4.1. Therapeutic indications

Melphalan Injection, at conventional intravenous dosage, is indicated in the treatment of multiple myeloma and ovarian cancer.

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

Melphalan Injection, 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 drugs.

4.2. Posology and method of administration

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

Parenteral administration

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

For intravenous administration, it is recommended that Melphalan Injection solution 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 Injection solution may be administered diluted in an infusion bag.

Melphalan is not compatible with infusion solutions containing dextrose and it is recommended that only sodium chloride intravenous infusion 0.9% w/v is used.

When further diluted in an infusion solution, Melphalan has reduced stability and the rate of degradation increases rapidly with rise in temperature. If Melphalan is infused at a room temperature of approximately 25°C, the total time from preparation of the injection solution to the completion of infusion should not exceed 1.5 hours.

Should any visible turbidity or crystallisation appear in the reconstituted or diluted solutions, the preparation must be discarded.

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.

If high dose Melphalan Injection is administered with or without autologous bone marrow transplantation, administration via a central venous line is recommended.

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

Multiple myeloma

Melphalan Injection is administered on an intermittent basis alone, or in combination with other cytotoxic drugs. Administration of prednisone has also been included in a number of regimens.

When used as a single agent, a typical intravenous Melphalan dosage 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 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 Hydration and forced diuresis are also recommended.

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 drugs, 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 drugs

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 body weight 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. 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.

Paediatric population

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

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

Elderly population

Although Melphalan is frequently used at conventional dosage in older people, there is no specific information available relating to its administration to this patient sub-group.

Experience in the use of high dose Melphalan in older patients is limited. Consideration should therefore be given to ensure adequate performance status and organ function before using high dose Melphalan Injection in older patients.

Dosage in renal impairment

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 Tablets to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established.

When Melphalan Injection 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.

Melphalan Injection should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m2.

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 (above 140 mg/m2) without haematopoietic stem cell rescue should not be used 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.

Method of administration

Injection / infusion

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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

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 disease 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 53.48 mg sodium per vial, equivalent to 2.72% of the WHO recommended maximum daily intake of 1.995 g sodium for an adult.

This medicinal product contains 5 % ethanol (alcohol) per vial, 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 6 ml of propylene glycol per vial when reconstituted. May cause alcohol-like symptoms.

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

While propylene glycol has not been shown to cause reproductive or developmental toxicity in animals or humans, it may reach the foetus and was found in milk. As a consequence, administration of propylene glycol to pregnant or lactating patients should be considered on a case by case basis.

Medical monitoring is required in patients with impaired renal or hepatic functions because various adverse events attributed to propylene glycol have been reported such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction.

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 children 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 received high dose intravenous melphalan and who subsequently received cyclosporin 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).

Body System

Frequency

Side Effects

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 leucopenia, thrombocytopenia and anaemia

Rare

haemolytic anaemia

Immune System Disorders

Rare

hypersensitivity1 (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 dose2: nausea, vomiting and diarrhoea; stomatitis

Rare

stomatitis at conventional dose

Hepatobiliary Disorders

Rare

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

Skin and Subcutaneous Tissue Disorders

Very common

alopecia at high dose

Common

alopecia at conventional dose

Rare

rash maculo-papular and pruritus (see Immune System Disorders)

Musculoskeletal and Connective Tissue Disorders3

Very common

muscle atrophy, muscle fibrosis, myalgia, blood creatine phosphokinase increased

Common

compartment syndrome

Not known

muscle necrosis, rhabdomyolysis

Renal and Urinary Disorders

Common

blood urea increased4

Not known

Acute kidney injury

Reproductive system and breast disorders

Not known

azoospermia, amenorrhoea

Vascular Disorders5

Not known

deep vein thrombosis and pulmonary embolism

General Disorders and Administration Site Conditions

Very common

subjective and transient: hot and/or application site paraesthesia, pyrexia

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.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 pre treatment appears to reduce the severity of gastro- intestinal damage induced by high-dose melphalan and the literature should be consulted for details.

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

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. 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, Website: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The immediate effects of acute intravenous overdosage are nausea and vomiting. Damage to the gastro-intestinal mucosa may also ensue and diarrhoea, sometimes haemorrhagic, has been reported after overdosage.

The principal toxic effect is bone marrow suppression, leading to leucopenia, thrombocytopenia and anaemia.

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 overdosage until there is evidence of recovery.