PHELINUN 200mg powder+solvent for concentrate for solution for infusion medication leaflet

PHELINUN 50 mg powder and solvent for concentrate for solution for infusion

PHELINUN 200 mg powder and solvent for concentrate for solution for infusion

PHELINUN 50 mg powder and solvent for concentrate for solution for infusion

One vial of powder for concentrate for solution for infusion contains 50 mg melphalan (as melphalanhydrochloride).

After reconstitution with 10 ml of solvent, the final concentration of the solution is 5 mg/ml.

When reconstituted, one vial contains 0.68 mmol (15.63 mg) of sodium, 400 mg of ethanol and 6.2 gof propylene glycol.

PHELINUN 200 mg powder and solvent for concentrate for solution for infusion

One vial of powder for concentrate for solution for infusion contains 200 mg melphalan (as melphalanhydrochloride).

After reconstitution with 40 ml of solvent, the final concentration of the solution is 5 mg/ml.

When reconstituted, one vial contains 2.72 mmol (62.52 mg) of sodium, 1.6 g of ethanol and 24.9 g ofpropylene glycol.

For the full list of excipients, see section 6.1.

Powder and solvent for concentrate for solution for infusion

Powder: white to pale yellow freeze-dried powder or cake.

Solvent: clear colourless liquid solution.

The pH of the reconstituted solution is between 6.0 and 7.0 and the osmolality is 75 mOsmol/kg.

High-dose of PHELINUN used alone or in combination with other cytotoxic medicinal productsand/or total body irradiation is indicated in the treatment of:

- multiple myeloma,

- malignant lymphoma (Hodgkin, non-Hodgkin lymphoma),

- acute lymphoblastic and myeloblastic leukemia,

- childhood neuroblastoma,

- ovarian cancer,

- mammary adenocarcinoma.

PHELINUN in combination with other cytotoxic medicinal products is indicated as reduced intensityconditioning (RIC) treatment prior to allogeneic haematopoietic stem cell transplantation (allo-HSCT)in malignant haematological diseases in adults.

PHELINUN in combination with other cytotoxic medicinal products is indicated as conditioningregimen prior to allogeneic haematopoietic stem cell transplantation in haematological diseases in thepaediatric population as:

- Myeloablative conditioning (MAC) treatment in case of malignant haematological diseases

- RIC treatment in case of non-malignant haematological diseases.

PHELINUN administration must be supervised by a physician experienced in the use ofchemotherapeutic medicinal products and in conditioning treatment prior to haematopoietic stem celltransplantation.

Multiple myeloma, malignant lymphoma (Hodgkin, non-Hodgkin lymphoma), acute lymphoblastic andmyeloblastic leukaemia (ALL and AML), ovarian cancer and mammary adenocarcinoma at ahigh-dose

The dose regimen is as follows: one dose between 100 and 200 mg/m2 body surface area(approximatively 2.5 to 5.0 mg/kg body weight). The dose can be divided equally over 2 or 3consecutive days. Autologous hematopoietic stem cell transplantation is required following dosesabove 140 mg/m2 body surface area.

Malignant haematological diseases before allogeneic haematopoietic stem cell transplantation

The recommended dose is 140 mg/m2 as a single daily infusion or 70 mg/m2 once daily for twoconsecutive days.

Acute lymphoblastic and myeloblastic leukaemia at high-dose

The dose regimen is as follows: one dose between 100 and 200 mg/m2 body surface area(approximatively 2.5 to 5.0 mg/kg body weight). The dose can be divided equally over 2 or 3consecutive days. Autologous hematopoietic stem cell transplantation is required following dosesabove of 140 mg/m2 body surface area.

Childhood neuroblastoma

The recommended dose to consolidate a response obtained with a conventional treatment is one singledose between 100 mg/m2 and 240 mg/m2 body surface area (sometimes divided equally over 3consecutive days) together with autologous haematopoietic stem cell transplantation. The infusion isused either alone or in combination with radiotherapy and/or other cytotoxic medicinal products.

Haematological diseases before allogeneic haematopoietic stem cell transplantation

The recommended dose is as follows:

- malignant haematological diseases: 140 mg/m2 as a single daily infusion;

- non-malignant haematological diseases: 140 mg/m2 as a single daily infusion or 70 mg/m2once daily for two consecutive days.

Thromboembolic complications

Thrombosis prophylaxis needs to be administered during at least the first 5 months of the treatment, inparticular to patients who are more at risk of thrombosis. The decision to take antithromboticprophylactic measures needs to be taken after a thorough assessment of the underlying risks for theindividual patient (see sections 4.4 and 4.8).

There is no dose recommendation for the administration of PHELINUN to elderly.

However, frequently conventional doses of melphalan are applied in the elderly.

Experience in the use of high dose melphalan in elderly patients is limited. Consideration shouldtherefore be given to ensure adequate performance status and organ function, before using high dosemelphalan in elderly patients.

The posology should be adjusted in patients with renal impairment (see section 4.4).

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 dialysisdependent patients with end-stage renal failure.

As a guide, for high dose Melphalan treatment without haematopoietic stem cell rescue in patientswith moderate renal impairment (creatinine clearance 30 to 50 ml/min) a dose reduction of 50% isusual. High dose Melphalan (above 140 mg/m2) without haematopoietic stem cell rescue should notbe used in patients with more severe renal impairment. For high intravenous doses of melphalan (100to 240 mg/m2 body surface area), the need for dose reduction depends upon the degree of renalimpairment, whether haematopoietic stem cells are re-infused, and the therapeutic need. Melphalaninjection should be given with haematopoietic stem cell rescue at doses above 140 mg/m2.

No dose adjustment is required for patients with mild hepatic impairment and that there areinsufficient data in patients with moderate or severe heptic impairment.

It is recommended to ensure patients’ adequate hydration and forced diuresis and the prophylacticadministration of anti-infective agents (bacterial fungal, viral) (see sections 4.4).

Cyclophosphamide pre-treatment appears to reduce the severity of gastrointestinal damage induced byhigh-dose PHELINUN and the literature should be consulted for details (see sections 4.8).

Adoption of prohylactic measures such as the administration of anti-infective agents can be useful(seesections 4.8).

The occurrence of GvHD can be prevented by using immunosuppressive therapy after haematopoieticstem cell transplantation as prophylaxis (see sections 4.8).

PHELINUN is for intravenous use only.

Risk of extravasation could be observed when PHELINUN is administered via peripheral intravenousroute. In case of extravasation, the administration should be interrupted immediately and a centralvenous line route should be used.

If high-dose is administered with or without transplantation, the administration as dilution via a centralvenous line is recommended to avoid extravasation.

It is recommended that PHELINUN as concentrate (5 mg/ml) is injected slowly into the port of a fast-running infusion solution.

If the injection of the concentrate (5 mg/ml) slowly into a fast-running infusion solution is notappropriate, PHELINUN may be administered further diluted with sodium chloride 9 mg/ml (0.9%)solution for injection in a “slow-running” solution in a infusion bag. The total time from preparation ofthe solution to the completion of infusion should not exceed 1 hour and 30 minutes. When furtherdiluted in an infusion solution, PHELINUN has reduced stability and the rate of degradation increasesrapidly with rise in temperature.

It is recommended to let the infusion run at a temperature below 25°C.

Precaution to be taken before handling or administering the medicinal product

The preparation of injectable cytotoxic solutions must be carried out by qualified healthcareprofessionals with knowledge of alkylating agents handling, under conditions that ensure theenvironment protection and the healthcare professional safety.

Excreta and vomit must be handled with care. Pregnant staff should be warned and avoid handling

PHELINUN.

If PHELINUN accidentally contacts the skin, this must be immediately washed thoroughly with soapand water.

In case of accidental contact with the eyes or mucous membranes, rinse abundantly with water.

Inhalation of the product should be avoided.

Remnants of the medicinal product as well as all materials that have been used for reconstitution andadministration must be disposed of according to standard procedures applicable to cytotoxic products,with due regard to local requirements related to the disposal of hazardous waste.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

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

- Pregnancy (only with respect to the treatment prior to HSCT) and breat-feeding (see section4.6).

Melphalan can cause local tissue damage. Should extravasation occur, it should not be administered bydirect injection into a peripheral vein (see section 4.2).

Hepatic veno-occlusive disease is a major complication that can occur during treatment withmelphalan.

Since melphalan is a potent myelosuppressive agent, it is essential that careful attention is paid to themonitoring of blood counts to avoid the possibility of excessive myelosuppression and the risk ofirreversible 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, largefall in leukocyte or severe thrombocytopenia, treatment should be temporarily interrupted.

PHELINUN should be used with caution in patients who have undergone recent radiotherapy orchemotherapy in view of increased bone marrow toxicity.

It is recommended to ensure patients’ adequate hydration and forced diuresis and the prophylacticadministration of anti-infective agents (bacterial fungal, viral). The administration of blood productsshould 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 patientsgiven high intravenous doses of PHELINUN in association with autologous bone marrowtransplantation. Cyclophosphamide pre-treatment appears to reduce the severity of gastrointestinaldamage 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 beingtreated with the medicinal product.

Acute myeloide leukemia (AML) and myelodysplastic syndromes.

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 asamyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome andovarian cancer.

The leukaemogenic risk must be balanced against the potential therapeutic benefit when consideringthe use of melphalan, in particular when used in combination with thalidomide or lenalidomide andprednisone, 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 detectcancer 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 toa lesser extent in combination with thalidomide and prednisone, it has been linked to an increasedchance of solid SPM for elderly patients with newly diagnosed multiple myeloma.

Thromboembolic complications

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

Especially in patients with increased risk factors for thrombosis, antithrombotic prophylactic measuresneed to be taken into consideration (see section 4.2 and 4.8).

Should thromboembolic complications occur for the patient, treatment needs to be stopped and thestandard anticoagulant therapy needs to be started. As soon as the patient is stabilised by theanticoagulant therapy and the complications of the thromboembolic incident are under control,melphalan can be used in combination with lenalidomide and prednisone, or thalidomide andprednisone or dexamethasone can be resumed in the original dose contingent on the assessment of therisks and benefits. The patient needs to continue the anticoagulant therapy during the melphalantreatment.

Since patients with renal impairment may have marked bone marrow suppression, these patientsshould be closely monitored.

Melphalan clearance may be reduced in patients with renal impairment who may also have uraemicmarrow suppression. Dose reduction may therefore be necessary and these patients should be closelycontrolled (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 reportedseparately 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 inchildren 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 conditioningtreatment followed by allo-HSCT because of an increased rate of transplant-related mortality (seesection 5.1).

PHELINUN 50 mg powder and solvent for concentrate for solution for infusion

This medicinal product contains 0.4 g of alcohol (ethanol) in each solvent vial which is equivalent to42 mg/ml (0.42% w/v). The amount in 10 ml of this medicine is equivalent to 10 ml beer or 4 ml wine.

PHELINUN 200 mg powder and solvent for concentrate for solution for infusion

This medicinal product contains 1.6 g of alcohol (ethanol) in each solvent vial which is equivalent to42 mg/ml (0.42 % w/v). The amount in 40 ml of this medicine is equivalent to 40 ml beer or 17 mlwine.

For comparison, for an adult drinking a glass of wine or 500 ml of beer, the blood alcoholconcentration (BAC) is likely to be about 50 mg/100 ml.

Co-administration with medicinal products containing propylene glycol or ethanol may lead toaccumulation of ethanol and induce adverse effects, in particular in young children with low orimmature metabolic capacity.

A dose of 200 mg/m2 of this medicine administered to adult weighing 70 kg would result in exposureto 40 mg/kg of ethanol which may cause a rise in BAC of about 6.67 mg/100 ml.

The amount of alcohol in this medicine is not likely to have an effect in adults.

Children and adolescents

A dose of 240 mg/m2 of this medicine administered to a child 8 years of age and weighing 30 kgwould result in exposure to 76.8 mg/kg of ethanol which may cause a rise in blood alcoholconcentration (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 weighing40 kg would result in exposure to 110 mg/kg of ethanol which may cause a rise in blood alcoholconcentration (BAC) of about 18.3 mg/100 ml.

The alcohol in this preparation is likely to affect children and adolescents. These effects may includefeeling sleepy and changes in behaviour. It may also affect their ability to concentrate and take part inphysical activities.

To be taken into account in children and adolescents and high risk groups such as patients with liverdisease or epilepsy.

PHELINUN 50 mg powder and solvent for concentrate for solution for infusion

This medicinal product contains 6.2 g propylene glycol in each 10 ml of solvent which is equivalent to0.62 g/ml.

PHELINUN 200 mg powder and solvent for concentrate for solution for infusion

This medicinal product contains 24.9 g propylene glycol in each 40 ml of solvent which is equivalentto 0.62 g/ml.

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

While propylene glycol has not been shown to cause reproductive or developmental toxicity inanimals or humans, it may reach the foetus and was found in milk. As a consequence, administrationof 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 variousadverse events attributed to propylene glycol have been reported such as renal dysfunction (acutetubular necrosis), acute renal failure and liver dysfunction.

With high doses or prolonged use of propylene glycol have been reported various adverse events, suchas 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 (intravascularhaemolysis) and haemoglobinuria; or multisystem organ dysfunction.

Adverse events usually reverse following weaning off of propylene glycol, and in more severe casesfollowing hemodialysis.

Medical monitoring is required.

PHELINUN 50 mg powder and solvent for concentrate for solution for infusion

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially“sodium free”.

PHELINUN 200 mg powder and solvent for concentrate for solution for infusion

This medicinal product contains 62.52 mg sodium per vial, equivalent to 3% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Nalidixic acid

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

Busulfan

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

Cyclosporin

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

Attenuated live vaccines

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

As with all cytotoxic treatments, male and female patients that receive melphalan should use effectivereliable 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 inanimals have shown reproductive toxicity (see section 5.3). Risk for human is not know, but due to themutagenic properties and structural similarity of melphalan with known teratogenic compounds, it ispossible 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 thepotential risk to the fetus should be evaluated.

HSCT is contraindicated in pregnant women. Therefore melphalan is contraindicated duringpregnancy for this indication (see section 4.3).

It is unknown whether melphalan or its metabolites are excreted in human milk. Due to its mutagenicproperties, melphalan is contraindicated during breast-feeding (see section 4.3).

Melphalan causes suppression of ovarian function in pre-menopausal women resulting in amenorrhoeain 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 sterilityin 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 certainadverse reactions of melphalan, like nausea and vomiting, could affect this ability. This medicinalproduct 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, andimmune 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 ofmorbidity and mortality in the allo HSCT setting. Bone marrow failure, stomatitis, mucosalinflammation, gastrointestinal haemorrhage, diarrhea, nausea, vomiting, amenorrhoea, ovariandisorders and premature menopause were also commonly reported.

The adverse drug reactions (ADRs) described in this section were identified from informationincluded 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 regimensfor allo-HSCT setting. With the exception of Stevens-Johnson syndrome and Toxic epidermalnecrolysis identified for only one patient, ADRs reported for at least two patients have been capturedin the table below.

Frequencies are described as very common (1/10), common (1/100 to <1/10), uncommon (1/1 000to <1/100), rare (1/10 000 to <1/1,000), very rare (<1/10 000), and not known (cannot be estimatedfrom the available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

MedDRA System Organ Class Frequency Adverse Drug Reactions

Common Infection

Uncommon Septic shock

Secondary primary malignancy,

Neoplasms benign, malignant and unspecified Secondary acute myeloid

Uncommon(incl cysts and polyps) leukaemia

Myelodysplastic syndrome

Myelosuppression leading to

Very Neutropenia,

Common Thrombocytopenia

Blood and lymphatic system disorders Anaemia

Uncommon Thrombotic microangiopathy

Rare Haemolytic anaemia

Acute graft versus host disease,

Very

Chronic graft versus hostcommondisease

Hypersensitivity (urticaria,

Immune system disorders oedema,

Rareskin rashes,and anaphylactic shock)

Haemophagocytic

Not knownlymphohistiocytosis

Nervous system disorders Uncommon Haemorrhage intracranial

Rare Cardiac arrest

Cardiac disorders Cardiac failure,

Not known Cardiomyopathy,

Pericardial effusion

Haemorrhage,

Vascular disorders Not known Deep venous thrombosisand Lung embolism

Interstitial lung disease,

Pulmonary fibrosis,

Idiopathic pneumoniasyndrome,

Respiratory, thoracic and mediastinal Uncommon Pulmonary haemorrhage,disorders Respiratory failure,

Acute respiratory distresssyndrome,

Pneumonitis

Not known Pulmonary hypertension

Gastrointestinal disorders Common Diarrhoea,

MedDRA System Organ Class Frequency Adverse Drug Reactions

Nausea,

Vomiting,

Stomatitis,

Gastrointestinal haemorrhage

Hepatotoxicity,

Uncommon

Venoocclusive liver disease

Liver function test abnormal,

Rare

Jaundice

Very Alopecia after high dosecommon

Common Alopecia after conventionaldose

Skin and subcutaneous tissue disorders Rash maculo-papular,

Uncommonalopecia

Rare Pruritus

Stevens-Johnson syndrome,

Not known

Toxic epidermal necrolysis

Acute kidney injury,

Uncommon

Cystitis haemorrhagic,

Not known

Nephrotic syndrome

Amenorrhoea,

Ovarian failure,

Reproductive system and breast disorders Common Ovarian disorder,

Premature menopause,

Azoospermia

Mucosal inflammation,

Common Multiple organ dysfunction

General disorders and administration sitesyndrome,conditions

PFeyerelixniga hot,

Uncommon

Paraesthesia

Investigations Not known Blood creatinine increased

Infections and GvHD although not directly related to melphalan, were the major causes of morbidityand 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 thedevelopment of infections which may have fatal outcome in the most severe manifestations. Adoptionof 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 developacute and/or chronic GvHD. The severity of GvHD may vary from mild to fatal in the most severemanifestations of the disease.

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

On the basis of the identified safety reports in the literature, the paediatric population appears moresusceptible to develop respiratory complications than adults. In particular, fatal respiratorycomplications 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 moresusceptible to develop gastrointestinal complications.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms and signs

Gastro-intestinal effects, including nausea and vomiting are the most likely signs of acute intravenousoverdose. Damage to the gastro-intestinal mucosa may also occur. Diarrhoea, sometimeshaemorrhagic, has been reported after intravenous overdose. The principal toxic effect is bone marrowsuppression, leading to anaemia, neutropenia and thrombocytopenia.

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

The treatment should be symptomatic: blood transfusion, antibiotic therapy, haematopoietic growthfactors if necessary.

Pharmacotherapeutic group: antineoplastic agents, nitrogen mustard analogues, ATC code: L01AA03.

Melphalan is a bifunctional alkylating agent that prevents the separation and replication of DNA.

Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enablesalkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking the two

DNA strands and thereby preventing cell replication.

Documentation on the safety and efficacy of PHELINUN in combination with other cytotoxicmedicinal products derives from literature review. In total the studies report efficacy results for3,096 patients of whom 607 were from studies reporting results only in the paediatric population(under the age of 18 years). Endpoints in these studies were overall survival (OS), disease-freesurvival (DFS), event-free survival (EFS) and non-relapse mortality (NRM).The results of publishedclinical studies supporting the efficacy of melphalan are summarised below divided between adult andpediatric population.

Baron et al., 2015

This retrospective study, performed by the Acute Leukemia Working Party of the European Group for

Blood and Marrow Transplantation, compared the outcomes for a cohort of 394 AML patientsreceiving a sibling HSCT after fludarabine-busulfan (n=218) or fludarabine-melphalan (n=176).

Busulfan dose was ranging from 7.1 to 8.9 mg/kg [oral] or from 6.0 to 6.9 mg/kg [intravenous];melphalan dose was ranged between 130 to 150 mg/m2. Both are considered RIC.

There was a statistically significant reduction in relapse risk at 2 years for fludarabine-melphalan (FM)versus fludarabine-busulfan (FB) in AML patients (FM 20%, FB 30%; p=0.007) which was confirmedin multivariate analysis (HR 0.5, 95%CI 0.3-0.8, p=0.01).

Kawamura et al., 2017

This retrospective study performed in Japan compared the transplant outcomes of patients aged50 years or older with AML, ALL or MDS after fludarabine with melphalan (140 mg/m2 i.v.) (FM,n=423), fludarabine with intermediate doses of busulfan (6.4 mg/kg i.v.) (FB2, n=463) and fludarabinewith higher doses of busulfan (12.8 mg/kg i.v.) (FB4, n=721). FM and FB2 are considered RIC-regimens and FB4 is considered a MAC regimen. There was a statistically significant reduction inrelapse risk at 3 years for fludarabine-melphalan versus fludarabine-busulfan intermediate dose (FB2)in AML/ALL/MDS patients (FM 27.4%, FB2 37.2%; p=0.0027), confirmed in multivariate analysis(HR 0.56, 95% CI 0.42-0.74, p<0.001).

Eom et al., 2013

This case-control study performed in South Korea in high-risk ALL patients in first or secondcomplete remission, compared outcomes after RIC (melphalan 140 mg/m2 and fludarabine 150 mg/m2;n=60) or MAC (TBI 13,2 Gy + cyclophosphamide 120 mg/kg; n=120) allo-HSCT. OS rate at 5 yearsfor fludarabine-melphalan was 54.5%. There was no statistically significant difference in OS-rate at5 years for fludarabine-melphalan versus TBI-cyclophosphamide in high-risk ALL patients, despite

RIC-patients being older or having more co-morbidities and therefore ineligible for myeloablativeconditioning.

Malignant haematological diseases

Three retrospective studies demonstrated the safety and efficacy of PHELINUN in combination withother cytotoxic medicinal products prior to allogeneic HPCT in the paediatric population withmalignant haematological diseases including AML and MDS.

Lucchini et al. 2017

This retrospective study, performed by the Acute Leukemia Working Party of the European Group for

Blood and Marrow Transplantation, compared the outcomes for children > 2 to <18 years of ageundergoing a first allogeneic HSCT from a matched sibling or unrelated donor for AML in CR1 aftereither Busulfan-Cyclophosphamide-Melphalan (140 mg/m2) (n=133), Busulfan-Cyclophosphamide(n=389) or TBI-cyclophosphamide (n=109). All are considered MAC.

There was a statistically significant reduction in relapse rate at 5 years for busulfan-cyclophosphamide-melphalan (BuCyMel) versus TBI-cyclophosphamide (TBICy) andbusulfan-cyclophosphamide (BuCy): (BuCyMel 14.7%, TBICy 30%, BuCy 31.5%; p<0.01) confirmedin multivariate analysis (OR 0.44, 95% CI 0.25-0.80; p<0.01).

OS-rate and NRM-rate at 5 years for the BuCyMel regimen were 76.6% and 10.8%, with nostatistically significant differences between groups in OS or NRM-rate at 5 years in multivariateanalysis.

Locatelli et al., 2015

This retrospective study, performed by the AIEOP group analysed the results of 143 childrenincluding 39 patients between 0-1 years of age and 17 between 1-2 years who were given an allo-

HSCT for consolidating remission after achievement of CR1 in AML. The conditioning regimen wasbusulfan, cyclophosphamide and melphalan (140 mg/m2).

In a subgroup analysis of different age categories (<1 year, 1-2 year, 2-10 year, >10 year) there was nostatistically significant difference in disease-free survival at 8 years. Analysis of the association of ageand the endpoints OS and TRM was not reported.

Strahm et al., 2011

This retrospective study, performed by the European Working Group of MDS in Childhood, analysed97 children with MDS treated with an allo-HSCT following induction by BuCyMel (melphalan140 mg/m2 single dose). OS-rate was 63%, EFS-rate was 59% and relapse rate was 21% at 5 years.

The study by Lucchini et al., 2017, did not include children below the age of two, and the study by

Locatelli et al., 2015, did not report OS, safety data and TRM separately for this age category.

Furthermore, in the study by Sauer et al., 2019, assessing the BuCyMel regimen in children with

AML, TRM correlated with age with a rate of 9% in children younger than 12 years and 31% in olderchildren and adolescents. Therefore, safety and efficacy in children <2 years of age with AML havenot been established and melphalan should not be used in children with AML >12 years of age (seesection 4.4).

Non-malignant haematological diseases

Ten studies assessed the safety and efficacy of PHELINUN in combination with other cytotoxicmedicinal products prior to allogeneic HSCT in a total of 504 patients including the paediatricpopulation (age range 2 months - 18 years) with non malignant haematological diseases includingthalassaemia, sickle-cell disease, hemophagocytic lymphohistiocytosis (HLH) and X-linkedlymphoproliferative disease, combined immune deficiency and common variable immunodeficiency,severe combined immune deficiency (SCID), non-Fanconi anaemia marrow failure disorders andmetabolic disorders.

Most studies used a RIC-regimen of alemtuzumab, fludarabine and melphalan 140 mg/m2. The largeststudy was performed by Marsh et al. 2015.

Marsh et al. 2015

In this restrospective study on allo-HSCT in non-malignant haematological diseases, 210 childrenreceived a RIC regimen of alemtuzumab, fludarabine, and melphalan 140 mg/m2. The OS reported at 1year was 78% and at 3 years was 69%. Three-year EFS was 84% for patients who underwenttransplantation with an HLA-matched related donor compared with 64%, 57% and 14% for patientswho underwent transplantation with a matched unrelated donor, 1 allele mismatched donor, or 2 allelemismatched donor, respectively (P < .001). Five % of patients required retransplantation due to graftloss.

The absorption of oral melphalan is highly variable with respect to both the time to first appearance ofthe medicinal product in plasma and peak plasma concentration.

In studies of the absolute bioavailability of melphalan, the mean absolute bioavailability ranged from56 to 85%.

Intravenous administration can be used to avoid variability in absorption associated withmyeloablative treatment.

Melphalan is distributed in most tissues of the body. It is moderately bound to plasma proteins withreported binding ranging from 69% to 78%. There is evidence that the protein binding is linear in therange of plasma concentrations usually achieved in standard dose therapy, but that the binding maybecome concentration-dependent at the concentrations observed in high-dose therapy. Serum albuminis the major binding protein, accounting for about 55 to 60% the binding, and 20% is bound to α1-acidglycoprotein. In addition, melphalan binding studies have revealed the existence of an irreversiblecomponent attributable to the alkylation reaction with plasma proteins.

In 28 patients with various malignancies who were given doses between 70 and 200 mg/m2 bodysurface area as a 2 to 20 min infusion, the mean volumes of distribution at steady state and centralcompartment were, respectively, 40.2 ± 18.3 litres and 18.2 ± 11.7 litres.

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

Biotrasformation

The chemical hydrolysis of melphalan to monohydroxymelphalan and dihydroxy melphalan is themost important metabolic route in humans. These metabolites are inactive.

In vivo and in vitro data suggest that spontaneous degradation rather than enzymatic metabolism is themajor determinant of the medicinal product's half-life in man.

In 15 children and 11 adults given high-dose intravenous melphalan (140 mg/m2 body surface area)with forced diuresis, the mean initial and terminal half-lives were found to be 6.5 ± 3.6 min and 41.4 ±16.5 min, respectively. Mean initial and terminal half-lives of 8.8 ± 6.6 min and 73.1 ± 45.9 min,respectively, were recorded in 28 patients with various malignancies who were given doses of between70 and 200 mg/m2 body surface area as a 2 to 20 min infusion. The mean clearance was 564.6 ±159.1 ml/min.

Melphalan clearance may be decreased in renal impairment (see sections 4.2 and 4.4).

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

Melphalan was mutagenic in Salmonella typhimurium. Melphalan caused chromosomal aberrations invitro (mammalian cells) and in vivo (rodents).

Clinical information on potential toxicity of melphalan is provided in sections 4.4 and 4.6.

Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic. Therehave been reports of acute leukaemia occurring after melphalan treatment for diseases such asamyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome andovarian cancer.

The potential therapeutic benefit when considering the use of melphalan must be balanced against therisk that may occur.

Melphalan was teratogenic in rats after single dose exposure in reproductive toxicity studies. Inrepeated dose reproductive toxicity studies, melphalan was maternal toxic and induced congenitalmalformations.

A single dose of melphalan in male mice induced cytotoxicity and chromosomal aberrations in spermcells. In female mice a reduction in number of pups per litter was observed. After recovery, thenumber of pups per litter was also reduced over time, which was related to a reduced number offollicles.

Hydrochloric acid (pH adjustment) (E507)

Povidone (E1201)

Water for injections

Propylene glycol (E1520)

Sodium citrate (E331)

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 insection 6.6.

PHELINUN 50 mg powder and solvent for concentrate for solution for infusion

Unopened vial3 years.

PHELINUN 200 mg powder and solvent for concentrate for solution for infusion

Unopened vial3 years.

After reconstitution and dilution, chemical and physical stability has been demonstrated for1 hour and 30 minutes at 25°C. Therefore the total time from reconstitution and dilution to thecompletion of infusion should not exceed 1 hour and 30 minutes.

From a microbiological point of view, the product should be used immediately after reconstitution. Ifnot used immediately, in-use storage times and conditions prior to use are the responsibility of theuser.

The reconstituted solution should not be refrigerated as this will cause precipitation.

Do not refrigerate.

Keep the vials in the outer carton in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Type I glass vial closed with coated chlorobutyl rubber stopper and sealed with aluminium flip-offcap.

Type I glass vial closed with coated chlorobutyl rubber stopper and sealed with aluminium flip-offcap.

Pack size: one vial containing 50 mg or 200 mg melphalan and one vial containing 10 ml or 40 ml ofsolvent.

Preparation of PHELINUN solution

The powder should be reconstituted immediately after opening the vial.

PHELINUN should be prepared at a temperature below 25°C, by reconstituting the freeze-dried powderwith 10 ml or 40 ml solvent and immediately shaking vigorously until a clear solution, without visibleparticles, is obtained. Only clear solution free from particles should be used.

Unless the concentrate is administered into a fast-running infusion solution via injection port, thereconstituted solution must be further diluted prior to administration with an appropriate volume ofsodium chloride 9 mg/ml (0.9%) solution for injection in order to obtain a final concentration between0.45 and 4.0 mg/ml.

PHELINUN concentrate and solution have limited stability and should be prepared immediately beforeuse.

The maximum time between reconstitution and dilution of the solution in sodium chloride9 mg/ml (0.9%) solution for injection and the end of the infusion is 1 hour 30 minutes.

Handling and disposal

PHELINUN should be prepared for use in a dedicated preparation area. Healthcare professionals musthave a suitable equipment, including long-sleeved clothes, face protection, protective caps, safetygoggles, sterile disposable gloves, worktop protection shields, containers and bags for collectingwaste. Any broken container should be treated with the same precautions and considered ascontaminated waste. The procedures for the safe handling and disposal of antineoplastic agents mustbe followed by healthcare professionals or medical personnel and should comply with the currentrecommendations for cytotoxic medicinal products (see section 4.2).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

ADIENNE S.r.l. S.U.

Via Galileo Galilei, 1920867 Caponago (MB)

Italytel: + 39 0240700445e-mail: adienne@adienne.com

EU/1/20/1487/001

EU/1/20/1487/002

Date of first authorisation: 16 November 2020

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.