Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Pfizer Laboratories (Pty) Ltd, 85 Bute Lane, Sandton 2196, South Africa Tel: +27(0)11 320 6000 / 0860 734 937 (Toll-free South Africa)
Only medical practitioners experienced in cancer chemotherapy should use CYTOSAR. For induction therapy, patients should be treated in a facility with laboratory and supportive resources sufficient to monitor medicine tolerance and protect and maintain a patient compromised by toxicity of CYTOSAR. The main toxic effect of CYTOSAR is bone marrow suppression with leukopenia, thrombocytopenia and anaemia. Other manifestations include nausea, vomiting, diarrhoea and abdominal pain, oral ulceration and hepatic dysfunction.
Seizures and other manifestations of neurotoxicity may occur after intrathecal administration.
Before beginning treatment, the medical practitioner should be familiar with the following text.
CYTOSAR is a potent bone marrow suppressant; the severity depends on the dose of the medicine and schedule of administration. Therapy should be started cautiously in patients with pre-existing medicine-induced bone marrow suppression. Patients receiving CYTOSAR must be under close medical supervision, and during induction therapy, should have leukocyte and platelet counts performed daily. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood. Consider suspending or modifying therapy when medicineinduced marrow depression has resulted in a platelet count under 50 000 or a polymorphonuclear granulocyte count under 1 000/mm³. Counts of formed elements in the peripheral blood may continue to fall after CYTOSAR is stopped and reach lowest values after medicine-free intervals of 12 to 24 days. When indicated, restart therapy when definite signs of marrow recovery appear. Patients whose medicine is withheld until “normal” peripheral blood values are attained may escape from control. Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defences and haemorrhage secondary to thrombocytopenia).
Anaphylactic reactions have occurred with CYTOSAR treatment. Anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of CYTOSAR.
Severe and fatal cardiomyopathy, CNS, GI and pulmonary toxicity have been reported following CYTOSAR therapy, more so with high dose (2-3 g/m²) schedules of CYTOSAR.
Other reactions include cerebral and cerebellar dysfunction (which may be irreversible), including personality changes, somnolence, convulsion and coma, severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis, leading to peritonitis, sepsis and liver abscess, pulmonary oedema, liver damage with increased hyperbilirubinaemia, bowel necrosis, and necrotising colitis.
Severe and fatal pulmonary toxicity, adult respiratory distress syndrome and pulmonary oedema have occurred, more so following high dose schedules with CYTOSAR therapy.
A syndrome of sudden respiratory distress, rapidly progressing to pulmonary oedema and radiographically pronounced cardiomegaly has been reported following therapy with CYTOSAR, especially at high doses used for the treatment of relapsed leukaemia.
Cases of cardiomyopathy with subsequent death have been reported following CYTOSAR and cyclophosphamide therapy when used for stem cell transplant preparation. This may be schedule and dose dependent.
Ophthalmological toxicity including corneal toxicity and haemorrhagic conjunctivitis, which may be diminished by prophylaxis with a local corticosteroid eye drop.
Peripheral motor and sensory neuropathies after consolidation with CYTOSAR, daunorubicin, and asparaginase have occurred in adult patients with acute non-lymphocytic leukaemia (ANLL).
Patients treated with CYTOSAR should be observed for neuropathy since dose schedule alterations may be needed to avoid irreversible neurological disorders.
Severe skin rash, leading to desquamation has been reported. Complete alopecia is very commonly seen with high dose CYTOSAR therapy.
When large intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours post-injection. This problem tends to be less severe when the medicine is infused.
Anti-emetic therapy should be given to reduce, and if possible, prevent nausea and vomiting, since once experienced, it may become a conditioned response, and may not respond to anti-emetics.
Abdominal tenderness (peritonitis) and guaiac positive colitis, with concurrent neutropenia and thrombocytopenia, have been reported in patients treated with conventional doses of CYTOSAR in combination with other medicines. Patients have responded to nonoperative medical management. Delayed progressive ascending paralysis resulting in death has been reported in children with acute myelocytic leukaemia (AML) following intrathecal and intravenous CYTOSAR at conventional doses in combination with other medicines.
The human liver apparently detoxifies a substantial fraction of an administered dose of CYTOSAR. In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high dose treatment with CYTOSAR. Use CYTOSAR with caution and possibly at reduced doses in patients whose liver or kidney function is poor.
Periodic checks of bone marrow, liver and kidney functions should also be performed in patients receiving CYTOSAR.
Cases of severe neurological adverse reactions that ranged from headache to paralysis, cerebellar syndrome, coma and stroke-like episodes have been reported mostly in juveniles and adolescents given intravenous CYTOSAR.
CYTOSAR may induce hyperuricaemia secondary to rapid lysis of neoplastic cells. The medical practitioner should monitor the patient’s blood uric acid level and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem.
Acute pancreatitis has been reported to occur in patients being treated with CYTOSAR.
Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic medicines including CYTOSAR may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving CYTOSAR (see section 4.3).
Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
CYTOSAR does not contain benzyl alcohol as an excipient; however, benzyl alcohol is contained in the diluent co-packaged with the freeze-dried powder for injection. The preservative benzyl alcohol has been associated with serious adverse events, including the “gasping syndrome”, and death in paediatric patients. Although normal therapeutic doses of CYTOSAR ordinarily deliver low amounts of benzyl alcohol, the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the liver and kidneys' capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity (see section 4.6).
If CYTOSAR is used in high dose or as intrathecal therapy, do not use a diluent containing benzyl alcohol. The preservative-free 0,9% sodium chloride can be used for reconstitution (see section 4.2).
Decreases in steady-state plasma digoxin concentrations and renal digoxin excretion was observed in patients receiving digoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without CYTOSAR or procarbazine. Therefore, monitoring of plasma digoxin levels is indicated in patients receiving similar combination chemotherapy regimens.
An in-vitro interaction study between gentamicin and CYTOSAR showed a CYTOSAR related antagonism for the susceptibility of K. pneumoniae and Pseudomonas aeruginosa strains. This study suggests that in patients on CYTOSAR being treated with gentamicin for a K. pneumoniae infection, the lack of a prompt therapeutic response may indicate the need for re-evaluation of antibacterial therapy.
Clinical evidence showed possible inhibition of fluorocytosine efficacy therapy with CYTOSAR. This may be due to potential competitive inhibition of its uptake.
Intravenous CYTOSAR given concomitantly with intrathecal methotrexate increases the risk of severe neurological adverse reactions such as headache, paralysis, coma and stroke-like episodes (see section 4.4).
Hepatic dysfunction was associated with the combined use of CYTOSAR and daunorubicin. Veno-occlusive disease was associated with combined thioguanine and CYTOSAR therapy. Allopurinol, colchicine, probenecid or sulfinpyrazone may interact with CYSTOSAR.
Combinations containing any of the following medicines may also interact with CYTOSAR: Blood dyscrasia-causing medicines (increase in leukopenia and/or thrombocytopenic effects), bone marrow depressants or radiotherapy (additive bone marrow depression), cyclophosphamide (increased cardiomyopathy), killed vaccines (decreased response), live vaccines (replication of virus may be potentiated, increased side effects and decreased antibody response).
CYTOSAR is contraindicated during pregnancy and lactation (see section 4.3).
Women of childbearing potential should be advised to avoid becoming pregnant and to use highly effective contraceptive methods while receiving CYTOSAR. If a woman’s male partner is receiving CYTOSAR, the woman should use highly effective contraceptive methods as well. It is generally advised to continue using contraception up to 6 months following the last administered dose of CYTOSAR.
CYTOSAR is known to be teratogenic in some animals.
In human pregnancies, congenital abnormalities have been reported, more so when the foetus has been exposed to systemic therapy with CYTOSAR during the first trimester. The risks in the second and third trimester are still present. These include upper and lower distal limb defects, and extremity and ear deformities. Enlarged spleens and Trisomy C chromosome abnormalities have been reported.
Reports of pancytopenia, leukopenia, anaemia, thrombocytopenia, electrolyte abnormalities, transient eosinophilia, increased lgM levels and hyperpyrexia, sepsis and death have occurred during the neonatal period to infants exposed to CYTOSAR in utero. Some of these infants were also premature.
Any infant born to a mother exposed to CYTOSAR must be followed up for normal development.
Benzyl alcohol which is contained in the diluent can cross the placenta (see section 4.4).
Mothers receiving CYTOSAR must not breastfeed their infants.
Serious central nervous system and eye side effects may occur that make driving or using machinery dangerous. Patients and their caregivers must be informed of these dangers.
As CYTOSAR is a bone marrow suppressant, anaemia, leukopenia, thrombocytopenia, megaloblastosis and reduced reticulocytes can be expected as a result of its administration. The severity of these reactions is dose and schedule dependent. Cellular changes in the morphology of bone marrow and peripheral smears can be expected.
Following 5-day constant infusions or acute injections of 50 mg/m² to 600 mg/m², white cell depression follows a biphasic course. Regardless of initial count, dosage level, or schedule, there is an initial fall starting the first 24 hours with a nadir at days 7–9. This is followed by a brief rise which peaks around the twelfth day. A second and deeper fall reaches nadir at days 15–24. Then there usually is a rapid rise to above baseline in the next 10 days. Platelet depression is noticeable at 5 days with a peak depression occurring between days 12–15. Thereupon, a rapid rise to above baseline usually occurs in the next 10 days.
Viral, bacterial, fungal, parasitic, or saprophytic infections, in any location of the body, may be associated with the use of CYTOSAR alone or in combination with other immunosuppressive medicines following immunosuppressant doses that affect cellular or humoral immunity. These infections may be mild, moderate or severe and fatal.
The Cytarabine Syndrome: A cytarabine syndrome is characterised by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs within 6 – 12 hours following administration of the medicine. Corticosteroids have been shown to be beneficial in treating or preventing this syndrome. If the symptoms of the syndrome are deemed treatable, corticosteroids should be contemplated and the need for continuation of therapy with CYTOSAR should be considered.
The following side effects have been reported. Frequencies are defined as: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); and frequency not known (post-marketing reports).
Table 1. Adverse events associated with conventional and high dose therapy:
| MedDRA system organ class | Frequency | Side effect |
|---|---|---|
| Infections and infestations | Very common | Sepsis, pneumonia, infectiona |
| Not known | Injection site cellulitis | |
| Blood and lymphatic system disorders | Very common | Bone marrow failure, thrombocytopenia, anaemia, megaloblastic anaemia, leukopenia, decreased reticulocyte count |
| Immune system disorders | Not known | Anaphylactic reaction, allergic oedema |
| Metabolism and nutrition disorders | Not known | Decreased appetite |
| Nervous system disorders | Not known | Neurotoxicity, neuritis, dizziness, headache |
| Eye disorders | Not known | Conjunctivitisb |
| Cardiac disorders | Not known | Pericarditis, sinus bradycardia |
| Vascular disorders | Not known | Thrombophebitis |
| Respiratory, thoracic and mediastinal disorders | Not known | Dyspnoea, oropharyngeal pain, interstitial lung oedema, acute respiratory distress syndrome (ARDS) |
| Gastrointestinal disorders | Very common | Stomatitis, mouth ulceration, anal ulcer, anal inflammation, diarrhoea, vomiting, nausea, abdominal pain |
| Not known | Pancreatitis, oesophageal ulcer, oesophagitis | |
| Hepatobiliary disorders | Very common | Abnormal hepatic function |
| Not known | Jaundice | |
| Skin and subcutaneous tissue disorders | Very common | Alopecia, rash |
| Common | Skin ulcer | |
| Not known | Palmar-plantar erythrodysaesthesia syndrome, urticaria, pruritus, ephelides | |
| Musculoskeletal, connective tissue and bone disorders | Very common | Cytarabine Syndrome (see above) |
| Renal and urinary disorders | Not known | Renal impairment, urinary retention |
| General disorders and administration site conditions | Very common | Pyrexia |
| Not known | Chest pain, injection site reactionc | |
| Investigations | Very common | Abnormal bone marrow biopsy, abnormal blood smear test |
a may be mild, but can be severe and at times fatal
b may occur with rash and may be haemorrhagic with high dose therapy
c pain and inflammation at subcutaneous injection site
The incidence of side effects is higher with continuous intravenous administration than with rapid intravenous injection. Adverse reactions reported in association with high dose therapy are included in the following table (also see section 4.4).
Table 2. Adverse reactions associated with high dose therapy:
| MedDRA system organ class | Frequency | Side effect |
|---|---|---|
| Infections and infestations | Not known | Liver abscess |
| Psychiatric Disorders | Not known | Personality changea |
| Nervous system disorders | Very common | Cerebral disorder, cerebellar disorder, somnolence |
| Not known | Coma, convulsion, peripheral motor neuropathy, peripheral sensory neuropathy | |
| Eye disorders | Very common | Corneal disorder, keratitis |
| Cardiac disorders | Not known | Cardiomyopathyb |
| Respiratory, thoracic and mediastinal disorders | Very common | Acute respiratory distress syndrome, pulmonary oedema |
| Gastrointestinal disorders | Common | Necrotising colitis |
| Not known | Gastrointestinal necrosis, gastrointestinal ulcer, pneumatosis intestinalis, peritonitis | |
| Hepatobiliary disorders | Not known | Liver injury, hyperbilirubinaemia |
| Skin and subcutaneous tissue disorders | Common | Skin exfoliation |
a personality change was reported in association with cerebral and cerebellar dysfunction
b with subsequent death
A diffuse interstitial pneumonitis has been reported.
Peripheral motor and sensory neuropathies have been reported (see section 4.4).
An increase in cardiomyopathy with subsequent death has been reported when used in combination with cyclophosphamide (see section 4.4).
A syndrome of sudden respiratory distress, rapidly progressing to pulmonary oedema and a radiographically pronounced cardiomegaly has been reported following therapy with CYTOSAR in relapsed leukaemia. This may prove fatal.
Acute pancreatitis has been reported (see section 4.4).
Severe skin rash, leading to desquamation, has been reported. Complete alopecia may occur (see section 4.4).
The most frequently reported reactions after intrathecal administration were nausea, vomiting and fever. Paraplegia has been reported. Necrotising leuko-encephalopathy with or without convulsion has been reported; in some cases, patients had also been treated with intrathecal methotrexate and/or hydrocortisone, as well as by central nervous system radiation. Isolated neurotoxicity has been reported including blindness.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.
CYTOSAR has been known to be physically incompatible with heparin, insulin, methotrexate, 5-fluorouracil, penicillins and methylprednisolone.
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