Israel - English - Ministry of Health
QUALITATIVE AND QUANTITATIVE COMPOSITION
In one presentation; 100 mg/vial
Clear colourless solution for injection contains 20 mg/1ml Cytarabine - vials of 5 ml.
In three presentations as follows; 500 mg/vial, 1000 mg/vial and 2000 mg/vial
Clear colourless solution for injection contains 50 mg/1ml Cytarabine - vials of 10 ml, vials of 20 ml, vials
of 40 ml.
For induction and maintenance of clinical remission in patients with acute myeloid leukaemia, acute non-
lymphoblastic leukaemias, acute lymphoblastic leukaemias, blast crises of chronic myeloid leukaemia, diffuse
histiocytic lymphomas (non-Hodgkin’s lymphomas of high malignancy).
Posology and Method of Administration
Effective plasma levels are assumed to range between 0.01 and 0.15
g/ml. The dose must be determined
exactly for each individual patient, ideally in relation to the body surface area (BSA).
Unless otherwise specified for certain combinations, Alexan shall be administered in the below indicated
Induction therapy in patients with acute leukaemia
Intravenous injection 100-200 mg/m
of body surface area, daily.
Intravenous infusion of 100 mg/m
of body surface area, daily.
The above doses are suggested as a guideline and may be exceeded during therapy.
The duration of therapy is dependent on the clinical and morphological findings (bone marrow).
The patient may receive a treatment course of up to 7 days, which is followed by a treatment-free interval
of 7-9 days to allow for sufficient recovery of the bone marrow; consolidation courses (often shorter) may
subsequently be undertaken until remission or toxicity occurs.
Alternatively, therapy may be continued until bone marrow hypoplasia occurs, which is to be regarded as
the tolerance limit.
Each consecutive treatment course (often shorter) must be preceded by a therapy-free interval of at least
14 days or until the bone marrow has sufficiently recovered.
Maintenance therapy in patients with leukaemia
of body surface area daily are administered once a month on five consecutive days, or once
Doses range from 5 mg/m
to 75 mg/m
of body surface once daily for 4 days or once every 4 days. The
most common dose is 30 mg/m
of body surface every 4 days, until cerebrospinal fluid findings are 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.
This disease is generally treated using an appropriate combination therapy.
Unless otherwise specified, a high-dose of cytarabine is administered 3 g/m
I.V. every 12 hours for 4-12
doses (repeated at 2-3 week intervals).
Therapies using 4-6 doses every 2 weeks or 9 doses every 3 weeks appear equally effective and less toxic.
Total dosage and duration of therapy must be determined by the treating clinician. Depending on the number
of infusions given, the treatment course may be repeated after the bone marrow has sufficiently recovered.
In cases of persistent leukaemia, administer additional courses (complete or modified) of any combination,
as necessary, at 2-4 week intervals.
/day, by continuous I.V. infusion, on days 1-10
/day, by I.V. infusion over 30 minutes, on days 1-3
/day, by I.V. infusion over 30 minutes every 12 hours, on days 1-7
/day, orally, every 12 hours, on days 1-7
/day, by I.V. infusion, on days 5-7
/day, by continuous I.V. infusion, on days 1-7
/day, by I.V. infusion, on days 1-3
/day, by I.V. infusion, on days 1 and 5
/day, by I.V. infusion, every 12 hours, on days 1-5
/day, by I.V. infusion, every 12 hours, on days 1-7
/day, by I.V. infusion, on days 1-3
/day, orally, every 12 hours, on days 1-7
/day, orally, on days 1-7
/day, by I.V. infusion, on days 1 and 7
/day, by continuous I.V. infusion, on days 1-7
/day, by I.V. push, on days 1-3
Type and duration of therapy
Alexan may be administered:
intravenously as a continuous infusion,
in exceptional cases, also as a subcutaneous injection.
Due to the short half-life of cytarabine when applied intravenously, plasma levels in most patients fall below
the minimum therapeutic value in less than one hour. Therefore, it is essential to split the daily dose in two
or more separate doses to be given at equal intervals. Alexan solution for infusion may be prepared using
physiological sodium chloride solution or 5% glucose solution. Duration of long-term infusions reportedly
is in the range of 8-12 hours and 120-168 hours. Compared to single intravenous injection, administration
of the same doses as a continuous infusion results in more pronounced adverse effects on the gastrointestinal
In case of administration via the intrathecal route, the recommended procedure is to extract 5-8 ml of
cerebrospinal fluid, mix it with the solution for injection in the same syringe and slowly re-inject the mixture.
Systemic toxicity is not expected with this method of application.
Subcutaneous injection is only applied in exceptional cases and generally only when used in maintenance
Intracutaneous injection must be avoided due to the risk of oedemas.
Alexan is administered as an intravenous infusion for 1-3 hours.
If administered by means of a perfusor, Alexan may also be given in its undiluted form.
For preparation of a diluted solution for infusion, physiological sodium chloride solution or 5% glucose
solution may be used.
All Alexan preparations are compatible with each other and may be combined to prepare an individually
prescribed dose. Thus no residual amounts of the medicinal product are generated.
Note: Cytarabine has been used intrathecally with hydrocortisone sodium succinate and methotrexate,
both as prophylaxis in children with newly-diagnosed acute lymphocytic leukaemia, and in the treatment
of meningeal leukaemia.
Prophylactic triple therapy has been reported to prevent CNS disease, and gives overall cure and survival
rates similar to those seen in patients in whom CNS radiation and intrathecal methotrexate were used as
initial CNS prophylaxis. The dose of Alexan was 30 mg/m
, hydrocortisone sodium succinate 15 mg/m
methotrexate 15 mg/m
Use in children
Children appear to tolerate higher doses than adults and where dose ranges are quoted, the children should
receive the higher dose and the adults the lower.
Use in the elderly
There is no information to suggest that a change in dosage is warranted in the elderly.
Nevertheless, the elderly patient does not tolerate drug toxicity as well as the younger patient, and particular
attention should thus be given to drug induced leucopenia, thrombocytopenia and anaemia with appropriate
initiation of supportive therapy when indicated.
Use in infants
The safety of this drug for use in infants has not been established.
Patients with existing bone marrow suppression should be excluded from treatment with cytarabine,
unless the physician considers that the benefit of such treatment outweighs the risks for the individual
Known hypersensitivity to cytarabine or to any other ingredient of the medicinal product.
Leukopenia and/or thrombocytopenia of non-malignant origin are also a contraindication.
High-dose therapy with cytarabine in patients older than 60 years should only be carried out after carefully
weighing the benefits and risks.
Patients with severe hepatic and/or renal impairment, underlying serious infections, gastrointestinal
ulcerations and patients who have recently undergone surgery.
Pregnancy and lactation (see section “Use During Pregnancy and Lactation”).
Special Warnings and Special Precautions for Use
Cytarabine should only be administered to in-patients and only by physicians who are specially trained and
experienced in the use of cancer-related chemotherapy. Conventional precautionary measures when handling
vials must be observed (safety glasses, gloves, mouth and nose protection, if possible an adequate ventilation
Existence of adequate facilities for monitoring the effects on the patient and taking adequate counter-
measures if necessary must be ensured.
Leukocyte and platelet counts should be undertaken frequently and monitored regularly even after the
termination of treatment. This also applies in the case of intrathecal administration.
The recommended standard minimum values for blood counts are 1000 for granulocytes and 50,000 for
platelets. In such cases termination or modification of treatment must be considered.
In patients with high blast counts or large tumour masses (non-Hodgkin’s lymphoma) prophylaxis against
hyperuricaemia is recommended. Adequate facilities for carrying out supportive measures should be available.
Special care must be exercised in patients with slightly impaired hepatic and renal function.
Hepatic and renal impairment are regarded as predisposing factors for an increased CNS toxicity of cytarabine.
Since cytarabine is largely metabolised in the liver, its efficacy may be enhanced in patients with hepatic
damage. Efficacy of the substance is also increased in patients with renal impairment. Appropriate dose
reductions with careful monitoring of blood levels must be carried out in patients with hepatic and/or renal
Regular monitoring of hepatic and renal function parameters as well as uric acid levels is required.
Cytarabine, especially high-dose cytarabine, may only be administered to patients with pre-existing hepatic
impairment while exercising utmost caution and after a careful risk-benefit evaluation.
Abundant hydration is indicated.
When large intravenous doses are given quickly, patients are frequently nauseated and may vomit for several
hours post-injection. The problem tends to be less severe when the drug is infused slowly.
Antiemetic and other supportive measures need to be taken in case of severe adverse effects on the
High-dose treatment with cytarabine requires regular monitoring of CNS and lung function parameters by
a physician experienced in this field of therapy.
To avoid ophthalmological complications, regular rinsing of the eyes during high-dose treatment is essential.
If severe bone marrow depression occurs, patients should be kept in a sterile isolation room throughout the
Immunisation with live virus vaccines should be avoided during cytarabine therapy.
As with other cytotoxic agents, treatment with cytarabine bears the risk of haemorrhagic complications and
serious infections due to bone marrow depression. CNS disturbances, gastrointestinal disorders, hepatic
impairment, skin reactions and eye disorders may occur during high-dose cytarabine therapy.
A careful risk-benefit evaluation is necessary if CNS toxicity or allergic reactions occur.
Contact with skin and mucous membranes, especially in the area of the eyes, must be avoided.
Cytarabine may have a mutagenic effect. Male patients are therefore advised not procreate during and up
to six months after treatment. Since there is the possibility of irreversible infertility after cytarabine therapy,
men should also be advised to seek counseling on sperm preservation before starting the treatment.
Cytarabine is a teratogenic and mutagenic agent.
Patients who wish to have children after the termination of therapy are urgently advised to seek genetic
Interactions with Other Medicinal Products
In patients who had previously undergone therapy with L-asparaginase, acute pancreatitis may occur during
treatment with cytarabine.
Myelotoxic interactions with other treatment methods which have a toxic effect on the bone marrow
(especially treatment with other cytotoxic agents and radiation therapy) must be expected according to the
In individual cases, cytarabine has been shown to reduce the antimycotic efficacy of flucytosine.
Digoxin: combination chemotherapy (including cytarabine) may decrease digoxin absorption even days after
discontinuing chemotherapy. Digitoxin does not seem to be affected.
For incompatibilities see section “Incompatibilities”.
Use During Pregnancy and Lactation
Alexan must not be given to pregnant and breastfeeding women.
Since cytarabine has demonstrated a mutagenic and teratogenic effect in some experimental animals, the
possibility of pregnancy must be avoided. Both male and female patients of child-bearing potential must
use effective contraception during treatment with Alexan. If treatment with Alexan appears to be unavoidable
in a pregnant woman, the adverse side effects for the foetus resulting from this kind of treatment must be
If pregnancy does occur during treatment with Alexan, appropriate genetic counseling must be provided
(see section “Preclinical Safety Data”).
Breastfeeding must be discontinued before starting therapy with Alexan.
Effects on the Ability to Drive and Use Machines
The ability to drive or operate machinery may be impaired in patients receiving cytarabine therapy.
The undesirable effects caused by cytarabine are dependent on dosage, method of administration and
duration of therapy.
Cytarabine administration is in general well tolerated locally. Inflammations at the injection site are occasionally
The most important adverse effect of cytarabine is bone marrow depression.
Hematological disorders (leucopenia, thrombocytopenia, anemia, megaloblastosis) are dose-dependent.
At conventional dosage: leucopenia appears with lowest number of blood cells on days 12 to 24.
High-dose therapy leads to significant myelotoxicity.
Cellular changes in the morphology of bone marrow and peripheral smears can be expected. Following a
5-day course of constant infusions or acute injections of 50-600 mg/m
of body surface area, white cell
depression follows a biphasic course.
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 humoural immunity. The infections range from mild to
severe and in some cases even fatal.
Gastrointestinal disorders such as nausea, vomiting and diarrhoea are common. Oesophagitis, oesophageal
ulcerations, abdominal pain, jaundice, severe disorders of the gastrointestinal mucosa including ulcerations,
intestinal emphysema and infections may occur. These may lead to intestinal necrosis and necrotic colitis.
Mucositis and ulcerations of the oral and anal mucosa must be expected especially at high dosages, possibly
leading to severe diarrhoea with loss of potassium and proteins. Cystoid pneumatosis and intestinal necrosis
with ileus and peritonitis may occur occasionally, in particular during high-dose treatment.
Skin and subcutaneous tissue disorders
Toxic skin reactions such as maculopapular exanthema, ulceration, erythrodermia or erythema, speckled skin
and pruritus have occasionally been observed at conventional dosage, exfoliating dermatitis is seen at high
dosage. Alopecia may also occur.
Individual cases of neutrophil eccrine hidradenitis have also been observed.
After administration of high-dose cytarabine, generalised erythema occurs in up to 75% of patients, in some
cases accompanied by formation of blisters and scales. Burning sensation on palms and soles may occur.
Nervous system disorders
CNS disturbances have been observed in particular at high dosage, mostly manifesting themselves as
cerebral/cerebellar disorders (nystagmus, dysarthria, ataxia, confusion and personality changes), headache,
dizziness, cognitive and motor disturbances, somnolence, lethargia, coma, convulsions, and anorexia. Total
doses of less than 36 g of cytarabine/m
of body surface area per treatment course rarely result in CNS
toxicity. Predisposing factors are old age, hepatic and renal impairment, previous CNS treatment (radiation
therapy, intrathecal application of cytotoxic agents) and alcohol abuse. CNS disturbances are in most cases
reversible. Intrathecal administration of cytarabine may occasionally lead to nausea, vomiting, headache
and/or fever. These symptoms may also be caused by lumbar puncture. Symptoms are often mild and
reversible. Intrathecal use of cytarabine at doses exceeding 30 mg/m
of body surface area often leads to
neurotoxic reactions. Especially short dosage intervals may lead to cumulative neurotoxicity (also see section
“Posology and Method of Administration”).
Individual cases of necrotising leukoencephalopathy, paraplegia and loss of vision have been reported after
intrathecal treatment with cytarabine.
Intrathecal application of benzyl alcohol or other solvent additives must be strictly avoided.
Neuritis and, after administration of high doses, individual cases of peripheral nerve lesions were reported,
as well as cases of retarded progressive ascending paralysis, meningitis and encephalitis.
Musculoskeletal system disorders
Myalgia and/or arthralgia have been occasionally observed after high-dose cytarabine therapy. Occurrence
of rhabdomyolysis has been described.
Eye disorders such as conjunctivitis, keratitis, photophobia, burning, increased lacrimation and visual
disturbance are dose-dependent and have been observed after high-dose treatment in 25-80% of patients.
Haemorrhagic conjunctivitis and ulcerating keratitis occur in severe cases. Regular rinsing of the eyes or
prophylactic use of corticoid-containing eye drops may help to prevent or alleviate these symptoms.
Hepatic and pancreatic disorders
Hepatic impairment with an increase in cholestase-including enzymes and hyperbilirubinaemia were observed
in 25-50% of patients receiving high-dose therapy, as well as liver abscesses and hepatomegaly. Individual
cases of hepatic venous thrombosis (Budd-Chiari syndrome) have been reported.
Individual cases of pancreatitis have been reported after treatment with high-dose cytarabine.
Pulmonary oedemas resulting from increased permeability of the alveolar capillaries have rarely been observed
at conventional dosage, and in approximately 10-30% of patients at high dosage.
These pulmonary complications are in most cases reversible. Dyspnoea, pneumonia and pulmonary toxicity
have been reported.
Diffuse interstitial pneumonia occurred in 10 out of 52 patients receiving average doses (1 g of cytarabine/m
of body surface area) concurrently with other cytotoxic agents. However, a causal relationship with the use
of cytarabine could not be confirmed.
Cardiovascular system disorders
Myocardial damage was reported. Also individual cases of acute pericarditis and transient cardiac arrhythmias
Renal and urinary tract disorders
Ischuria and impairment of renal function may occur.
An increase in creatinine plasma concentrations was observed in 5-20% of patients after treatment with
high-dose cytarabine. However, a causal relationship with the use of cytarabine could not be firmly established.
In case of massive cellular degeneration, measures should be taken to avoid uric acid nephropathy.
Other side effects
Inadequate antidiuretic hormonal incretion was observed in individual cases in patients receiving high-dose
Other adverse effects were inflammation of the throat, allergic oedemas, gonadal dysfunction, thoracic pain,
ascites, immunosuppression, sepsis, thrombophlebitis, and haemorrhages.
Fever occurred in 20-50% of patients receiving high-dose therapy.
Immediate allergic reactions (urticaria, anaphylaxis) are very rare.
Cytarabine (Ara-C) syndrome
This syndrome described in the literature is characterised by fever, myalgia, bone pain, occasional thoracic
pain, maculopapulous exanthema, conjunctivitis and nausea.
It generally occurs 6-12 hours after administration. Corticosteroids have proven useful for prophylaxis and
therapy. If corticosteroids prove effective, therapy with cytarabine may be continued.
As with all other cytotoxic agents, use of cytarabine may result in hypocalcaemia and secondary hyperuricaemia
due to cell lysis, in the event of which appropriate counter-measures are required.
If cytarabine is given as a high-dose continuous infusion (more than 200 mg/m
of body surface area daily
for 5 to 7 days), the adverse effects are more pronounced than in standard therapy.
Polyserositis as well as “early deaths” resulting from unmanageable haemorrhages or septicaemia and death
caused by prolonged bone marrow depression were observed. The maximum tolerable dose assessed for
humans is 4.5 g/m
. At doses exceeding 3 g/m
cerebral toxicity is much more pronounced.
An antidote against cytarabine has not yet been established.
If toxic reactions occur, immediate discontinuation of high-dose cytarabine therapy and careful patient
monitoring are essential.
Chronic overdose may lead to severe bone marrow depression, including massive haemorrhages, life-
threatening infections and neurotoxicity.
Myelotoxicity is a dose-limiting factor of cytarabine. Therapy with cumulative doses of approximately 18 to
36 g cytarabine per treatment course, severe myelotoxicity progressing to myelophthisis must be expected,
the full clinical symptoms of which become manifest only after 1 or 2 weeks. It is dependent both on the
dosage and on other factors including a patient’s age, clinical condition and bone marrow reserves as well
as any additional myelotoxic therapy. Therefore, if overdosage is suspected, careful monitoring of hematological
parameters over a prolonged period is essential. Since no effective antidote has yet been established, utmost
care must be exercised with any form of administration. Effective supportive measures (e.g. blood transfusion,
antibiotic treatment) must be taken in case of overdosage. If accidental severe overdosing occurs during
intrathecal administration, the cerebrospinal fluid must be immediately replaced with isotonic sodium chloride
Cytarabine is haemodialysable. However, no data are available as to the effect in case of overdosage.
Doses of 4.5 g/m
by I.V. infusion over 1 hour every 12 hours for 12 doses have caused an unacceptable
increase in irreversible CNS toxicity and death.
Pharmacotherapeutic group: antimetabolites/pyrimidine analogues.
ATC code: LO1B CO1.
Alexan contains cytarabine (4-amino-1-(ß-D-arabino-furanosyl)-1H-pyrimidine-2-one), a cytotoxic agent
belonging to the group of antimetabolites. It is distinguished from the human body’s pyrimidine nucleosides
cytidine and 2’-deoxycytidine only by the sugar (arabinose instead of ribose), which makes it an analogue
After being absorbed by the cell via the transport mechanism for pyrimidine nucleosides, cytarabine is
deaminated to inactive uracil arabinoside and phosphorylated to active nucleotides (cytarabine mono-, di-
and triphosphate). These cytarabine nucleotides inhibit DNA synthesis in the S phase of the cell cycle. The
molecular mechanism of action of this effect appears to be inhibition of cytidine phosphate reductase,
incorporation of cytarabine into DNA and RNA - impairing the function of these nucleic acids - and inhibition
of DNA polymerase.
Especially the virus-induced RNA-dependent DNA polymerase (reverse transcriptase) is significantly inhibited.
What probably adds to the cytostatic effect of cytarabine is its ability to “recruit” cells from the G
for proliferation, thus making them accessible to the chemotherapeutic effect of cell phase-specific cytotoxic
Sensitivity of a tissue to cytarabine depends on the ratio between cytidine deaminase and cytidine kinase
activity. In the framework of cytarabine therapy, both pre-existing and acquired resistances to this cytotoxic
agent are observed, which is probably caused by the ratio in which the above enzymes occur in the tumour
Efficacy of cytarabine in remission induction and maintenance therapy in patients with acute myeloid
leukaemia has been demonstrated in clinical practice, with the response rate being particularly high among
Cytarabine has, moreover, proven effective in the treatment of acute lymphatic leukaemia.
Cytarabine also has an immunosuppressive effect.
The pharmacokinetic properties of cytarabine are determined by its high solubility in water and its low
solubility in lipids. Cytarabine should be administered via parenteral route. After an initial distribution phase,
plasma levels of cytarabine decline with a half-life of 2-2.5 hours. In this second elimination phase, about
80% are available as inactive uracil arabinoside. 80% of the administered dose is recovered in the urine
within 24 hours, mostly as uracil arabinoside. Cerebrospinal fluid levels of cytarabine normally reach up to
40% of plasma levels after intravenous administration. If applied intrathecally, cerebrospinal fluid levels of
cytarabine decline with a half-life of 2-11 hours; as deaminase activity in the cerebrospinal fluid is low, mainly
unchanged cytarabine is available.
Blood levels of cytarabine remain constant even after repeated administration and are not affected by
corticosteroids and other cytotoxic agents.
Constant, dose-dependent blood levels are achieved 30-60 minutes after intravenous infusion.
Peak plasma levels are achieved about 20-60 minutes after subcutaneous application. At comparable doses,
they are significantly lower than the plasma levels achieved after intravenous administration.
Preclinical Safety Data
Subchronic and chronic toxicity
In animal tests, subchronic toxicity has mainly been observed in the form of bone marrow depression with
haematological disorders and damage of the intestinal mucosa.
Trials to determine the chronic toxicity of cytarabine have not been performed.
Mutagenicity and carcinogenicity
Cytarabine has been shown to be mutagenic in experimental studies with animals. Chromosomal aberrations
in peripheral lymphocytes after treatment with cytarabine have been observed in humans.
Long-term trials to determine the carcinogenic potential of cytarabine have not been performed.
Studies conducted over a period of 6 months in mice and rats did not demonstrate an increase in carcinogenicity.
Cytarabine has demonstrated a teratogenic effect in various animal species. Malformations of the skeleton,
eyes, brain and kidneys have been observed. Insufficient data are available for humans. The observed
malformations involve the extremities, the outer ear and the auditory canal. Exposure to cytarabine in the
third trimester of pregnancy may lead or contribute to growth retardation and pancytopenia in the
List of Excipients
Alexan 100 mg:
Sodium chloride, sodium lactate solution, lactic acid, water for injection.
Alexan 500 mg & 1000 mg & 2000 mg:
Sodium lactate solution, lactic acid, water for injection.
Cytarabine has proven to be incompatible with the following solutions for injection or infusion: 5-fluorouracil,
heparin, gentamicin, insulin, methotrexate, methyl prednisolone, nafcillin, oxacillin and penicillin G.
Due to the possibility of further incompatibilities, mixing with other pharmaceutical agents should generally
Special Precautions for Storage
Shelf Life - 36 months.
Do not store above 25
Keep container in the outer carton, in order to protect from light.
Nature and Contents of Container
Glass vial with rubber stopper and aluminum overseal.
Cytarabine 100 mg/5 ml
- 1 vial
Cytarabine 500 mg/10 ml
- 1 vial
Cytarabine 1000 mg/20 ml
- 1 vial
Cytarabine 2000 mg/40 ml
- 1 vial
Instructions for Handling and Disposal
Do not use Alexan beyond the expiry date indicated on the packaging.
Any residual quantities and primary packaging must be disposed of as hazardous waste.
EBEWE Pharma, Unterach, Austria
License Holder and Importer:
Pharmalogic Ltd. P.O.B 3838, Petah-Tikva 49130
The format of this leaflet was determined by the Ministry of Health and its content was checked and
approved in November 2005
ALEX INJ PHY SH 191108_Size1