Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: ADIENNE S.r.l. S.U., Via Galileo Galilei, 19, 20867 Caponago (MB), Italy, tel: +39 0240700445, e-mail: adienne@adienne.com
Melphalan can cause local tissue damage. Should extravasation occur, it should not be administered by direct injection into a peripheral vein (see section 4.2).
PHELINUN should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity.
Hepatic veno-occlusive disease is a major complication that can occur during treatment with melphalan.
Patients who have received prior radiation therapy greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk (see section 4.8).
Since melphalan is a potent myelosuppressive agent, it is essential that careful attention is paid to the monitoring of blood counts to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia or irreversible bone marrow failure. Cytopenia may continue to fall after treatment is stopped. So, at the first sign of an abnormally, large fall in leukocyte or severe thrombocytopenia, treatment should be temporarily interrupted.
It is recommended to ensure patients' adequate hydration and forced diuresis and the prophylactic administration of anti-infective agents (bacterial fungal, viral). The administration of blood products should be considered if required. It is recommended to monitor the general and renal status of patients receiving high-doses of PHELINUN.
The incidence of diarrhoea, vomiting and stomatitis becomes the dose-limiting toxicity in patients given high intravenous doses of PHELINUN in association with autologous bone marrow transplantation. Cyclophosphamide pre-treatment appears to reduce the severity of gastrointestinal damage induced by high-dose PHELINUN and the literature should be consulted for details.
Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the medicinal product.
Melphalan has been reported to be leukaemogenic (acute leukemia and myelodysplastic syndromes). 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.
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.
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. Especially in patients with increased risk factors for thrombosis, antithrombotic prophylactic measures need to be taken into consideration (see section 4.2 and 4.8).
Since patients with renal impairment may have marked bone marrow suppression, these patients should be closely monitored.
Melphalan clearance may be reduced in patients with renal impairment who may also have uraemic marrow suppression. Dose reduction may therefore be necessary and these patients should be closely controlled (see sections 4.2 and 4.8).
The safety and efficacy of melphalan followed by allo-HSCT in children below the age of 2 years with AML has not been established because safety and overall survival (OS) data are not reported separately for this age category (see sections 4.8 and 5.1).
The safety and efficacy of melphalan as part of the conditioning regimen prior to allo-HSCT in children below the age of 2 years with ALL has not been established.
Melphalan should not be used in adolescents over the age of 12 years with AML as conditioning treatment followed by allo-HSCT because of an increased rate of transplant-related mortality (see section 5.1).
This medicinal product contains 0.4 g of alcohol (ethanol) in each solvent vial which is equivalent to 42 mg/ml (0.42% w/v). The amount in 10 ml of this medicine is equivalent to 10 ml beer or 4 ml wine.
This medicinal product contains 1.6 g of alcohol (ethanol) in each solvent vial which is equivalent to 42 mg/ml (0.42% w/v). The amount in 40 ml of this medicine is equivalent to 40 ml beer or 17 ml wine.
For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC is likely to be about 50 mg/100 ml.
Co-administration with medicinal products containing propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects, in particular in young children with low or immature metabolic capacity.
A dose of 200 mg/m² of this medicine administered to adult weighing 70 kg would result in exposure to 40 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 6.67 mg/100 ml. The amount of alcohol in this medicine is not likely to have an effect in adults.
A dose of 240 mg/m² of this medicine administered to a child 8 years of age and weighing 30 kg would result in exposure to 76.8 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 12.8 mg/100 ml.
A dose of 240 mg/m² of this medicine administered to an adolescent 12 years of age and weighing 40 kg would result in exposure to 110 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 18.3 mg/100 ml.
The alcohol in this preparation is likely to affect children and adolescents. These effects may include feeling sleepy and changes in behaviour. It may also affect their ability to concentrate and take part in physical activities.
To be taken into account in children and adolescents and high risk groups such as patients with liver disease or epilepsy.
This medicinal product contains 6.2 g propylene glycol in each 10 ml of solvent which is equivalent to 0.62 g/ml.
This medicinal product contains 24.9 g propylene glycol in each 40 ml of solvent which is equivalent to 0.62 g/ml.
Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce serious 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.
With high doses or prolonged use of propylene glycol have been reported various adverse events, such as hyperosmolality, lactic acidosis; renal dysfunction (acute tubular necrosis), acute renal failure; cardiotoxicity (arrhythmia, hypotension); central nervous system disorders (depression, coma, seizures); respiratory depression, dyspnoea; liver dysfunction; haemolytic reaction (intravascular haemolysis) and haemoglobinuria; or multisystem organ dysfunction.
Adverse events usually reverse following weaning off of propylene glycol, and in more severe cases following hemodialysis.
Medical monitoring is required.
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially “sodium free”.
This medicinal product contains 62.52 mg sodium per vial, equivalent to 3% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
The administration of high-dose intravenous PHELINUN together with nalidixic acid in children has caused haemorrhagic entercolitis with fatal outcome.
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.
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).
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.
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 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 (see section 4.3).
It is unknown whether melphalan or its metabolites are excreted in human milk. Due to its mutagenic properties, melphalan is contraindicated during breast-feeding (see section 4.3).
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 (see section 5.3). 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. This medicinal product also contains alcohol, which is likely to affect children and adolescents (see section 4.4).
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.
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 alloHSCT 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), yare (≥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.
| MedDRA System Organ Class | Frequency | Adverse Drug Reactions |
|---|---|---|
| Infections and infestations | Common | Infection |
| Uncommon | Septic shock Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| Uncommon | Secondary primary malignancy, Secondary acute myeloid leukaemia and Myelodysplastic syndrome | |
| Blood and lymphatic system disorders | Very Common | Myelosuppression leading to Neutropenia, Thrombocytopenia and Anaemia |
| Uncommon | Thrombotic microangiopathy | |
| Rare | Haemolytic anaemia | |
| Immune system disorders | Very common | Acute graft versus host disease, Chronic graft versus host disease |
| Rare | Hypersensitivity (urticaria, oedema, skin rashes, and anaphylactic shock) | |
| Not known | Haemophagocytic lymphohistiocytosis | |
| Nervous system disorders | Uncommon | Haemorrhage intracranial |
| Cardiac disorders | Rare | Cardiac arrest |
| Not known | Cardiac failure, Cardiomyopathy, Pericardial effusion | |
| Vascular disorders | Not known | Haemorrhage, Deep venous thrombosis and Lung embolism |
| Respiratory, thoracic and mediastinal disorders | Uncommon | Interstitial lung disease, Pulmonary fibrosis, Idiopathic pneumonia syndrome, Pulmonary haemorrhage, Respiratory failure, Acute respiratory distress syndrome, Pneumonitis |
| Not known | Pulmonary hypertension | |
| Gastrointestinal disorders | Common | Diarrhoea, Nausea, Vomiting, Stomatitis, Gastrointestinal haemorrhage |
| Uncommon | Hepatotoxicity, Venoocclusive liver disease | |
| Rare | Liver function test abnormal, Jaundice | |
| Skin and subcutaneous tissue disorders | Very common | Alopecia after high dose |
| Common | Alopecia after conventional dose | |
| Uncommon | Rash maculo-papular, alopecia | |
| Rare | Pruritus | |
| Not known | Stevens-Johnson syndrome, Toxic epidermal necrolysis | |
| Renal and urinary disorders | Uncommon | Acute kidney injury, Renal failure |
| Not known | Cystitis haemorrhagic, Nephrotic syndrome | |
| Reproductive system and breast disorders | Common | Amenorrhoea, Ovarian failure, Ovarian disorder, Premature menopause, Azoospermia |
| General disorders and administration site conditions | Common | Mucosal inflammation, Multiple organ dysfunction syndrome, Pyrexia |
| Uncommon | Feeling hot, Paraesthesia | |
| Investigations | Not known | Blood creatinine increased |
Infections and GvHD although not directly related to melphalan, were the major causes of morbidity and mortality, especially in the setting of allogeneic transplantation.
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.
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.
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.
On the basis of the identified safety reports in the literature, the paediatric population appears more susceptible to develop gastrointestinal complications.
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 national reporting system listed in Appendix V.
PHELINUN is not compatible with infusion solutions containing glucose. Only sodium chloride 9 mg/ml (0.9%) solution for injection is recommended to be used.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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