NEW ZEALAND DATA SHEET

1. PRODUCT NAME
DBL™ Cytarabine Injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

DBL™ Cytarabine Injection 20 mg/mL, 50 mg/mL and 100 mg/mL is a solution of
Cytarabine BP in Water for Injections.

3. PHARMACEUTICAL FORM
Solution for injection

DBL™ Cytarabine Injection is a clear colourless sterile solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Cytarabine may be used alone or in combination with other chemotherapeutic agents. It is
indicated for induction of remission of leukaemia, particularly for acute myeloid leukaemia,
in adults and children.

Cytarabine has been used for remission induction in acute lymphocytic leukaemia, chronic
myeloid leukaemia and erythroleukaemia; and in the treatment and maintenance therapy of
meningeal leukaemia and other meningeal neoplasms.

Children with non-Hodgkin's lymphoma have benefitted from a combination drug

programme (LSA2L2) that includes Cytarabine.

4.2 Dose and method of administration

Being orally inactive, cytarabine is administered by a variety of parenteral routes:
subcutaneously, intravenously either as a bolus “push” or as a continuous infusion, or
intrathecally.

N.B.: DBL™ Cytarabine Injection 100 mg/mL is hypertonic and therefore unsuitable
for intrathecal use.

Thrombophlebitis has occurred at the site of drug injection or infusion in some patients. Pain
and inflammation at subcutaneous injection sites are rare. Subcutaneous injection sites
should be rotated around the areas of body fat: the abdomen, thighs and flank region. The
drug is generally well tolerated in most instances.

Higher total doses can be better tolerated when administered by rapid IV injection as
compared to slow infusion. Such a phenomenon can be explained by the rapid inactivation of

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the drug and the brief exposure of susceptible normal neoplastic cells to significant levels
after rapid injection.

Normal and neoplastic cells appear to respond in almost parallel manner to these two modes
of administration and no distinct advantage has been established for either.

Clinical experience to date indicates that success with cytarabine therapy depends more on
adeptness in modifying day-to-day dosage to obtain maximum leukaemic cell kill with
tolerable toxicity, than on the fundamental treatment protocol selected at the start of therapy.
Toxicity necessitating dosage modification almost always occurs.

Dosage of cytarabine must be based on the clinical and haematological response and
tolerance of the patient so as to obtain optimum therapeutic results with minimum adverse
effects. Even though higher total doses of cytarabine can be given by IV injection compared
to continuous IV infusion with similar haematologic toxicity, the most effective dosage
schedule and method of administration are yet to be established. Moreover, cytarabine is
often used in combination with other cytotoxic drugs, thereby necessitating dose modification
of cytarabine and other chemotherapeutic agents, and the method as well as the sequence of
administration.

Following is an outline of dosage schedules for cytarabine therapy as reported in the

literature.

Dosage schedules:

Single-Drug Therapy in induction remission in adults with Acute Myelocytic Leukaemia:

2
Cytarabine 200 milligrams/m daily by continuous IV infusion over 24 hours for 5 days (120
2
hours) - total dose 1000 milligrams/m . The course is repeated approximately every 2 weeks.
Modifications based on haematologic response should be made.

Cytarabine combination therapy:

Before a combined chemotherapy protocol is instituted, the clinician should be familiar with
current literature, precautions, contraindications, adverse reactions and warnings applicable to
all the drugs involved in the protocol.

Cytarabine, Daunorubicin
2
Cytarabine: 100 milligrams/m /day, continuous IV infusion (days 1 to 7)
2
Daunorubicin: 45 milligrams/m /day, IV push (days 1 to 3)

Additional courses (complete or modified) as required at 2 to 4 week intervals if leukaemia is

persistent.

Cytarabine, Thioguanine, Daunorubicin

2
Cytarabine: 100 milligrams/m /day, IV infusion over 30 minutes every 12 hours (days 1 to
7)
2
Thioguanine: 100 milligrams/m , orally every 12 hours (days 1 to 7)

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 2
Daunorubicin: 60 milligrams/m /day, IV infusion (days 5 to 7)

Additional courses (complete or modified) as required at 2 to 4 week intervals if leukaemia is

persistent.

Cytarabine, Doxorubicin
2
Cytarabine: 100 milligrams/m /day, continuous IV infusion (days 1 to 10)
2
Doxorubicin: 30 milligrams/m /day, IV infusion over 30 minutes (days 1 to 3)

Additional courses (complete or modified) as required at 2 to 4 week intervals if leukaemia is

persistent.

Cytarabine, Doxorubicin, Vincristine, Prednisolone

2
Cytarabine: 100 milligrams/m /day, continuous IV infusion (days 1 to 7)
2
Doxorubicin: 30 milligrams/m /day, IV infusion (days 1 to 3)
2
Vincristine: 1.5 milligrams/m /day, IV infusion (days 1, 5)
2
Prednisolone: 40 milligrams/m /day, IV infusion every 12 hours (days 1 to 5)

Additional courses (complete or modified) as required at 2 to 4 week intervals if leukaemia is

persistent.

Cytarabine, Daunorubicin, Thioguanine, Prednisone, Vincristine

2
Cytarabine: 100 milligrams/m /day, IV every 12 hours (days 1 to 7)
2
Daunorubicin: 70 milligrams/m /day, IV infusion (days 1 to 3)
2
Thioguanine: 100 milligrams/m orally every 12 hours (days 1 to 7)
2
Prednisone: 40 milligrams/m /day, orally (days 1 to 7)
2
Vincristine: 1 milligram/m /day, IV infusion (days 1,7)

Additional courses (complete or modified) as required at 2 to 4 week intervals, if leukaemia

is persistent.

Maintenance of Acute Myelocytic Leukaemia (AML) in adults:

Maintenance programs are generally modifications of induction programs. Similar schedules
of drug therapy to those used for induction are normally employed. Most programs have a
greater interval between courses of therapy during remission maintenance.

Induction and maintenance of Acute Myelocytic Leukaemia (AML) in children:

Childhood AML has been shown to respond better than adult AML given similar regimens.
Where the adult dosage is given in terms of body weight or surface area, the paediatric

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dosage may be calculated on the same basis, being adjusted on the consideration of such
factors as age, body weight or body surface area.

Acute Lymphocytic Leukaemia (ALL):

Dosage schedules used in ALL are normally similar to those used in AML with some
modifications.

Intrathecal use in Meningeal Leukaemia:

2
Cytarabine has been used intrathecally in acute leukaemia in doses ranging from 5 mg/m to
2
75 mg/m of body surface area. The frequency of administration varied from once a day for 4
2
days to once every 4 days. The most frequently used dose was 30 mg/m every 4 days until
cerebrospinal fluid findings were normal, followed by one additional treatment. The dosage
schedule is usually governed by the type and severity of central nervous system
manifestations and the response to previous therapy (See section 4.8).

Dosage modification:
Suspension or modification of cytarabine therapy should be considered at the appearance of
signs of serious haematologic depression, for example, if the polymorphonuclear granulocyte
count falls below 1000/mm3 or the platelet count falls below 50,000/mm3. Such guidelines
may be modified, depending on signs of toxicity in other systems and on the speed of fall in
levels of formed blood elements. Therapy should be recommended when definite signs of
bone marrow recovery appear and the above granulocyte and platelet levels are attained. If
therapy is withheld until peripheral counts of blood elements return to normal, cytarabine
may be ineffective.

Cytarabine Injection is a ready to use solution with a concentration of 100 milligrams per mL.
It is suitable for intravenous use and in small volumes may also be used subcutaneously.
Cytarabine Injection 100 milligrams per mL is hypertonic and therefore unsuitable for
intrathecal use unless diluted appropriately.

Directions for use of ONCO•VIAL™

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Cytarabine Injection 100 millligrams per mL is hypertonic and unsuitable for intrathecal use.

The potency of cytarabine is retained for 24 hours at 25°C in the following IV fluids:

1. Water for Injection

2. Glucose 5% in water

3. Sodium Chloride 0.9%

4. Ringer’s injection, lactated

Although stability of cytarabine is well retained for 24 hours in intravenous vehicles noted
above, it is recommended that, as with all intravenous admixtures, dilution should be made
just prior to administration and the resulting solution used within 24 hours.

4.3 Contraindications
Cytarabine is contraindicated in patients with known hypersensitivity to the drug.

Anaemia, leukopenia and thrombocytopenia of non-malignant etiology (e.g. bone marrow

aplasia), unless the benefits outweigh the risk.

Degenerative and toxic encephalopathies, especially after the use of methotrexate or

treatment with ionizing radiation.

During pregnancy, cytarabine should only be administered on strict indication, where the
benefits of the drug to the mother should be weighed against possible hazards to the
foetus.

4.4 Special warnings and precautions for use

Cytarabine Injection 100 milligrams per mL (ready prepared solution) is hypertonic and
therefore is unsuitable for intrathecal use.

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Cytarabine should be administered only under constant supervision by physicians
experienced in therapy with cytotoxic agents and only when the potential benefits of
cytarabine therapy outweigh the possible risks. 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. Appropriate facilities should be available
for adequate management of complications should they arise.

The main toxic effect of cytarabine is bone marrow suppression with leukopenia,
thrombocytopenia and anaemia. Less serious toxicity includes nausea, vomiting, diarrhoea
and abdominal pain, oral ulceration, and hepatic dysfunction.

Myelosuppression

Cytarabine is a potent bone marrow suppressant and the severity depends on the dose of the
drug and schedule of administration. Therapy should be started cautiously in patients with
pre-existing drug-induced bone marrow suppression. Patients should undergo close medical
supervision including daily assessment of leucocyte and platelet levels. 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
defences and haemorrhage secondary to thrombocytopenia). Therapy should be suspended or
modified when drug-induced bone marrow depression results in a platelet count of less than
50,000 or a polymorphonuclear count of under 1000 per mm3. 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. Therapy may be restarted when the bone marrow
appears to be recovering on successive bone marrow studies. Therapy should not wait until
the normal blood values are obtained to be re-initiated. If treatment is not resumed before
blood values return to normal, the disease can get out of control.

Intrathecal Use

Cytarabine given intrathecally may cause systemic toxicity and careful monitoring of the
haemopoietic system is indicated. Modification of other anti-leukaemia therapy may be
necessary (See section 4.2). When cytarabine is administered both intrathecally and
intravenously within a few days, there is an increased risk of spinal cord toxicity.

Hepatic and/or Renal Effects

The liver is the main site of inactivation of cytarabine and the normal dosage regimen should
be used with caution in patients with pre-existing liver dysfunction or poor renal function. In
particular, patients with renal or hepatic function impairment may have a higher likelihood of
CNS toxicity after high-dose treatment with cytarabine.

Monitoring

Periodic checks of bone marrow, liver and kidney functions should be performed in patients
receiving cytarabine, the drug should be used with caution in patients with impaired hepatic
function.

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Neurological

Cases of severe neurological adverse reactions that ranged from headache to paralysis, coma
and stroke-like episodes have been reported mostly in juveniles and adolescents given
intravenous cytarabine in combination with intrathecal methotrexate.

Hyperuricaemia

Like other cytotoxic drugs, cytarabine may induce hyperuricaemia secondary to rapid lysis of
neoplastic cells; serum uric acid concentrations should be monitored. The clinician should
monitor the patient's blood uric acid level and be prepared to use such supportive and
pharmacological measures as may be necessary to control this problem.

Anaphylaxis

Anaphylactic reactions have occurred with cytarabine treatment. Anaphylaxis that resulted in
acute cardiopulmonary arrest and required resuscitation has been reported. This occurred
immediately after intravenous administration of cytarabine.

Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live-attenuated vaccines in patients immunocompromised by

chemotherapeutic agents including cytarabine, may result in serious or fatal infections.
Vaccination with a live vaccine should be avoided in patients receiving cytarabine. Killed or
inactivated vaccines may be administered; however, the response to such vaccines may be
diminished.

Vomiting

When large intravenous doses are given quickly, patients are frequently nauseated and may
vomit for several hours post injection. The severity is less if the solution is infused.

Conventional Dose Schedules

Abdominal tenderness (peritonitis) and guaiac positive colitis, with concurrent neutropenia
and thrombocytopenia, have been reported in patients treated with conventional doses of
cytarabine in combination with other drugs. Patients have responded to nonoperative medical
management.

Delayed progressive ascending paralysis resulting in death has been reported in children with
AML following intrathecal and intravenous cytarabine at conventional doses in combination
with other drugs.

Concurrent granulocyte-transfusion should be avoided as severe respiratory insufficiency has

been reported.

Severe and at times fatal central nervous system (CNS), gastrointestinal (GI) and pulmonary
toxicity (different from that seen with conventional therapy regimens of cytarabine) have
been reported following some experimental dose schedules of cytarabine. These reactions
include reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible;
somnolence; convulsion; severe gastrointestinal ulceration, including pneumatosis cystoides
intestinallis, leading to peritonitis; sepsis and liver abscess and pulmonary oedema.

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Corneal and conjunctival toxicities including reversible corneal lesion and haemorrhagic
conjunctivitis have been reported. This may be prevented or diminished by prophylaxis with
a local corticosteroid eye drop.

High dose therapy

Peripheral motor and sensory neuropathies after consolidation with high dose cytarabine,
daunorubicin and asparaginase have occurred in adult patients with acute non-lymphocytic
leukemia. Patients treated with high dose cytarabine should be observed for neuropathy since
dose schedule adjustments may be needed to avoid irreversible neurologic disorders.

Severe sometimes fatal pulmonary toxicity, adult respiratory distress syndrome and
pulmonary oedema have occurred following high dose schedules with cytarabine therapy. A
syndrome of sudden respiratory distress, rapidly progressing to pulmonary oedema and
radiographically pronounced cardiomegaly has been reported following experimental high
dose therapy with cytarabine used for the treatment of relapsed leukaemia. The outcome of
this syndrome can be fatal.

Cases of cardiomyopathy with subsequent death have been reported following experimental
high dose therapy with cytarabine and cyclophosphamide therapy when used for bone
marrow transplant preparation. This may be schedule dependent.

Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is
more commonly seen with experimental high dose therapy than with standard cytarabine
treatment programs.

Hepatic and/or Renal Effects

The liver is the main site of inactivation of cytarabine and the normal dosage regimen should
be used with caution in patients with pre-existing liver dysfunction or poor renal function.
Periodic determinations of renal and hepatic function and bone marrow should also be
performed.

Use the drug with caution and at reduced doses in patients whose liver function is poor as the
liver apparently detoxifies a substantial fraction of an administered dose and in patients with
renal function impairment as they may have a higher likelihood of CNS toxicity after high-
dose treatment with cyarabine.

Acute Pancreatitis

Acute pancreatitis has been reported to occur in patients being treated with cytarabine who
have had prior treatment with L-asparaginase.

Use in the Elderly

Although studies with cytarabine have not been performed in the geriatric population,
geriatric-specific problems that would limit the usefulness of this medication in the elderly
are not expected. Elderly patients are, however, more likely to have age-related renal
function impairment, which may require reduction of dosage in patients receiving cytarabine.

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Paediatric population

Appropriate studies with cytarabine have not been performed in the paediatric population.
However, paediatric-specific problems that would limit the usefulness of this medication in
children are not expected.

4.5 Interaction with other medicines and other forms of interaction

The incidence and severity of haematologic toxicity induced by cytarabine is exacerbated
when other myelosuppressive drugs are given concurrently.

Use with care following prior treatment with L-asparaginase (See section 4.4)

 Allopurinol, Colchicine, Probenecid or Sulphinpyrazone: Cytarabine may raise the

concentration of blood uric acid. Dosage adjustment of antigout agents may be
necessary to control hyperuricaemia and gout. Allopurinol may be preferred to
prevent or reverse cytarabine-induced hyperuricaemia because of risk of uric acid
nephropathy with uricosuric antigout agents.

 Blood Dyscrasia Causing Medications: Leukopenic and/or thrombocytopenic

effects of cytarabine may be increased with concurrent or recent therapy if these
medications cause the same effects, dosage adjustment of cytarabine, if necessary,
should be based on blood counts.

 Bone Marrow Depressants or Radiation Therapy: Additive bone marrow

depression may occur; dosage reduction may be required when two or more bone
marrow depressants, including radiation, are used concurrently or consecutively.

 Cyclophosphamide: Concurrent use with high-dose cytarabine therapy for bone

marrow transplant preparation has been reported to result in an increase in
cardiomyopathy with subsequent death.

 Flucytosine: Fluorocytosine should not be administered with cytarabine as the

therapeutic efficacy of Fluorocytosine has been shown to be abolished during such
therapy.

Clinical evidence in one patient showed possible inhibition of fluorocytosine efficacy

therapy with cytarabine. This may be due to potential competitive inhibition of its
uptake.

Flucytosine should not be administered concomitantly with cytarabine. Cytarabine

has been reported to antagonise the antifungal activity of flucytosine by competitive
inhibition.

 Methotrexate: Intravenous cytarabine given concomitantly with intrathecal

methotrexate may increase the risk of severe neurological adverse reactions such as
headache, paralysis, coma and stroke like episodes (See section 4.4).

Cytarabine has been reported to inhibit the cellular uptake of methotrexate, thus
reducing its effectiveness. Conversely, methotrexate has been reported to decrease

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 the intracellular activation of cytarabine. These factors should be considered when
using the medicines concurrently.

There is evidence of pharmacodynamics interaction between methotrexate and

cytarabine leading to encephalopathy.

 Digoxin: GI absorption of oral digoxin tablets may be substantially reduced in

patients receiving combination chemotherapy regimens (including regimens
containing cytarabine), possibly as a result of temporary damage to intestinal mucosa
caused by the cytotoxic agents. 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. 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 utilisation of digitoxin for such patients may be
considered as an alternative.

 Gentamicin: 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 re-evaluation of antibacterial therapy.

 Immunosuppressive agents: Due to the immunosuppressive action of cytarabine,

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 time fatal.

4.6 Fertility, pregnancy and lactation

Fertility

Fertility studies to assess the reproductive toxicity of cytarabine have not been conducted.
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking
cytarabine therapy, especially in combination with alkylating agents. In general, these effects
appear to be related to dose and length of therapy and may be irreversible. Given that
cytarabine has a mutagenic potential which could induce chromosomal damage in the human
spermatozoa, males undergoing cytarabine treatment and their partner should be advised to
use a reliable contraceptive method.

Pregnancy

Cytarabine is suspected to have caused or may be expected to cause an increased incidence of

human fetal malformations or irreversible damage. It may also have adverse
pharmacological effects. Cytarabine has been shown to be teratogenic in some animal species
and should not be used during pregnancy, especially during the first trimester, nor in women
likely to become pregnant.

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Cytarabine should only be used in women of child-bearing potential if the expected benefits
outweigh the risks of therapy and adequate contraception is used.

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 6 weeks to 7 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, and the other with extremity and ear deformities. 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, haematocrit 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 foetuses 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 foetus 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.

Lactation

It is not known whether cytarabine is excreted in human milk. Women should be advised not
to breast feed while being treated with cytarabine, because of the risks to the infant (See
section 4.8, section 5.3).

4.7 Effects on ability to drive and use machinery

DBL™ Cytarabine for Injection has no influence on the ability to drive and use machines,
nevertheless it is likely to produce severe adverse effects, which may impair the patient's
ability to concentrate and react and therefore constitute a risk in the ability to drive and use
machines.

4.8 Undesirable effects

Haematological

The major adverse effect of cytarabine is haematologic toxicity. Myelosuppression is

normally manifested by megaloblastosis, leucopenia, anaemia, reticulocytopenia and
thrombocytopenia. Leucopenia follows mainly from granulocyte depression; lymphocytes
are minimally affected. The severity of these adverse effects is dependent on the dose of the

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drug and schedule of administration. Cellular changes in the morphology of bone marrow and
peripheral smears can be expected.

The incidence and severity of haematologic toxicity is minimal after a single intravenous
dose of cytarabine, but myelosuppression occurs in almost all patients with daily IV
injections or continuous IV infusions of the drug.

Following 5-day constant infusions or acute injections of 50 mg/m2 to 600 mg/m2 , 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 a 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.

Gastrointestinal

Nausea and vomiting may occur in patients on cytarabine therapy, and usually occur more
frequently and severely following rapid IV administration as opposed to continuous infusion
of the drug.

Especially in treatment with high doses of cytarabine, more severe reactions may appear in
addition to common symptoms. Intestinal perforation or necrosis with ileus and peritonitis
has been reported. Pancreatitis has also been observed after high-dose therapy.

Infectious Complications

Viral, bacterial, fungal parasitic or saprophytic infection which can be mild, severe and at
times fatal, may be associated with the use of cytarabine when used alone or in combination
with other immunosuppressive agents following immunosuppressive doses that affect cellular
or humoral immunity. These infections may be mild, but can be severe and at times fatal.

Neurotoxicity following intrathecal cytarabine has been associated with preservative-

containing diluents and many clinicians recommend the use of preservative-free diluents
instead.

Cytarabine (Ara-C) Syndrome

A cytarabine syndrome (immunoallergic effect) characterised by fever, myalgia, bone pain,

malaise, maculopapular rash, conjunctivitis, and occasionally chest pain, has been reported. A
"flu-like" syndrome has been reported, which may be treated with corticosteroid therapy if
severe. Anaphylactoid reactions have occurred. It normally occurs at 6 to 12 hours after
administration of the drug; corticosteroids have been shown to be of benefit in the treatment
and prevention of the syndrome. If treatment of the symptoms of the syndrome is required,
administration of corticosteroids should be considered, as well as continuation of cytarabine
therapy.

Two patients with adult nonlymphocytic leukaemia developed peripheral motor and sensory
neuropathies after consolidation with high dose cytarabine, daunorubicin and asparaginase.

Summary of Safety Profile (See section 4.4)

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Blood and lymphatic system disorders

Haematological toxicity has been seen as profound pancytopenia which may last 15-25 days
along with more severe bone marrow aplasia than that observed at conventional doses.

Eye disorders

Reversible corneal lesion and haemorrhagic conjunctivitis have been reported. These can be
prevented or decreased by prophylactic use of corticosteroid eye drops.

Hepatobiliary disorders

Liver abscesses, hepatomegaly and Budd-Chiari-syndrome (hepatic venous thrombosis) have

been observed after high-dose therapy.

Respiratory, thoracic and mediastinal disorders

Clinical signs as present in pulmonary oedema/ARDS may develop, particularly in high-dose

therapy. The reaction is probably caused by an alveolar capillary injury. It is difficult to make
an assessment of frequencies (stated as 10-26% in different publications), since the patients
usually have been in relapse where other factors may contribute to this reaction.

Tabulated Summaries of Adverse Effects

The reported adverse reactions are listed below by System Organ Class and by frequency.
Frequencies are defined as: Very common (>10%), Common (≥1% to <10%), Uncommon
(≥0.001% to <1%), Rare (>0.0001% to <0.001%), Very Rare (<0.0001) and Frequency not
known (cannot be estimated from available data).

Adverse Effects Table

Infections and Infestations

Very common Sepsis (immunosuppression), pneumonia, infectiona

Uncommon Injection site cellulitis

Blood and Lymphatic System Disorders

Very common Anaemia, megaloblastosis, leucopenia,

thrombocytopenia, bone marrow failure reticulocyte
count decreased

Reticulocytopenia

Frequency not known

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon Lentigo

Immune System Disorders

Uncommon Anaphylactic reactionb, allergic oedema

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Metabolism and Nutrition Disorders

Common Anorexia, hyperuricemia

Nervous System Disorders

Common At high doses cerebellar or cerebral influence with

deterioration of the level of consciousness, dysarthria,
nystagmus

Neurotoxicity, neuritis, dizziness, headache, peripheral

neuropathy, paraplegia at intrathecal administration
Uncommon
Dizziness, neurotoxicity rash.

Frequency not known

Eye Disorders

Common Reversible haemorrhagic conjunctivitis (photophobia,

burning, visual disturbance, increased lacrimation),
keratitis

Conjunctivitisc

Uncommon

Cardiac Disorders

Uncommon Pericarditis

Very rare Arrhythmia, cardiomyopathy

Vascular Disorders

Common Bleeding (all sites), thrombophlebitis

Respiratory, Thoracic and Mediastinal Disorders

Uncommon Pneumonia, dyspnea, sore throat, shortness of breath

Gastrointestinal Disorders

Very common Stomatitis, mouth ulceration, oral/anal ulcer, anal

inflammation or ulceration, diarrhoea, vomitingd,
nausead, abdominal pain

Uncommon Oesophagitis, oesophageal ulceration, bowel necrosis,

pneumatosis cytoides intestinalis, necrotising colitis,
peritonitis,

Frequency not known Gastrointestinal haemorrhage, pancreatitis

Hepatobiliary Disorders

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Very common Hepatic function abnormal, reversible effects on the
liver with increased enzyme levels

Uncommon Jaundice

Frequency not known Hepatic dysfunction

Skin and Subcutaneous Tissue Disorders

Very common Alopecia, rash

Common Skin ulceration, reversible undesirable effects to the –

erythema, bullous dermatitis, urticarial, vasculitis,
pruritus, burning pain of palms and soles

Uncommon Palmar-plantar erythrodysaesthesia syndrome,

freckling

Neutrophilic eccrine hidradenitis

Very rare
Rash, freckling, skin bleeding
Frequency not known

Musculoskeletal, Connective Tissue and Bone Disorders

Very common Cytarabine syndrome

Uncommon Myalgia, joint pain

Renal and Urinary Disorders

Uncommon Renal dysfunction, urinary retention

Frequency not known Renal dysfunction

General Disorders and Administration Site Conditions

Very common Pyrexia, fever, thrombophlebitis at the site of injection

Uncommon Cellulitis at the injection site, chest pain

Frequency not known Injection site reactione

Reproductive system and breast disorders

Frequency not known Amenorrheoa and azoospermia

Investigations

Very common Biopsy bone marrow abnormal, blood smear test

abnormal

a
May be mild, but can be severe and at times fatal

b
Resulting in cardiopulmonary arrest has been reported following intravenous administration

c
May occur with rash and may be hemorrhagic with high dose therapy

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 d
Nausea and vomiting are most frequent following rapid intravenous injection

e
Pain and inflammation at subcutaneous injection site

Intrathecal Administration

The most frequently reported adverse reactions after intrathecal administration were nausea,
vomiting and fever; these reactions are mild and self-limiting. Paraplegia has been reported.
Necrotising leucoencephalopathy with or without convulsions has also been reported; in
some cases patients had also been treated with intrathecal methotrexate and/or
hydrocortisone, as well as by central nervous system radiation. Isolated neurotoxicity has
been reported. Blindness occurred in two patients in remission whose treatment consisted of
combination systemic chemotherapy, prophylactic central nervous system radiation and
intrathecal cytarabine. Delayed progressive ascending paralysis resulting in death has been
reported in children with acute myelogenous leukaemia (AML) following intrathecal and
intravenous cytarabine at conventional doses in combination with other drugs.

Adverse Effects Table (Experimental Dose Therapy) (See section 4.4)

Infections and Infestations

Frequency not known Sepsis, liver abscess

Blood and lymphatic system disorders

Frequency not known Pancytopenia – may last 15-25 days with

more sever bone marrow aplasia

Psychiatric Disorders

Frequency not known Personality changea

Nervous System Disorders

Very common Cerebral disorder, cerebellar disorder,

somnolence

Frequency not known Coma, convulsion, peripheral motor

neuropathy, peripheral sensory neuropathy

Eye Disorders

Very common Haemorrhagic conjunctivitis, corneal

disorder, reversible corneal lesion

Cardiac Disorders

Frequency not known Cardiomyopathyb

Respiratory, Thoracic and Mediastinal

Disorders

Very common
Acute respiratory distress syndrome,

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 pulmonary oedema

Reproductive system and breast disorders

Amenorrhoea and azoospermia
Frequency not known

Gastrointestinal Disorders

Common Necrotising colitis

Frequency not known Bowel necrosis, gastrointestinal ulcer,
pneumatosis intestinalis, peritonitis,
pancreatitis

Hepatobiliary Disorders

Frequency not known Liver abscesses, liver injury, hepatomegaly,

Budd-Chiari-syndrome (hepatic venous
syndrome), hyperbilirubinaemia

Skin and Subcutaneous Tissue Disorders

Common Skin rash leading to desquamation, alopecia

a
Personality change was reported in association with cerebral and cerebellar dysfunction.
b
With subsequent death

Other Adverse Reactions

Following cytarabine therapy, cardiomyopathy and rhabdomyolysis have been reported.

The gastrointestinal undesirable effects are reduced if cytarabine is administered as infusion.

Local glucocorticoids are recommended as prophylaxis of haemorrhagic conjunctivitis.

Experimental Dose Schedule

A syndrome of sudden respiratory distress, rapidly progressing to pulmonary oedema and a

radiographically pronounced cardiomegaly has been reported following experimental high
dose therapy with cytarabine used for the treatment of relapsed leukemia; fatal outcome has
been reported.

Intermediate Dose Schedule

A diffuse interstitial pneumonitis without clear cause that may have been related to
cytarabine was reported in patients treated with experimental intermediate doses of
cytarabine (1 g/m2) with and without other chemotherapeutic agents (meta-AMSA,
daunorubicin, VP-16).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

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professionals are asked to report any suspected adverse reactions
https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose
There is no antidote for cytarabine overdosage. Cessation of therapy followed by
management of ensuing bone marrow depression including whole blood or platelet
transfusion and antibiotics as required.

Doses of 4.5 g/m2 by intravenous infusion over 1 hour every 12 hours for 12 doses has caused
an unacceptable increase in irreversible CNS toxicity and death. Symptoms of overdose
include nausea, vomiting, diarrhoea, ulceration and bleeding of the gastrointestinal tract,
myelosuppression, severe skin rash, CNS toxicity (including cerebral and cerebellar
dysfunction), cardiac disorders, pulmonary and corneal toxicity, fever, myalgia, bone pain,
chest pain and conjunctivitis.

Cytarabine may be removed by haemodialysis.

In bone marrow depression, transfusions of blood products may be required and active
measures may be necessary to combat infection.

Hyperuricaemia is avoided by the addition of allopurinol to treatment schedules and measures

such as alkalinisation of the urine and hydration may also be adopted.

Techniques attempting to prevent the occurrence of alopecia have met with varying success.
Scalp tourniquets and ice packs have been used to minimize concentrations of antineoplastic
agents in the scalp after intravenous injection. Such methods, however, may allow the
development of a cancer-cell sanctuary and should not be used in patients with leukaemia or
other conditions with circulating malignant cells.

The treatment of extravasation is controversial. Warm moist soaks or ice packs have been
applied and a corticosteroid may sometimes be instilled into the affected area.

Antiemetic therapy should be given in an attempt to prevent or control nausea and vomiting.

For advice on the management of overdose please contact the National Poisons Centre on
0800 POISON (0800 764766).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Mechanism of action

Cytarabine is an antineoplastic agent. Cytarabine is a synthetic pyrimidine nucleoside, which

is converted intracellularly to the nucleotide, cytarabine triphosphate. The exact mechanism
of action of cytarabine is not fully understood, but cytarabine triphosphate appears to inhibit
DNA synthesis by the inhibition of DNA polymerase. The enzyme responsible for this
conversion is deoxycytidine kinase which is found predominantly in the liver and possibly
the kidney. Cytarabine is inactivated by the enzyme cytidine deaminase found in the

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intestine, kidney and liver. The ratio of the activating enzyme (deoxycytidine kinase) to the
inactivating enzyme (cytidine deaminase) in cells, determines the susceptibility of the tissue
to the cytotoxic effects of cytarabine. Tissues with a high susceptibility have high levels of
the activating enzyme. Cytarabine’s actions are cell-cycle specific as it has no effect on non-
proliferating cells, or on proliferating cells unless in the S or DNA synthesis phase.
Cytarabine is also immunosuppressant and has demonstrated antiviral activity in vitro;
however efficacy against herpes zoster or smallpox could not be demonstrated in controlled
clinical trials.

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. 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.

5.2 Pharmacokinetic properties

Absorption

Cytarabine is not effective when administered orally, less than 20% of a dose is absorbed
from the gastrointestinal tract and is ineffective by this route. Subcutaneously or
intramuscularly, tritium labelled cytarabine produces peak plasma concentrations of
radioactivity within 20 – 60 minutes and are considerably lower than those attained after
intravenous administration. Continuous intravenous infusions produce relatively constant
plasma levels in 8 – 24 hours.

Distribution

It is rapidly and widely distributed into tissues including liver, plasma and peripheral
granulocytes. Cytarabine crosses the blood-brain barrier to a limited extent and also
apparently crosses the placenta. It is not known if cytarabine is distributed into breast milk.

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.

Biotransformation

Metabolism occurs also in the kidneys, gastrointestinal mucosa, granulocytes and other
tissues. Cytarabine is rapidly metabolised, mainly in the liver, to the inactive metabolite 1--
D-arabinofuranosyluracil.

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Elimination

After rapid IV injection, plasma concentrations of cytarabine appear to decline in a biphasic

manner with an initial distribution half-life of about 10 minutes, followed by a secondary
elimination half-life of about 1-3 hours.

About 70 to 80% of a dose is excreted in the urine of a dose administered by any route within
24 hours; approximately 90% as the metabolite and 10% as unchanged cytarabine.

Immunosuppressive Action

Cytarabine is capable of obliterating immune responses in man during administration with

little or no accompanying toxicity. Suppression of antibody responses to E.coli-V1 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 phytohaemaglutinin. A few days after termination of therapy there was a
rapid return to normal.

5.3 Preclinical safety data

Genotoxicity

Cytarabine may cause chromosomal damage, including chromatoid breaks, in humans.

Malignant transformation of rodent cells in culture has been reported.

Carcinogenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although
it is not clear whether the effect is related to their mutagenic or immunosuppressive action.
The effect of dose and duration of therapy is also unknown, although risk seems to increase
with long-term use.

Antimetabolites have been shown to be carcinogenic in animals and may be associated with
an increased risk of development of secondary carcinomas in humans.

Reproductive and developmental toxicity

No data available.

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6. PHARMACEUTICAL PARTICUALRS

6.1 List of excipients

Water for injection

6.2 Incompatibilities
No information available.

6.3 Shelf life

No data available.

6.4 Special precautions for storage

Store at 15°C to 25°C Protect from light.

If a precipitate has formed as a result of exposure to low temperatures, redissolve by warming

up to 55°C for no longer than 30 minutes and shake until the precipitate has dissolved. Allow
to cool prior to use.

6.5 Nature and contents of container and special equipment for use,
administration or implantation
DBL™ Cytarabine Injection is presented in vials containing cytarabine as a sterile solution:

Strength Pack Size

100 milligrams per 1mL 1 vial per pack

6.6 Special precautions for disposal

Any unused medicine or waste material should be disposed of in accordance with local
requirements.

7. MEDICINE SCHEDULE
Prescription Medicine.

8. SPONSOR
Pfizer New Zealand Limited

P O Box 3998

Auckland, New Zealand

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Toll Free Number: 0800 736 363

9. DATE OF FIRST APPROVAL

25 June 1992

10. DATE OF REVISION OF THE TEXT

17 January 2019

Summary table of changes

Section changed Summary of new information

All Reformatting according to new New Zealand datasheet template

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