Medicinal Products

ARACYTINE 500 mg

Generic drug of the therapeutic class: Oncology and Hematology
active ingredients: Cytarabine
laboratory: Pfizer Holding France

Lyophilisate for parenteral use
Box of 1 vial of 500 mg
All forms

Indication

- Acute myeloblastic leukemias, especially in relapse.
- Refractory myeloblastic acute leukemia (relapsing during treatment).
- Acute lymphoblastic leukemia in relapse and secondary leukemias.

Dosage ARACYTINE 500 mg Lyophilisate for parenteral use Box of 1 vial of 500 mg

Cytarabine should be administered in hospital, under strict medical supervision.

· Before use, cytarabine can be reconstituted with the following solvent:

o water for injection.

The solvent volumes to be used for reconstitution are as follows:

o Cytarabine 500 mg is reconstituted with 10 ml of solvent.

o Cytarabine 1 g is reconstituted with 10 ml of solvent.

o Cytarabine 2 g is reconstituted with 20 ml of solvent.

· At this high dose, cytarabine 500 mg is administered by intravenous infusion in 250 ml isotonic glucose solution or isotonic sodium chloride solution lasting 1 to 3 hours, at a dosage of 2 to 3 g / m² every 12 hours; either 4 to 6 g / m² / 24 hours for 6 days (ie 12 doses in total per treatment).

· In the case of high dosages, do not use solvents containing benzyl alcohol.

DOSAGE ADAPTATION:

· 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 platelets are less than 50 000 / mm 3,

o neutrophils 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 alone and in combination. Different treatment regimens were used. ARA-C, at a dose of 3 g / m² IV infusion for 1 to 3 hours every 12 hours for 4 to 6 days, could be combined with adriamycin (30 mg / m² D6 and D7), asparaginase (6000 units / m²), rubidazone, AMSA (150 to 200 mg / m² / day x 3), with significant therapeutic results. The haematological toxicity is often more pronounced, as is the digestive toxicity, especially in the form of mucositis.

Warning :

It is extremely important to make sure the administration is intravenous. Extravasation may produce necrosis of the surrounding tissues. In this case, the injection should be stopped immediately.

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 may be envisaged within the framework of the oncology network (circular DGS / DH / 98 N ° 98/188 of 24 March 1998) in collaboration with any suitable and qualified structure.

Against indications

· 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.

· 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 ).

Aracytine side effects

Investigations:

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.

Heart conditions:

Pericarditis.

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.

Eye disorders:

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.

Gastrointestinal disorders:

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.

Alopecia total.

Cutaneous ulcerations.

General disorders and reactions at the site of administration:

Thrombophlebitis and cellulitis at the injection site.

Febrile thrusts.

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.

Anaphylactic reactions:

Allergic edema.

Hepatobiliary disorders:

Hepatic abscess and hepatic functional impairment with elevated bilirubin.

Jaundice.

Disorders of the reproductive organs and the breast:

Amenorrhea, azoospermia.

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.

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