CYTARABINE
DESCRIPTION:
*************************************************
* *
* WARNINGS: *
* Only physicians experienced in cancer *
* chemotherapy should use CYTARABINE Sterile *
* Powder. *
* For induction therapy patients should be *
* treated in a facility with laboratory and *
* supportive resources sufficient to monitor *
* drug tolerance and protect and maintain a *
* patient compromised by drug toxicity. The *
* main toxic effect of CYTARABINE is bone *
* marrow suppression with leukopenia, *
* thrombocytopenia and anemia. Less serious *
* toxicity includes nausea, vomiting, *
* diarrhea and abdominal pain, oral *
* ulceration, and hepatic dysfunction. *
* The physician must judge possible benefit *
* to the patient against known toxic effects *
* of this drug in considering the *
* advisability of therapy with CYTARABINE. *
* Before making this judgment or beginning *
* treatment, the physician should be familiar *
* with the following text. *
* *
*************************************************
CYTARABINE (cytarabine) Sterile Powder, commonly known as ara-C, an
antineoplastic, is a sterile lyophilized material for reconstitution and
intravenous, intrathecal or subcutaneous administration. It is available in
multi-dose vials containing 100 mg, 500 mg, 1 g or 2 g sterile cytarabine. The
pH of CYTARABINE was adjusted, when necessary, with hydrochloric acid and/or
sodium hydroxide.
Cytarabine is chemically 4-amino-1-beta-D- arabinofuranosyl-2 (1H)-pyrimidinone.
Cytarabine is an odorless, white to off-white, crystalline powder which is
freely soluble in water and slightly soluble in alcohol and in chloroform.
PHARMACOLOGY
CELL CULTURE STUDIES
Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in
culture. It exhibits cell phase specificity, primarily killing cells undergoing
DNA synthesis (S-phase) and under certain conditions blocking the progression of
cells from the G1 phase to the S- phase. Although the mechanism of action is not
completely understood, it appears that cytarabine acts through the inhibition of
DNA polymerase. A limited, but significant, incorporation of cytarabine into
both DNA and RNA has also been reported. Extensive chromosomal damage, including
chromatoid breaks, have been produced by cytarabine and malignant transformation
of rodent cells in culture has been reported. Deoxycytidine prevents or delays
(but does not reverse) the cytotoxic activity.
Cell culture studies have shown an antiviral effect. (REF. 1) However, efficacy
against herpes zoster or smallpox could not be demonstrated in controlled
clinical trials. (REF. 2-4)
CELLULAR RESISTANCE AND SENSITIVITY
Cytarabine is metabolized by deoxycytidine kinase and other nucleotide kinases
to the nucleotide triphosphate, an effective inhibitor of DNA polymerase; it is
inactivated by a pyrimidine nucleoside deaminase, which converts it to the
nontoxic uracil derivative. It appears that the balance of kinase and deaminase
levels may be an important factor in determining sensitivity or resistance of
the cell to cytarabine.
ANIMAL STUDIES
In experimental studies with mouse tumors, cytarabine was most effective in
those tumors with a high growth fraction. The effect was dependent on the
treatment schedule; optimal effects were achieved when the schedule (multiple
closely spaced doses or constant infusion) ensured contact of the drug with the
tumor cells when the maximum number of cells were in the susceptible S-phase.
The best results were obtained when courses of therapy were separated by
intervals sufficient to permit adequate host recovery.
HUMAN PHARMACOLOGY
Cytarabine is rapidly metabolized and is not effective orally; less than 20
percent of the orally administered dose is absorbed from the gastrointestinal
tract.
Following rapid intravenous injection of cytarabine labeled with tritium, the
disappearance from plasma is biphasic. There is an initial distributive phase
with a half-life of about 10 minutes, followed by a second elimination phase
with a half-life of about 1 to 3 hours. After the distributive phase, more than
80 percent of plasma radioactivity can be accounted for by the inactive
metabolite 1-beta- D-arabinofuranosyluracil (ara-U). Within 24 hours about 80
percent of the administered radioactivity can be recovered in the urine,
approximately 90 percent of which is excreted as ara-U.
Relatively constant plasma levels can be achieved by continuous intravenous
infusion.
After subcutaneous or intramuscular administration of cytarabine labeled with
tritium, peak-plasma levels of radioactivity are achieved about 20 to 60 minutes
after injection and are considerably lower than those after intravenous
administration.
Cerebrospinal fluid levels of cytarabine are low in comparison to plasma levels
after single intravenous injection. However, in one patient in whom
cerebrospinal levels were examined after 2 hours of constant intravenous
infusion, levels approached 40 percent of the steady state plasma level. With
intrathecal administration, levels of cytarabine in the cerebrospinal fluid
declined with a first order half-life of about 2 hours. Because cerebrospinal
fluid levels of deaminase are low, little conversion to ara-U was observed.
IMMUNOSUPPRESSIVE ACTION
CYTARABINE Sterile Powder is capable of obliterating immune responses in man
during administration with little or no accompanying toxicity. (REF. 5-6)
Suppression of antibody responses to E-coli-VI antigen and tetanus toxoid have
been demonstrated. This suppression was obtained during both primary and
secondary antibody responses.
CYTARABINE also suppressed the development of cell-mediated immune responses such
as delayed hypersensitivity skin reaction to dinitrochlorobenzene. However, it
had no effect on already established delayed hypersensitivity reactions.
Following 5-day courses of intensive therapy with CYTARABINE the immune response
was suppressed, as indicated by the following parameters: macrophage ingress
into skin windows; circulating antibody response following primary antigenic
stimulation; lymphocyte blastogenesis with phytohemagglutinin. A few days after
termination of therapy there was a rapid return to normal. (REF. 7)
INDICATIONS AND USAGE:
CYTARABINE in combination with other approved anticancer drugs is indicated for
remission induction in acute nonlymphocytic leukemia of adults and pediatric
patients. It has also been found useful in the treatment of acute lymphocytic
leukemia and the blast phase of chronic myelocytic leukemia. Intrathecal
administration of CYTARABINE is indicated in the prophylaxis and treatment of
meningeal leukemia.
CONTRAINDICATIONS:
CYTARABINE Sterile Powder is contraindicated in those patients who are
hypersensitive to the drug.
WARNINGS (SEE BOXED WARNING)
Cytarabine is a potent bone marrow suppressant. Therapy should be started
cautiously in patients with pre-existing drug-induced bone marrow suppression.
Patients receiving this drug must be under close medical supervision and, during
induction therapy, should have leukocyte and platelet counts performed daily.
Bone marrow examinations should be performed frequently after blasts have
disappeared from the peripheral blood. Facilities should be available for
management of complications, possibly fatal, of bone marrow suppression
(infection resulting from granulocytopenia and other impaired body defenses, and
hemorrhage secondary to thrombocytopenia). One case of anaphylaxis that resulted
in acute cardiopulmonary arrest and required resuscitation has been reported.
This occurred immediately after the intravenous administration of CYTARABINE
Sterile Powder.
Severe and at times fatal CNS, GI and pulmonary toxicity (different from that
seen with conventional therapy regimens of CYTARABINE) has been reported
following some experimental dose schedules for CYTARABINE. (REF. 8-11) These
reactions include reversible corneal toxicity, and hemorrhagic conjunctivitis,
which may be prevented or diminished by prophylaxis with a local corticosteroid
eye drop; cerebral and cerebellar dysfunction, including personality changes,
somnolence and coma, usually reversible; severe gastrointestinal ulceration,
including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and
liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia;
bowel necrosis; and necrotizing colitis. Rarely, severe skin rash, leading to
desquamation has been reported. Complete alopecia is more commonly seen with
experimental high dose therapy than with standard treatment programs using
CYTARABINE. If experimental high dose therapy is used, do not use a diluent
containing benzyl alcohol.
Cases of cardiomyopathy with subsequent death have been reported following
experimental high dose therapy with cytarabine in combination with
cyclophosphamide when used for bone marrow transplant preparation. (REF. 12)
A syndrome of sudden respiratory distress, rapidly progressing to pulmonary
edema and radiographically pronounced cardiomegaly has been reported following
experimental high dose therapy with cytarabine used for the treatment of
relapsed leukemia from one institution in 16/72 patients. The outcome of this
syndrome can be fatal. (REF. 13)
Benzyl alcohol is contained in the diluent for this product. Benzyl alcohol has
been reported to be associated with a fatal "Gasping Syndrome" in premature
infants.
Two patients with childhood acute myelogenous leukemia who received intrathecal
and intravenous CYTARABINE at conventional doses (in addition to a number of
other concomitantly administered drugs) developed delayed progressive ascending
paralysis resulting in death in one of the two patients. (REF. 14)
USE IN PREGNANCY (CATEGORY D)
CYTARABINE can cause fetal harm when administered to a pregnant woman. (See
ANIMAL TOXICOLOGY). There are no adequate and well-controlled studies in
pregnant women. If CYTARABINE is used during pregnancy, or if the patient becomes
pregnant while taking CYTARABINE, the patient should be apprised of the potential
hazard to the fetus. Women of childbearing potential should be advised to avoid
becoming pregnant.
A review of the literature has shown 32 reported cases where CYTARABINE was given
during pregnancy, either alone or in combination with other cytotoxic agents:
Eighteen normal infants were delivered. Four of these had first trimester
exposure. Five infants were premature or of low birth weight. Twelve of the 18
normal infants were followed up at ages ranging from six weeks to seven years,
and showed no abnormalities. One apparently normal infant died at 90 days of
gastroenteritis.
Two cases of congenital abnormalities have been reported, one with upper and
lower distal limb defects, (REF. 16) and the other with extremity and ear
deformities (REF. 17) Both of these cases had first trimester exposure.
There were seven infants with various problems in the neonatal period, including
pancytopenia; transient depression of WBC, hematocrit or platelets; electrolyte
abnormalities; transient eosinophilia; and one case of increased IgM levels and
hyperpyrexia possibly due to sepsis. Six of the seven infants were also
premature. The child with pancytopenia died at 21 days of sepsis.
Therapeutic abortions were done in five cases. Four fetuses were grossly normal,
but one had an enlarged spleen and another showed Trisomy C chromosome
abnormality in the chorionic tissue.
Because of the potential for abnormalities with cytotoxic therapy, particularly
during the first trimester, a patient who is or who may become pregnant while on
CYTARABINE should be apprised of the potential risk to the fetus and the
advisability of pregnancy continuation. There is a definite, but considerably
reduced risk if therapy is initiated during the second or third trimester.
Although normal infants have been delivered to patients treated in all three
trimesters of pregnancy, follow-up of such infants would be advisable.
WARNINGS:
*************************************************
* *
* WARNINGS *
* Only physicians experienced in cancer *
* chemotherapy should use CYTARABINE Sterile *
* Powder. *
* For induction therapy patients should be *
* treated in a facility with laboratory and *
* supportive resources sufficient to monitor *
* drug tolerance and protect and maintain a *
* patient compromised by drug toxicity. The *
* main toxic effect of CYTARABINE is bone *
* marrow suppression with leukopenia, *
* thrombocytopenia and anemia. Less serious *
* toxicity includes nausea, vomiting, *
* diarrhea and abdominal pain, oral *
* ulceration, and hepatic dysfunction. *
* The physician must judge possible benefit *
* to the patient against known toxic effects *
* of this drug in considering the *
* advisability of therapy with CYTARABINE. *
* Before making this judgment or beginning *
* treatment, the physician should be familiar *
* with the following text. *
* *
*************************************************
PRECAUTIONS:
1. GENERAL PRECAUTIONS
Patients receiving CYTARABINE Sterile Powder must be monitored closely. Frequent
platelet and leukocyte counts and bone marrow examinations are mandatory.
Consider suspending or modifying therapy when drug-induced marrow depression has
resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte
count under 1000/mm(cubed). Counts of formed elements in the peripheral blood
may continue to fall after the drug is stopped and reach lowest values after
drug-free intervals of 12 to 24 days. When indicated, restart therapy when
definite signs of marrow recovery appear (on successive bone marrow studies).
Patients whose drug is withheld until "normal" peripheral blood values are
attained may escape from control.
When large intravenous doses are given quickly, patients are frequently
nauseated and may vomit for several hours postinjection. This problem tends to
be less severe when the drug is infused.
The human liver apparently detoxifies a substantial fraction of an administered
dose. In particular, patients with renal or hepatic function impairment may have
a higher likelihood of CNS toxicity after high-dose CYTARABINE treatment. (REF.
46, 47) Use the drug with caution and possibly at reduced dose in patients whose
liver or kidney function is poor.
Periodic checks of bone marrow, liver and kidney functions should be performed
in patients receiving CYTARABINE.
Like other cytotoxic drugs, CYTARABINE may induce hyperuricemia secondary to
rapid lysis of neoplastic cells. The clinician should monitor the patient's
blood uric acid level and be prepared to use such supportive and pharmacologic
measures as might be necessary to control this problem. Acute pancreatitis has
been reported to occur in patients being treated with CYTARABINE who have had
prior treatment with L=asparaginase. (REF. 15)
2. INFORMATION FOR PATIENT
Not applicable
3. LABORATORY TESTS
(See General Precautions.)
4. DRUG INTERACTIONS
REVERSIBLE DECREASES IN STEADY-STATE PLASMA DIGOXIN CONCENTRATIONS AND RENAL
GLYCOSIDE EXCRETION WERE OBSERVED IN PATIENTS RECEIVING BETA-ACETYLDIGOXIN AND
CHEMOTHERAPY REGIMENS CONTAINING CYCLOPHOSPHAMIDE, VINCRISTINE AND PREDNISONE
WITH OR WITHOUT CYTARABINE OR PROCARBAZINE. (REF. 39) STEADY-STATE PLASMA
DIGITOXIN CONCENTRATIONS DID NOT APPEAR TO CHANGE. THEREFORE, MONITORING OF
PLASMA DIGOXIN LEVELS MAY BE INDICATED IN PATIENTS RECEIVING SIMILAR COMBINATION
CHEMOTHERAPY REGIMENS. THE UTILIZATION OF DIGITOXIN FOR SUCH PATIENTS MAY BE
CONSIDERED AS AN ALTERNATIVE.
An In Vitro interaction study between gentamicin and cytarabine showed a
cytarabine related antagonism for the susceptibility of K. Pneumoniae strains.
This study suggests that in patients on cytarabine being treated with gentamicin
for a K. Pneumoniae infection, the lack of a prompt therapeutic response may
indicate the need for reevaluation of antibacterial therapy. (REF. 40)
Clinical evidence in one patient showed possible inhibition of fluorocytosine
efficacy during therapy with CYTARABINE. (REF. 41) This may be due to potential
competitive inhibition of its uptake. (REF. 42)
5. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Extensive chromosomal damage, including chromatoid breaks have been produced by
cytarabine and malignant transformation of rodent cells in culture has been
reported.
6. PREGNANCY
Pregnancy Category D. (See WARNINGS.)
7. LABOR AND DELIVERY
Not applicable
8. 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 in nursing infants from cytarabine, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
9. PEDIATRIC USE
(See INDICATIONS AND USAGE.)
DRUG INTERACTIONS:
REVERSIBLE DECREASES IN STEADY-STATE PLASMA DIGOXIN CONCENTRATIONS AND RENAL
GLYCOSIDE EXCRETION WERE OBSERVED IN PATIENTS RECEIVING BETA-ACETYLDIGOXIN AND
CHEMOTHERAPY REGIMENS CONTAINING CYCLOPHOSPHAMIDE, VINCRISTINE AND PREDNISONE
WITH OR WITHOUT CYTARABINE OR PROCARBAZINE. (REF. 39) STEADY-STATE PLASMA
DIGITOXIN CONCENTRATIONS DID NOT APPEAR TO CHANGE. THEREFORE, MONITORING OF
PLASMA DIGOXIN LEVELS MAY BE INDICATED IN PATIENTS RECEIVING SIMILAR COMBINATION
CHEMOTHERAPY REGIMENS. THE UTILIZATION OF DIGITOXIN FOR SUCH PATIENTS MAY BE
CONSIDERED AS AN ALTERNATIVE.
An In Vitro interaction study between gentamicin and cytarabine showed a
cytarabine related antagonism for the susceptibility of K. Pneumoniae strains.
This study suggests that in patients on cytarabine being treated with gentamicin
for a K. Pneumoniae infection, the lack of a prompt therapeutic response may
indicate the need for reevaluation of antibacterial therapy. (REF. 40)
Clinical evidence in one patient showed possible inhibition of fluorocytosine
efficacy during therapy with CYTARABINE. (REF. 41) This may be due to potential
competitive inhibition of its uptake. (REF. 42)
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
EXPECTED REACTIONS
Because cytarabine is a bone marrow suppressant, anemia, leukopenia,
thrombocytopenia, megaloblastosis and reduced reticulocytes can be expected as a
result of administration with CYTARABINE Sterile Powder. The severity of these
reactions are dose and schedule dependent. (REF. 18) Cellular changes in the
morphology of bone marrow and peripheral smears can be expected. (REF. 19)
Following 5-day constant infusions or acute injections of 50 mg/M(squared) to
600 mg/M(squared), white cell depression follows a biphasic course. Regardless
of initial count, dosage level, or schedule, there is an initial fall starting
the first 24 hours with a nadir at days 7-9. This is followed by a brief rise
which peaks around the twelfth day. A second and deeper fall reaches nadir at
days 15-24. Then there is rapid rise to above baseline in the next 10 days.
Platelet depression is noticeable at 5 days with a peak depression occurring
between days 12-15. Thereupon, a rapid rise to above baseline occurs in the next
10 days. (REF. 20)
INFECTIOUS COMPLICATIONS
INFECTION: Viral, bacterial, fungal, parasitic, or saprophytic infections, in
any location in the body may be associated with the use of CYTARABINE alone or in
combination with other immunosuppressive agents following immunosuppressant
doses that affect cellular or humoral immunity. These infections may be mild,
but can be severe and at times fatal.
THE CYTARABINE (ARA-C) SYNDROME
A cytarabine syndrome has been described by Castleberry. (REF. 21) It is
characterized by fever, myalgia, bone pain, occasionally chest pain,
maculopapular rash, conjunctivitis and malaise. It usually occurs 6-12 hours
following drug administration. Corticosteroids have been shown to be beneficial
in treating or preventing this syndrome. If the symptoms of the syndrome are
deemed treatable, corticosteroids should be contemplated as well as continuation
of therapy with CYTARABINE.
MOST FREQUENT ADVERSE REACTIONS
anorexia
nausea
vomiting
diarrhea
oral and anal inflammation or ulceration
hepatic dysfunction
fever
rash
thrombophlebitis
bleeding (all sites)
Nausea and vomiting are most frequent following rapid intravenous injection.
LESS FREQUENT ADVERSE REACTIONS
sepsis
pneumonia
cellulitis at injection site
skin ulceration
urinary retention
renal dysfunction
neuritis
neural toxicity
sore throat
esophageal ulceration
esophagitis
chest pain
pericarditis
bowel necrosis
abdominal pain
freckling
jaundice
conjunctivitis (may occur with rash)
dizziness
alopecia
anaphylaxis (See WARNINGS)
allergic edema
pruritus
shortness of breath
urticaria
headache
EXPERIMENTAL DOSES
Severe and at times fatal CNS, GI and pulmonary toxicity (different from that
seen with conventional therapy regimens of CYTARABINE) has been reported
following some experimental dose schedules of CYTARABINE. (REF. 8-11) These
reactions include reversible corneal toxicity and hemorrhagic conjunctivitis,
which may be prevented or diminished by prophylaxis with a local corticosteroid
eye drop; cerebral and cerebellar dysfunction, including personality changes,
somnolence and coma, usually reversible; severe gastrointestinal ulceration,
including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and
liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia;
bowel necrosis; and necrotizing colitis. Rarely, severe skin rash leading to
desquamation has been reported. Complete alopecia is more commonly seen with
experimental high dose therapy than with standard treatment programs using
CYTARABINE. If experimental high dose therapy is used, do not use a diluent
containing benzyl alcohol.
Cases of cardiomyopathy with subsequent death have been reported following
experimental high dose therapy with cytarabine in combination with
cyclophosphamide when used for bone marrow transplant preparation. (REF. 12)
THIS CARDIAC TOXICITY MAY BE SCHEDULE DEPENDENT. (REF. 45)
A syndrome of sudden respiratory distress, rapidly progressing to pulmonary
edema and radiographically pronounced cardiomegaly has been reported following
experimental high dose therapy with cytarabine used for the treatment of
relapsed leukemia from one institution in 16/72 patients. The outcome of this
syndrome can be fatal. (REF. 13)
Two patients with adult acute non-lymphocytic leukemia developed peripheral
motor and sensory neuropathies after consolidation with high-dose CYTARABINE,
daunorubicin, and asparaginase. Patients treated with high-dose CYTARABINE should
be observed for neuropathy since dose schedule alterations may be needed to
avoid irreversible neurologic disorders. (REF. 22)
Ten patients treated with experimental intermediate doses of CYTARABINE (1
g/M(squared)) with and without other chemotherapeutic agents (meta-AMSA,
daunorubicin, etoposide) at various dose regimen developed a diffuse
interstitial pneumonitis without clear cause that may have been related to the
CYTARABINE. (REF. 43)
Two cases of pancreatitis have been reported following experimental doses of
CYTARABINE and numerous other drugs. CYTARABINE could have been the causative
agent. (REF. 44)
OVERDOSAGE:
There is no antidote for overdosage of CYTARABINE. Doses of 4.5 g/M(squared) by
intravenous infusion over 1 hour every 12 hours for 12 doses has caused an
unacceptable increase in irreversible CNS toxicity and death. (REF. 9)
Single doses as high as 3 g/M(squared) have been administered by rapid
intravenous infusion without apparent toxicity. (REF. 23)
DOSAGE AND ADMINISTRATION:
CYTARABINE Sterile Powder is not active orally. The schedule and method of
administration varies with the program of therapy to be used. CYTARABINE may be
given by intravenous infusion or injection, subcutaneously, or intrathecally.
Thrombophlebitis has occurred at the site of drug injection or infusion in some
patients, and rarely patients have noted pain and inflammation at subcutaneous
injection sites. In most instances, however, the drug has been well tolerated.
Patients can tolerate higher total doses when they receive the drug by rapid
intravenous injection as compared with slow infusion. This phenomenon is related
to the drug's rapid inactivation and brief exposure of susceptible normal and
neoplastic cells to significant levels after rapid injection. Normal and
neoplastic cells seem to respond in somewhat parallel fashion to these different
modes of administration and no clear-cut clinical advantage has been
demonstrated for either.
In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine
dose in combination with other anticancer drugs is 100 mg/M(squared)/day by
continuous IV infusion (Days 1-7) or 100 mg/M(squared) IV every 12 hours (Days
1-7).
The literature should be consulted for the current recommendations for use in
acute lymphocytic leukemia.
INTRATHECAL USE IN MENINGEAL LEUKEMIA
CYTARABINE has been used intrathecally in acute leukemia in doses ranging from 5
mg/M(squared) to 75 mg/M(squared) of body surface area. The frequency of
administration varied from once a day for 4 days to once every 4 days. The most
frequently used dose was 30 mg/M(squared) every 4 days until cerebrospinal fluid
findings were normal, followed by one additional treatment. (REF. 24-28) The
dosage schedule is usually governed by the type and severity of central nervous
system manifestations and the response to previous therapy.
IF USED INTRATHECALLY, DO NOT USE A DILUENT CONTAINING BENZYL ALCOHOL. MANY
CLINICIANS RECONSTITUTE WITH AUTOLOGOUS SPINAL FLUID OR PRESERVATIVE-FREE 0.9%
SODIUM CHLORIDE, USP, FOR INJECTION AND USE IMMEDIATELY.
CYTARABINE given intrathecally may cause systemic toxicity and careful monitoring
of the hemopoietic system is indicated. Modification of other anti-leukemia
therapy may be necessary. Major toxicity is rare. The most frequently reported
reactions after intrathecal administration were nausea, vomiting and fever;
these reactions are mild and self-limiting. Paraplegia has been reported. (REF.
29) Necrotizing leukoencephalopathy occurred in 5 children; these patients had
also been treated with intrathecal methotrexate and hydrocortisone, as well as
by central nervous system radiation. (REF. 30) Isolated neurotoxicity has been
reported. (REF. 31) Blindness occurred in two patients in remission whose
treatment had consisted of combination systemic chemotherapy, prophylactic
central nervous system radiation and intrathecal CYTARABINE. (REF. 32)
When CYTARABINE is administered both intrathecally and intravenously within a few
days, there is an increased risk of spinal cord toxicity, however, in serious
life-threatening disease, concurrent use of intravenous and intrathecal CYTOSAR-
U is left to the discretion of the treating physician. (REF. 48)
Focal leukemic involvement of the central nervous system may not respond to
intrathecal CYTARABINE and may better be treated with radiotherapy.
The 100 mg vial may be reconstituted with 5 mL of Bacteriostatic Water for
Injection with Benzyl Alcohol 0.945% w/v added as preservative . The resulting
solution contains 20 mg of cytarabine per mL. (Do not use Bacteriostatic Water
for Injection with Benzyl Alcohol 0.945% w/v as a diluent for intrathecal use.)
(See WARNINGS).
The 500 mg vial may be reconstituted with 10 mL Bacteriostatic Water for
Injection with Benzyl Alcohol 0.945% w/v added as preservative. The resulting
solution contains 50 mg of cytarabine per mL. (Do not use Bacteriostatic Water
for Injection with Benzyl Alcohol 0.945% w/v as a diluent for intrathecal use.)
(See WARNINGS).
The 1 gram vial may be reconstituted with 10 mL of Bacteriostatic Water for
Injection with Benzyl Alcohol 0.945% w/v added as preservative. The resulting
solution contains 100 mg of cytarabine per mL. (Do not use Bacteriostatic Water
for Injection with Benzyl Alcohol 0.945% w/v as a diluent for intrathecal use.)
(See WARNINGS).
The 2 gram vial may be reconstituted with 20 mL of Bacteriostatic Water for
Injection with Benzyl Alcohol 0.945% w/v added as preservative. The resulting
solution contains 100 mg of cytarabine per mL. (Do not use Bacteriostatic Water
for Injection with Benzyl Alcohol 0.945% w/v as a diluent for intrathecal use.)
(See WARNINGS).
IF USED INTRATHECALLY MANY CLINICIANS RECONSTITUTE WITH PRESERVATIVE-FREE 0.9%
SODIUM CHLORIDE FOR INJECTION AND USE IMMEDIATELY.
The pH of the reconstituted solutions is about 5. Solutions reconstituted with
Bacteriostatic Water for Injection with Benzyl Alcohol 0.945% w/v may be stored
at controlled room temperature, 15 deg to 30 deg C (59 deg to 86 deg F) for 48
hours. Discard any solutions in which a slight haze develops.
Solutions reconstituted without a preservative should be used immediately.
CHEMICAL STABILITY OF INFUSION SOLUTIONS:
Chemical stability studies were performed by ultraviolet assay on CYTARABINE in
infusion solutions. These studies showed that when reconstituted CYTARABINE was
added to Water for Injection, 5% Dextrose in Water or Sodium Chloride Injection,
94 to 96 percent of the cytarabine was present after 192 hours storage at room
temperature.
Parenteral drugs should be inspected visually for particulate matter and
discoloration, prior to administration, whenever solution and container permit.
Procedures for proper handling and disposal of anticancer drugs should be
considered. Several guidelines on this subject have been published. (REF. 33-38)
There is no general agreement that all of the procedures recommended in the
guidelines are necessary or appropriate.
ANIMAL PHARMACOLOGY:
ANIMAL TOXICOLOGY
Toxicity of cytarabine in experimental animals, as well as activity, is markedly
influenced by the schedule of administration. For example, in mice, the LD10 for
single intraperitoneal administration is greater than 6000 mg/M(squared).
However, when administered as 8 doses, each separated by 3 hours, the LD10 is
less than 750 mg/M(squared) total dose. Similarly, although a total dose of 1920
mg/M(squared) administered as 12 injections at 6-hour intervals was lethal to
beagle dogs (severe bone marrow hypoplasia with evidence of liver and kidney
damage), dogs receiving the same total dose administered in 8 injections (again
at 6-hour intervals) over a 48-hour period survived with minimal signs of
toxicity. The most consistent observation in surviving dogs was elevated
transaminase levels. In all experimental species the primary limiting toxic
effect is marrow suppression with leukopenia. In addition, cytarabine causes
abnormal cerebellar development in the neonatal hamster and is teratogenic to
the rat fetus.
REFERENCES:
1. Zaky DA, Betts RF, Douglas RG, et al: Varicella-Zoster Virus and Subcutaneous
Cytarabine: Correlation of In Vitro Sensitivities to Blood Levels. Antimicrob
Agents Chemother 1975; 7:229-232.
2. Davis CM, VanDersarl JV, Coltman CA Jr: Failure of Cytarabine in Varicella-
Zoster Infections. JAMA 1973; 224: 122-123.
3. Betts RF, Zaky DA, Douglas RG, et al: Ineffectiveness of Subcutaneous
Cytosine Arabinoside in Localized Herpes Zoster. Ann Intern Med 1975; 82:778-
783.
4. Dennis DT, Doberstyn EB, Awoke S, et al: Failure of Cytosine Arabinoside in
Treatment Smallpox; A Double-blind Study, Lancet 1974; 2:377-379.
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