Firma Vai Hong
Full Prescribing Info
1 ml contains 50 mg cytarabine in stabilised aqueous solution.
Excipient/Inactive Ingredients: Sodium lactate solution 50%, lactic acid, water for injections.
Pharmacology: Pharmacodynamics: Alexan contains cytarabine (4-Amino-1-(β-D-arabinofuranosyl)-1H-pyrimidin-2-one), a cytostatic agent belonging to the class of antimetabolites. It differs from the endogenous pyrimidine nucleosides cytidine and 2'-deoxycytidine only in term of its sugar residue (arabinose instead or ribose) and is therefore a pyrimidine analogue.
Following its uptake into the cell via the transport mechanism for pyrimidine nucleosides, cytarabine is deaminated, on the one hand, to the inactive uracil arabinoside and phosphorylated, on the other, to active nucleotides (cytarabine monophosphate, diphosphate and triphosphate).
These cytarabine nucleotides inhibit DNA synthesis in the S-phase of the cell cycle. Inhibition of cytidine phosphate reductase, incorporation of cytarabine into DNA and RNA (resulting in dysfunction of these nucleic acids) and inhibition of DNA polymerase have been discussed as the molecular mechanism of action underlying this effect. Virally induced RNA-dependent DNA polymerase (reverse transcriptase), in particular, is severely inhibited. The cytostatic effect of cytarabine is probably also attributable to its ability to prompt the progression of quiescent cells (GO-phase) to the proliferation cycle (recruitment), as a result of which these cells become susceptible to the chemotherapeutic action of cell-phase-specific cytostatic agents.
The sensitivity of a tissue to cytarabine depends on the ratio of its cytidine deaminase activity to cytidine kinase activity. Both pre-existing and acquired resistance to treatment with cytarabine is observed. This is attributed to the ratio of these enzymes in tumour tissue.
The clinical efficacy of cytarabine has been demonstrated for remission induction and maintenance therapy of acute myeloid leukaemia, with children in particular exhibiting a high responder rate. Cytarabine has also proved effective against acute lymphoblastic leukaemia. Furthermore, cytarabine has immunosuppressant action.
Pharmacokinetics: The pharmacokinetic properties of cytarabine are determined by its high water solubility and low lipid solubility. The drug is for administration by the parenteral route. After an initial distribution phase, plasma concentrations decline with a half-life of 2-2.5 hours. In this second elimination phase, approximately 80% exists in the form of inactive uracil arabinoside. 80% of the dose administered is excreted in the urine within 24 hours, predominantly in the form of uracil arabinoside. Concentrations of cytarabine in the cerebrospinal fluid (CSF) after i.v. administration are generally 40% of those in the plasma. Following intrathecal administration, the cytarabine concentration in the CSF, consisting predominantly of unchanged cytarabine on account of low deaminase activity in the CSF, declines with a half-life of 2-11 hours.
The kinetics of blood concentrations of cytarabine remain constant even after repeated administration and are not affected by corticosteroids and other cytostatic agents.
Following i.v. infusion, constant dose-dependent concentrations in the blood are attained after 30-60 minutes. Peak plasma concentrations following subcutaneous administration are attained after 20-60 minutes. At comparable dosages, they are markedly lower than those attained in the plasma after i.v. administration.
Toxicology: Preclinical safety data: a) Subchronic and chronic toxicity: Subchronic toxicity observed in animal experiments consisted essentially of bone marrow depression with blood count changes.
No studies have been performed on the chronic toxicity of cytarabine.
b) Mutagenic and carcinogenic potential: Cytarabine has proved mutagenic in an animal model. In humans, chromosomal defects in peripheral lymphocytes occurred after cytarabine therapy.
No long-term studies on carcinogenic potential have been performed. Studies over a period of 6 months in mice and rats provided no indication of any increased carcinogenic potential.
c) Reproduction toxicity: Cytarabine exhibited teratogenic action in various species. Abnormalities of the skeleton, the eyes, the brain and the kidneys were observed. The available data in humans are insufficient.
The malformations observed to date involved the limbs, the external ear and the auditory canal.
Exposure to the drug in the third trimester of pregnancy may lead or contribute to delayed growth and pancytopenia in the fetus/neonate.
Standard therapy: Alexan is a cytostatic agent used for the induction of clinical remission and/or as maintenance therapy in patients with acute non-lymphoblastic leukaemia, acute lymphoblastic leukaemia, acute myeloid leukaemia; diffuse histiocytic lymphoma (non-Hodgkin's lymphoma of high malignancy).
High-dose cytarabine therapy is indicated in patients with: refractory acute non-lymphoblastic leukaemias, refractory acute lymphoblastic leukaemias; blast crisis of chronic myeloid leukaemia; leukaemias that confer a particular risk, such as acute leukaemias as a secondary malignancy following previous chemotherapy and/or radiotherapy, refractory non-Hodgkin's lymphomas.
Dosage/Direction for Use
Effective plasma concentrations are to be assumed to be between 0.01 and 0.15 μg/ml. The dose needs to be determined precisely in each individual case, preferably on the basis of body surface area (BSA).
Unless envisaged otherwise in particular combinations, Alexan dosages are as follows.
Standard dosage: a) Induction therapy of acute leukaemias: i.v. injection of 100-200 mg/m2 BSA/day.
i.v. infusion of 100 mg/m2 BSA/day.
These doses are given merely for guidance and may be exceeded during therapy.
The duration of therapy is determined by the clinical and morphological findings (bone marrow).
The patient can either be treated for up to 7 days, followed by a treatment-free interval of 7-9 days to allow the bone marrow to recover; consolidation cycles (often shortened) may then be administered until remission is achieved or toxicity occurs. Alternatively, treatment may be continued until the onset of bone marrow hypoplasia, which is to be considered the tolerability threshold.
Before repeating an (often shortened) treatment cycle, there must have been a treatment-free interval of at least 14 days or until the occurrence of bone marrow recovery.
b) Maintenance therapy of leukaemia: 75-100 mg/m2 BSA/day once a month on 5 consecutive days or once a week.
c) CNS involvement: 10-30 mg/m2 BSA/day three times a week intrathecally.
d) lymphoma: This disease is generally treated with appropriate combination therapy.
High-dose therapy: Unless otherwise stipulated, the regimen is 2-3 g/m2 BSA every 12 hours for 4-12 doses.
The total dose and duration of treatment should be at the discretion of the prescribing doctor.
Depending on how many infusions are administered, the treatment cycle may be repeated once the bone marrow has recovered.
Method and duration of administration: 1) In the case of standard therapy: Alexan can be administered as follows: continuous i.v. infusion, i.v. injection, intrathecal injection or exceptionally also subcutaneous injection.
Following i.v. injection, a minimum therapeutic plasma concentration is not attained in most patients in less than an hour as a result of the short half-life of cytarabine. It is therefore necessary to administer the daily dosage in two or more divided doses at equal intervals. Physiological saline or 5% glucose solution can be used to prepare an Alexan solution for infusion. Data on the duration of long-term infusions range from 8-12 hours to 120-168 hours. Compared with a single i.v. injection, the same doses administered by continuous i.v. infusion give rise to more marked gastrointestinal toxicity.
For intrathecal administration, it is advisable to draw up 5-8 ml cerebrospinal fluid, mix it with the solution for injection in the syringe and then slowly re-inject it. Systemic side effects are unlikely to occur if this procedure is followed. Subcutaneous injection is used only in exceptional circumstances and generally only for maintenance therapy. Intradermal injection should be avoided on account of the risk of oedema.
2) In the case of high-dose therapy: Alexan is administered as an i.v. infusion over 1-3 hours.
If an infusion pump is used, Alexan can also be administered undiluted.
Physiological saline or 5% glucose solution can be used to prepare a diluted solution for infusion.
All formulations of Alexan are mutually compatible and may be combined to make up the individually required dose, thereby eliminating product residues.
Treatment of overdose: There is no known antidote to cytarabine.
If signs of overdose occur, high-dose cytarabine therapy should be discontinued immediately and the patient should be carefully monitored.
Chronic overdose may lead to severe bone marrow depression, characterised by manifestations including massive haemorrhages and life-threatening infections as well as neurotoxicity.
The myelotoxicity of cytarabine is dose-limiting. Even at cumulative doses of approximately 18 to 36 g cytarabine per treatment cycle in the context of high-dose therapy, patients are likely to experience severe bone marrow toxicity to the point of myelophthisis, the full extent of which is not clinically detectable for the first 1-2 weeks. It is dependent on the dose and on the other factors such as the patient's age, clinical condition and bone marrow reserve and additional myelotoxic therapy. The patient's blood count should therefore be closely monitored for some time at the slightest suspicion of overdose. Since there are no effective antidotes, each dose should be administered only with the utmost caution. Appropriate supportive measures (e.g. blood transfusion, antibiotics) should be instituted in the event of overdose. Unintentional severe overdose during intrathecal administration necessitates immediate replacement of the cerebrospinal fluid with isotonic sodium chloride solution.
Cytarabine is haemodialysable. No information is available on whether this is effective in the event of overdose, however.
Hypersensitivity to cytarabine or any of the other ingredients of the product.
Patients with pre-existing bone marrow suppression should be excluded from treatment.
Severely impaired hepatic and/or renal function, pre-existing severe infections, peptic ulcers and recent surgery.
Leukopenia and/or thrombocytopenia of non-malignant aetiology.
Pregnancy and lactation (see Use in Pregnancy & Lactation).
Special Precautions
Cytarabine should be administered only in a hospital setting and by clinicians with appropriate expertise in the administration of cancer chemotherapy. The usual precautionary measures (goggles, gloves, mouth and nose mask and, where possible, air extraction) are necessary when handling the vials. In particular, it is important to ensure that facilities are available for monitoring the effects of treatment on patients and for taking emergency action where necessary.
White cell and platelet counts should be determined as frequently as possible and should still be monitored regularly even once treatment has ended. This also applies where treatment is administered by the intrathecal route. The recommended lower limit for the neutrophil count is 1,000 and for the platelet count is 50,000. If these levels are reached, consideration should be given to discontinuation or modification therapy.
In patients with high blast counts or extensive tumour masses (non-Hodgkin's lymphoma), prophylaxis of hyperuricaemia is advisable. Facilities for supportive measures should be available.
Particular caution must be exercised in patients with mild impairment of hepatic and renal function.
Hepatic and renal dysfunction are predisposing factors for increased CNS toxicity of cytarabine.
As cytarabine is metabolized largely in the liver, the effect of the substance may be enhanced in patients with liver damage. Enhancement of its effect also occurs in patients with impaired renal function. In patients with hepatic and/or renal failure, the dose should be reduced accordingly while monitoring concentrations of the substance in the blood. Regular monitoring of hepatic and renal function and of uric acid is necessary. In patients with pre-existing disturbances of liver function, cytarabine should be administered only with caution and only after strict risk/benefit evaluation, particularly in the case of high-dose therapy.
Patients should drink plenty of fluids.
High-dose cytarabine therapy in patients over the age of 60 is possible only after particularly careful risk/benefit assessment.
Contraceptive measures: Cytarabine may have mutagenic effects. Men should not therefore father a child during treatment and for up to six months after it has ended. Furthermore, they should be informed prior to treatment of the possibility of sperm banking, as cytarabine therapy may give rise to irreversible infertility.
If patients wish to have a child on completion of therapy, genetic counselling is recommended at all costs.
Severe gastrointestinal side effects necessitate antiemetic and other supportive measures.
High-dose treatments necessitate regular monitoring of CNS and lung function by a doctor with experience of administering this type of treatment.
In order to avoid ophthalmological complications, the eyes should be irrigated regularly during high-dose therapy.
If severe bone marrow depression occurs, patients should be placed in a sterile isolation room during treatment.
Immunisation with live vaccines should not be performed during cytarabine therapy.
As with other tumour-inhibiting substances, there is a risk of haemorrhagic complications and severe infections with cytarabine therapy on account of bone marrow depression. During high-dose therapy there is a possibility of CNS disorders, gastrointestinal disorders, disturbances of liver function, skin reactions and ocular disorders.
If signs of CNS toxicity occur or an allergy develops, careful risk/benefit assessment should be undertaken.
Contact with skin and mucous membranes, particularly in the region of the eyes, should be avoided.
Cytarabine is a teratogenic and mutagenic substance.
Effects on Ability to Drive and Use Machines: Administration of this medicinal product may transiently impair responsiveness and consequently also a person's ability to drive.
Use In Pregnancy & Lactation
Cytarabine must not be used during pregnancy and lactation.
Since cytarabine exhibits mutagenic and teratogenic action in some animal species, the possibility of pregnancy must be excluded. Patients of either sex who have reached sexual maturity must use adequate contraception during treatment with Alexan.
If Alexan therapy would appear to be unavoidable in a pregnant patient, the side effects on the fetus associated with this treatment must be evaluated in depth.
If a pregnancy occurs during treatment with Alexan, genetic counselling must be given (see Pharmacology: Toxicology: Preclinical data under Actions).
Breastfeeding should be ceased before commencing treatment with Alexan.
Adverse Reactions
The undesirable effects caused by cytarabine are dependent on dosage, method of administration and duration of therapy.
Local tolerability is generally good; inflammation at the site of injection may sometimes occur.
Haematopoietic System: The most important side effect of cytarabine is bone marrow depression.
Blood count changes (leukopenia, thrombocytopenia, anaemia, megaloblastosis) are dose-dependent.
At conventional dosages: Leukopenia with trough values on days 12 to 24.
High-dose therapy gives rise to significant myelotoxicity.
Gastrointestinal Tract: Gastrointestinal disorders such as nausea, vomiting and diarrhoea occur commonly. Oesophagitis, oesophageal ulcers, abdominal pain, jaundice, severe changes to the gastrointestinal mucosae with ulceration, intestinal emphysema and infections may additionally occur. This may lead to intestinal necrosis and necrotising colitis.
Mucositis and mucosal ulceration (oral, anal) are to be expected, particularly at a high-dosage; this can lead to severe diarrhoea with potassium and protein depletion. Pneumatosis cystoides intestinalis and intestinal necrosis with ileus and peritonitis may occasionally occur, particularly at high dosages.
Skin and skin structure: Toxic skin reactions such as a maculopapular rash, ulceration, erythroderma or erythema, mottled skin and pruritus have occasionally been observed after conventional doses. Exfoliative dermatitis has also been observed after high doses. Alopecia may additionally occur.
In isolated instances, neutrophilic eccrine hidradenitis has been observed.
After high doses of cytarabine, up to 75% of patients develop a generalized erythema, with blister formation and desquamation in a few cases. Burning pain on the palms of the hand and soles of feet may occur.
Nervous system: CNS disorders have been observed, particularly at high dosages, manifested in most cases as cerebral/cerebellar disorders (nystagmus, dysarthria, ataxia, confusional states and personality changes), headaches, dizziness, disturbances of thought processes and movements, somnolence, lethargy, coma, convulsions and anorexia. Total doses of less than 36 g cytarabine/m2 BSA per treatment cycle scarcely give rise to any CNS toxicity. Predisposing factors are advanced age, hepatic and renal dysfunction, previous CNS treatments (radiotherapy, intrathecal administration of cytostatic agents) and alcoholism. CNS disorders are usually reversible.
Intrathecal administration of cytarabine may occasionally give rise to nausea, vomiting, headaches and/or fever. Such phenomena may also result from lumbar puncture, however. The symptoms are often mild and reversible. Intrathecal administration of cytarabine at doses of over 30 mg/m2 BSA often leads to neurotoxic reactions. In particular, short dosing intervals may lead to cumulative neurotixicity (see Dosage & Administration).
Isolated instances of necrotising leukoencephalopathy as well as of paraplegia and loss of vision have been described after intrathecal administration of cytarabine. Intrathecal administration of benzyl alcohol or other solubilising additives must be avoided at all costs.
Neuritis and, after high doses, isolated instances of peripheral nerve lesions have been described, as have cases of delayed progressive ascending paralysis, meningitis and encephalitis.
Locomotor apparatus: Myalgia and/or arthralgia have occasionally been observed after high doses of cytarabine. The occurrence of rhabdomyolisis has been described.
Sensory organs: Ocular disorders such as conjunctivitis, keratitis, photophobia, sore eyes, severe lacrimation and visual disturbances are dose-dependent and have been observed in 25 to 80% of patients on high-dose therapy. In severe cases, haemorrhagic conjunctivitis and ulcerative keratitis occur.
Regular irrigation of the eyes or prophylactic use of corticosteroid-containing eye-drops may prevent or alleviate such phenomena.
Liver and pancreas: Impairment of liver function with elevation of cholestasis-inducing enzymes and hyperbilirubinaemia has been observed in 25 to 50% of patients on high-dose treatment, likewise liver abscesses and hepatomegaly. There are isolated reports of the occurrence of hepatic venous thrombosis (Budd-Chiari syndrome).
Isolated instances of pancreatitis have been reported on high doses of cytarabine.
Lung: Pulmonary oedema as a result of the increased permeability of the alveolar capillaries has been observed occasionally on conventional doses and in approximately 10 to 30 % of patients after high cytarabine doses. These pulmonary complications are usually reversible. Shortness of breath, pneumonia and pulmonary toxicity has occurred.
Patients who received mean doses (1 g cytarabine/m2 BSA) concomitantly with other cytostatic agents developed diffuse interstitial pneumonia in 10 out of 52 cases. A definite causal relationship with use of cytarabine could not be established, however.
Cardiovascular system: Damage to the myocardium has been reported. In addition, isolated instances of acute pericarditis and transient cardiac arrhythmias have been observed.
Kidney and urinary tract: Urinary retention and renal dysfunction may occur.
Elevation of plasma creatinine has been observed in 5 to 20% of patients on high-dose cytarabine therapy. A definite causal relationship with cytarabine could not be proven. However, if massive cell degeneration occurs, action should be taken to prevent the onset of uric acid nephropathy.
Other undesirable effects: The syndrome of inappropriate antidiuretic hormone secretion has been observed in isolated instances in patients on high-dose treatment with cytarabine.
Furthermore, sore throats, allergic oedema, gonadal dysfunction, pain in the chest region, ascites, immunosuppression, sepsis, thrombophlebitis and haemorrhages have occurred.
Fever occurs in 20 to 50% of patients on high-dose therapy.
Immediate-type allergic reactions (urticaria, anaphylaxis) are very rare.
Cytarabine (Ara-C) syndrome: This syndrome described in the literature is characterised by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and nausea. It generally occurs 6-12 hours after administration. Corticosteroids have proved beneficial in the treatment or prevention of this syndrome. If corticosteroids are effective in this respect, continuation of treatment with cytarabine can be contemplated.
As with all cytostatic agents, hypocalcaemia and secondary hyperuricaemia resulting from cell destruction may occur on cytarabine therapy. Appropriate countermeasures may be required.
Following high-dose continuous infusion (more than 200 mg/m² BSA/day for 5-7 days), the side-effects are more marked than with the standard therapy.
Polyserositis and early deaths as a result of uncontrollable haemorrhaging or sepsis as well as fatalities resulting from prolonged bone marrow depression have occurred. The maximum tolerable dose in humans has been found to be 4.5 g/m². At dosages in excess of 3 g/m², cerebral toxicity is significantly more marked.
Drug Interactions
Patients with previously treated with L-asparagine may experience acute pancreatitis on cytarabine.
Myelotoxic interactions with other treatment methods that have a toxic effect on the bone marrow (particularly other cytostatic agents and radiotherapy) are to be expected depending on the comedication in question.
It has been shown in isolated cases that the antifungal action of flucytosine may be inhibited by cytarabine.
Caution For Usage
Instructions for use and handling and disposal: Alexan must not be used after the expiry date.
Any residues and the primary packaging should be disposed of as hazardous waste.
Incompatibilities: In solutions for injection or infusion, cytarabine is incompatible with 5-fluorouracil, heparin, gentamicin, insulin, methotrexate, methylprednisolone, nafcillin, oxacillin and penicillin G. Since other incompatibilities are possible, it is generally inadvisable to mix cytarabine with other drugs.
Do not store above 25°C. Protect from light.
Shelf life: 24 months.
ATC Classification
L01BC01 - cytarabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.
Soln for inj (vial) 50 mg/mL x 10 mL x 1's.
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