Generic drug of the therapeutic class: Oncology and Hematology
active ingredients: Cytarabine
laboratory: Pfizer Holding France
Powder and solvent for solution for injection
Box of 1 Bottle of powder + 5 ml solvent ampoule
· Acute myeloblastic leukemia in adults and children.
· Acute lymphoblastic leukemia and meningeal location of the disease.
· Acute transformation of chronic myeloid leukemia and myelodysplasia.
Dosage ARACYTINE 100 mg Powder and solvent for solution for injection Box of 1 vial of powder + ampoule of solvent of 5 ml
The dosage and the mode of administration vary according to the protocol of therapeutic associations used.
Different therapeutic regimens using cytarabine have been proposed:
Acute myeloblastic leukemia and acute transformation of chronic myeloid leukemia and myelodysplasia:
The dosages given in mg / m 2 of body surface area can be used in adults and children.
Combination chemotherapy (always with an anthracycline, sometimes with other anti-neoplastics):
100 mg / m 2 / day for 7 to 10 days
200 mg / m 2 / d for 5 to 7 days.
A second cure can be administered in case of failure of the first.
Maintenance and consolidation:
Consolidation can be done with the same chemotherapy protocol as the one that achieved remission. Cytarabine may be administered at lower doses, alone or in combination with other antineoplastics, at intervals of 4 to 6 weeks during maintenance treatments.
In maintenance treatments, the subcutaneous route may be used: 20 mg / m 2 / day, administered in 1 or 2 injections for 5 to 10 days.
Acute lymphoblastic leukemia:
Induction and maintenance treatment:
The protocols used are quite similar to those used in the treatment of acute myeloid leukemias.
They use combinations mainly comprising: cytarabine-vincristine-prednisolone.
Treatment of intrathecal meningeal sites:
As a preventive measure, cytarabine is proposed: 20 mg / m 2, sometimes associated with methotrexate and hydrocortisone.
For children under 3 years, the dose of cytarabine is 30 mg / m 2 .
As a curative, the dose of 20 mg / m 2 is usually used once or twice a week.
Benzyl alcohol should not be used for reconstitution of the solution in the case of intrathecal administration.
· The frequency of treatment depends on the therapeutic result and the hematological and extra-haematological toxicity.
· Repeated blood and bone marrow controls should be performed, especially at the beginning of treatment. Hepatic and renal function will also be monitored.
· Dosage adjustment is based on the results of blood and bone marrow tests (myelogram).
· Usually the treatment is interrupted if:
o The platelets are less than 50 000 / mm 3,
o Neutrophil polynuclear cells are less than 1000 / mm 3 .
· Resumption of treatment is done as soon as the numbers allow and as soon as the blast cells reappear in the blood or in the marrow. Waiting for normalization of the count to resume treatment is detrimental to subsequent control of the disease.
· Dosages will also be modified in case of toxic phenomena other than hematological and in case of combination with other chemotherapeutic agents.
Cytarabine can be used by different routes of administration.
· Intravenous direct injection or continuous infusion: when cytarabine is administered rapidly, the doses injected may be greater than those given by slow infusion; this is due to the rapid inactivation of the product and its very short contact time with sensitive neoplastic and normal cells.
· Subcutaneous route: Cytarabine is particularly well tolerated. There is very rarely pain and inflammation at the injection site.
· Intrathecal route: Cytarabine is used in the preventive and curative treatment of meningeal sites of acute lymphoblastic leukemia in children.
If used intrathecally, reconstitution is with autologous CSF or with isotonic sodium chloride solution; the use must be immediate.
Benzyl alcohol should not be used for reconstitution of the solution in the case of intrathecal administration.
Regardless of the route of administration, clinical experience suggests that cytarabine results are highly dependent on dosage changes to destroy the most blast cells with the least toxicity. A multidrug therapy combination results in dosage modifications for each of the constituents of the protocol.
How to handle:
The preparation of injectable cytotoxic solutions must be carried out by specialized and trained personnel with knowledge of the drugs used, under conditions ensuring the protection of the environment and especially the protection of the personnel handling. It requires a preparation room reserved for this purpose. It is forbidden to smoke, eat, drink in this room. Manipulators must have a set of materials suitable for handling, including long-sleeved gowns, face masks, hood, goggles, sterile disposable gloves, worktop protection fields, containers and collection bags. garbage. Excreta and vomit must be handled with care. Pregnant women should be warned and avoid manipulation of cytotoxics. Any broken container must be treated with the same precautions and considered as contaminated waste. Disposal of contaminated waste is by incineration in rigid containers labeled for this purpose.
These provisions can be envisaged within the framework of the oncology network (circular DGS / DH / 98 n ° 98/188 of March 24th, 1998) in collaboration with any adapted and fulfilling the necessary conditions.
Instruction for a correct opening of the bulbs:
Important: The bulb is preloaded at one point of the throttle. The colored stain on the olive allows the orientation of the latter (Figure 1). Grasp the bulb, the colored point directed towards you, the bulb opens easily by placing the thumb on the point colored and by exerting a slight bending of the top down (figure 2). Do not open the bulb at the line.
· Hypersensitivity to cytarabine.
· Those common to any cytotoxic therapy.
· Pre-existing medullary aplasia.
Degenerative and toxic encephalopathies, especially after use of methotrexate or treatment with ionizing radiation.
· Patients with progressive meningeal infection.
· Breastfeeding (see section on Pregnancy and breastfeeding ).
· In combination with yellow fever vaccine (see section Interactions with other medicinal products and other forms of interaction ).
· The benzyl alcohol solvent should not be used for reconstitution of the solution in the case of intrathecal administration. In other cases, the solution reconstituted with this solvent is contraindicated in neonates.
Aracytine side effects
In rare cases, hyperuricemia secondary to blast lysis may be induced by cytarabine treatment; it will therefore be necessary to monitor the level of uric acid in the blood and urine.
Cases of fatal cardiomyopathy have been reported following the experimental use of high-dose cytarabine and cyclophosphamide in bone marrow transplantation.
Hematological and lymphatic system disorders:
Cytarabine is an antineoplastic agent that causes myelosuppression. Its administration therefore leads to aplasia or medullary hypoplasia responsible for anemia, granulopenia , thrombocytopenia, megaloblastosis and drop in reticulocyte levels.
The severity of aplasia depends on the dose administered and the treatment regimen used. In connection with aplasia, serious hemorrhagic or infectious complications may complicate secondarily the chemotherapy treatment.
Viral, bacterial, fungal, parasitic and saprophytic infections may be associated with the use of cytarabine alone or in combination with other immunosuppressive drugs affecting cellular or humoral immunity. These infections can be mild, but they can also be serious and sometimes fatal.
Nervous system disorders:
Neurocerebellar toxicity for high doses.
Cerebellar lesions in the form of, at least, dysarthria and nystagmus, at most a large ataxia which may be delayed onset and definitive. Episodes of comas, behavioral disorders and peripheral sensory and motor neuropathies have also been reported. Serious or lethal cases have been observed in patients who have previously received other treatments on the central nervous system (encephalic irradiation): it is recommended not to exceed the validated individual dose and we will be very careful in patients who have already received radiotherapeutic or intrathecal treatment.
Neurological toxicity seems to be related to a rapid rate of administration.
Reversible lesions of the cornea and bleeding conjunctivitis have been reported following the use of high doses of cytarabine. These phenomena can be prevented or diminished by the instillation of an eyewash containing corticosteroids.
Respiratory, thoracic and mediastinal disorders:
Serious pulmonary toxicity, sometimes fatal, respiratory distress syndromes and pulmonary edema have been reported following the use of high doses of cytarabine.
Rare cases of interstitial lung disease have been reported in patients treated with intermediate doses of cytarabine with or without other chemotherapy agents, but this has not been clearly associated with cytarabine.
Nausea, vomiting, anorexia are common with the use of cytarabine, on the other hand risk of stomatitis and mucositis. Nausea and vomiting are more common after a rapid infusion. Some rare cases of severe gastrointestinal ulceration with perforation and peritonitis, intestinal necrosis have been described.
Cases of acute pancreatitis have been reported in patients treated with cytarabine in combination with other drugs.
Kidney and urinary disorders:
Renal insufficiency and urinary retention.
Skin and subcutaneous tissue disorders:
Skin rashes or exfoliative dermatitis.
General disorders and reactions at the site of administration:
Thrombophlebitis and cellulitis at the injection site.
Immune system disorders:
In rare cases: Cytarabine syndrome which is characterized by thermal elevation, myalgia, bone pain accompanied in some cases by chest pain, maculopapular rash, conjunctivitis and feeling of general malaise. This syndrome occurs 6 to 12 hours after administration of the product.
Its treatment and prevention respond to corticosteroids.
Hepatic abscess and hepatic functional impairment with elevated bilirubin.
Disorders of the reproductive organs and the breast:
Side effects and toxicity of the intrathecal route of cytarabine:
The most commonly reported effects after intrathecal administration are nausea, vomiting and fever. These reactions are mild.
Severe neurotoxicity events including paraplegia have been reported in intrathecal administrations combined with methotrexate and corticosteroids and in combination with intrathecal injection with systemic administration of high doses of methotrexate and cytarabine.
Cases of necrotizing leukoencephalitis with or without convulsion have been reported. Some of these patients have also been treated with methotrexate and / or hydrocortisone intrathecally and with encephalic irradiation.
Two cases of blindness have been described in subjects who were put into remission after intravenous polychemotherapy and preventive treatment of meningeal grafts with intrathecal cytarabine and radiotherapy of the brain.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals declare any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (Ansm) and the network of Regional Pharmacovigilance Centers www.ansm.sante.fr.