. according to either of the following 2 protocols. Strict adherence to these regimens is advisable.

1. The dose of vindesine is 4 mg/mfor children, and 3 mg/mfor adults, administered by i.v. bolus at 7 to 10 day intervals repeated for 8 cycles. The injection should be completed over a 1 to 3 minute period.

2. Alternatively for children with leukemia, a regimen of 2 mg/mday by i.v. bolus injection can be employed for 2 consecutive days, followed by 5 to 7 days without the drug. The cycle is then repeated for 8 cycles.

The optimum dose is that which produces mild to moderate leukopenia. The dose for adults with normal marrow function is 3 mg/mby rapid i.v. injection once a week while that for children is 4 mg/monce a week by bolus injection. The maximum decrease in white-blood-cell count will usually occur 3 to 5 days thereafter, with recovery by the seventh to the tenth day. Sustained white-blood-cell counts lower than 2 500/mm(2.5 times 10m) due to vindesine are to be avoided.

In adult patients with leukemia, it may be necessary to adjust the dosage upward to achieve the desired effect. Adults whose bone marrow function is decreased due to other previous treatment will need lower doses. Those with decreased marrow function induced by disease will require full doses in order to attempt to restore marrow function. This must be done under close supervision.

The use of small amounts of vindesine daily for long periods in the treatment of acute lymphocytic leukemia in children is not advisable, even though the resulting weekly dosage may be similar to the recommended dosage. Little or no added therapeutic advantage has been demonstrated when such regimens have been used, and adverse reactions are increased. Strict adherence to the recommended dosage schedule is very important.

Reconstitution: Reconstitution of the vial with 5 mL Bacteriostatic Sodium Chloride Injection, USP will provide 1 mg/mL.

After reconstitution, Eldisine is stable for 24 hours at room temperature and 14 days under refrigeration (2 to 8°C).

Vindesine should not be mixed with other chemotherapeutic agents or medications in the same vessel.

The solution may be injected either directly into a vein or into the tubing of a running i.v. infusion.

Note: It is extremely important to choose the largest accessible vein and to be certain that the needle is properly positioned in the vein before any vindesine is injected. If leakage into surrounding tissue should occur during i.v. administration, it may cause considerable irritation.

The injection should be discontinued as soon as leakage occurs, and any remaining portion of the dose should then be introduced into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage help disperse the drug and are thought to minimize discomfort and the possibility of cellulitis. After proper injection, the extremity should be elevated so that the site is above the heart level to reduce intravenous pressure to the minimum for a few minutes in order to prevent postinjection leakage.

Availability And Storage: Each 5 mL vial contains: vindesine sulfate 5 mg and mannitol 25 mg. Sodium hydroxide and/or sulfuric acid may have been added during manufacture to adjust the pH. The product is supplied in a lyophilized form. Vindesine is for i.v. administration only. Store at 2 to 8°C.

ELDISINE® INJECTION Lilly Vindesine Sulfate Antineoplastic