INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ALEXAN 100 mg

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ALEXAN 100 mg

  Single dose solution for intravenous, intramuscular, subcutaneous and intrathecal injection.
COMPOSITION:
Each vial with 5 mL solution contains: 100 mg
cytarabine (cytosine arabinoside) as a ready to use injection solution.

PHARMACOLOGICAL CLASSIFICATION:
Category A.26 –Cytostatic agents.

PHARMACOLOGICAL ACTION:
Alexan is an antimetabolite of the series of pyrimidine antagonists and inhibits the formation of desoxycytidine triphosphate, and thus DNA synthesis, by blocking the reduction of cytidine phosphate to desoxycytidine phosphate.

INDICATIONS:
In cytostic therapy.
Acute non-lymphoblastic leukaemia (ANLL).
Acute lymphoblastic leukaemia (ALL).
Blast crisis in chronic myeloid leukaemia (CML).
Malignant lymphomas:
Diffuse histiocytic lymphomas (Non-Hodgkin Lymphomas of high malignancy)

CONTRA-INDICATIONS:
Patients with a drug-induced bone marrow suppression should be excluded from treatment with Alexan, unless this therapy is considered to be vital and promising.
Alexan is contra-indicated during pregnancy.
Alexan is contra-indicated in those patients who are hypersensitive to cytarabine.

WARNINGS:
Only physicians experienced in cancer chemotherapy should use Alexan injection solution.

For induction therapy, patients should be treated in a facility with laboratory and supportive resources sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The main toxic effect of Alexan is bone marrow suppression with leucopenia, 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.
The physician must judge possible benefit to the patient against known toxic effects of this drug in considering the advisability of therapy with Alexan. Before making this judgement or beginning treatment, the physician should be familiar with the following text:
Alexan is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression.
Patients receiving this drug must be under close medical supervision and during induction therapy, should have leucocyte and platelet counts performed daily.
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 haemorrhage secondary to thrombocytopenia). Anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported.

DOSAGE AND DIRECTIONS FOR USE:
In cytostatic therapy:
If not otherwise defined in specific combinations:
3 - 6 mg/kg/day or 100 - 200 mg/m²/day.
For induction, Alexan is administered as a rapid i.v. injection, short infusion or 8 –24 hours continuous infusion. The duration of therapy is dependent on the haematological tolerance (bone marrow) and the clinical findings. With i.v. injection or short infusion, the daily dosage should be uniformly divided into several, at least two, administrations given at appropriate levels.

See warnings.

For maintenance of remission, Alexan may also be administered i.m. or s.c.
Intracutaneous injection must be avoided.

Alexan can also be administered directly intrathecally.

The solution for infusion may be prepared with a suitable diluent, such as physiological saline solution, 5% glucose solution or sodium chloride-lactate for intrathecal use.

Alexan 100 mg vials are intended for one use only. Discard the unused portion.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Because Alexan (cytarabine) is a bone marrow suppressant, anaemia, leucopenia, thrombocytopenia, megaloblastosis and reduced reticulocytes can be expected as a result of its administration. The severity of these reactions are to a certain degree dose and dosage schedule dependent. Cellular changes in the morphology of bone marrow and peripheral smears can be expected.

The Alexan (Ara-C) Syndrome
This is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs 6 - 12 hours following drug administration. 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 as well as continuation of therapy with Alexan.

Frequent Adverse Reactions
Anorexia hepatic dysfunction
nausea fever
vomiting rash
diarrhoea thrombophlebitis
oral and anal inflammation or ulceration bleeding (all sites)
Nausea and vomiting are most frequent following rapid intravenous injection and may continue for several hours after injection.

Other Adverse Reactions
sepsis abdominal pain
pneumonia freckling
cellulitis at injection site jaundice
skin ulceration conjunctivitis (may occur with rash)
urinary retention dizziness
renal dysfunction alopecia
neuritis anaphylaxis (See Warnings)
neural toxicity allergic oedema
sore throat pruritus
oesophageal ulceration shortness of breath
oesophagitis urticaria
chest pain headache
peripheral sensitivity 
Severe and fatal central nervous system, gastrointestinal and pulmonary toxicity has been reported following high dose Alexan dosage schedules. These reactions include corneal toxicity, cerebral and cerebellar dysfunction, severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; and pulmonary oedema. Alexan given intrathecally may cause systemic toxicity and careful monitoring of the haemopoietic system is indicated. Modification of the anti-leukaemia therapy may be necessary. Reactions after intrathecal administration are nausea, vomiting and fever. Paraplegia has been reported as well as necrotizing leucoencephalopathy. Neurotoxicity has been reported and blindness occurred in patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal Alexan.

Focal leukaemic involvement of the central nervous system may not respond to intrathecal Alexan and may better be treated with radiotherapy.

Patients receiving Alexan must be monitored closely. Daily platelet and leucocyte counts and frequent bone marrow examination are mandatory. Consider suspending or modifying therapy when drug-induced marrow depression has resulted in a platelet count below 50 000 or a polymorphonuclear granulocyte count below 1 000/mm3. Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped and reach lowest values after drug-free intervals of 12 to 24 days. When indicated, restart therapy when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until "normal" peripheral blood values are attained may escape from control. The human liver apparently detoxifies a substantial fraction of an administered dose. Use the drug with caution and at reduced dose in patients whose liver function is poor. Regular checks of liver and kidney functions should also be performed in patients receiving Alexan.
Alexan may induce hyperuricaemia secondary to rapid lysis of neoplastic cells. The clinician 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.

Use in pregnancy:
Alexan is known to be teratogenic. Infants can be premature or of low birth mass. Cases of congenital abnormalities have been reported with upper and lower distal limb detects, and with extremity and ear deformities.

Infants can have various problems in the neonatal period, including pancytopenia; depression of WBC, haematocrit or platelets; electrolyte abnormalities; eosinophilia; and increased IgM levels and hyperpyrexia possibly due to sepsis.

Because of the potential for abnormalities with cytotoxic therapy, particularly during the first trimester, a patient who is or may become pregnant while on Alexan should be advised of the potential risk to the foetus and the advisability of pregnancy continuation. There is a definite risk if therapy is initiated during the second or third trimester.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
There is no antidote for Alexan overdosage.
Refer to "Side-effects and special precautions".
Delayed or long-term adverse effects may result from the action on rapidly dividing normal cells in the bone marrow, lymphoreticular tissue, gastrointestinal mucosa, skin, gonad, and foetus.

Treatment: Control of nausea and vomiting may be attempted by giving phenothiazines such as perphenazine, prochlorperazine, promethazine, or thiethylperazine, before antineoplastic agents are administered. In bone marrow depression, transfusions of blood or platelets are given to diminish the risk of life-threatening haemorrhage. Granulocyte transfusions and injections of antibiotics may be necessary to combat infection in the neutropenic patient.

Hyperuricaemia is avoided by the addition of allopurinol to treatment schedules and measures such as alkalinisation of the urine and hydration may also be adopted.

IDENTIFICATION:
Clear, colourless solution in clear vials.

PRESENTATION:
Alexan 100 mg: Containers containing 10 vials.

STORAGE INSTRUCTIONS:
Store below 25°C.
KEEP OUT OF REACH OF CHILDREN.
PROTECT FROM LIGHT.

REGISTRATION NUMBERS:
Alexan 100 mg : T/26/83

NAME AND BUSINESS ADDRESS OF APPLICANT:
Intramed (Pty) Ltd
6 Gibaud Road
PORT ELIZABETH
6001

DATE AND PUBLICATION OF THIS PACKAGE INSERT:
March 1990 12-725/10-94
  Tradepak PE

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