Melphalan 2 mg Tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Melphalan 2 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2mg melphalan

3 PHARMACEUTICAL FORM

Film-coated tablets

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

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Melphalan Tablets are indicated in the treatment of multiple myeloma and advanced ovarian adenocarcinoma.

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

Melphalan is effective in the treatment of a proportion of patients suffering from polycythaemia vera.

4.2 Posology and method of administration

Since Melphalan is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary (see section 4.4).

Thromboembolic events

Thromboprophylaxis should be administered for at least the first 5 months of treatment especially in patients with additional thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient's underlying risk factors (see sections Warning and Precaution and Adverse Reactions).

If the patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic event have been managed, melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone may be restarted at the original dose dependent upon a benefit-risk assessment. The patient should continue anticoagulation therapy during the course of melphalan treatment.

Posology

Multiple Myeloma

Numerous regimes have been used and the scientific literature should be consulted for details. The administration of Melphalan and prednisone may be more effective than Melphalan alone. The combination is usually given on an intermittent basis, although the superiority of this technique over continuous therapy is not established. A typical oral dosage schedule is 0.15 mg/kg bodyweight/day in divided doses for 4 days repeated at intervals of six weeks. Prolonging treatment beyond one year in responders does not appear to improve results.

Ovarian adenocarcinoma

A typical regimen is 0.2 mg/kg bodyweight/day orally for 5 days. This is repeated every 4-8 weeks, or as soon as the bone marrow has recovered. Melphalan has also been used intravenously in the treatment of ovarian carcinoma.

Advanced carcinoma of the breast

Melphalan has been given orally at a dose of 0.15 mg/kg bodyweight or 6 mg/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 the usual dose is 6-10 mg daily for 5-7 days, after which 2-4 mg daily is given until satisfactory disease control is achieved. Therapy is maintained with a dose of 2-6 mg per week. During maintenance therapy, careful haematological control is essential with dosage adjustment according to the results of frequent blood counts.

Paediatric population

Melphalan is very rarely indicated in paediatrics and dosage guidelines cannot be stated.

Elderly population

There is no specific information available on the use of Melphalan in older patients.

Dosage in renal impairment

Melphalan clearance, though variable, may be decreased in renal impairment (see section 4.4).

In patients with moderate to severe renal impairment currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering the oral preparation to these patients, but it may be prudent to use a reduced dose initially.

Method of administration

Oral administration in adults: the absorption of Melphalan after oral administration is variable. Dosage may need to be cautiously increased until myelosuppresion is seen, in order to ensure that potentially therapeutic levels have been reached.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section

  6.1.

• Lactation.

4.4 Special warnings and precautions for use

Melphalan is a cytotoxic drug, 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.

As with all high dose chemotherapy, precautions should be taken to prevent tumour lysis syndrome.

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

Since Melphalan is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary.

Melphalan Injection solution can cause local tissue damage, should extravasation occur and consequently, it should not be administered by direct injection into a peripheral vein. It is recommended that Melphalan Injection solution is administered by injecting slowly into a fast-running intravenous infusion via a swabbed injection port, or via a central venous line.

In view of the hazards involved and the level of supportive care required, the administration of high dose Melphalan Injection should be confined to specialist centres, with the appropriate facilities and only be conducted by experienced clinicians.

In patients receiving high dose Melphalan Injection, consideration should be given to the prophylactic administration of anti-infective agents and the administration of blood products as required.

Consideration should be given to ensure adequate performance status and organ function before using high dose Melphalan Injection. Melphalan Injection should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m².

Safe handling of Melphalan

The handling of Melphalan formulations should follow guidelines for the handling of cytotoxic drugs according to the Royal Pharmaceutical Society of Great Britain Working Party on the handling of cytotoxic drugs.

Monitoring

Since Melphalan 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. Melphalan should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity.

Renal Impairment

Melphalan clearance may be reduced in patients with renal impairment who may also have uraemic marrow suppression. Dose reduction may therefore be necessary (see section 4.2 and 4.8).

The use of high dose melphalan has the potential to cause acute kidney injury in patients, especially those with underlying renal impairment and potential risk factors for reduced renal function (e.g., concomitant use of nephrotoxic medications, amyloidosis etc).

Mutagenicity

Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.

Carcinogenicity (secondary primary malignancy)

Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS)

Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic especially in older patients after long combination therapy and radiotherapy. There have been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloidosis, 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.

Before the start of the treatment, the leukaemogenic risk (AML and MDS) must be balanced against the potential therapeutic benefit in particular if the use of melphalan in combination with thalidomide or lenalidomide and prednisone is considered, as it has been shown that these combinations increase the leukaemogenic risk. Before, during and after treatment doctors must therefore examine the patient at all times by usual measurements to ensure the early detection of cancer and initiate treatment if necessary.

Contraception

Ovulation inhibitory progesterone-only pills (i.e., desogestrel). Because of the increased risk of venous thromboembolism in patients with multiple myeloma, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception, she should switch to another effective and reliable contraceptive method. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception.

The recommended duration of contraception in females should be during treatment and for a period of six months following the cessation of treatment (see section 4.6).

Male patients should use effective and reliable contraceptive methods during treatment and for a period of three months following the cessation of treatment (see section 4.6).

Fertility

Male patients should and that they have a consultation on sperm preservation before treatment due to the possibility of irreversible infertility as a result of melphalan treatment (see section 4.6).

Excipients with known effects

This medicinal product contains 2mmol (46 mg) sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

This medicinal product contains 5 % ethanol (alcohol), equivalent to 10 ml beer or 4.2 ml wine. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

This medicinal product contains propylene glycol. May cause alcohol-like symptoms.

Solid tumours

Use of alkylating agents has been linked with the development of second primary malignancy (SPM). In particular, melphalan in combination with lenalidomide and prednisone and, to a lesser extent, thalidomide and prednisone has been associated with the increased risk of solid SPM in elderly newly diagnosed multiple myeloma patients.

Patient characteristics (e.g. age, ethnicity), primary indication and treatment modalities (e.g. radiation therapy, transplantation), as well as environmental risk factors (e.g., tobacco use) should be evaluated prior to melphalan administration.

4.5 Interaction with other medicinal products and other forms of interaction

Live organism vaccines

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see section 4.4).

Nalidixic acid

Nalidixic acid together with high-dose intravenous melphalan has caused deaths in paediatrics due to haemorrhagic enterocolitis.

In paediatric population, for the Busulfan-Melphalan regimen it has been reported that the administration of melphalan less than 24 hours after the last oral busulfan administration may influence the development of toxicities.

Cyclosporin

Impaired renal function has been described in bone marrow transplant patients who were pre-conditioned with high dose intravenous melphalan and who subsequently received ciclosporin to prevent graft-versus-host disease.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

Female patients should use effective and reliable contraceptive methods during treatment and for a period of six months, following the cessation of treatment.

Male patients should use effective and reliable contraceptive methods during treatment and for a period of three months following the cessation of treatment.

The final decision regarding the additional time period on contraception should be taken by the doctor and/or the patient (see section 4.4).

Pregnancy

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.

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

Breast-Feeding

Mothers receiving Melphalan should not breast-feed.

Fertility

Melphalan 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 Melphalan can have an adverse effect on spermatogenesis (see section 5.3.). Therefore, it is possible that Melphalan may cause temporary or permanent sterility in male patients. It is recommended that men who are receiving treatment with Melphalan have a consultation on sperm preservation before treatment due to the possibility of irreversible infertility as a result of Melphalan treatment (see section 4.4).

Teratogenicity

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.

4.7 Effects on ability to drive and use machines

Effects on the ability to drive and operate machinery in patients taking this medicine have not been studied.

4.8 Undesirable effects

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, not known (cannot be estimated from the available data).

1. 1. 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.
2. 2. The incidence of diarrhoea, vomiting and stomatitis becomes the dose-limiting toxicity in patients given high intravenous doses of melphalan in association with autologous bone marrow transplantation. Cyclophosphamide pretreatment appears to reduce the severity of gastro-intestinal damage induced by high-dose melphalan and the literature should be consulted for details.
3. 3. Only with melphalan infusion after administration of regional perfusion in the limb
4. 4. Temporary significant elevation of the blood urea has been commonly seen in the early stages of melphalan therapy in myeloma patients with renal damage
5. 5. The clinically important adverse reactions associated with the use of melphalan in combination with thalidomide and prednisone or dexamethasone and to a lesser extend melphalan with lenalidomide and prednisone include: deep vein thrombosis and pulmonary embolism (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms and signs

Gastro-intestinal effects, including nausea, vomiting and diarrhoea are the most likely signs of acute oral overdosage. Diarrhoea, sometimes haemorrhagic, has been reported after intravenous overdosage. The principal toxic effect is bone marrow aplasia, leading to leucopoenia, 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 four weeks following overdosage until there is evidence of recovery.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Mechanism of action

Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-2-chlorethyl 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%.

Distribution

Melphalan displays limited penetration of the blood-brain barrier. Several investigators have sampled cerebrospinal fluid and found no measurable drug. Low concentrations (~10% of that in plasma) were observed in a single high-dose study in children.

Elimination

In 13 patients given oral melphalan at 0.6 mg/kg bodyweight, the plasma mean terminal elimination half-life was 90 ± 57 min with 11% of the drug being recovered in the urine over 24 h.

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 section 4.2 and 4.4).

Elderly

No correlation has been shown between age and melphalan clearance or with melphalan terminal elimination half-life (see section 4.2).

5.3 Preclinical safety data

Fertility Studies

In mice, melphalan administered intraperitoneally at a dose of 7.5 mg/kg, showed reproductive effects attributable to cytotoxicity in specific male germ cell stages and induced dominant lethal mutations and heritable translocations in post-meiotic germ cells, particularly in mid to late stage spermatids.

A study was performed to measure the total reproductive capacity of melphalan in female mice. Females received a single intraperitoneal dose of 7.5 mg/kg melphalan and were then housed with an untreated male for most of their reproductive life span (a minimum of 347 days post-treatment). A pronounced reduction in litter size occurred within the first post-treatment interval, followed by an almost complete recovery. Thereafter, a gradual decline in litter size occurred. This was simultaneous with a reduction in the proportion of productive females, a finding associated with an induced reduction in the number of small follicles (see section 4.6).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet Core:

Microcrystalline cellulose

Crospovidone

Colloidal anhydrous silica

Magnesium stearate

Tablet Film Coating:

Hypromellose

Titanium dioxide

Macrogol

6.2 Incompatibilities

None known.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Store between 2 - 8°C

6.5 Nature and contents of container

Supplied in amber glass bottles with a child resistant closure containing 25 or 50 tablets.

6.6 Special precautions for disposal and other handling

Safe handling of MELPHALAN tablets

The handling of Melphalan tablets should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations and/or regulations (for example Royal Pharmaceutical Society of Great Britain Working Party on the Handling of Cytotoxic Drugs). Provided the outer coating of the tablet is intact, there is no risk in handling Melphalan tablets.

Melphalan tablets should not be divided.

Disposal

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

7 MARKETING AUTHORISATION HOLDER

Aspen Pharma Trading Limited

3016 Lake Drive

Citywest business Campus

Dublin 24

Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PL 39699/0043

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11 November 2002

10 DATE OF REVISION OF THE TEXT

05/03/2025