Vinblastine

INDICATIONS AND USAGE: Vinblastine Sulfate Injection is indicated in the palliative treatment of the following: I. 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) II. 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 sulf

DOSAGE AND ADMINISTRATION: This preparation is for intravenous use only (see WARNINGS ). Special Dispensing Information - 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 . Adult Patients 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 ). 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/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. 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 o

ADVERSE REACTIONS: 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). 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 and 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 the 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.

Drug Interactions 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 ).