Source: Medicines Authority (MT) Revision Year: 2015 Publisher: 1 A Pharma GmbH, Keltenring 1+3, 82041 Oberhaching, Germany
Patients who have already received a drug which can induce bone marrow suppression should not be treated with Alexan, unless the clinician deems such a treatment to be vitally important to the patient.
Hypersensitivity to cytarabine or of one of the other ingredients.
Alexan must only be administered by specialists with experience in chemotherapy of malignant disorders.
Alexan is a cytotoxic product. Patients treated with Alexan must therefore be kept under strict supervision.
Rapid intravenous doses are gastro-intestinally better tolerated than slow intravenous infusions.
In view of the fact that the product is to a large extent broken down in the liver, the drug must be administered with extreme caution and in a low dosage to patients with liver function disorders.
Cytarabine must not be administered to patients with acute and/or serious infections.
Both male and female patients who are sexually mature must take contraceptive measures during and until six months after the therapy with Alexan.
No effects have been observed as a result of exposure during handling. Slight irritation of the eye is possible. Repeated or continuous contact with the skin can lead to irritation. After accidental contact, wash the area of skin with copious amounts of water and soap.
Each treatment of a patient with acute leukaemia will unavoidably result in a more or less serious – but temporary – bone marrow depression. Control of the number of platelets and granulocytes in the blood is necessary to determine whether support treatment is necessary. The effect of the treatment is determined by measuring the number of leukaemic blast cells in the blood and bone marrow.
It is important that liver and kidney function tests are carried out regularly.
Cytarabine can lead to increased uric acid levels in the blood, as a result of a lysis of the neoplastic cells. Regular monitoring of the uric acid levels in the blood is therefore recommended. If necessary, supporting and pharmacological measures should be taken to get the hyperuricaemia under control. In the case of patients with a high number of blast cells or large tumour masses (non-Hodgkin’s lymphomas) prophylaxis of hyperuricaemia is required.
In addition to the predictable haematological toxicity, in some cases serious or life-threatening side effects can occur to the CNS, the gastrointestinal tract or the lungs.
Patients with gastrointestinal ulcers, or who have recently had an operation must be kept under close observation for indications which point to haemorrhaging, and if necessary platelets must be administered by transfusion, as required.
The toxicity of high dose cytarabine can be more severe than the toxicity of normal dose of cytarabine, and may include cerebellar and cerebral toxicity, conjunctivitis (make sure the patient is on steroid eye drops during therapy), corneal keratitis, exanthema, hyperbilirubinaemia, liver damage, GI perforation, pancreatitis, pulmonary oedema, pericarditis, and tamponade.
Combining Alexan with other oncolytic agents, myelosuppressive drugs or radiation treatment can sometimes reduce the immunosuppressive effect of these drugs. Modification of the dosage may be necessary. Cytarabine is often administered in combination with other drugs.
The absorption of digoxin may be reduced if digoxin is combined with chemotherapeutics (including cytarabine). This is probably dependent on temporary damage to the mucosa. The plasma levels of digoxin must therefore be monitored.
An in vitro study has shown that cytarabine can counteract the effect of gentamicin against Klebsiella pneumoniae.
The concomitant administration of cytarabine with other cytotoxic drugs can potentiate toxicity, especially bone marrow toxicity.
Combination of fluorocytosine with cytarabine can lead to a reduced effectiveness of fluorocytosine.
During pregnancy, cytarabine may only be administered on strict indication, in which context the benefits of the drug for the mother must be weighed against the possible dangers to the foetus. Animal studies have shown that cytarabine has embryotoxic and teratogenic effects (see section 5.3 Preclinical safety data).
Men and women must use effective contraceptives during treatment and for six months thereafter.
It is not known whether cytarabine is secreted in mother’s milk. As many drugs are secreted in mother’s milk and as cytarabine can be responsible for serious side effects in the neonate, breastfeeding should be stopped during treatment with Alexan.
Cytarabine has no effect on psychomotor performance. Nevertheless, patients receiving chemotherapy have a reduced ability to drive or operate machinery, and should be warned of the risk and advised to avoid this type of activity if this occurs.
Patients who are subject to incidental occurrences of vomiting, dizziness and eye complaints are advised not to drive vehicles or operate machinery.
Undesirable effects are listed by frequency: common >1/100, <1/10); uncommon >1/1,000, <1/100); rare >1/10,000, <1/1,000); very rare (<1/10,000). The following undesirable effects for cytarabine have been observed.
Side effects of cytarabine are dose dependent. The most common are gastrointestinal side effects, and cytarabine is toxic to the bone marrow (myelosuppression) and causes haematological side effects.
Common: Anaemia, megaloblastosis, leukopenia, granulocytopenia, thrombocytopenia, bleeding.
Uncommon: Sepsis, immunosuppression.
Very common: Cytarabine (Ara-C) syndrome: fever, myalgia, bone pain, incidental chest pain, exanthema, conjunctivitis and nausea may occur 6-12 hours after the start of the therapy. Corticosteroids can be used as prophylaxis and therapy. If these are effective, the therapy with cytarabine can be continued. Myelosuppression can be severe and prolonged.
Uncommon: Allergic oedema, anaphylaxis. One case of anaphylaxis has been reported, which resulted in cardiopulmonary arrest for which resuscitation had to be applied. This occurred immediately after intravenous administration of cytarabine.
The chance of CNS toxicity increases if cytarabine is administered intrathecally, the intrathecally cytarabine treatment is combined with other treatments which are toxic to the CNS, such as radiation, high dose therapy, or intrathecal methotrexate, or if the cytarabine treatment is intrathecally administered with short intervals or in doses above 30 mg/m².
Common: In the event of high dosages, cerebellar or cerebral toxicity with decreased of consciousness level, dysarthria, nystagmus, seizure (when given intrathecally), headache, dizziness, neuritis.
Uncommon: Paraplegia in the case of intrathecal administration.
Very rare: Necrotising leukoencephalopathy, paraplegia or quadriplegia have been reported after intrathecal treatment.
Common: Reversible haemorrhagic conjunctivitis (photophobia, stinging, visual disorders, increased lacrymation), keratitis. Locally administered glucocorticoids are recommended as prophylaxis against haemorrhagic conjunctivitis.
Very rare: Blindness has been reported after intrathecal treatment.
Uncommon: Pericarditis, chest pain.
Very rare: Arrhythmia. Cardiomyopathy has been reported after cytarabine therapy.
Uncommon: Pneumonia, dyspnoea, sore throat, interstitial pneumonitis, syndrome of sudden respiratory distress progressing to pulmonary oedema.
The side effects to the gastrointestinal tract are reduced if cytarabine is administered as an infusion.
Common: Mucositis, stomatitis, anorexia, dysphagia, abdominal pain, nausea, vomiting, diarrhoea, oral/anal inflammation or ulceration.
Uncommon: Oesophagitis, oesophageal ulceration, pneumatosis, cystoides intestinalis, necrotising colitis, GI perforation, nausea, vomiting after intrathecal administration.
Common: Reversible effects on the liver with increased enzyme values.
Uncommon: Jaundice.
Common: Reversible side effects to the skin, such as erythema, bullosis, urticaria, vasculitis, alopecia.
Uncommon: Lentigo, cellulitis at the injection site, skin ulceration, pruritis, burning pain on the palms of the hands and soles of the feet.
Very rare: Neutrophilic eccrine hidradenitis.
Uncommon: Myalgia, arthralgia.
Very rare: Rhabdomyolysis has been reported after cytarabine therapy.
Uncommon: Kidney function disorders, urinary retention.
Common: Fever, thrombophlebitis at the injection site, hyperuricaemia.
Uncommon: Fever after intrathecal administration.
Cytarabine is physically incompatible with heparin, insulin, methotrexate, 5-fluorouracil, nafcillin, oxacillin, benzylpenicillin and methylprednisolone sodium succinate.
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