Vinblastine Sulfate for Injection USP is vincaleukoblastine, sulfate (1:1) (salt). It 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 indicates that vinblastine sulfate has the molecular formula C₄₆H₅₈O₉N₄•H₂SO₄ and that it is a dimeric alkaloid containing both indole and dihydroindole moieties.

The structural formula is as follows:

M.W.= 909.07

Vinblastine sulfate is a white to off-white powder. It is freely soluble in water, soluble in methanol, and slightly soluble in ethanol. It is insoluble in benzene, ether, and naphtha.

The clinical formulation is supplied in a sterile form for intravenous use only. Vials of Vinblastine Sulfate for Injection USP contain 10 mg (0.011 mmol) of vinblastine sulfate, in the form of a white, amorphous, solid lyophilized plug, without excipients. After reconstitution with sodium chloride solution, the pH of the resulting solution lies in the range of 3.5 to 5.

Last updated on RxList: 1/13/2009

Vinblastine sulfate is indicated in the palliative treatment of the following:

Frequently Responsive Malignancies

Generalized Hodgkin's disease (Stages III and IV, Ann Arbor modification of Rye staging system)

Lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated)

Histiocytic lymphoma

Mycosis fungoides (advanced stages)

Advanced carcinoma of the testis

Kaposi's sarcoma

Letterer-Siwe disease (histiocytosis X)

Less Frequently Responsive Malignancies

Choriocarcinoma resistant to other chemotherapeutic agents

Carcinoma of the breast, unresponsive to appropriate endocrine surgery and hormonal therapy

Current principles of chemotherapy for many types of cancer include the concurrent administration of several antineoplastic agents. For enhanced therapeutic effect without additive toxicity, agents with different dose-limiting clinical toxicities and different mechanisms of action are generally selected. Therefore, although vinblastine sulfate is effective as a single agent in the aforementioned indications, it is usually administered in combination with other antineoplastic drugs. Such combination therapy produces a greater percentage of response than does a single-agent regimen. These principles have been applied, for example, in the chemotherapy of Hodgkin's disease.

Hodgkin's Disease: 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 6 to 8 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.

This preparation is for intravenous use only (see WARNINGS).

Special Dispensing Information: WHEN DISPENSING VINBLASTINE SULFATE IN OTHER THAN THE ORIGINAL CONTAINER, IT IS IMPERATIVE THAT IT BE PACKAGED IN THE PROVIDED OVERWRAP WHICH BEARS THE FOLLOWING STATEMENT: “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY” (see WARNINGS). A syringe containing a specific dose must be labeled, using the auxiliary sticker provided, to state: “FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY”.

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 help disperse the drug and minimize discomfort and the possibility of cellulitis.

There are variations in the depth of the leukopenic response which follows therapy with vinblastine sulfate. For this reason, it is recommended that the drug be given no more frequently than once every 7 days.

Adult patients: It is wise to initiate therapy for adults by administering a single intravenous dose of 3.7 mg/m² 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/m² bsa

Second dose ...................... 5.5 mg/m² bsa

Third dose .......................... 7.4 mg/m² bsa

Fourth dose ........................ 9.25 mg/m² bsa

Fifth dose ........................... 11.1 mg/m² bsa

The above-mentioned increases may be used until a maximum dose not exceeding 18.5 mg/m² bsa for adults is reached. The dose should not be increased after that dose which reduces the white-cell count to approximately 3000 cells/mm³. In some adults, 3.7 mg/m² bsa may produce this leukopenia; other adults may require more than 11.1 mg/m² bsa; and, very rarely, as much as 18.5 mg/m² bsa may be necessary. For most adult patients, however, the weekly dosage will prove to be 5.5 to 7.4 mg/m² bsa.

When the dose of vinblastine sulfate which will produce the above degree of leukopenia has been established, a dose of 1 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 7 days have elapsed, the next dose of vinblastine sulfate should not be given until the white-cell count has returned to at least 4000/mm³. In some cases, oncolytic activity may be encountered before leukopenic effect. When this occurs, there is no need to increase the size of the subsequent doses (See PRECAUTIONS).

Pediatric Patients: 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/m². 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/m². For testicular germ cell carcinomas, the initial dose of vinblastine sulfate was reported as 3 mg/m² in a combination regimen. Dose modifications should be guided by hematologic tolerance.

Patients with Renal or Hepatic Impairment: 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 2 years, often result in early relapse.

To prepare a solution containing 1 mg/mL of vinblastine sulfate, add 10 mL of Bacteriostatic Sodium Chloride Injection (preserved with benzyl alcohol) or 10 mL of Sodium Chloride Injection (unpreserved) to the 10 mg of Vinblastine Sulfate for Injection in the sterile vial. Do not use other solutions. The drug dissolves instantly to give a clear solution.

Unused portions of the remaining solutions made with normal saline that do not contain preservatives should be discarded immediately. Unused preservative-containing solutions made with normal saline may be stored in a refrigerator for future use for a maximum of 28 days.

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 1 minute. If care is taken to insure 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, 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.

Note: 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.^1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Vinblastine Sulfate for Injection USP is supplied in packs of ten individually-boxed vials containing 10 mg lyophilized vinblastine sulfate.

NDC 55390-091-10.

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

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.

2. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics. JAMA,1985; 253 (11) :1590-1592.

3. National Study Commission on Cytotoxic Exposure – Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

4. Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426-428.

5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA – A Cancer Journal for Clinicians,1983; (Sept/Oct) 258-263.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J. Hosp Pharm,1990; 47:1033-1049.

7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am J. Hosp Pharm, 1986; 43:1193-1204.

Manufactured by: Ben Venue Laboratories Bedford, OH 44146. Manufactured for: Bedford Laboratories Bedford, Ohio 44146. FDA Rev date: 8/22/2002

Last updated on RxList: 1/13/2009

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 which have been reported as adverse reactions, in decreasing order of frequency. The most common adverse reactions are underlined:

Hematologic: Leukopenia (granulocytopenia), anemia, thrombocytopenia (myelosuppression).

Dermatologic: Alopecia is common. A single case of light sensitivity associated with this product has been reported.

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

Neurologic: 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 platinum-containing oncolytics.

Cardiovascular: 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.

Pulmonary: See PRECAUTIONS.

Miscellaneous: 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.

Solutions should be made with normal saline (with or without preservative) and should not be combined in the same container with any other chemical. Unused portions of the remaining solutions that do not contain preservatives should be discarded immediately.

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vinblastine sulfate has been reported to have reduced blood levels of the anticonvulsant and to have increased seizure activity. Dosage adjustment should be based on serial blood level monitoring. The contribution of vinblastine sulfate to this interaction is not certain. The interaction may result from either reduced absorption of phenytoin or an increase in the rate of its metabolism and elimination.

Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinblastine sulfate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects. Enhanced toxicity has been reported in patients receiving concomitant erythromycin (see ADVERSE REACTIONS).

Last updated on RxList: 1/13/2009

Usage In Pregnancy: 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 the DOSAGE AND ADMINISTRATION. Stomatitis and neurologic toxicity, although not common or permanent, can be disabling.

General

Toxicity may be enhanced in the presence of hepatic insufficiency.

If leukopenia with less than 2,000 white blood cells/mm³ occurs following a dose of vinblastine sulfate, the patient should be watched carefully for evidence of infection until the white-blood-cell count has returned to a safe level.

When cachexia or ulcerated areas of the skin surface are present, there may be a more profound leukopenic response to the drug; therefore, its use should be avoided in older persons suffering from either of these conditions.

In patients with malignant-cell infiltration of the bone marrow, the leukocyte and platelet counts have sometimes fallen precipitously after moderate doses of vinblastine sulfate. Further use of the drug in such patients is inadvisable.

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 and may require aggressive treatment, particularly when there is pre-existing pulmonary dysfunction. The onset may be within minutes or several hours after the vinca is injected and may occur up to 2 weeks following a dose of mitomycin. Progressive dyspnea requiring chronic therapy may occur. Vinblastine should not be readministered.

Care should be recommended in patients with ischemic cardiac disease.

The use of small amounts of vinblastine sulfate daily for long periods is not advised, even though the resulting total weekly dosage may be similar to that recommended. Little or no added therapeutic effect has been demonstrated when such regimens have been used. Strict adherence to the recommended dosage schedule is very important. When amounts equal to several times the recommended weekly dosage were given in 7 daily installments for long periods, convulsions, severe and permanent central-nervous-system damage, and even death occurred.

Care must be taken to avoid contamination of the eye with concentrations of vinblastine sulfate used clinically. If accidental contamination occurs, severe irritation (or, if the drug was delivered under pressure, even corneal ulceration) may result. The eye should be washed with water immediately and thoroughly.

It is not necessary to use preservative-containing solvents if unused portions of the remaining solutions are discarded immediately. Unused preservative-containing solutions shouId be refrigerated for future use.

Laboratory Tests

Since dose-limiting clinical toxicity is the result of depression of the white-blood-cell count, it is imperative that this count be obtained just before the planned dose of vinblastine sulfate. Following administration of vinblastine sulfate, a fall in the white-blood-cell count may occur. The nadir of this fall is observed from 5 to 10 days following a dose. Recovery to pretreatment levels is usually observed from 7 to 14 days after treatment. These effects will be exaggerated when preexisting bone marrow damage is present and also with the higher recommended doses (See DOSAGE AND ADMINISTRATION). The presence of this drug or its metabolites in blood or body tissues is not known to interfere with clinical laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Aspermia has been reported in man. Animal studies suggest that teratogenic effects may occur. See WARNINGS regarding impaired fertility. Animal studies have shown metaphase arrest and degenerative changes in germ cells. Amenorrhea has occurred in some patients treated with the combination consisting of an alkylating agent, procarbazine, prednisone and vinblastine sulfate. Its occurrence was related to the total dose of these 4 agents used. Recovery of menses was frequent. The same combination of drugs given to male patients produced azoospermia; if spermatogenesis did return, it was not likely to do so with less than 2 years of unmaintained remission.

Mutagenicity: Tests in Salmonella typhimurium and with the dominant lethal assay in mice failed to demonstrate mutagenicity. Sperm abnormalities have been noted in mice. Vinblastine sulfate has produced an increase in micronuclei formation in bone marrow cells of mice; however, since vinblastine sulfate inhibits mitotic spindle formation, it cannot be concluded that this is evidence of mutagenicity. Additional studies in mice demonstrated no reduction in fertility of males. Chromosomal translocations did occur in male mice. First-generation male offspring of these mice were not heterozygous translocation carriers.

In vitro tests using hamster lung cells in culture have produced chromosomal changes, including chromatid breaks and exchanges, whereas tests using another type of hamster cell failed to demonstrate mutation. Breaks and aberrations were not observed on chromosome analysis of marrow cells from patients being treated with this drug.

It is not clear from the literature how this drug affects synthesis of DNA and RNA. Some believe that there is no interference. Others believe that vinblastine interferes with nucleic acid metabolism but may not do so by direct effect but possibly as the result of biochemical disturbance in some other part of the molecular organization of the cell. No inhibition of RNA synthesis occurred in rat hepatoma cells exposed in culture to noncytotoxic levels of vinblastine. Conflicting results have been noted by others regarding interference with DNA synthesis.

Carcinogenesis: There is no currently available evidence to indicate that vinblastine sulfate itself has been carcinogenic in humans since the inception of its clinical use in the late 1950's. Patients treated for Hodgkin's disease have developed leukemia following radiation therapy and administration of vinblastine sulfate in combination with other chemotherapy including agents known to intercalate with DNA. It is not known to what extent vinblastine sulfate may have contributed to the appearance of leukemia. Available data in rats and mice have failed to demonstrate clearly evidence of carcinogenesis when the animals were treated with the maximum tolerated dose and with one-half that dose for 6 months. This testing system demonstrated that other agents were clearly carcinogenic, whereas vinblastine sulfate was in the group of drugs causing slightly increased or the same tumor incidence as controls in one study and 1.5 to 2-fold increase in tumor incidence over controls in another study.

Preganancy

Teratogenic Effects; Pregnancy Category D (See WARNINGS). Vinblastine sulfate should be given to a pregnant woman only if clearly needed. Animal studies suggest that teratogenic effects may occur.

Pediatric Use

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

Nursing Mothers

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.

Last updated on RxList: 1/13/2009

Signs and Symptoms

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.

Treatment

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.

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.

Last updated on RxList: 1/13/2009

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 in vitro and in vivo studies 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 sulfate 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 48 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. (See PRECAUTIONS). Following injection of tritiated vinblastine in the human cancer patient, 10% of the adio ctiv y was found in the feces and 14% in the urine; the remaining activity was not accounted for. Similar studies in dogs demonstrated that, over 9 days, 30% to 36% of radioactivity was found in the bile and 12% 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 2 hours after injection.

Hematologic Effects

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 5 to 10 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/mm³). When other chemotherapy or radiation has not been employed previously, thrombocyte reduction below the level 200,000/mm³ 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.

Last updated on RxList: 1/13/2009

The patient should be warned to report immediately the appearance of sore throat, fever, chills, or sore mouth. Advice should be given to avoid constipation, and the patient should be made aware that alopecia may occur and that jaw pain and pain in the organs containing tumor tissue may occur. The latter is thought possibly to result from swelling of tumor tissue during its response to treatment. Scalp hair will regrow to its pretreatment extent even with continued treatment with vinblastine sulfate. Nausea and vomiting, although not common, may occur. Any other serious medical event should be reported to the physician.

Last updated on RxList: 1/13/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

VINBLASTINE - INJECTION

(vin-BLASS-teen)

WARNING: If vinblastine accidentally leaks into tissue around the injection site, the skin and/or muscle may be severely damaged. Tell your doctor immediately if you feel pain or irritation at the injection site. This drug is injected into a vein only. Do not inject under the skin, into a muscle, or into the spine.

Deaths have occurred when vinblastine was injected into the spine. This medication should be clearly labeled for injection into a vein only. To prevent accidental injection into the spine, do not remove the syringe from its labeled outside cover until immediately before use.

USES: Vinblastine is used to treat cancer. It works by slowing or stopping the growth of cancer cells.

HOW TO USE: Learn all preparation and usage instructions in the product package. If any of the information is unclear, consult your doctor or pharmacist. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid.

This medication is given by injection into a vein by a health care professional, usually once a week or as directed by your doctor. To prevent leakage of the medication into tissue around the vein, vinblastine should be injected over 1 minute. Tell your health care professional immediately if you experience pain, burning, or redness at the injection site. Do not mix this medication in a large amount of solution and/or inject over a long time (e.g., 30 to 60 minutes) unless directed by your doctor. Doing so may increase the risk of leakage. If the medication starts to leak into tissue, stop the injection and give the remaining solution into a different vein.

The dosage is based on your medical condition, body size, and response to treatment. Your doctor will do blood tests (complete blood count) to find the right dose for you. Your next dose may need to be rescheduled if your white blood cell count is too low.

Learn how to handle, use, and discard chemotherapy and medical supplies safely. Consult your pharmacist. Wash your hands carefully after handling this drug. Avoid getting this medication in your eye. If this occurs, wash the affected eye(s) well and contact your doctor.

Unless your doctor instructs you otherwise, drink plenty of fluids while taking this medication. Doing so helps your kidneys to remove the drug from your body and avoid some of the side effects.

SIDE EFFECTS: See also Warning section.

Pain/redness at the injection site, nausea, vomiting, constipation, tiredness, and loss of appetite may occur. Nausea and vomiting can be severe. In some cases, your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals, not eating before treatment, or limiting activity may help lessen some of these effects. If these effects persist or worsen, tell your doctor or pharmacist promptly.

To reduce constipation, increase your intake of fiber, drink plenty of water, and exercise. Stool softeners may be helpful. Ask your doctor or pharmacist about stool softeners and laxatives.

Temporary hair loss is another common side effect. Normal hair growth should return after treatment has ended.

Many people using this medication may have serious side effects. However, your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.

Painful sores on the lips, mouth, and throat may occur. To decrease the risk, limit hot foods and drinks, brush your teeth carefully, avoid using mouthwash that contains alcohol, and rinse your mouth frequently with cool water.

Tell your doctor immediately if any of these unlikely but serious side effects occur: easy bleeding/bruising, fast/pounding heartbeat, abdominal/stomach pain, bone/jaw pain, severe headache, hearing problems, unusual lumps/skin changes, dizziness/feeling of spinning, mental/mood changes (e.g., depression), pale/bluish fingers/toes, pain/coldness in fingers/toes, numbness/tingling, difficult/painful urination, pink/bloody urine.

Seek immediate medical attention if any of these rare but very serious side effects occur: sudden shortness of breath/wheezing, black/tarry stools, chest/left arm pain, confusion, seizures, slurred speech, weakness on one side of the body, vision changes, vomit that looks like coffee grounds.

This medication can lower the body's ability to fight an infection. Tell your doctor promptly if you develop any signs of an infection such as fever, chills, or persistent sore throat.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using vinblastine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: bone marrow problems (e.g., low white count/platelets from previous chemotherapy/radiation treatment, tumor in the bone marrow), untreated bacterial infection.

Before using this medication, tell your doctor or pharmacist your medical history, especially: blood vessel problems (e.g., blood clots, stroke, Raynaud's disease, varicose veins), heart disease (e.g., angina, heart attack), poor nutrition, liver disease, lung problems, stomach/intestinal sores (e.g., peptic ulcer), skin sores (ulcers).

Wash your hands well to prevent the spread of infections. Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.

To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

A preservative (benzyl alcohol) that might be found in this product or in the liquid used to mix this product can infrequently cause serious (sometimes fatal) problems if given in large amounts (more than 100 milligrams per kilogram daily) to an infant during the first months of life. The risk is also greater with low-birth-weight infants. Symptoms include sudden gasping, low blood pressure, or very slow heartbeat. If you notice any of these symptoms in your newborn, report them to the doctor immediately. If possible, a preservative-free product should be used when treating newborns.

Caution is advised when using this drug in the elderly, especially if they have poor nutrition or skin sores, because they may be more sensitive to the risk of infection.

This medication is not recommended for use during pregnancy. It may harm the unborn baby. Consult your doctor for more details. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: aspirin and other NSAIDs (e.g., ibuprofen), hydantoins (e.g., phenytoin), tolterodine, drugs that may harm the ears (e.g., cisplatin, carboplatin, aminoglycosides such as gentamicin), drugs affecting liver enzymes that remove vinblastine from your body (such as aprepitant, azole antifungals including itraconazole, ketoconazole, voriconazole, macrolide antibiotics including erythromycin, rifamycins including rifabutin).

Check all prescription and nonprescription medicine labels carefully since many contain pain relievers/fever reducers (NSAIDs such as ibuprofen, naproxen, or aspirin) that may increase your risk of bleeding. Low-dose aspirin should be continued if prescribed by your doctor for heart attack or stroke prevention (usually at dosages of 81-325 milligrams a day). Consult your doctor or pharmacist for more details.

Your doctor may direct you to limit citrus (and other foods/products that increase the acid level of urine) during treatment. Consult your doctor.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: seizures.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood counts) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. Keep all your medical/lab appointments. If you miss a dose, contact your doctor to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store in the original carton in the refrigerator between 36-46 degrees F (2-8 degrees C). Protect from light and moisture. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.