CytaCedal

• Hypersensitivity to the active substance or to any of the excipients
• pregnancy or breastfeeding
• leukopenia and/or thrombocytopenia,
• severe liver or kidney diseases.

Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving the drug should be kept under close medical supervision. Leucocyte, and platelet counts should be performed frequently and daily during induction. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood.

Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses, and hemorrhage secondary to thrombocytopenia).

One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitiation 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 cytarabine) has been reported following some experimental cytarabine dose schedules. These reactions include reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; somnolence; convulsion; severe gastrointestinal ulceration including pneumatosis cysteroides intestinalis, leading to peritonitis; sepsis and liver abscess; and pulmonary oedema.

Rarely, neurological effects such as quadriplegia and paralysis 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.

Delayed progressive ascending paralysis resulting in death has been reported in children with AML following intravenous cytarabine at conventional doses in combination with other drugs.

Cytarabine has been shown to be mutagenic and carcinogenic in animals. The possibility of a similar effect should be borne in mind when designing the long-term management of the patient.

Cytarabine should only be used under the constant supervision by physicians experienced in therapy with cytotoxic agents. Hyperuricaemia secondary to rapid lysis of neoplastic cells may occur in patients receiving cytarabine; serum uric acid concentrations should be monitored. The physician should be prepared to use such supportive and pharmacological measures as may be necessary to control this problem.

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. If treatment is not resumed before blood values return to normal, the disease can get out of control.

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.

Abdominal tenderness (peritonitis) and guaiac positive colitis, with concurrent neutropenia and thrombocytopenia, have been reported in patients treated with conventional doses of cytarabine in combination with other drugs. Patients have responded to nonoperative medical management.

Concurrent granulocyte-transfusion should be avoided as severe respiratory insufficiency has been reported.

Immunosuppressant effects/Increased susceptibility to infections

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including cytarabine, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving cytarabine. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

High dose therapy

Peripheral motor and sensory neuropathies after consolidation with high doses of cytarabine, daunorubicin, and asparaginase have occurred in adult patients with acute non lymphocytic leukemia.

Patients treated with high doses of cytarabine should be observed for neuropathy since dose adjustments may be needed to avoid irreversible neurologic disorders.

Severe and sometimes fatal pulmonary toxicity, adult respiratory distress syndrome, and pulmonary edema have occurred following high dose schedules with cytarabine therapy.

Cases of cardiomyopathy with subsequent death have been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation.

The risk of CNS toxicity increases if high dose cytarabine is given in combination with another CNS toxic treatment such as radiation therapy or in patients who have previously had CNS treatment as chemotherapy intrathecally. When given intrathecally, as with any other intrathecal drug, care must be taken with radiotherapy given either during or after treatment; it is well recognised that this can exacerbate the toxicity of radiotherapy.

• Cardiovascular: Angina pectoris, chest pain, local thrombophlebitis, pericarditis
• Central nervous system: Aseptic meningitis, cerebral dysfunction, dizziness, headache, neuritis, neurotoxicity, paralysis (intrathecal and IV combination therapy), reversible posterior leukoencephalopathy syndrome
• Dermatologic: Acute generalized exanthematous pustulosis, alopecia, dermal ulcer, ephelis, pruritus, skin rash, urticaria
• Endocrine & metabolic: Hyperuricemia
• Gastrointestinal: Abdominal pain, anal fissure, anorexia, diarrhea, esophageal ulcer, esophagitis, increased serum amylase, increased serum lipase, intestinal necrosis, mucositis, nausea, pancreatitis, sore throat, toxic megacolon, vomiting
• Genitourinary: Urinary retention
• Hematologic & oncologic: Anemia, bone marrow depression, hemorrhage, leukopenia, megaloblastic anemia, neutropenia (onset: 1 to 7 days; nadir [biphasic]: 7 to 9 days and at 15 to 24 days; recovery [biphasic]: 9 to 12 days and at 24 to 34 days), reticulocytopenia, thrombocytopenia (onset: 5 days; nadir: 12 to 15 days; recovery 15 to 25 days)
• Hepatic: Hepatic insufficiency, hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease), increased serum transaminases (acute), jaundice
• Hypersensitivity: Allergic edema, anaphylaxis
• Infection: Sepsis
• Local: Cellulitis at injection site, inflammation at injection site (SC injection),local inflammation (anus), pain at injection site (SC injection)
• Neuromuscular & skeletal: Rhabdomyolysis
• Ophthalmic: Conjunctivitis
• Renal: Renal insufficiency
• Respiratory: Acute respiratory distress, dyspnea, interstitial pneumonitis
• Miscellaneous: Drug toxicity (cytarabine syndrome; chest pain, conjunctivitis, fever, maculopapular rash, malaise, myalgia, ostealgia), fever

• Cardiovascular: Cardiomegaly, cardiomyopathy (in combination with cyclophosphamide)
• Central nervous system: Neurotoxicity (patients with renal impairment: ?55%), coma, drowsiness, neurocerebellar toxicity, peripheral neuropathy (motor and sensory), personality changes
• Dermatologic: Alopecia (complete), desquamation, skin rash (severe)
• Gastrointestinal: Gastrointestinal ulcer, necrotizing enterocolitis, pancreatitis, peritonitis, pneumatosis cystoides intestinalis
• Hepatic: Hepatic abscess, hepatic injury, hyperbilirubinemia
• Infection: Sepsis
• Ophthalmic: Corneal toxicity, hemorrhagic conjunctivitis
• Respiratory: Acute respiratory distress, pulmonary edema
• Adverse events associated with intrathecal cytarabine administration
• Central nervous system: Aphonia, leukoencephalopathy (necrotizing; with concurrent cranial irradiation, intrathecal methotrexate, and intrathecal hydrocortisone), nerve palsy (accessory nerve), neurotoxicity, paraplegia
• Gastrointestinal: Dysphagia, nausea, vomiting
• Ophthalmic: Blindness (with concurrent systemic chemotherapy and cranial irradiation), diplopia
• Respiratory: Cough, hoarseness
• Miscellaneous: Fever

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. Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine or procarbazine. 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. Steady-state plasma digitoxin concentrations did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens. The utilization of digitoxin for such patients may be considered as an alternative.

• Anti-Infective Agents

One in vitro study indicates that cytarabine may antagonise the activity of gentamicin against Klebsiella pneumoniae. In patients on cytarabine being treated with gentamicin for a K.pneumoniae infection, a lack of a prompt therapeutic response may indicate the need for re-evaluation of antibacterial therapy.

• 5-Fluorocytosine:

5-Fluorocytosine should not be administered with cytarabine as the therapeutic efficacy of 5-Fluorocytosine has been shown to be abolished during such therapy.

• Immunosuppressive Agents:

Due to the immunosuppresive action of cytarabine, 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 humoral immunity. These infections may be mild, but can be severe and at times fatal.

• Methotrexate:

There is evidence of pharmacodynamic interaction between methotrexate and cytarabine leading to encephalopathy.

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 who may become, pregnant during treatment with cytarabine should be informed of the risks.

Men and women have to use effective contraception during and up to 6 months after treatment.

Breast feeding

It is not known if cytarabine or its metabolite is distributed into breast milk, and it should not be used in mothers who are breastfeeding.

Fertility

Fertility studies to assess the reproductive toxicity of cytarabine have not been conducted. Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking cytarabine therapy, especially in combination with alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Given that cytarabine has a mutagenic potential which could induce chromosomal damage in the human spermatozoa, males undergoing cytarabine treatment and their partner should be advised to use a reliable contraceptive method.

How Supplied

Cytacedal^® is a solution for injection, supplied in a single dose glass vial.

Handling and disposal

Caution should be exercised in the handling of Cytacedal^®.

For single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Storage

• Store below 25 °C and protect from freezing
• Do not store in refrigerator.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user