Melphalan

A risk of general illness which may lead to fatal outcome has described. This risk is increased in patients who are already immunosuppressed by their underlying disease. An inactivated vaccines should be used when such a vaccine exists (poliomyelitis).

The posology should be adjusted in patients with renal impairment. The clearance of melphalan, although variable, may be reduced with impaired renal function. High-dose melphalan with haematopoietic stem cell rescue has been used successfully even in dialysis dependent patients with end-stage renal failure.

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. 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 the therapeutic need. Melphalan injection should be given with haematopoietic stem cell rescue at doses above 140 mg/m².

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.

There are insufficient data in patients with moderate or severe hepatic impairment.

Melphalan causes suppression of ovarian function in pre-menopausal women resulting in amenorrhoea in a significant number of patients.

There is evidence from animal studies that melphalan can have an adverse effect on spermatogenesis. Therefore, it is possible that melphalan may cause temporary or permanent sterility in male patients. Cryopreservation of semen before treatment is advised.

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.

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

Acute myeloide leukemia (AML) and myelodysplastic syndromes

The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of melphalan, in particular when used in combination with thalidomide or lenalidomide and prednisone, as it has been determined that these combinations increase the leukaemogenic risk. Before, during and after treatment the doctor needs to examine the patients with the usual checks to detect cancer early and start treatment if necessary.

Solid tumors

The use of alkylating agents has been linked to the development of a second primary malignancy (SPM). In particular when melphalan is used in combination with lenalidomide and prednisone, and to a lesser extent in combination with thalidomide and prednisone, it has been linked to an increased chance of solid SPM for elderly patients with newly diagnosed multiple myeloma.

The use of melphalan in combination with lenalidomide and prednisone or thalidomide or dexamethasone has been associated with an increased risk of thromboembolic complications.

The administration of high-dose intravenous melphalan together with nalidixic acid in children has caused haemorrhagic entercolitis with fatal outcome. Combined treatment of melphalan with nalidixic acid should be avoided.

There are no or limited amount of data from the use of melphalan in pregnant women. Studies in animals have shown reproductive toxicity. Risk for human is not know, 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.

The use of melphalan as anti-cancer treatment should be avoided whenever possible during pregnancy, particularly during the first trimester. In each case, the benefit of the treatment outweighing the potential risk to the fetus should be evaluated.

HSCT is contraindicated in pregnant women. Therefore melphalan is contraindicated during pregnancy for this indication.

It is unknown whether melphalan or its metabolites are excreted in human milk. Due to its mutagenic properties, melphalan is contraindicated during breast-feeding.

Women of childbearing potential/Contraception in males and females

As with all cytotoxic treatments, male and female patients that receive melphalan should use effective reliable contraceptive methods up until six months after cessation of treatment.

Fertility

Melphalan causes suppression of ovarian function in pre-menopausal women resulting in amenorrhoea in a significant number of patients.

There is evidence from animal studies that melphalan can have an adverse effect on spermatogenesis. Therefore, it is possible that melphalan may cause temporary or permanent sterility in male patients. Cryopreservation of semen before treatment is advised.

Melphalan has moderate influence on the ability to drive and use machines. It is likely that certain adverse reactions of melphalan, like nausea and vomiting, could affect this ability.

IV administration

Summary of the safety profile

The most frequently reported adverse reactions were haematologic and gastrointestinal toxicities, and immune system disorders, these being considered as expected consequences of myelosuppression. Infections, acute and chronic Graft versus Host Disease (GvHD) were reported as the major causes of morbidity and mortality in the allo HSCT setting. Bone marrow failure, stomatitis, mucosal inflammation, gastrointestinal haemorrhage, diarrhea, nausea, vomiting, amenorrhoea, ovarian disorders and premature menopause were also commonly reported.

Tabulated list of adverse reactions

The adverse drug reactions (ADRs) described in this section were identified from information included in other melphalan containing products, the screening of the published literature and the European database EudraVigilance concerning the use of melphalan as part of combination regimens for allo-HSCT setting. With the exception of Stevens-Johnson syndrome and Toxic epidermal necrolysis identified for only one patient, ADRs reported for at least two patients have been captured in the table below.

Frequencies are described as 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), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions

Infections and GvHD although not directly related to melphalan, were the major causes of morbidity and mortality, especially in the setting of allogeneic transplantation.

Infections and infestations

All patients in the target population are at risk of infections due to their immunodeficient status. Myelosuppression and immunosuppressive effects induced by melphalan may facilitate the development of infections which may have fatal outcome in the most severe manifestations. Adoption of prohylactic measures such as the administration of anti-infective agents can be useful.

Graft versus host disease

GvHD is a very common complication in the allogeneic HSCT setting. Up to ≈ 60% patients develop acute and/or chronic GvHD. The severity of GvHD may vary from mild to fatal in the most severe manifestations of the disease.

The occurrence of GvHD can be prevented by using immunosuppressive therapy after haematopoietic stem cell transplantation as prophylaxis.

Paediatric population

Respiratory, thoracic and mediastinal disorders

On the basis of the identified safety reports in the literature, the paediatric population appears more susceptible to develop respiratory complications than adults. In particular, fatal respiratory complications were reported as higher for infants below 2 years than for children and adolescents.

Gastrointestinal disorders

On the basis of the identified safety reports in the literature, the paediatric population appears more susceptible to develop gastrointestinal complications.

Oral administration

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 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 Gastrointestinal effects such as nausea and vomiting have been reported in up to 30% of patients receiving conventional oral doses of melphalan.

³ Temporary significant elevation of the blood urea has been commonly seen in the early stages of melphalan therapy in myeloma patients with renal damage.

⁴ 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.