VELBASTINE

Vinblastine sulfate is the salt of an alkaloid extracted from Vinca rosea Linn., a common flowering herb known as the periwinkle (more properly known as Catharanthus roseus G. Don).

Previously, the generic name was vincaleukoblastine, abbreviated VLB.

It is a stathmokinetic oncolytic agent.

When treated in vitro with this preparation, growing cells are arrested in metaphase.

Chemical and physical evidence indicate that vinblastine sulfate is a dimeric alkaloid containing both indole and dihydroindole moieties.

The accompanying structural formula has been proposed.

C 46 H 58 N 4 O 9 •H 2 SO 4 M.W. 909.06 Each mL contains: Vinblastine sulfate 1 mg; sodium chloride 9 mg; benzyl alcohol 0.9% (v/v) as a preservative; water for injection, q.s. (pH 3.5 to 5.0). vinbl-struc-01.jpg.

The testicular cancer is used in the Hawdgkins lymphoma, the tumor-breakfast Sarcuma Kapuzi (Gren Kabozzi) of many female coroners (Litter Seoy disease) of the tumor.

The treatment consists of a pulmonary chemical (causing a dermal excretion).

The treatment may cause inhibition in the bone marrow.

The treatment may cause neurotoxic but rare.

Experimental data indicate that the action of vinblastine sulfate is different from that of other recognized antineoplastic agents.

Tissue-culture studies suggest an interference with metabolic pathways of amino acids leading from glutamic acid to the citric acid cycle and to urea.

In vivo experiments tend to confirm the in vitro results.

A number of studies in vitro and in vivo have demonstrated that vinblastine sulfate produces a stathmokinetic effect and various atypical mitotic figures.

The therapeutic responses, however, are not fully explained by the cytologic changes, since these changes are sometimes observed clinically and experimentally in the absence of any oncolytic effects.

Reversal of the antitumor effect of vinblastine sulfate by glutamic acid or tryptophan has been observed.

In addition, glutamic acid and aspartic acid have protected mice from lethal doses of vinblastine sulfate.

Aspartic acid was relatively ineffective in reversing the antitumor effect.

Other studies indicate that vinblastine sulfate has an effect on cell-energy production required for mitosis and interferes with nucleic acid synthesis.

The mechanism of action of vinblastine has been related to the inhibition of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.

Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid intravenous injection.

The initial, middle and terminal half-lives are 3.7 minutes, 1.6 hours and 24.8 hours, respectively.

The volume of the central compartment is 70% of body weight, probably reflecting very rapid tissue binding to formed elements of the blood.

Extensive reversible tissue binding occurs.

Low body stores are present at and 72 hours after injection.

Since the major route of excretion may be through the biliary system, toxicity from this drug may be increased when there is hepatic excretory insufficiency.

The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily.

This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes such as erythromycin.

Enhanced toxicity has been reported in patients receiving concomitant erythromycin.

Following injection of tritiated vinblastine in the human cancer patient, 10% of the radioactivity was found in the feces and 14% in the urine; the remaining activity was not accounted for.

Similar studies in dogs demonstrated that, over nine days, 30 to 36% of radioactivity was found in the bile and to 17% in the urine.

A similar study in the rat demonstrated that the highest concentrations of radioactivity were found in the lung, liver, spleen and kidney two hours after injection.

Clinically, leukopenia is an expected effect of vinblastine sulfate, 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.

The fact that the white blood cell count returns to normal levels after drug-induced leukopenia is an indication that the white cell-producing mechanism is not permanently depressed.

Usually, the white count has completely returned to normal after the virtual disappearance of white cells from the peripheral blood.

Following therapy with vinblastine sulfate, the nadir in white blood cell count may be expected to occur five to ten days after the last day of drug administration.

Recovery of the white blood count is fairly rapid thereafter and is usually complete within another to 14 days.

With the smaller doses employed for maintenance therapy, leukopenia may not be a problem.

Although the thrombocyte count ordinarily is not significantly lowered by therapy with vinblastine sulfate, patients whose bone marrow has been recently impaired by prior therapy with radiation or with other oncolytic drugs may show thrombocytopenia (less than 200,000 platelets/mm 3 ).

When other chemotherapy or radiation has not been employed previously, thrombocyte reduction below the level of 200,000/mm is rarely encountered, even when vinblastine sulfate may be causing significant leukopenia.

Rapid recovery from thrombocytopenia within a few days is the rule.

The effect of vinblastine sulfate upon the red cell count and hemoglobin is usually insignificant when other therapy does not complicate the picture.

It should be remembered, however, that patients with malignant disease may exhibit anemia even in the absence of any therapy.

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Prior to the use of the drug, patients should be advised of the possibility of untoward symptoms.

In general, the incidence of adverse reactions attending the use of vinblastine sulfate appears to be related to the size of the dose employed.

With the exception of epilation, leukopenia and neurologic side effects, adverse reactions generally have not persisted for longer than 24 hours.

Neurologic side effects are not common; but when they do occur, they often last for more than 24 hours.

Leukopenia, the most common adverse reaction, is usually the dose-limiting factor.

The following are manifestations that have been reported as adverse reactions, in decreasing order of frequency.

The most common adverse reactions are underlined: Hematologic.

• Leukopenia (granulocytopenia), anemia, thrombocytopenia (myelosuppression).

• Alopecia is common.

A single case of light sensitivity associated with this product has been reported.

• Constipation, anorexia, nausea, vomiting, abdominal pain, ileus, vesiculation of the mouth, pharyngitis, diarrhea, hemorrhagic enterocolitis, bleeding from an old peptic ulcer and rectal bleeding.

• Numbness of digits (paresthesias), loss of deep tendon reflexes, peripheral neuritis, mental depression, headache, convulsions.

Treatment with vinca alkaloids has resulted rarely in both vestibular and auditory damage to the eighth cranial nerve.

Manifestations include partial or total deafness which may be temporary or permanent, and difficulties with balance including dizziness, nystagmus and vertigo.

Particular caution is warranted when vinblastine sulfate is used in combination with other agents known to be ototoxic such as the platinum-containing oncolytics.

• Hypertension —Cardiac effects such as myocardial infarction, angina pectoris and transient abnormalities of ECG related to coronary ischemia have been reported very rarely.

Cases of unexpected myocardial infarction and cerebrovascular accidents have occurred in patients undergoing combination chemotherapy with vinblastine, bleomycin and cisplatin.

Raynaud’s phenomenon has also been reported with this combination.

• Malaise, bone pain, weakness, pain in tumor-containing tissue, dizziness, jaw pain, skin vesiculation, hypertension, Raynaud’s phenomenon when patients are being treated with vinblastine sulfate in combination with bleomycin and cis-platinum for testicular cancer.

The syndrome of inappropriate secretion of antidiuretic hormone has occurred with higher than recommended doses.

Nausea and vomiting usually may be controlled with ease by antiemetic agents.

When epilation develops, it frequently is not total; and, in some cases, hair regrows while maintenance therapy continues.

Extravasation during intravenous injection may lead to cellulitis and phlebitis.

If the amount of extravasation is great, sloughing may occur.

Side effects following the use of vinblastine sulfate are dose related.

Therefore, following administration of more than the recommended dose, patients can be expected to experience these effects in an exaggerated fashion.

There is no specific antidote.

In addition, neurotoxicity similar to that with vincristine sulfate may be observed.

Since the major route of excretion may be through the biliary system, toxicity from this drug may be increased when there is hepatic insufficiency.

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center.

Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR) .

In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs and unusual drug kinetics in your patient.

Overdoses of vinblastine sulfate have been reported rarely.

The following is provided to serve as a guide should such an overdose be encountered.

Supportive care should include the following: prevention of side effects that result from the syndrome of inappropriate secretion of antidiuretic hormone (this would include restriction of the volume of daily fluid intake to that of the urine output plus insensible loss and perhaps the administration of a diuretic affecting the function of the loop of Henle and the distal tubule); administration of an anticonvulsant; prevention of ileus: monitoring the cardiovascular system; and determining daily blood counts for guidance in transfusion requirements and assessing the risk of infection.

The major effect of excessive doses of vinblastine sulfate will be myelosuppression, which may be life-threatening.

There is no information regarding the effectiveness of dialysis nor of cholestyramine for the treatment of overdosage.

Vinblastine sulfate in the dry state is irregularly and unpredictably absorbed from the gastrointestinal tract following oral administration.

Absorption of the solution has not been studied.

If vinblastine is swallowed, activated charcoal in a water slurry may be given by mouth along with a cathartic.

The use of cholestyramine in this situation has not been reported.

Symptoms of overdose will appear when greater-than-recommended doses are given.

Any dose of vinblastine sulfate that results in elimination of platelets and neutrophils from blood and marrow and their precursors from marrow should be considered life-threatening.

The exact dose that will do this in all patients is unknown.

Overdoses occurring during prolonged consecutive-day infusions may be more toxic than the same total dose given by rapid intravenous injection.

The intravenous median lethal dose in mice is 10 mg/kg body weight; in rats, it is 2.9 mg/kg. The oral median lethal dose in rats is 7 mg/kg. Protect the patient’s airway and support ventilation and perfusion.

Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc.

Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying if the drug has been swallowed.

Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed.

Safeguard the patient’s airway when employing gastric emptying or charcoal.

This preparation is for intravenous use only.

It should be administered by individuals experienced in the administration of vinblastine sulfate.

The intrathecal administration of vinblastine sulfate usually results in death.

To reduce the potential for fatal medication errors due to incorrect route of administration, vinblastine sulfate injection should be diluted in a flexible plastic container and prominently labeled (as indicated) “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.’’ After inadvertent intrathecal administration of vinca alkaloids, immediate neurosurgical intervention is required in order to prevent ascending paralysis leading to death.

In a very small number of patients, life-threatening paralysis and subsequent death was averted but resulted in devastating neurological sequelae, with limited recovery afterwards.

There are no published cases of survival following intrathecal administration of vinblastine sulfate to base treatment on.

However, based on the published management of survival cases involving the related vinca alkaloid vincristine sulfate 1-3, if vinblastine sulfate is mistakenly given by the intrathecal route, the following treatment should be initiated immediately after the injection: 1.

Removal of as much

CSF as is safely possible through the lumbar access. 2.

Insertion of an epidural catheter into the subarachnoid space via the intervertebral space above initial lumbar access and CSF irrigation with lactated Ringer’s solution.

Fresh frozen plasma should be requested and, when available, 25 mL should be added to every 1 liter of lactated Ringer’s solution. 3.

Insertion of an intraventricular drain or catheter by a neurosurgeon and continuation of CSF irrigation with fluid removal through the lumbar access connected to a closed drainage system.

Ringer’s solution should be given by continuous infusion at 150 mL/hour, or at a rate of 75 mL/hour when fresh frozen plasma has been added as above.

The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150 mg/dL.

The following measures have also been used in addition but may not be essential: Glutamic acid, 10 grams, has been given intravenously over 24 hours, followed by 500 mg three times daily by mouth for 1 month.

Folinic acid has been administered intravenously as a 100 mg bolus and then infused at a rate of 25 mg/hour for 24 hours, then bolus doses of 25 mg every 6 hours for 1 week.

Pyridoxine has been given at a dose of 50 mg every 8 hours by intravenous infusion over 30 minutes.

Their roles in the reduction of neurotoxicity are unclear.

Caution is necessary with the administration of all oncolytic drugs during pregnancy.

Information on the use of vinblastine sulfate during human pregnancy is very limited.

Animal studies with vinblastine sulfate suggest that teratogenic effects may occur.

Vinblastine sulfate can cause fetal harm when administered to a pregnant woman.

Laboratory animals given this drug early in pregnancy suffer resorption of the conceptus; surviving fetuses demonstrate gross deformities.

There are no adequate and well-controlled studies in pregnant women.

If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus.

Women of childbearing potential should be advised to avoid becoming pregnant.

Aspermia has been reported in man.

Animal studies show metaphase arrest and degenerative changes in germ cells.

Leukopenia (granulocytopenia) may reach dangerously low levels following administration of the higher recommended doses.

It is therefore important to follow the dosage technique recommended under DOSAGE AND ADMINISTRATION.

Stomatitis and neurologic toxicity, although not common or permanent, can be disabling.

Vinblastine sulfate is contraindicated in patients who have significant granulocytopenia unless this is a result of the disease being treated.

It should not be used in the presence of bacterial infections.

Such infections must be brought under control prior to the initiation of therapy with vinblastine sulfate.

This preparation is for intravenous use only See WARNINGS.

• To reduce the potential for fatal medication errors due to incorrect route of administration, vinblastine sulfate injection should be diluted in a flexible plastic container and prominently labeled (as indicated), “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.” See WARNINGS.

Preparation for flexible plastic container

Vinblastine sulfate injection when diluted with 0.9% sodium chloride injection to concentrations of 0.1 mg/mL to 0.4 mg/mL is stable at room temperature for up to 24 hours when protected from light or 8 hours in normal light.

Caution–It is extremely important that the intravenous needle or catheter be properly positioned before any vinblastine sulfate is injected.

Leakage into surrounding tissue during intravenous administration of vinblastine sulfate may cause considerable irritation.

If extravasation occurs, the injection should be discontinued immediately 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 will help disperse the drug and may minimize discomfort and the possibility of cellulitis.

There are variations in the depth of the leukopenic response that follows therapy with vinblastine sulfate.

For this reason, it is recommended that the drug be given no more frequently than once every seven days.

It is wise to initiate therapy for adults by administering a single intravenous dose of 3.7 mg/m of body surface area (bsa).

Thereafter, white blood cell counts should be made to determine the patient’s sensitivity to vinblastine sulfate.

A simplified and conservative incremental approach to dosage at weekly intervals for adults may be outlined as follows: First dose. 3.7 mg/m 2 bsa Second dose. 5.5 mg/m 2 bsa Third dose. 7.4 mg/m 2 bsa Fourth dose. 9.25 mg/m 2 bsa Fifth dose. 11.1 mg/m 2 bsa The above-mentioned increases may be used until a maximum dose not exceeding 18.5 mg/m 2 bsa for adults is reached.

The dose should not be increased after that dose which reduces the white cell count to approximately 3,000 cells/mm 3.

In some adults, 3.7 mg/m 2 bsa may produce this leukopenia; other adults may require more than 11.1 mg/m 2 bsa; and, very rarely, as much as 18.5 mg/m 2 bsa may be necessary.

For most adult patients, however, the weekly dosage will prove to be 5.5 to 7.4 mg/m 2 bsa.

When the dose of vinblastine sulfate which will produce the above degree of leukopenia has been established, a dose of one increment smaller than this should be administered at weekly intervals for maintenance.

Thus, the patient is receiving the maximum dose that does not cause leukopenia.

It should be emphasized that, even though seven days have elapsed, the next dose of vinblastine sulfate should not be given until the white cell count has returned to at least 4,000 / mm 3.

In some cases, oncolytic activity may be encountered before leukopenic effect.

When this occurs, there is no need to increase the size of subsequent doses.

A review of published literature from to 1995 showed that initial doses of vinblastine sulfate in pediatric patients varied depending on the schedule used and whether vinblastine sulfate was administered as a single agent or incorporated within a particular chemotherapeutic regimen.

As a single agent for

Letterer-Siwe disease (histiocytosis X), the initial dose of vinblastine sulfate was reported as 6.5 mg/m 2.

When vinblastine sulfate was used in combination with other chemotherapeutic agents for the treatment of Hodgkin’s disease, the initial dose was reported as 6 mg/m 2.

For testicular germ cell carcinomas, the initial dose of vinblastine sulfate was reported as 3 mg/m in a combination regimen.

Dose modifications should be guided by hematologic tolerance.

A reduction of 50% in the dose of vinblastine sulfate is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL.

Since metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.

The duration of maintenance therapy varies according to the disease being treated and the combination of antineoplastic agents being used.

There are differences of opinion regarding the duration of maintenance therapy with the same protocol for a particular disease; for example, various durations have been used with the MOPP program in treating Hodgkin’s disease.

Prolonged chemotherapy for maintaining remissions involves several risks, among which are life-threatening infectious diseases, sterility and possibly the appearance of other cancers through suppression of immune surveillance.

In some disorders, survival following complete remission may not be as prolonged as that achieved with shorter periods of maintenance therapy.

On the other hand, failure to provide maintenance therapy in some patients may lead to unnecessary relapse; complete remissions in patients with testicular cancer, unless maintained for at least two years, often result in early relapse.

The calculated dose of vinblastine sulfate may be infused from a flexible plastic container directly into an intravenous catheter/needle or into a running intravenous infusion.

If care is taken to ensure that the needle is securely within the vein and that no solution containing vinblastine sulfate is spilled extravascularly, cellulitis and/or phlebitis will not occur.

To minimize further the possibility of extravascular spillage, flush the infusion line with normal saline prior to removal of the intravenous catheter or needle.

The dose should not be diluted in large volumes of diluent (i.e. greater than 100 mL) or given intravenously for prolonged periods (longer than 30 minutes), since this frequently results in irritation of the vein and increases the chance of extravasation.

Because of the enhanced possibility of thrombosis, it is considered inadvisable to inject a solution of vinblastine sulfate into an extremity in which the circulation is impaired or potentially impaired by such conditions as compressing or invading neoplasm, phlebitis or varicosity.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Procedures for proper handling and disposal of anti-cancer drugs should be considered.

Several guidelines on this subject have been published. 4-10 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Vinblastine Sulfate Injection is supplied as follows: Product Code NDC No.

Strength 27810 63323-278-10 10 mg per 10 mL (1 mg per mL) 10 mL flip-top vial, individually packaged.

Store products in refrigerator 2° to 8°C (36° to 46°F) to assure extended stability.

Retain vial in carton until time of use.

Vinblastine sulfate should be given to a pregnant woman only if clearly needed.

Animal studies suggest that teratogenic effects may occur.

It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from vinblastine sulfate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.

The dosage schedule for pediatric patients is indicated under DOSAGE AND ADMINISTRATION.