Alkeran

Pharmacology: Pharmacodynamics: Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the 2 bis-2-chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking 2 DNA strands and thereby preventing cell replication.
Pharmacokinetics: The absorption of melphalan was found to be highly variable in 13 patients given 0.6 mg/kg body weight orally, with respect to both the time to 1st appearance of melphalan in the plasma (range 0-336 min) and the peak plasma concentration (range 70-630 ng/mL). In 5 of the patients who were given an equivalent IV dose, the mean absolute bioavailability of melphalan was found to be 56±27%. The plasma mean terminal elimination half-life was 90±57 min with 11% of melphalan being recovered in the urine over 24 hrs.
In a study of 18 patients administered melphalan 0.2-0.25 mg/kg body weight orally, maximum plasma concentration (range 87-350 ng/mL) was reached within 0.5-2 hrs. The mean elimination half-life was 1.12±0.15 hrs. The administration of Alkeran 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%. Toxicology: Preclinical Safety Data: Melphalan is mutagenic in animals.

Treatment of multiple myeloma and advanced ovarian adenocarcinoma.
Alkeran may also be used in the treatment of breast carcinoma. Alkeran either alone or in combination with other drugs has a significant therapeutic effect in a proportion of patients suffering from advanced breast carcinoma. It has also been used as an adjuvant to surgery in the management of breast carcinoma.
Polycythaemia Rubra Vera: Alkeran is effective in the treatment of a proportion of patients suffering from polycythaemia vera.

Alkeran is a cytotoxic drug which falls into the general class of alkylating agents. It should only be prescribed 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 delayed or adjusted if necessary (see 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.
Adults: Multiple Myeloma: 0.15 mg/kg body weight/day in divided doses for 4 days repeated at 6-week intervals. Numerous regimens have, however, 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 1 year in responders does not appear to improve results.
Advanced Ovarian Adenocarcinoma: 0.2 mg/kg body weight/day for 5 days, repeated every 4-8 weeks, or as soon as the peripheral blood count has recovered.
Breast Carcinoma: 0.15 mg/kg body weight or 6 mg/m² body surface area/day for 5 days, repeated every 6 weeks. The dose should be decreased if bone marrow toxicity was observed.
Polycythaemia Rubra Vera: For remission induction, 6-10 mg daily for 5-7 days; after which, 2-4 mg given daily until satisfactory disease control was achieved.
Maintenance Therapy: 2-6 mg once weekly. In view of the possibility of severe myelosuppression if Alkeran is given on a continuous basis, it is essential that frequent blood counts are taken throughout therapy, with dosage adjustment or breaks in treatment, as appropriate, to maintain careful haematological control.
Children: Alkeran, within the conventional dosage range, is only rarely indicated in children and absolute dosage guidelines cannot be provided.
Elderly: Although Alkeran is frequently used at a conventional dosage in the elderly, there is no specific information available relating to its administration to this patient subgroup.
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 to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established (see Precautions).

Symptoms: Gastrointestinal effects, including nausea, vomiting and diarrhoea are the most likely early 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 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 4 weeks following overdosage until there is evidence of recovery.

Previous hypersensitivity reaction to melphalan.
Use in lactation: Mothers receiving Alkeran should not breastfeed.

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisation with live organism vaccines is not recommended.
For the safe handling of Alkeran, see Cautions for Usage.
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 1st sign of an abnormally large fall in leucocyte 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.
Renal Impairment: Alkeran clearance may be reduced in patients with renal impairment, who may also have uraemic bone marrow suppression. Dosage reduction may therefore be necessary (see Dosage & Administration), and these patients should be closely observed.
Carcinogenicity & Mutagenicity: Chromosome aberrations have been observed in patients being treated with Alkeran.
Alkeran, in common with other alkylating agents, may be leukaemogenic in man. There have been reports of acute leukaemia occurring after prolonged Alkeran treatment for diseases eg, 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 Alkeran, significantly increased the incidence of acute leukaemia.
The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of Alkeran.
Use in pregnancy: The teratogenic potential of Alkeran has not been studied. In view of its mutagenic properties and structural similarity to known teratogenic compounds, it is possible that melphalan could cause congenital defects in the offspring of patients treated with Alkeran.
Alkeran causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients.
There is evidence from some animal studies that Alkeran can have an adverse effect on spermatogenesis. Therefore, it is possible that Alkeran may cause temporary or permanent sterility in male patients.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be practised when either partner is receiving Alkeran.
The use of melphalan should be avoided whenever possible during pregnancy, particularly during the 1st trimester. In any individual case, the potential hazard to the foetus must be balanced against the expected benefit to the mother.

Use in pregnancy: The teratogenic potential of Alkeran has not been studied. In view of its mutagenic properties and structural similarity to known teratogenic compounds, it is possible that melphalan could cause congenital defects in the offspring of patients treated with Alkeran.
Alkeran causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients.
There is evidence from some animal studies that Alkeran can have an adverse effect on spermatogenesis. Therefore, it is possible that Alkeran may cause temporary or permanent sterility in male patients.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be practised when either partner is receiving Alkeran.
The use of melphalan should be avoided whenever possible during pregnancy, particularly during the 1st trimester. In any individual case, the potential hazard to the foetus must be balanced against the expected benefit to the mother.
Use in lactation: Mothers receiving Alkeran should not breastfeed.

For Alkeran, there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the indication and dose received and also when given in combination with other therapeutic agents.
The following convention has been utilised for the classification of frequency: Very common (≥1/10); common (≥1/100, <1/10); uncommon (1/1000 and <1/100); rare (≥1/10,000 and <1/1000); very rare (<1/10,000).
Blood and Lymphatic System Disorders: Very Common: Bone marrow depression leading to leucopenia, thrombocytopenia. Rare: Haemolytic anaemia.
Immune System Disorders: Rare: Allergic reactions (see text on Skin and Subcutaneous Tissue Disorders as follows).
Allergic reactions to melphalan eg, urticaria, oedema, skin rashes and anaphylactic shock have been reported uncommonly following initial or subsequent dosing, particularly after IV administration. Cardiac arrest has also been reported rarely in association with such events.
Respiratory, Thoracic and Mediastinal Disorders: Rare: Interstitial pneumonitis and pulmonary fibrosis (including fatal reports).
Gastrointestinal Disorders: Very Common: Nausea, vomiting and diarrhoea; stomatitis (high dose). Rare: Stomatitis (conventional dose).
Gastrointestinal effects eg, nausea and vomiting have been reported in up to 30% of patients receiving conventional oral doses of melphalan.
Hepatobiliary Disorders: Rare: Hepatic disorders ranging from abnormal liver function tests to clinical manifestations eg, hepatitis and jaundice.
Skin and Subcutaneous Tissue Disorders: Very Common: Alopecia (high dose). Common: Alopecia (conventional dose). Rare: Maculopapular rashes and pruritus (see previous text on 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.

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Precautions).
Nalidixic acid together with high-dose Alkeran IV has caused deaths in children due to haemorrhagic enterocolitis.
Impaired renal function has been described in bone marrow transplant patients who were conditioned with high-dose Alkeran IV and who subsequently received cyclosporin to prevent graft-versus-host disease.

Instructions for Use/Handling: Safe Handling of Alkeran: The handling of Alkeran 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. Alkeran should not be divided.

Store in a refrigerator at 2-8°C. Do not freeze.

Cytotoxic Chemotherapy

L01AA03 - melphalan ; Belongs to the class of alkylating agents, nitrogen mustard analogues. Used in the treatment of cancer.

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