4.1. Therapeutic indications

• Melphalan, at conventional intravenous dose, is indicated in the treatment of multiple myeloma and advanced ovarian cancer.

• Melphalan, at high intravenous dose, is indicated, with or without haematopoietic stem cell transplantation, for the treatment of multiple myeloma and childhood neuroblastoma.

• Melphalan, administered by regional arterial perfusion, is indicated in the treatment of localised malignant melanoma of the extremities and localised soft tissue sarcoma of the extremities.

In the above indications, melphalan may be used alone or in combination with other cytotoxic medicinal products.

4.2. Posology and method of administration

Treatment with melphalan should be supervised by a physician experienced in the use of anticancer therapies.

In view of the hazards involved and the level of supportive care required (see section 4.4), the administration of high dose melphalan should be confined to specialist centres, with the appropriate facilities and only be conducted by experienced clinicians. 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).

Protect the patient during intravenous administration against external contact with the melphalan solution for injection/infusion (see section 4.4).

Thromboembolic events

Melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone is associated with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism). 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 4.4 and 4.8).

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

Adults

Intravenous

General information

Melphalan is for intravenous use and regional arterial perfusion only. Melphalan should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m2.

For intravenous administration, it is recommended that melphalan is injected slowly into a fast-running infusion solution via a swabbed injection port. If direct injection into a fast-running infusion is not appropriate, melphalan may be administered diluted in an infusion bag.

Care should be taken to avoid possible extravasation of melphalan and in cases of poor peripheral venous access, consideration should be given to use of a central venous line.

Multiple myeloma

Conventional dose

Melphalan is administered on an intermittent basis alone, or in combination with other cytotoxic medicinal products at doses varying between 8 mg/m2 body surface area and 30 mg/m2 body surface area, given at intervals of between 2 to 6 weeks. Administration of prednisone has also been included in a number of regimens. The literature should be consulted for precise details on treatment protocols.

When used as a single agent, a typical intravenous melphalan dose schedule is 0.4 mg/kg body weight (16 mg/m2 body surface area) repeated at appropriate intervals (e.g. once every 4 weeks), provided there has been recovery of the peripheral blood count during this period.

High dose

High-dose regimens generally employ single intravenous doses of between 100 and 200 mg/m2 body surface area (approximately 2.5 to 5.0 mg/kg body weight), but haematopoietic stem cell rescue becomes essential following doses in excess of 140 mg/m2 body surface area.

In cases of renal impairment, the dose should be reduced by 50%. In view of the severe myelosuppression induced by high-dose melphalan injection, treatment should be confined to specialist centres with the appropriate facilities, and only be administered by experienced clinicians (see section 4.4).

Advanced ovarian adenocarcinoma

When used intravenously as a single agent, a dose of 1 mg/kg body weight (approximately 40 mg/m2 body surface area) given at intervals of 4 weeks has often been used.

When combined with other cytotoxic medicinal products, intravenous doses of between 0.3 and 0.4 mg/kg body weight (12 to 16 mg/m2 body surface area) have been used at intervals of 4 to 6 weeks.

Advanced neuroblastoma

Doses of between 100 and 240 mg/m2 body surface area (sometimes divided equally over 3 consecutive days) together with haematopoietic stem cell rescue, have been used either alone or in combination with radiotherapy and/or other cytotoxic medicinal products.

Malignant melanoma

Hyperthermic regional perfusion with melphalan has been used as an adjuvant to surgery for early malignant melanoma and as palliative treatment for advanced but localised disease. The scientific literature should be consulted for details of perfusion technique and dosage used. A typical dose range for upper extremity perfusions is 0.6-1.0 mg/kg bodyweight and for lower extremity perfusions is 0.8-1.5 mg/kg body weight.

Soft tissue sarcoma

Hyperthermic regional perfusion with melphalan has been used in the management of all stages of localised soft tissue sarcoma, usually in combination with surgery. The scientific literature should be consulted for details of perfusion technique and dosage used. A typical dose range for upper extremity perfusions is 0.6-1.0 mg/kg body weight and for lower extremity perfusions is 1-1.4 mg/kg body weight. Melphalan has also been given with actinomycin D, and the scientific literature should be consulted for details of dosage regimens.

Special populations

Paediatric population

Melphalan, at conventional dosage, is only rarely indicated in children and dosage guidelines cannot be stated.

High dose melphalan, in association with haematopoietic stem cell rescue, has been used in childhood neuroblastoma and dosage guidelines based on body surface area may be used.

Please refer also to the paragraph on Propylene glycol in section 4.4.

Elderly

Although melphalan is frequently used at conventional dose 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 melphalan in elderly patients is limited. Consideration should therefore be given to ensure adequate performance status and organ function, before using high dose melphalan in elderly patients.

The limited data available do not support specific dosage adjustment recommendations for older patients receiving intravenous melphalan and suggested that current practice of dosage adjustment based upon the general condition of the older patient and the degree of myelosuppression incurred during therapy should be continued.

Patients with impaired renal function

Melphalan clearance, though variable, may be decreased in renal impairment.

Currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering melphalan to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established. When melphalan is used at conventional intravenous dosage (8-40 mg/m2 body surface area), it is recommended that the initial dose should be reduced by 50% and subsequent dosage determined according to the degree of haematological suppression.

For high intravenous doses of melphalan (100 to 240 mg/m2 body surface area), the need for dose reduction depends upon the degree of renal impairment, whether haematopoietic stem cells are re-infused, and therapeutic need. As a guide, for high dose melphalan treatment without haematopoietic stem cell rescue in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min) a dose reduction of 50% is usual.

High dose melphalan without haematopoietic stem cell rescue is not recommended in patients with more severe renal impairment. High dose melphalan with haematopoietic stem cell rescue has been used successfully even in dialysis dependent patients with end-stage renal failure. The relevant literature should be consulted for details.

Please refer also to the paragraph on Propylene glycol in section 4.4.

Patients with impaired hepatic function

Please refer to the paragraph on Propylene glycol in section 4.4.

Method of Administration

Injection/Infusion

For instructions on reconstitution, and if applicable dilution, of the medicinal product before administration, see section 6.6.

After reconstitution the appearance of the medicinal product should be a clear solution, see section 6.6.

Melphalan Injection solution may 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.

If high-dose melphalan Injection is administered with or without transplantation (autologous bone marrow, allogenic or haematopoietic stem cell), administration via a central venous line is recommended as extravasation and subsequent local tissue damage may occur if peripheral administration is used (see section 4.4).

For regional arterial perfusion, the literature should be consulted for detailed methodology.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Breastfeeding (see section 4.6)

4.4. Special warnings and precautions for use

Melphalan is a cytotoxic drug, which falls into the general class of alkylating agents.

Melphalan should be administered under the direction of a specialist oncology service having the facilities for a regular monitoring of clinical biochemical and haematological effects during and after administration. In view of the hazards involved and the level of supportive care required, the administration of high-dose melphalan Injection should only be conducted by experienced clinicians.

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.

The eyes, skin and the mucous membranes of patients need to be protected against contact with the melphalan solution for injection/infusion or reconstituted solution.

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

Melphalan can cause local tissue damage, should extravasation occur and consequently, it should not be administered by direct injection into a peripheral vein.

In patients receiving high dose melphalan, 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.

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

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be practiced when receiving melphalan, up to three months for male patients and 6 months for female patients after end of treatment. For ovarian cancer, non-hormonal contraceptive methods are advised.

Monitoring

Bone marrow depression, with leucopenia and thrombocytopenia, is the main side effect. The time of maximum depression is variable, and careful attention should be paid to the monitoring of blood counts, both during and after treatment, to avoid the possibility of excessive myelosuppression and 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.

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.

Thromboembolic events

Patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone, have an increased risk of deep vein thrombosis and pulmonary embolism (see section 4.8). The risk appears to be greatest during the first 5 months of therapy, especially in patients with additional thrombotic risk factors (e.g. smoking, hypertension, hyperlipidaemia and history of thrombosis). These patients should be closely monitored and actions to minimize all modifiable risk factors should be undertaken. Thromboprophylaxis and dosing/anticoagulation therapy recommendations are provided in section 4.2.

Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. If a patient experiences any thromboembolic events, discontinue the treatment immediately and initiate the standard anticoagulation therapy. 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 throughout the course of treatment.

Neutropenia and thrombocytopenia

Elderly

Increased rate of haematological toxicities, particularly, neutropenia and thrombocytopenia, was observed in newly diagnosed elderly multiple myeloma in patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone. Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in patients receiving combination drug regimens described (section 4.8).

Mutagenicity

Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug. Melphalan has also been shown to be carcinogenic in animals (section 5.3), and the possibility of a similar effect should be borne in mind when designing the long-term management of the patient.

Suppression of ovarian function with resultant amenorrhoea occurs in a significant number of pre-menopausal patients. There is evidence from some animal studies that melphalan can have an adverse effect on spermatogensis. Therefore, it is possible that melphalan may cause temporary or permanent sterility in male patients.

Carcinogenicity

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

Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic in man, 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 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 especially if the use of melphalan in combination with thalidomide or lenalidomide and prednisone is considered, as it has been shown that these combinations may 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.

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. Risk must be balanced against the potential therapeutic benefit when considering the use of melphalan.

Contraception

Due to an increased risk of venous thromboembolism in patients undergoing treatment with melphalan in combination with lenalidomide and prednisone or in combination with thalidomide and prednisone or dexamethasone, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception, she should switch to another reliable contraceptive method (i.e. ovulation inhibitory progesterone-only pills such as desogestrel, barrier method etc). The risk of venous thromboembolism continues for 4-6 weeks after discontinuing combined oral contraception.

Renal Impairment

In patients with moderate to severe renal impairment the initial dose of the intravenous preparation should be reduced by 50% being determined thereafter according to haematological response. Such patients should be closely observed for uraemic marrow suppression. Temporary significant elevation of blood urea has been seen in the early stages of treatment in myeloma patients with renal damage (see sections 4.2 and 4.8).

5% Ethanol (alcohol)

This medicinal product contains 5 % ethanol (alcohol), i.e. 0.4 g per vial.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant women, children and high-risk groups such as patients with liver disease or epilepsy.

Propylene glycol

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

Medical monitoring is required if used in patients with impaired renal or hepatic function.

Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce adverse effects in children less than 5 years old.

Sodium

This medicinal product contains 53.5 mg sodium per vial, equivalent to 2.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Seven vials reflect the lowest number of vials for which the threshold of 17 mmol (391 mg) of sodium is reached/ exceeded.

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 children due to haemorrhagic enterocolitis. Combined treatment of melphalan with nalidixic acid should be avoided.

Busulfan

In the 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.

Ciclosporin

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

Ethanol: please refer to the paragraph on Propylene glycol in section 4.4 above.

4.6. Fertility, pregnancy and lactation

Contraception for men and women of childbearing potential

As with all cytotoxic treatments, male and female patients who use melphalan should use effective and reliable contraceptive methods up until three months for male patients and 6 months for female patients after end of treatment. The use of hormonal contraceptives should be avoided in ovarian cancer.

Pregnancy

There are no or limited amount of data from the use of melphalan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Risk for human is not known, but due to the mutagenic properties and structural similarity of melphalan with known teratogenic compounds, it is possible that melphalan can induce congenital malformations in offspring of treated patients.

Melphalan should not be used during pregnancy and particularly during the first trimester, unless considered absolutely essential by the physician. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.

Breast-feeding

It is unknown whether melphalan or its metabolites are excreted in human milk. Due to its mutagenic properties, melphalan is contraindicated during breastfeeding (see section 4.3).

Fertility

Melphalan causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of premenopausal patients.

Studies in animals have shown melphalan can have adverse effects on spermatogenesis (see section 5.3). Therefore, it is possible that melphalan may cause temporary or permanent adverse effects on male fertility.

It is recommended that men who are receiving treatment with melphalan not father a child during treatment and up to 3 months afterwards and that they have a consultation on sperm preservation before treatment due to the possibility of irreversible infertility as a result of melphalan treatment.

4.7. Effects on ability to drive and use machines

There are no data regarding the effect of melphalan treatment on the ability to drive and use machines. Based on the pharmacological profile such an effect is not anticipated. When advising patients treated for malignant disease it is recommended to consider their general health status.

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 to <1/10), uncommon (≥1/1,000 to <1/100), rare ≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

MedDRA system organ class

Frequency

Adverse reactions

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Not known

Secondary acute myeloid leukaemia and myelodysplastic syndrome (see section 4.4)

Blood and lymphatic system disorders

Very common

Bone marrow depression, leading to leukopenia, thrombocytopenia neutropenia1 and anaemia

Rare

Haemolytic anaemia

Immune system disorders

Rare

Hypersensitivity2 (see skin and subcutaneous tissue disorders)

Respiratory, thoracic and mediastinal disorders

Rare

Interstitial lung disease and pulmonary fibrosis (including fatal reports)

Gastrointestinal disorders

Very common

At high dose: nausea, vomiting and diarrhoea; stomatitis

Rare

Stomatitis at conventional dose

Hepato-biliary disorders

Rare

Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice; veno-occlusive disease following high-dose therapy

Skin and subcutaneous tissue disorders

Very common

Alopecia at high dose.

Common

Alopecia at conventional dose

Rare

Maculopapular rashes and prurtitis (see also immune system disorders)

Musculoskeletal and connective tissue disorders3

Very common

Muscular atrophy, muscle fibrosis, myalgia, increase in creatinine phosphokinase in the blood

Common

Compartment Syndrome

Not known

Muscle necrosis, rhabdomyolysis

Renal and urinary disorders

Common

Blood urea increased4

Uncommon

Acute kidney injury

Reproductive system and breast disorders

Common

Azoospermia and amenorrhoea

Vascular disorders5

Not known

Deep vein thrombosis and pulmonary embolism

General disorders and administration site conditions

Very common

Subjective and transient heat sensation of warmth and / or tingling

Common

Mucosal inflammation (mucositis)

1Increased rate of haematological toxicities, particularly, neutropenia and thrombocytopenia, was observed in newly diagnosed elderly multiple myeloma in patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone (see sections 4.4)

2Allergic 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

3Only with melphalan infusion after administration of regional perfusion in the limb

4Temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage

5The 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms and signs

Gastro-intestinal effects, including nausea, vomiting and diarrhoea are the most likely signs of acute oral overdosage. The immediate effects of acute intravenous overdose are nausea and vomiting. Damage to the gastro-intestinal mucosa may also ensue and diarrhoea, sometimes haemorrhagic, has been reported after overdose. 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, antibiotic cover, the use of haematological growth factors.

There is no specific antidote. The blood picture should be closely monitored for at least four weeks following overdose until there is evidence of recovery.