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 7 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 ³ 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.

Vinblastine sulfate has been shown to be one of the most effective single agents for the treatment of Hodgkin’s disease.  Advanced Hodgkin’s disease has also been successfully treated with several multiple-drug regimens that included vinblastine sulfate.  Patients who had relapses after treatment with the MOPP program— mechlorethamine hydrochloride (nitrogen mustard), vincristine sulfate, prednisone and procarbazine—have likewise responded to combination-drug therapy that included vinblastine sulfate.  A protocol using cyclophosphamide in place of nitrogen mustard and vinblastine sulfate instead of vincristine sulfate is an alternative therapy for previously untreated patients with advanced Hodgkin’s disease.

Advanced testicular germinal-cell cancers (embryonal carcinoma, teratocarcinoma and choriocarcinoma) are sensitive to vinblastine sulfate alone, but better clinical results are achieved when vinblastine sulfate is administered concomitantly with other antineoplastic agents.  The effect of bleomycin is significantly enhanced if vinblastine sulfate is administered six to eight hours prior to the administration of bleomycin; this schedule permits more cells to be arrested during metaphase, the stage of the cell cycle in which bleomycin is active.

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.  (See CLINICAL PHARMACOLOGY , CONTRAINDICATIONS , WARNINGS ,  PRECAUTIONS  and ADVERSE REACTIONS .)  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: (1) 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); (2) administration of an anticonvulsant; (3) prevention of ileus: (4) monitoring the cardiovascular system; and (5) 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.

It is wise to initiate therapy for adults by administering a single intravenous dose of 3.7 mg/m ² 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 (see PRECAUTIONS ).

A review of published literature from 1993 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 ² 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 dose of vinblastine sulfate (calculated to provide the desired amount) may be injected either into the tubing of a running intravenous infusion or directly into a vein.  The latter procedure is readily adaptable to outpatient therapy.  In either case, the injection may be completed in about one minute.  If care is taken to ensure that the needle is securely within the vein and that no solution containing vinblastine sulfate is spilled extra-vascularly, cellulitis and/or phlebitis will not occur.  To minimize further the possibility of extravascular spillage, it is suggested that the syringe and needle be rinsed with venous blood before withdrawal of the needle.  The dose should not be diluted in large volumes of diluent (i.e., 100 to 250 mL) or given intravenously for prolonged periods (ranging from 30 to 60 minutes or more), 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.