1. Name Of The Medicinal Product
Cytarabine 100 mg/ml Injection
2. Qualitative And Quantitative Composition
Each 1 ml contains 100 mg of cytarabine
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For excipients see 6.1
3. Pharmaceutical Form
Solution for injection.
Clear, colourless solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Cytarabine may be used alone or in combination with other antineoplastic agents. It is indicated alone or in combination for induction of remission and/or maintenance in patients with acute myeloid leukaemia, acute non-lymphoblastic leukaemias, acute lymphoblastic leukaemias, acute lymphocytic leukaemia, erythroleukaemia, blast crises of chronic myeloid leukaemia, diffuse histiocytic lymphomas (non-Hodgkin's lymphomas of high malignancy), meningeal leukaemia and meningeal neoplasms. Clinicians should refer to the current literature on combination therapy before initiating treatment.
4.2 Posology And Method Of Administration
Cytarabine 100 mg/ml Injection is a ready to use injection and can be administered by the intravenous and subcutaneous routes. Cytarabine 100 mg/ml Injection should not be administered by the intrathecal route due to the slight hypertonicity of this formulation. (See section 4.8 Undesirable effects).
Cytarabine Injection can be diluted with Sterile Water for Injections BP, Glucose Intravenous Infusion BP or Sodium Chloride Intravenous Infusion BP. Prepared infusions, in the recommended diluents, should be used immediately. Alternatively, the diluted infusion fluids may be stored at 2-8°C, protected from light, but portions remaining unused after 24 hours must be discarded.
Remission Induction: Adults
Continuous Dosing: The usual dose in leukaemia, is 2 mg/kg by rapid intravenous injection daily for ten days. If after ten days neither therapeutic response nor toxicity has been observed, the dose may be increased to 4 mg/kg until a therapeutic response or toxicity is evident. Daily blood counts should be taken. Almost all patients can be carried to toxicity with these doses.
Alternatively, 0.5 to 1 mg/kg may be infused daily in 1-24 hours for ten days, and then at a rate of 2 mg/kg/day until toxicity is observed. Continue to toxicity or until remission occurs. Results from one hour infusions have been satisfactory in the majority of patients.
Intermittent dosing: Cytarabine may be given as intermittent intravenous doses of 3-5 mg/kg daily, for five consecutive days. This course of treatment can be repeated after an interval of 2 to 9 days, and repeated until the therapeutic response or toxicity is exhibited.
Evidence of bone marrow improvement has been reported to occur 7-64 days after the beginning of therapy.
In general, if a patient shows neither remission nor toxicity after a trial period, then cautiously administered higher doses can be administered. Generally patients tolerate higher doses given by rapid intravenous injection rather than slow infusion.
As a single agent for induction of remissions in patients with acute leukaemia, cytarabine has been given in doses of 200 mg/m2 by continuous intravenous infusion for five days at approximately 2 week intervals.
Maintenance therapy: To maintain remission, doses of 1-1.5 mg/kg may be given intravenously or subcutaneously, once or twice weekly.
Leukaemic Meningitis: Therapy for established meningitis employs a wide variety of dose regimens but a recommended total daily dose not exceeding 100 mg, alternating with methotrexate is recommended.
Myelosuppression, anaemia and thrombocytopenia occur almost to all patients given daily infusions or injections. Myelosuppression is biphasic and nadirs at 7-9 and 15-24 days. Evidence of bone marrow improvement may be expected 7-64 (mean 28) days after the beginning of treatment.
Children: Children appear to tolerate higher doses of cytarabine than adults, and where the range of doses is given, children should receive the higher dose.
Elderly: No data is available to suggest that a change in dose is necessary in the elderly. However, the elderly patient is more susceptible to toxic reactions and therefore particular attention should be paid to drug induced leucopenia, thrombocytopenia and anaemia.
4.3 Contraindications
Cytarabine is contraindicated in patients with known hypersensitivity to the drug. Therapy with cytarabine should not be considered in patients with pre-existing drug-induced bone marrow suppression, unless in the opinion of the physician the potential benefits outweigh the hazards. Cytarabine should not be used in the management of non-malignant disease, except for immunosuppression.
4.4 Special Warnings And Precautions For Use
Cytarabine is a potent bone marrow suppressant. Patients receiving the drug should be kept under close medical supervision. Leucocyte and platelet counts should be performed frequently and daily during induction. One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitation has been reported. This occurred immediately after intravenous cytarabine was administered.
Severe and at times fatal central nervous system (CNS), gastrointestinal (GI) and pulmonary toxicity (different from that seen with conventional therapy regimens of dosage schedules). These reactions include reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; severe gastrointestinal ulceration including pneumatosis cysteroides intestinalis, leading to peritonitis; sepsis and liver abscess; and pulmonary oedema.
Central Nervous System: Rarely, neurological effects such as severe spinal cord toxicity even leading to necrotising encephalopathy, quadriplegia and paralysis and blindness have been reported with cytosine arabinoside and have been predominantly associated with intrathecal administration. Isolated cases have also been reported with high intravenous doses during combination chemotherapeutic regimens (see section 4.8 Undesirable effects).
Cytarabine has been shown to be mutagenic and carcinogenic in animals.
Cytarabine should only be used under the constant supervision by physicians experienced in therapy with cytotoxic agents. Hyperuricaemia secondary to lysis of neoplastic cells may occur in patients receiving cytarabine; serum uric acid concentrations should be monitored.
Periodic determinations of renal and hepatic functions and bone marrow should also be performed and the drug should be used with caution in patients with impaired hepatic function.
However, dosage reduction does not appear to be necessary in patients with impaired renal function. The human liver apparently detoxifies a substantial fraction of the administered dose. The drug should be used with caution and at a reduced dose when liver function is poor. Frequent platelet and leucocyte counts are mandatory. 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 may continue to fall after the therapy has been discontinued and may reach lowest values after five to seven 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.
When intravenous doses are given quickly, patients may become nauseated and may vomit for several hours afterwards. The problem tends to be less severe when infused.
The safety of the drug has not been established in infants.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
i) Cardiac Glycosides
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. Limited data suggest that the extent of GI absorption of digitoxin is not substantially affected by concomitant administration of combination chemotherapy regimens known to decrease absorption of digoxin.
ii) Anti-Infective Agents
One in vitro study indicates that cytarabine may antagonise the activity of gentamicin against Klebsiella pneumoniae. Limited data may suggest that cytarabine may antagonise the anti-infective activity of flucytosine, possibly by competitive inhibition of the anti-infective uptake by fungi.
4.6 Pregnancy And Lactation
Use in Pregnancy:
Cytarabine is teratogenic in some animal species. It should not be used in pregnant women (especially during the first trimester) or in those who may become pregnant, unless the possible benefits outweigh the potential risks. Women who are, or become, pregnant during treatment with cytarabine should be informed of the risks.
Use in Lactation:
It is not known if cytarabine or its metabolite is distributed into breast milk, and it should not be used.
4.7 Effects On Ability To Drive And Use Machines
No documented effect on ability to drive or operate machinery.
4.8 Undesirable Effects
Haematological Effects:
The major adverse effect of cytarabine is the haematological toxicity. Myelosuppression is manifested by megaloblastosis, reticulocytopenia, thrombocytopenia and anaemia.
These appear to be more evident after high doses and continuous infusions; the severity depends on the dose of the drug and schedule of administration.
GI Effects:
Nausea and vomiting occur and are generally more frequent following rapid IV administration than with continuous IV infusion of the drug.
Diarrhoea, anorexia, oral and anal inflammation or ulceration and less frequently abdominal pain, sore throat, oesophagitis, oesophageal ulceration and gastrointestinal haemorrhage may also occur.
Other reported adverse effects of cytarabine include fever, rash, alopecia, skin ulceration, conjunctivitis, chest pain, urinary retention, dizziness, neuritis, neurotoxicity or neural toxicity and pain, cellulitis and thrombophlebitis (including irritation or sepsis) at the site of injection. Cytarabine has also been associated with renal dysfunction, hepatic dysfunction and jaundice in some patients. It has also been associated with freckling, skin, mucosal bleeding and joint pain.
A cytarabine reaction is characterised by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs 6-12 hours after administration. Corticosteroids have been shown to be beneficial in treating or preventing this syndrome. If the symptoms of the syndrome are serious enough to warrant treatment, corticosteroids should be contemplated as well as continuation of cytarabine therapy.
Very rare cases of pericarditis have been reported.
Cases of pancreatitis have been reported.
Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of dosage schedules). These reactions include reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; severe gastrointestinal ulceration including pneumatosis cysteriodes intestinalis, leading to peritonitis; sepsis and liver abscess; and pulmonary oedema.
Hyperuricaemia (see section 4.4 Special warnings and precautions for use).
One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitation has been reported (see section 4.4 Special warnings and precautions for use).
Central Nervous System: Rarely neurological effects such as severe spinal cord toxicity even leading to necrotising encephalopathy, quadriplegia and paralysis, and blindness have been reported (see section 4.4 Special warnings and precautions for use).
4.9 Overdose
Cessation of therapy followed by management of ensuing bone marrow depression including whole blood or platelet transfusion and antibiotics as required.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Cytarabine (ARA-C) is metabolised in vivo to ARA-CTP phosphorylated compound. This competitively inhibits DNA polymerase and may also inhibit certain acid kinase enzymes. Primarily the drug acts as a false nucleoside and competes for enzymes involved in the conversion of cytidine nucleotide to deoxycytidine nucleotide and also incorporation into the DNA.
Cytarabine has no effect on non proliferating cells nor on proliferating cells unless in the S phase. It is a cell cycle specific antineoplastic drug.
5.2 Pharmacokinetic Properties
Oral administration is ineffective due to rapid deamination in the gut. Cytidine deaminase is concentrated in the liver and intravenous doses show biphasic elimination with half lives of approximately 10 minutes and 1-3 hours.
After 24 hours 80% of a dose has been eliminated either as the inactive metabolite or as the unchanged cytarabine, mostly in urine but some in bile.
CSF levels of 50% of plasma levels are achieved with intravenous infusion. Intrathecal dosing results in slower elimination (T1/2 2-11 hours).
Cytarabine is rapidly and widely distributed into tissues, crosses the blood brain barrier and also the placenta.
5.3 Preclinical Safety Data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Water for Injections
6.2 Incompatibilities
Solutions of cytarabine have been reported to be incompatible with various drugs, i.e. carbenicillin sodium, cephalothin sodium, fluorouracil, gentamicin sulphate, heparin sodium, hydrocortisone sodium succinate, insulin-regular, methylprednisolone sodium succinate, nafacillin sodium, oxacillin sodium, penicillin G sodium. However, the incompatibility depends on several factors (e.g. concentrations of the drug, specific diluents used, resulting pH, temperature). Specialised references should be consulted for specific compatibility information.
6.3 Shelf Life
Before use: 18 months
In use: Chemical and physical in-use stability has been demonstrated for 7 days at room temperature.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special Precautions For Storage
Do not store above 25°C. Keep container in the outer carton.
6.5 Nature And Contents Of Container
Clear Type I glass vial with rubber stopper.
Clear Type I glass Onco-Tain® vial with rubber stopper
Clear Type I glass Onco-Vial® with rubber stopper
Pack sizes singles, 5's, 10's and 20's.
Not all presentations and pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
7. Marketing Authorisation Holder
Mayne Pharma Plc
Queensway
Royal Leamington Spa
Warwickshire, CV31 3RW
United Kingdom
8. Marketing Authorisation Number(S)
PL 04515/0057
9. Date Of First Authorisation/Renewal Of The Authorisation
10th October 2006
10. Date Of Revision Of The Text
26th April 2007
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