elphalan.
Hepatobiliary Disorders
Rare: hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice
Skin and Subcutaneous Tissue Disorders
Very Common: alopecia at high dose
Common: alopecia at conventional dose
Rare: maculopapular rashes and pruritus (see Immune System Disorders)
Renal and Urinary Disorders
Common: temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage
4.9 Overdose
Symptoms and signs:-
Gastro-intestinal effects, including nausea, vomiting and diarrhoea are the most likely early signs of acute oral overdosage.
Treatment:-
General supportive measures, together with appropriate blood and platelet transfusions, should be instituted if necessary and consideration given to hospitalisation, cover with anti-infective agents, and the use of haematological growth factors.
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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Group +ATC code: Antineoplastic and Immunomodulation Agents (Nitrogen mustard analogues) L01AA03
Mode of Action:-
Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis- 2-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.
5.2 Pharmacokinetic properties
Absorption
The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the drug in plasma and peak plasma concentration.
In studies of the absolute bioavailability of melphalan the mean absolute bioavailability ranged from 56 to 85%.
Intravenous administration can be used to avoid variability in absorption associated with myeloablative treatment.
In a study of 18 patients administered melphalan 0.2 to 0.25 mg/kg bodyweight orally, a maximum plasma concentration (range 87 to 350 nanograms/ml) was reached within 0.5 to 2.0 h.
The administration of melphalan tablets immediately after food delayed the time to achieving peak plasma concentrations and reduced the area under the plasma concentration-time curves by between 39 and 45%.
Metabolism
In 18 patients administered melphalan 0.2 to 0.25 mg/kg bodyweight orally, the mean elimination half-life was 1.12 +/- 0.15 h.
Special Patient Populations
• Renal impairment
Melphalan clearance may be decreased in renal impairment (see Dosage and Administration - Renal impairment and Warnings and Precautions - Renal impairment).
• Elderly
No correlation has been shown between age and melphalan clearance or with melphalan terminal elimination half-life (see Dosage and Administration).
5.3 Preclinical safety data
Melphalan is mutagenic in animals.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Microcrystalline cellulose
Crosspovidone
Colloidal anhydrous silica
Magnesium stearate
Tablet film-coating:
Hypromellose
Titanium dioxide
Macrogol
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2years
6.4 Special precautions for storage
Store in a refrigerator at 2°C to 8°C.
6.5 Nature and contents of container
Alkeran T |
