VINBLASTINE
DESCRIPTION:
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* *
* WARNINGS *
* CAUTION--THIS PREPARATION SHOULD BE *
* ADMINISTERED BY INDIVIDUALS EXPERIENCED IN *
* THE ADMINISTRATION OF CYTOBLASTIN. IT IS *
* EXTREMELY IMPORTANT THAT THE NEEDLE BE *
* PROPERLY POSITIONED IN THE VEIN BEFORE THIS *
* PRODUCT IS INJECTED. IF LEAKAGE INTO *
* SURROUNDING TISSUE SHOULD OCCUR DURING *
* INTRAVENOUS ADMINISTRATION OF CYTOBLASTIN, IT *
* MAY CAUSE CONSIDERABLE IRRITATION. 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 ARE THOUGHT TO *
* MINIMIZE DISCOMFORT AND THE POSSIBILITY OF *
* CELLULITIS. *
* FATAL IF GIVEN INTRATHECALLY. FOR *
* INTRAVENOUS USE ONLY. See Warnings Section *
* For The Treatment Of Patients Given *
* Intrathecal CYTOBLASTIN. *
* *
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CYTOBLASTIN Sterile (Vinblastine Sulfate, USP) is vincaleukoblastine, sulfate
(1:1) (salt). It is the salt of an alkaloid extracted from Vinca Rosea Linn
(REF. 1-3), 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 (REF. 4, 5) indicate that CYTOBLASTIN has the
empirical formula C46H58N4O9.H2SO4 and that it is a dimeric alkaloid containing
both indole and dihydroindole moieties.
It has a molecular weight of 909.06.
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 CYTOBLASTIN 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.
ACTIONS/CLINICAL PHARMACOLOGY:
Experimental data indicate that the action of CYTOBLASTIN is different from that of
other recognized antineoplastic agents. (REF. 8-13) Tissue- culture studies
suggest an interference with metabolic pathways of amino acids leading from
glutamic acid to the citric acid cycle and to urea. (REF. 8-14) In vivo
experiments tend to confirm the in vitro results. (REF. 13-16) A number of
studies in vitro and in vivo have demonstrated that CYTOBLASTIN produces a
stathmokinetic effect and various atypical mitotic figures. (REF. 9, 15, 17-
25)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 CYTOBLASTIN by glutamic acid or tryptophan has
been observed. In addition, glutamic acid and aspartic acid have protected mice
from lethal doses of CYTOBLASTIN. (REF. 13) Aspartic acid was relatively ineffective
in reversing the antitumor effect.
Other studies indicate that CYTOBLASTIN has an effect on cell-energy production
required for mitosis (REF. 25) and interferes with nucleic acid synthesis. (REF.
26-29) The mechanism of action of CYTOBLASTIN 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 compartments 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. (REF. 30) 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. (See Precautions).
(REF. 31-32) Following injection of tritiated vinblastine in the human cancer
patient, 10% of the radioactivity was found in the feces and 14% in the urine;
the remaining activity was not accounted for. (REF. 33) 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. (REF. 34) 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. (REF. 35, 36)
Hematologic Effects--Clinically, leukopenia is an expected effect of CYTOBLASTIN 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 CYTOBLASTIN, 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 CYTOBLASTIN, 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(cube)). When other chemotherapy
or radiation has not been employed previously, thrombocyte reduction below the
level of 200,000/mm(cube) is rarely encountered, even when CYTOBLASTIN may be causing
significant leukopenia. Rapid recovery from thrombocytopenia within a few days
is the rule.
The effect of CYTOBLASTIN 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.
INDICATIONS AND USAGE:
Vinblastine sulfate 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) (REF. 37-41)
Lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated) (REF.
42, 43)
Histiocytic lymphoma (REF. 42, 43)
Mycosis fungoides (advanced stages) (REF. 44)
Advanced carcinoma of the testis
Kaposi's sarcoma (REF. 45, 46)
Letterer-Siwe disease (histiocytosis X) (REF. 47)
II. Less Frequently Responsive Malignancies--
Choriocarcinoma resistant to other chemotherapeutic agents (REF. 48, 49)
Carcinoma of the breast, unresponsive to appropriate endocrine surgery and
hormonal therapy (REF. 50, 53)
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 CYTOBLASTIN is effective as a single agent in the
aforementioned indications, it is usually administered in combination with other
antineoplastic drugs. (REF. 53, 56) 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. (REF. 50,
54-58)
Hodgkin's Disease--CYTOBLASTIN has been shown to be one of the most effective single
agents for the treatment of Hodgkin's disease. (REF. 50, 57-59) Advanced
Hodgkin's disease has also been successfully treated with several multiple-drug
regimens that included CYTOBLASTIN. (REF. 60-66) Patients who had relapses after
treatment with the MOPP program-- mechlorethamine hydrochloride (nitrogen
mustard), vincristine sulfate (Oncovin (Vincristine Sulfate Injection),
prednisone, and procarbazine-- have likewise responded to combination-drug
therapy that included CYTOBLASTIN. (REF. 54, 55, 67-69) A protocol using
cyclophosphamide in place of nitrogen mustard and CYTOBLASTIN instead of Oncovin is
an alternative therapy for previously untreated patients with advanced Hodgkin's
disease. (REF. 50, 57, 58, 70)
Advanced testicular germinal-cell cancers (embryonal carcinoma, teratocarcinoma,
and choriocarcinoma) are sensitive to CYTOBLASTIN alone, (REF. 71) but better
clinical results are achieved when CYTOBLASTIN is administered concomitantly with
other antineoplastic agents. (REF. 72-77) The effect of bleomycin is
significantly enhanced if CYTOBLASTIN 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.
(REF. 76, 77)
CONTRAINDICATIONS:
CYTOBLASTIN 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 CYTOBLASTIN.
WARNINGS:
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* *
* WARNINGS *
* CAUTION--THIS PREPARATION SHOULD BE *
* ADMINISTERED BY INDIVIDUALS EXPERIENCED IN *
* THE ADMINISTRATION OF CYTOBLASTIN. IT IS *
* EXTREMELY IMPORTANT THAT THE NEEDLE BE *
* PROPERLY POSITIONED IN THE VEIN BEFORE THIS *
* PRODUCT IS INJECTED. IF LEAKAGE INTO *
* SURROUNDING TISSUE SHOULD OCCUR DURING *
* INTRAVENOUS ADMINISTRATION OF CYTOBLASTIN, IT *
* MAY CAUSE CONSIDERABLE IRRITATION. 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 ARE THOUGHT TO *
* MINIMIZE DISCOMFORT AND THE POSSIBILITY OF *
* CELLULITIS. *
* FATAL IF GIVEN INTRATHECALLY. FOR *
* INTRAVENOUS USE ONLY. See Warnings Section *
* For The Treatment Of Patients Given *
* Intrathecal CYTOBLASTIN. *
* *
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* *
* This Product Is For Intravenous Use Only. *
* It Should Be Administered By Individuals *
* Experienced In The Administration Of *
* CYTOBLASTIN. The Intrathecal Administration Of *
* CYTOBLASTIN Has Resulted In Death. Syringes *
* Containing This Product Should Be Labeled *
* "WARNING--FOR IV USE ONLY." *
* Extemporaneously prepared syringes *
* containing this product must be packaged in *
* an overwrap that is labeled "DO NOT REMOVE *
* COVERING UNTIL MOMENT OF INJECTION. FATAL *
* IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE *
* ONLY." *
* The following treatment successfully *
* arrested progressive paralysis in a single *
* patient mistakenly given the related vinca *
* alkaloid, vincristine sulfate, *
* intrathecally. If CYTOBLASTIN is mistakenly *
* administered intrathecally, this treatment *
* is recommended and should be initiated *
* immediately after the intrathecal *
* injection. *
* 1. Remove as much spinal fluid as can be *
* safely done through the lumbar access. *
* 2. Insert a catheter in a lateral cerebral *
* ventricle for the purpose of flushing the *
* subarachnoid space from above with removal *
* through a lumbar access. *
* 3. Initiate flushing through the cerebral *
* catheter with lactated Ringer's solution *
* infused at the rate of 150 mL/h. *
* 4. As soon as fresh frozen plasma becomes *
* available, infuse fresh frozen plasma, *
* 25mL, diluted in 1 L of Lactated Ringer's *
* solution through the cerebral ventricular *
* catheter at the rate of 75 mL/h with *
* removal through the lumbar access. The *
* rate of infusion should be adjusted to *
* maintain a protein level in the spinal *
* fluid of 150 mg/dL. 5. Administer 10 g of *
* glutamic acid intravenously over 24 hours *
* followed by 500 mg 3 times daily by mouth *
* for 1 month or until neurological *
* dysfunction stabilizes. The role of *
* glutamic acid in this treatment is not *
* certain and may not be essential. *
* The use of this treatment has not been *
* reported following intrathecal vinblastine *
* sulfate. *
* *
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Usage In Pregnancy--Caution is necessary with the administration of all
oncolytic drugs during pregnancy. Information on the use of CYTOBLASTIN during human
pregnancy is very limited. (REF. 78-82) Animal studies with CYTOBLASTIN suggest that
teratogenic effects may occur. (REF. 83, 84) 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. (REF. 85) 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. (REF. 22, 86)
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
section. 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/mm(cube) occurs following a
dose of CYTOBLASTIN, 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
CYTOBLASTIN. 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. CYTOBLASTIN should not be
readministered.
The Use Of Small Amounts Of CYTOBLASTIN 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. (REF. 87) 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. (REF. 87)
Care must be taken to avoid contamination of the eye with concentrations of
CYTOBLASTIN 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 should be refrigerated for future use.
Information For Patients--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 CYTOBLASTIN. Nausea and vomiting, although
not common, may occur. Any other serious medical event should be reported to the
physician.
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 CYTOBLASTIN. Following administration of
CYTOBLASTIN, 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.
Drug Interactions--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. (REF. 88) 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 (See Adverse
Reactions).
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. (REF. 22) Amenorrhea has occurred in some
patients treated with the combination consisting of an alkylating agent,
procarbazine, prednisone, and CYTOBLASTIN. Its occurrence was related to the total
dose of these 4 agents used. Recovery of menses was frequent. (REF. 89-92) 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. (REF. 93-95)
Mutagenicity--Tests in Salmonella Typhimurium and with the dominant lethal assay
in mice failed to demonstrate mutagenicity. Sperm abnormalities have been noted
in mice. CYTOBLASTIN has produced an increase in micronuclei formation in bone marrow
cells of mice; however, since CYTOBLASTIN inhibits mitotic spindle formation, it
cannot be concluded that this is evidence of mutagenicity. (REF. 96) 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. (REF. 96, 97)
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. (REF. 96) Breaks and
aberrations were not observed on chromosome analysis of marrow cells from
patients being treated with this drug. (REF. 98)
It is not clear from the literature how this drug affects synthesis of DNA and
RNA. Some believe that there is no interference. (REF. 99) 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. (REF. 100) No inhibition of RNA
synthesis occurred in rat hepatoma cells exposed in culture to noncytotoxic
levels of vinblastine. (REF. 101) Conflicting results have been noted by others
(REF. 102-110) regarding interference with DNA synthesis.
Carcinogenesis--There is no currently available evidence to indicate that CYTOBLASTIN
itself has been carcinogenic in humans (REF. 96) since the inception of its
clinical use in the late 1950s. Patients treated for Hodgkin's disease have
developed leukemia following radiation therapy and administration of CYTOBLASTIN in
combination with other chemotherapy including agents known to intercalate with
DNA. It is not known to what extent CYTOBLASTIN 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
CYTOBLASTIN was in the group of drugs causing slightly increased or the same tumor
incidence as controls in one study and 1.5 to twofold increase in tumor
incidence over controls in another study. (REF. 96-111)
Usage In Pregnancy--Pregnancy Category D (see Warnings). CYTOBLASTIN should be given
to a pregnant woman only if clearly needed. Animal studies suggest that
teratogenic effects may occur. (REF. 83, 84)
Pediatric Usage (REF. 112, 113)--The dosage schedule for children 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 CYTOBLASTIN 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.
DRUG INTERACTIONS:
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. (REF. 88) 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 (See Adverse
Reactions).
(See Also PRECAUTIONS)
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 CYTOBLASTIN
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, 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. 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 CYTOBLASTIN 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.
OVERDOSAGE:
Signs And Symptoms--Side effects following the use of CYTOBLASTIN 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
Actions/Clinical Pharmacology, Contraindications, Warnings, Precautions, and
Adverse Reactions.) There is no specific antidote. In addition, neurotoxicity
similar to that with Oncovin 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(R)). In managing overdosage, consider the possibility of multiple
drug overdoses, interaction among drugs, and unusual drug kinetics in your
patient. Overdoses of CYTOBLASTIN 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 CYTOBLASTIN 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.
CYTOBLASTIN 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 CYTOBLASTIN 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. (REF. 114) The oral median lethal dose in rats is 7 mg/kg. (REF. 86)
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.
DOSAGE AND ADMINISTRATION:
CAUTION--IT IS EXTREMELY IMPORTANT THAT THE NEEDLE BE PROPERLY POSITIONED IN THE
VEIN BEFORE THIS PRODUCT IS INJECTED.
IF LEAKAGE INTO SURROUNDING TISSUE SHOULD OCCUR DURING INTRAVENOUS
ADMINISTRATION OF CYTOBLASTIN, IT MAY CAUSE CONSIDERABLE IRRITATION. 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
ARE THOUGHT TO MINIMIZE DISCOMFORT AND THE POSSIBILITY OF CELLULITIS.
There are variations in the depth of the leukopenic response that follows
therapy with CYTOBLASTIN. For this reason, it is recommended that the drug be given
no more frequently than Once Every 7 Days. It is wise to initiate therapy for
adults by administering a single intravenous dose of 3.7 mg/M(square) of body
surface area (bsa); the initial dose for children should be 2.5 mg/M(square).
Thereafter, white-blood-cell counts should be made to determine the patient's
sensitivity to CYTOBLASTIN. A reduction of 50% in the dose of CYTOBLASTIN 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.
A simplified and conservative incremental approach to dosage At Weekly Intervals
may be outlined as follows:
ADULTS CHILDREN
First dose..... 3.7 mg/M(square) bsa 2.5 mg/M(square) bsa
Second dose.... 5.5 mg/M(square) bsa 3.75 mg/M(square) bsa
Third dose..... 7.4 mg/M(square) bsa 5.0 mg/M(square) bsa
Fourth dose.... 9.25 mg/M(square) bsa 6.25 mg/M(square) bsa
Fifth dose..... 11.1 mg/M(square) bsa 7.5 mg/M(square) bsa
The above-mentioned increases may be used until a maximum dose (not exceeding
18.5 mg/M(square) bsa for adults and 12.5 mg/M(square) bsa for children) is
reached. The dose should not be increased after that dose which reduces the
white-cell count to approximately 3,000 cells/mm(cube). In some adults, 3.7
mg/M(square) bsa may produce this leukopenia; other adults may require more than
11.1 mg/M(square) bsa; and, very rarely, as much as 18.5 mg/M(square) bsa may be
necessary. For most adult patients, however, the weekly dosage will prove to be
5.5 to 7.4 mg/M(square) bsa.
When the dose of CYTOBLASTIN 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 CYTOBLASTIN Should Not Be Given Until The White-
Cell Count Has Returned To At Least 4,000/mm(cube). 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).
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. (REF. 55, 56, 115)
Prolonged chemotherapy for maintaining remissions involves several risks, among
which are life-threatening infectious diseases, sterility, (REF. 113) and
possibly the appearance of other cancers through suppression of immune
surveillance. (REF. 55, 116)
In some disorders, survival following complete remission may not be as prolonged
as that achieved with shorter periods of maintenance therapy. (REF. 37, 63) 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 of CYTOBLASTIN/mL, 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 CYTOBLASTIN in the sterile vial. Do
not use other solutions. The drug dissolves instantly to give a clear solution.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
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 CYTOBLASTIN (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 CYTOBLASTIN 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 (ie, 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 CYTOBLASTIN into an extremity in which the circulation is
impaired or potentially impaired by such conditions as compressing or invading
neoplasm, phlebitis, or varicosity.
Procedures for proper handling and disposal of anticancer drugs should be
considered. Several guidelines on this subject have been published. (REF. 117-
122) There is no general agreement that all of the procedures recommended in the
guidelines are necessary or appropriate.
Special Dispensing Information--When dispensing CYTOBLASTIN in other than the
original container, eg. a syringe containing a specific dose, it is imperative
that it be packaged in an overwrap bearing the statement: "DO NOT REMOVE
COVERING UNTIL MOMENT OF INJECTION, FATAL IF GIVEN INTRATHECALLY. FOR
INTRAVENOUS USE ONLY." (See Warnings)
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