Exal

Exal (Exal injection) 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 Exal (Exal injection) 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: Exal (Exal injection) 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 Exal (Exal injection). 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 Exal (Exal injection). A protocol using cyclophosphamide in place of nitrogen mustard and Exal (Exal injection) 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 Exal (Exal injection) alone, but better clinical results are achieved when Exal (Exal injection) is administered concomitantly with other antineoplastic agents. The effect of bleomycin is significantly enhanced if Exal (Exal injection) 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 Exal (Exal injection) 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 Exal (Exal injection) is injected. Leakage into surrounding tissue during intravenous administration of Exal (Exal injection) 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 Exal (Exal injection). 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 Exal (Exal injection).

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 Exal (Exal injection) 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 Exal (Exal injection) in pediatric patients varied depending on the schedule used and whether Exal (Exal injection) 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 Exal (Exal injection) 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 Exal (Exal injection) 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 Exal (Exal injection) 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 Exal (Exal injection) , 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 Exal (Exal injection) 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 Exal (Exal injection) (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 Exal (Exal injection) 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 Exal (Exal injection) 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.

Exal (Exal injection) 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 Exal (Exal injection).

WARNINGS

This product is for intravenous use only. It should be administered by individuals experienced in the administration of Exal (Exal injection). The intrathecal administration of Exal (Exal injection) usually results in death. Syringes containing this product should be labeled, using the auxiliary sticker provided to state ''FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY.”

Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labeled “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY.”

After inadvertent intrathecal administration of vinca alkaloids, immediate neurosurgical intervention is required in order to prevent ascending paralysis leading to death. In a vey 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 Exal (Exal injection) to base treatment on. However, based on the published management of survival cases involving the related vinca alkaloid vincristine sulfate, if Exal (Exal injection) is mistakenly given by the intrathecal route, the following treatment should be initiated immediately after the injection:

1. Remove 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. Lactated Ringer's solution should be given by continuous infusion at 150 mL/hour, or 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 evey 8 hours by intravenous infusion over 30 minutes. Their roles in the reduction of neurotoxicity are unclear.

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. Exal (Exal injection) 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.

PRECAUTIONS

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 Exal (Exal injection) , 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 Exal (Exal injection). 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 Exal (Exal injection) 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 Exal (Exal injection) 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 Exal (Exal injection). Following administration of Exal (Exal injection) , 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 Exal (Exal injection). 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. Exal (Exal injection) 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 Exal (Exal injection) 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 Exal (Exal injection) 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 Exal (Exal injection) 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). Exal (Exal injection) 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 Exal (Exal injection) 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.

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 Exal (Exal injection) 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 Exal (Exal injection) 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.

Signs and Symptoms

Side effects following the use of Exal (Exal injection) 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,