The undesirable effects caused by cytarabine are dependent on dosage, method of administration and duration of therapy.
Local tolerability is generally good; inflammation at the site of injection may sometimes occur.
The most important side effect of cytarabine is bone marrow depression.
Blood count changes (leukopenia, thrombocytopenia, anaemia, megaloblastosis) are dose-dependent.
At conventional dosages: Leukopenia with trough values on days 12 to 24.
High-dose therapy gives rise to significant myelotoxicity.
Gastrointestinal disorders such as nausea, vomiting and diarrhoea occur commonly. Oesophagitis, oesophageal ulcers, abdominal pain, jaundice, severe changes to the gastrointestinal mucosae with ulceration, intestinal emphysema and infections may additionally occur. This may lead to intestinal necrosis and necrotising colitis.
Mucositis and mucosal ulceration (oral, anal) are to be expected, particularly at a high-dosage; this can lead to severe diarrhoea with potassium and protein depletion. Pneumatosis cystoides intestinalis and intestinal necrosis with ileus and peritonitis may occasionally occur, particularly at high dosages.
Skin and skin structure:
Toxic skin reactions such as a maculopapular rash, ulceration, erythroderma or erythema, mottled skin and pruritus have occasionally been observed after conventional doses. Exfoliative dermatitis has also been observed after high doses. Alopecia may additionally occur.
In isolated instances, neutrophilic eccrine hidradenitis has been observed.
After high doses of cytarabine, up to 75% of patients develop a generalized erythema, with blister formation and desquamation in a few cases. Burning pain on the palms of the hand and soles of feet may occur.
CNS disorders have been observed, particularly at high dosages, manifested in most cases as cerebral/cerebellar disorders (nystagmus, dysarthria, ataxia, confusional states and personality changes), headaches, dizziness, disturbances of thought processes and movements, somnolence, lethargy, coma, convulsions and anorexia. Total doses of less than 36 g cytarabine/m2
BSA per treatment cycle scarcely give rise to any CNS toxicity. Predisposing factors are advanced age, hepatic and renal dysfunction, previous CNS treatments (radiotherapy, intrathecal administration of cytostatic agents) and alcoholism. CNS disorders are usually reversible.
Intrathecal administration of cytarabine may occasionally give rise to nausea, vomiting, headaches and/or fever. Such phenomena may also result from lumbar puncture, however. The symptoms are often mild and reversible. Intrathecal administration of cytarabine at doses of over 30 mg/m2
BSA often leads to neurotoxic reactions. In particular, short dosing intervals may lead to cumulative neurotixicity (see Dosage & Administration).
Isolated instances of necrotising leukoencephalopathy as well as of paraplegia and loss of vision have been described after intrathecal administration of cytarabine. Intrathecal administration of benzyl alcohol or other solubilising additives must be avoided at all costs.
Neuritis and, after high doses, isolated instances of peripheral nerve lesions have been described, as have cases of delayed progressive ascending paralysis, meningitis and encephalitis.
Myalgia and/or arthralgia have occasionally been observed after high doses of cytarabine. The occurrence of rhabdomyolisis has been described.
Ocular disorders such as conjunctivitis, keratitis, photophobia, sore eyes, severe lacrimation and visual disturbances are dose-dependent and have been observed in 25 to 80% of patients on high-dose therapy. In severe cases, haemorrhagic conjunctivitis and ulcerative keratitis occur.
Regular irrigation of the eyes or prophylactic use of corticosteroid-containing eye-drops may prevent or alleviate such phenomena.
Liver and pancreas:
Impairment of liver function with elevation of cholestasis-inducing enzymes and hyperbilirubinaemia has been observed in 25 to 50% of patients on high-dose treatment, likewise liver abscesses and hepatomegaly. There are isolated reports of the occurrence of hepatic venous thrombosis (Budd-Chiari syndrome).
Isolated instances of pancreatitis have been reported on high doses of cytarabine.
Pulmonary oedema as a result of the increased permeability of the alveolar capillaries has been observed occasionally on conventional doses and in approximately 10 to 30 % of patients after high cytarabine doses. These pulmonary complications are usually reversible. Shortness of breath, pneumonia and pulmonary toxicity has occurred.
Patients who received mean doses (1 g cytarabine/m2
BSA) concomitantly with other cytostatic agents developed diffuse interstitial pneumonia in 10 out of 52 cases. A definite causal relationship with use of cytarabine could not be established, however.
Damage to the myocardium has been reported. In addition, isolated instances of acute pericarditis and transient cardiac arrhythmias have been observed.
Kidney and urinary tract:
Urinary retention and renal dysfunction may occur.
Elevation of plasma creatinine has been observed in 5 to 20% of patients on high-dose cytarabine therapy. A definite causal relationship with cytarabine could not be proven. However, if massive cell degeneration occurs, action should be taken to prevent the onset of uric acid nephropathy.
Other undesirable effects:
The syndrome of inappropriate antidiuretic hormone secretion has been observed in isolated instances in patients on high-dose treatment with cytarabine.
Furthermore, sore throats, allergic oedema, gonadal dysfunction, pain in the chest region, ascites, immunosuppression, sepsis, thrombophlebitis and haemorrhages have occurred.
Fever occurs in 20 to 50% of patients on high-dose therapy.
Immediate-type allergic reactions (urticaria, anaphylaxis) are very rare.
Cytarabine (Ara-C) syndrome: This syndrome described in the literature is characterised by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and nausea. It generally occurs 6-12 hours after administration. Corticosteroids have proved beneficial in the treatment or prevention of this syndrome. If corticosteroids are effective in this respect, continuation of treatment with cytarabine can be contemplated.
As with all cytostatic agents, hypocalcaemia and secondary hyperuricaemia resulting from cell destruction may occur on cytarabine therapy. Appropriate countermeasures may be required.
Following high-dose continuous infusion (more than 200 mg/m² BSA/day for 5-7 days), the side-effects are more marked than with the standard therapy.
Polyserositis and early deaths as a result of uncontrollable haemorrhaging or sepsis as well as fatalities resulting from prolonged bone marrow depression have occurred. The maximum tolerable dose in humans has been found to be 4.5 g/m². At dosages in excess of 3 g/m², cerebral toxicity is significantly more marked.