Alkeran 2mg Film-coated Tablets

Each tablet contains 2mg melphalan.

For a full list of excipients, see section 6.1

Film-coated tablet.

White, film-coated round tablets engraved GXEH3 on one side and A on the other.

Melphalan tablets are indicated in the treatment of:

- multiple myeloma;

- advanced ovarian adenocarcinoma.

Melphalan tablets may be used in the treatment of:

-breast carcinoma: melphalan either alone or in combination with other drugs has a significant therapeutic effect in a proportion of patients suffering from advanced breast carcinoma.

Alkeran Tablets may be used in the management of polycythaemia vera.

Oral administration in adults: 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 0.15mg/kg bodyweight/day in divided doses for 4 days repeated at intervals of six weeks. 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 one year in responders does not appear to improve results.

Advanced ovarian adenocarcinoma: A typical regimen is 0.2mg/kg bodyweight/day given orally in divided doses for 5 days. This is repeated every 4 to 8 weeks, or as soon as the bone marrow has recovered.

Carcinoma of the breast: Alkeran has been given orally at a dose of 0.15 mg/kg bodyweight or 6mg/m² body surface area/day for 5 days and repeated every 6 weeks. The dose was decreased if bone marrow toxicity was observed.

Polycythaemia vera: For remission induction doses of 6 to 10mg daily for 5 to 7 days have been used, after which 2 to 4mg daily were given until satisfactory disease control was achieved. A dose of 2 to 6mg once per week has been used for maintenance therapy. 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.

Use in children: Alkeran is only rarely indicated in children and absolute dosage guidelines cannot be provided.

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. However, caution should be taken where there is renal impairment.

Dosage in renal impairment: (see also Special Warnings and Special Precautions for Use). 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.

Alkeran should not be given to patients who have suffered a previous hypersensitivity reaction to melphalan.

ALKERAN IS AN ACTIVE CYTOTOXIC AGENT FOR USE UNDER THE DIRECTION OF PHYSICIANS EXPERIENCED IN THE ADMINISTRATION OF SUCH AGENTS.

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised individuals. Therefore, immunisations with live organism vaccines are not recommended.

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.

Renal impairment: Alkeran clearance may be reduced in patients with renal impairment, who may also have uraemic bone marrow suppression. Dose reduction may therefore be necessary (see Posology and Method of Administration), and these patients should be closely observed.

Temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage.

Mutagenicity: Chromosome aberrations have been observed in patients being treated with the drug.

Carcinogenicity: The evidence is growing that melphalan in common with other alkylating agents may be leukaemogenic in man.

Alkeran, in common with other alkylating agents has been reported to be leukaemogenic.There have been reports of acute leukaemia occurring after 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.

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Warnings and Precautions).

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 pre-conditioned with high dose intravenous melphalan and who subsequently received cyclosporin to prevent graft-versus-host disease.

Teratogenicity:-

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 the drug.

Effects on fertility:

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.

Pregnancy:-

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be practised when either partner is receiving Alkeran.

The teratogenic potential of melphalan 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 the drug.

The use of melphalan should be avoided whenever possible during pregnancy, particularly during the first trimester. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.

This product should be not used during pregnancy unless absolutely considered absolutely essential by the physician.

Lactation:-

Mothers receiving Alkeran should not breastfeed.

No data.

For this product 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 and anaemia

Rare: haemolytic anaemia

Immune System Disorders

Rare: allergic reactions (see Skin and Subcutaneous Tissue Disorders)

Allergic reactions to melphalan such as urticaria, oedema, skin rashes and anaphylactic shock have been reported uncommonly following initial or subsequent dosing, particularly after intravenous 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 at high dose

Rare: stomatitis at conventional dose

Gastrointestinal effects such as 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 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

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.

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.

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).

Melphalan is mutagenic in animals.

Tablet core:

Microcrystalline cellulose

Crosspovidone

Colloidal anhydrous silica

Magnesium stearate

Tablet film-coating:

Hypromellose

Titanium dioxide

Macrogol

Not applicable

2 years

Store in a refrigerator at 2°C to 8°C.

Alkeran Tablets are supplied in amber glass bottles of 25 or 50 tablets with a child resistant closure.

Not all pack sizes may be marketed

The handling of Alkeran formulations should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations

Pregnant staff should not handle cytotoxics. Protective clothing, including gloves should be worn.

Alkeran Tablets should not be divided.

Provided the outer coating of the tablet is intact, there is no risk in handling Alkeran Tablets.

Disposal:-

Alkeran Tablets should be destroyed in accordance with relevant local regulatory requirements concerning the disposal of cytotoxic drugs.

Adequate care should be taken in the disposal of waste material, including containers and any other contaminated material.

Aspen Pharma Trading Limited

12/13 Exchange Place

I.F.S.C.

Dublin 1, Ireland

PA 1691/4/2

1^st April 1999/ 1^st April 2004

January 2011