Adverse reactions : תופעות לוואי

4.8   Undesirable effects

The undesirable effects caused by cytarabine depend on the posology, method of administration and duration of therapy.

The most common undesirable effects are gastrointestinal. Cytarabine has a toxic effect on the bone marrow, causing haemorrhagic undesirable effects.

Blood and lymphatic system disorders: Since cytarabine has a myelosuppressive effect, anaemia, leukopenia, thrombocytopenia, megaloblastic anaemia and reticulocyte reduction are to be expected as a result of administration of the medicinal product. The severity of these reactions depends on the dose and therapy regimen. Morphological cell changes to the bone marrow and peripheral blood count can be expected.



Cytarabine syndrome has been described. It is characterized by fever, myalgia, bone pain, occasional thoracic pain, maculopapular rash, conjunctivitis and malaise. It generally occurs 6−12 hours after administration of the medicinal product.
Corticosteroids have proved useful in the treatment or prevention of this syndrome. If the symptoms are serious enough to justify treatment, both corticosteroids and the continuation of cytarabine therapy should be considered.

The following definitions apply to the frequency terminology used hereafter: 
Very common (≥1/10)
Common (≥1/100, <1/10)
Uncommon (≥1/1,000, <1/100)
Rare (≥1/10,000, <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)

Infections and infestations
Viral, bacterial, fungal, parasitic or saprophytic infections of the whole body may be associated with the use of cytarabine alone or in combination with other immunosuppressant agents (in immunosuppressive doses which affect the cellular or humoral defences). These infections may be mild, but they can also be severe and occasionally fatal.

Very common:
Sepsis (immunosuppression), pneumonia, infection

Not known:
Cellulitis at the injection site, liver abscess
Blood and lymphatic system disorders
Very common:
Myelosuppression, blood cell abnormalities (leukopenia, thrombocytopenia, anaemia, megaloblastic anaemia, and reticulocytopenia) are dose dependent.
At conventional doses, leukopenia occurs with a nadir on days 12 to 24. The high-dose therapy is linked to pronounced myelotoxicity.

Metabolism and nutrition disorders
Common:
Anorexia, hyperuricaemia as a consequence of rapid lysis of neoplastic cells. Like all other cytostatics, cytarabine may cause hypocalcaemia and secondary hyperuricaemia due to cell breakdown, which may require appropriate countermeasures.

Nervous system disorders
Central nervous system disorders are mostly observed in high-dose therapy.
At total doses of below 36 g cytarabine/m2, toxic reactions of the CNS are rare. Predisposing factors include high age, renal and hepatic insufficiency, previous CNS treatment (irradiation, intrathecal cytostatic applications) and alcohol abuse.
The central nervous system disorders are mostly reversible.

Common:

Cerebral/cerebellar disorders (nystagmus, dysarthria, ataxia, confusion and personality changes), thinking and movement process disorders, somnolence, lethargy, coma, tremor, convulsions and anorexia

Uncommon:
Peripheral neuropathy

Rare:
Intrathecal application of cytarabine may lead to nausea, vomiting, fever and/or other symptoms of arachnoiditis. These symptoms can also be the consequence of a lumbar puncture. These symptoms are often mild and reversible. The intrathecal administration of cytarabine in doses of more than 30 mg/m2 BSA often leads to neurotoxic reactions. In particular, short dosing intervals may lead to cumulative neurotoxicity (see also section 4.2).

Very rare:
Isolated cases of necrotizing leukoencephalopathy, myelopathy up to paraplegia or quadriplegia, and vision loss were described following intrathecal application of cytarabine. The intrathecal application of benzyl alcohol or other solubilizing additives must absolutely be avoided.

Not known:
Neurotoxicity, vertigo, headache, neuritis, and – following high doses – isolated cases of peripheral nerve lesions have been described, as well as cases of delayed progressive ascending paralysis, meningitis and encephalitis.

Eye disorders
Very common:
Conjunctivitis (in high-dose therapy)

Common:
Conjunctivitis, keratitis, photophobia, stinging eyes and vision disturbances are dose dependent and have been reported in 25 to 80% of the patients undergoing high-dose therapy.
Reversible haemorrhagic conjunctivitis (photophobia, burning, vision disturbances, increased lacrimation), ulcerative keratitis.
These effects can be prevented or decreased by frequently rinsing the eyes or the prophylactic use of eye drops.

Cardiac disorders
Uncommon:
Acute pericarditis

Very rare:
Damage to the myocardium, transient heart rhythm disorders
Not known:
Sinus bradycardia

Respiratory, thoracic and mediastinal disorders
Uncommon:
Dyspnoea, sore throat

Pulmonary oedema due to increased permeability of the alveolar capillaries was uncommon at the conventional dose and observed in approximately 10 to 30% of the patients following high cytarabine doses. These pulmonary complications are reversible in most cases. Difficulty breathing, pneumonia and lung toxicity occurred.

Patients receiving the average doses (1 g of cytarabine/m2 BSA) concomitantly with other cytostatics developed diffuse interstitial pneumonia in 10 out of 52 cases. No causal correlation to the use of cytarabine has been found.

Gastrointestinal disorders
Common:
Abdominal pain, diarrhoea, dysphagia, mucositis, mucous ulceration (oral, anal) especially in the case of high-dose treatment; severe diarrhoea with corresponding potassium and protein loss, nausea and vomiting (especially after rapid intravenous injection).

Uncommon:
Oesophagitis, oesophageal ulceration, severe changes to the gastrointestinal mucous membranes with ulcerations, intestinal wall emphysema and infections may occur. This may lead to necrosis of the colon and necrotising colitis.
Especially in cases of high-dose therapy, cystoid pneumatosis and intestinal necrosis with ileus and peritonitis may occur.

Very rare:
Pancreatitis

Hepatobiliary disorders
Very common:
Hepatic dysfunction with an increase in cholestasis-indicating enzymes and hyperbilirubinaemia were observed in 25 to 50% of the patients under high-dose treatment.

Very rare:
Hepatomegaly
There have been individual reports of the occurrence of hepatic vein thrombosis (Budd-Chiari syndrome).

Not known:
Jaundice

Skin and subcutaneous tissue disorders
Very common:
Rash
Common:
Reversible undesirable skin reactions such as maculopapular exanthema, ulceration, erythrodermia, erythema, urticaria, vasculitis, mottled skin and pruritus.
At high doses, exfoliative dermatitis and alopecia may occur.
Following high doses of cytarabine, up to 75% of patients develop generalised erythema, sometimes with blistering and desquamation.


Uncommon:
Lentigo, skin ulceration, pruritus, burning pain on the palms and soles 
Very rare:
Neutrophilic eccrine hidradenitis

Not known:
Palmar-plantar erythrodysaesthesia syndrome
Musculoskeletal and connective tissue disorders
Uncommon:
Myalgia and/or arthralgia were observed following high doses of cytarabine 
Very rare:
The occurrence of rhabdomyolysis has been described.

Renal and urinary disorders
Common:
Urinary retention, renal dysfunction
An increase in plasma creatinine was observed in 5-20% of the patients in high dose cytarabine therapy but a causal connection to cytarabine could not be proven.

In case of massive cell degeneration, measures should be taken to prevent uric acid nephropathy.

General disorders and administration site conditions
Common:
Inflammation of the throat, allergic oedema, gonadal dysfunction, chest pains, ascites, immunosuppression, sepsis, thrombophlebitis and haemorrhage, thrombophlebitis at the injection site.
Fever occurs in 20−50% of the patients receiving high-dose therapy.

Very rare:
Immediate allergic reactions (urticaria, anaphylaxis) are very rare. One case of anaphylaxis was reported, which led to cardiopulmonary arrest, requiring resuscitation measures. This occurred immediately after IV administration of cytarabine.
The syndrome of inappropriate adiuretic hormone secretion was reported in patients undergoing high-dose treatment with cytarabine.

Cytarabine (Ara-C) syndrome
This syndrome, which has been described in the literature, is marked by fever, myalgia, bone pains, occasional chest pains, maculopapular exanthema, conjunctivitis and nausea. It generally occurs 6−12 hours after administration. Corticosteroids have proven effective in treating or preventing the syndrome. If corticosteroids are effective, the continuation of cytarabine therapy can be considered.

Undesirable effects in high-dose cytarabine therapy that were not observed at conventional doses:
Haematological toxicity


This is expressed as profound pancytopenia, which lasts for 15−25 days and is linked to a stronger bone marrow aplasia than is observed at conventional doses.

Nervous system disorders
Following treatment with high doses of cytarabine, cerebral or cerebellar symptoms such as personality changes, impaired attention, dysarthria, ataxia, tremor, nystagmus, headache, confusion, drowsiness, dizziness, coma, and convulsions occurred in 3−37% of patients. The incidence may be higher in elderly patients (>55 years). Other predisposing factors are hepatic or renal impairment, previous CNS treatment (e.g. radiation therapy) and alcohol abuse. CNS disorders are reversible in most cases.

The risk of CNS toxicity is increased if cytarabine treatment (high dose, IV) is combined with another CNS-toxic therapy, such as radiation therapy or high-dose therapy.

Corneal and conjunctival toxicity
Reversible lesions of the cornea and haemorrhagic conjunctivitis have been described. These can be prevented or reduced by use of corticosteroid-containing eye drops.

Gastrointestinal disorders
Especially in high-dose treatment with cytarabine, severe reactions may occur in addition to the normal symptoms. Intestinal perforation, pneumatosis cystoides intestinalis or necrosis with ileus and peritonitis have been reported.

Liver abscesses, Budd-Chiari syndrome (hepatic venous thrombosis) and pancreatitis have been reported following high-dose therapy.

Respiratory, thoracic and mediastinal disorders
Clinical signs such as pulmonary oedema/ARDS may develop, especially in high-dose therapy. This reaction is probably caused by damage to alveolar capillaries. It is difficult to determine the frequency (reported as 10−26% in various publications), since the patients were usually in relapse and other factors may have contributed to this response.

Others
Following cytarabine therapy, cardiomyopathy and rhabdomyolysis have been reported. One case of anaphylaxis has been reported, leading to a cardiopulmonary arrest, requiring resuscitation. This case occurred directly following intravenous administration of cytarabine.

Gastrointestinal undesirable effects are reduced if cytarabine is administered as an infusion. Local glucocorticoids are recommended as prophylaxis for haemorrhagic conjunctivitis.

Amenorrhoea and azoospermia (see section 4.6).

The following undesirable effects were observed following intrathecal administration: Expected systemic reactions: Bone marrow depression, nausea, vomiting. In some patients, severe spinal toxicity, which could even lead to quadriplegia and paralysis, necrotising encephalopathy, blindness and other isolated neurotoxicity were reported.

In cases of high-dose continuous infusion (more than 200 mg/m² BSA/day over 5–7 days), undesirable effects were more pronounced than in standard therapy.

Polyserositis and early deaths due to uncontrollable haemorrhage or septicaemia and death due to prolonged bone marrow depression. The maximum tolerable dose in humans was determined as 4.5 g/m2. In doses of more than 3 g/m² the cerebral toxicity is much more pronounced.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/