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

Logo ALKERAN* 2 mg Tablets

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form)

ALKERAN* 2 mg Tablets

COMPOSITION
Each ALKERAN tablet contains 2 mg
melphalan.

PHARMACOLOGICAL CLASSIFICATION:
A26 Cytostatic agents

PHARMACOLOGICAL ACTION:
Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking two DNA strands and thereby preventing cell replication.

INDICATIONS:
ALKERAN Tablets are indicated in the treatment of:
Multiple myeloma and advanced ovarian adenocarcinoma.
ALKERAN Tablets may be used in the treatment of:
Breast carcinoma:
either alone or in combination with other medicines. ALKERAN has been used as an adjuvant to surgery in the management of breast carcinoma.

CONTRA-INDICATIONS:
ALKERAN
should not be given to patients who have suffered a previous allergic reaction to melphalan.
Lactation:
Mothers receiving ALKERAN should not breast feed.
Pregnancy:
The use of melphalan is contra-indicated during pregnancy as mutagenicity has been demonstrated in animals.

WARNINGS:
ALKERAN IS AN ACTIVE CYTOTOXIC AGENT FOR USE ONLY UNDER THE DIRECTION OF PHYSICIANS EXPERIENCED IN THE ADMINISTRATION OF SUCH AGENTS.
Safe handling of ALKERAN formulations should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations and/or regulations.
Provided the outer coating of the tablet is intact, there is no risk in handling ALKERAN tablets. ALKERAN Tablets should not be divided.
It is essential that careful attention should be paid to the monitoring of blood counts. (Refer to SIDE-EFFECTS AND SPECIAL PRECAUTIONS)
Patients with renal impairment should be closely observed as they may have uraemic marrow suppression. Dosage reduction may be necessary. (Refer to DOSAGE AND DIRECTIONS FOR USE in renal impairment.)
Adequate contraceptive precautions should be advised when either partner is receiving ALKERAN and for at least a year after cessation of treatment.

DOSAGE AND DIRECTIONS FOR USE:
General:
ALKERAN
is a cytotoxic agent which falls into the general class of alkylating agents.
It should be prescribed only by physicians experienced in the management of malignant disease with such agents. Since ALKERAN is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be adjusted if necessary (see SIDE EFFECTS AND SPECIAL PRECAUTIONS). The absorption of ALKERAN after oral administration is variable. Dosage may need to be cautiously increased until myelosuppression is seen, in order to ensure that potentially therapeutic levels have been reached.
Multiple myeloma:
A typical oral dosage schedule is 0,15 mg/kg bodymass/day in divided doses for 4 days repeated at intervals of six weeks. Numerous regimens have been used and the scientific literature should be consulted for details. The administration of oral ALKERAN and prednisone may be more effective than ALKERAN alone. The combination is usually given on an intermittent basis. Prolonging treatment beyond one year in responders does not appear to improve results.
Advanced Ovarian Carcinoma:
A typical regimen is 0,2 mg/kg bodymass/day orally for 5 days. This is repeated every 4 to 8 weeks, or as soon as the peripheral blood count has recovered.
Carcinoma of the breast:
ALKERAN
has been given orally at a dose of 6 mg/m² body surface area per day for advanced carcinoma of the breast and as 0,15 mg/kg bodymass or 6 mg/m² body surface area per day as an adjuvant to surgery in primary breast cancer; in both cases treatment was for 5 days and repeated every 6 weeks. The dose was decreased if bone marrow toxicity was observed.
Use in children:
ALKERAN
, at conventional dosage, is only rarely indicated in children and dosage guidelines cannot be stated.
Use in the elderly:
Although ALKERAN is frequently used at conventional dosage in the elderly, there is no specific information available relating to its administration to this patient sub-group.
Experience in the use of high dose ALKERAN in elderly patients is limited.
Dosage in renal impairment:
ALKERAN
clearance though variable, is decreased in renal impairment.
Currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering ALKERAN Tablets to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Monitoring:
Since ALKERAN is a potent myelosuppressive agent, it is essential that careful attention should be paid to the monitoring of blood counts to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia.
Blood counts may continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in leukocyte or platelet counts, treatment should be temporarily interrupted.
ALKERAN should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity.
The most common side effect is bone marrow depression, leading to leucopenia and thrombocytopenia. Gastrointestinal effects such as nausea and vomiting have been reported in up to 30% of patients receiving conventional oral doses of ALKERAN.
Stomatitis occurs rarely following conventional doses of ALKERAN.
Allergic reactions of ALKERAN such as urticaria, oedema, skin rashes and anaphylaxis have been reported following initial or subsequent dosing, particularly after intravenous administration in patients who were treated over several months. Cardiac arrest has occurred in association with such events.
Maculopapular rashes and pruritus have been noted.
Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported, Veno-occlusive disease has been reported in association with these.
There have been case reports of interstitial pneumonitis and pulmonary fibrosis.; fatal reports of pulmonary fibrosis have been received.
There have also been case reports of haemolytic anaemia occurring after melphalan treatment.
Temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage.
Alopecia has been reported.
Patients with renal impairment should be closely observed as they may have uraemic marrow suppression.
Interactions:
Nalidixic acid together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis.
Impaired renal function has been described in bone marrow transplant patients who were preconditioned with high dose intravenous melphalan and who subsequently received cyclosporin to prevent graft-versus-host disease.
Mutagenicity:
ALKERAN
is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the medicine.
Carcinogenicity:
Melphalan, in common with other alkylating agents, may be leukaemogenic in man.
There have been reports of acute leukaemia occurring after prolonged melphalan treatment for diseases such as amyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer.
A comparison of patients with ovarian cancer who received alkylating agents with those who did not showed that the use of alkylating agents, including melphalan, significantly increased the incidence of acute leukaemia.
The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of melphalan.
Teratogenicity:
The teratogenic potential of ALKERAN has not been studied. In view of its mutagenic properties and structural similarity to known teratogenic compounds, melphalan could cause congenital defects in the offspring of patients treated with the drug.
Effects on fertility:
ALKERAN
causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients. It is possible that ALKERAN may cause temporary or permanent sterility in male patients.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Symptoms and signs:
Gastro-intestinal effects, including nausea, vomiting and diarrhoea are the most likely signs of acute oral overdosage. The principal toxic effect is bone marrow suppression, leading to leucopenia, thrombocytopenia and anaemia.
Treatment:
General supportive measures, together with appropriate blood transfusion, should be instituted if necessary. There is no specific antidote. The blood picture should be closely monitored for at least four weeks following overdosage until there is evidence of recovery and consideration given to hospitalisation, antibiotic cover, and the use of haemotological growth factors.

IDENTIFICATION:
White to off-white film-coated, round, biconvex tablets, engraved “GX EH3”on one side and “A”on the other side.

PRESENTATION:
Bottles of 25 tablets

STORAGE INSTRUCTIONS:
Store between 2°C and 8°C
Keep dry.
Keep out of reach of children.

REGISTRATION NUMBER:
H/26/2744

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
GlaxoSmithKline South Africa (Pty) Ltd
57 Sloane Street
Bryanston
2021

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
22 March 1994

Updated on this site: October 2005
Source: Hospital Pharmacy

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