Melphalan 50 mg powder and solvent for solution for injection/infusion

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

Melphalan, at high intravenous dosage, 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 localized malignant melanoma of the extremities and localized soft tissue sarcoma of the extremities.

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

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

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.

Posology

Multiple myeloma

Conventional dose

Melphalan 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

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.

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 localized 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, whereas for lower extremity perfusions, dose ranges of 0.8-1.5 mg/kg are typically used.

Soft tissue sarcoma

Hyperthermic regional perfusion with melphalan has been used in the management of all stages of localized soft tissue sarcoma, usually in combination with surgery. A typical dose range for upper extremity perfusions is 0.6-1.0 mg/kg, whereas for lower extremity perfusions, dose ranges of 1-1.4 mg/kg are typically used.

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.

Elderly

Although melphalan is frequently used at conventional dosage 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.

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 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.

Thromboembolic events

Patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone, have an increased risk of thromboembolic events (see section 4.8). Especially in patients with additional thrombotic risk factors antithrombotic prophylactic measures should be considered (see sections 4.4 and 4.8).

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.

Method of administration

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.

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

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

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

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.

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

- breastfeeding.

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.

Immunization using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunizations 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 either partner is receiving melphalan up to three months after end of treatment. For ovarian cancer, non-hormonal contraceptive methods are advised.

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.

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.

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). See section 4.8 for undesirable effects for elevation of blood urea. Patients with renal impairment should be closely monitored for signs/signals of overdose.

Thromboembolic events

Patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone, have an increased risk of thromboembolic events (see section 4.8). Especially in patients with additional thrombotic risk factors antithrombotic prophylactic measures should be considered (see sections 4.2 and 4.8).

Mutagenicity

Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.

Carcinogenicity (second primary malignancy)

Melphalan has been reported to be leukaemogenic. 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.

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.

5% Ethanol (alcohol)

This medicinal product contains 5 % ethanol (alcohol), equivalent to 10 ml beer or 2.4 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.

Propylene glycol

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

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 entercolitis. 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.

Cyclosporin

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

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 after cessation 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 unless the clinical condition of the woman requires treatment with melphalan.

Breastfeeding

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 ovary function in premenopausal women, resulting in amenorrhea in a large number of 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. Cryopreservation of semen before treatment is advised.

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.

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 utilized for the classification of frequency: very common ≥ 1/10, common ≥ 1/100 and <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).

¹Allergic 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

²Only with melphalan infusion after administration of regional perfusion in the limb

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

⁴The 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 authorization 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.

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 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.

Treatment

General supportive measures, together with appropriate blood and platelet transfusions, should be instituted if necessary and consideration given to hospitalization, 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.

Pharmacotherapeutic group: antineoplastic and immunomodulating agents, antineplastic agents, alkalating agents, nitrogen mustard analogues, ATC code: L01AA03.

Mechanism of action

Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking the two DNA strands and thereby preventing cell replication.

Absorption

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

In studies of the absolute bioavailability of melphalan the mean absolute bioavailability ranged from 56 to 85%.

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

Distribution

Melphalan is moderately bound to plasma proteins with reported percent binding ranging from 69% to 78%. There is evidence that the protein binding is linear in the range of plasma concentrations usually achieved in standard dose therapy, but that the binding may become concentration-dependent at the concentrations observed in high-dose therapy. Serum albumin is the major binding protein, accounting for about 55 to 60% the binding, and 20% is bound to α 1-acid glycoprotein. In addition, melphalan binding studies have revealed the existence of an irreversible component attributable to the alkylation reaction with plasma proteins.

Following administration of a two-minute infusion of doses ranging from 5 to 23 mg/m² body surface area (approximately 0.1 to 0.6 mg/kg bodyweight) to 10 patients with ovarian cancer or multiple myeloma, the mean volumes of distribution at steady state and central compartment were 29.1 ± 13.6 litres and 12.2 ± 6.5 litres, respectively.

In 28 patients with various malignancies who were given doses of between 70 and 200 mg/m² body surface area as a 2- to 20-min infusion, the mean volumes of distribution at steady state and central compartment 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 sampled cerebrospinal fluid and found no measurable drug. Low concentrations (~10% of that in plasma) were observed in a single high- dose study in children.

Biotransformation

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

Elimination

In 13 patients given oral melphalan at 0.6 mg/kg bodyweight, the plasma mean terminal elimination half-life was 90 ± 57 min with 11% of the drug being recovered in the urine over 24 h.

In 8 patients given a single bolus dose of 0.5 to 0.6 mg/kg bodyweight, the composite initial and terminal half-lives were reported to be 7.7 ± 3.3 min and 108 ± 20.8 min, respectively. Following injection of melphalan, monohydroxymelphalan and dihydroxymelphalan were detected in the patients' plasma, reaching peak levels at approximately 60 min and 105 min, respectively. A similar half-life of 126 ± 6 min was seen when melphalan was added to the patients' serum in vitro (37° C), suggesting that spontaneous degradation rather than enzymic metabolism may be the major determinant of the drug's half-life in man.

Following administration of a two-minute infusion of doses ranging from 5 to 23 mg/m² body surface area (approximately 0.1 to 0.6 mg/kg bodyweight) to 10 patients with ovarian cancer or multiple myeloma, the pooled initial and terminal half-lives were, respectively, 8.1 ± 6.6 min and 76.9 ± 40.7 min. A mean clearance of 342.7 ± 96.8 ml/min was recorded.

In 15 children and 11 adults given high-dose i.v. 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 between 70 and 200 mg/m² body surface area as a 2- to 20-min infusion. The mean clearance was 564.6 ± 159.1 ml/min.

Following hyperthermic (39° C) perfusion of the lower limb with 1.75 mg/kg bodyweight, mean initial and terminal half- lives of 3.6 ± 1.5 min and 46.5 ± 17.2 min, respectively, were recorded in 11 patients with advanced malignant melanoma. A mean clearance of 55.0 ± 9.4 ml/min was recorded.

Special patient populations

Renal impairment

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

Elderly

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

Mutagenicity

Melphalan is a cytostatic agent and mutagenicity has therefore not been thoroughly investigated in pre-clinical studies. Melphalan was mutagenic in vivo causing chromosomal aberrations. Clinical information on potential toxicity of melphalan is provided in sections 4.4 and 4.6.

Reproductive toxicity and fertility

Melphalan was teratogenic in rat after single dose exposure in reproductive toxicity studies. In repeated dose reproductive toxicity studies, melphalan was maternal toxic and induced congenital malformations, intra-uterine death, growth retardation and disrupted development.

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

Powder

Hydrochloric acid

Povidone

Solvent

Water for injection

Sodium citrate

Propylene glycol

Ethanol

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.

2 years.

Chemical and physical in use stability have been demonstrated for 1 hour at room temperature.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are responsibility of user. Any unused portion should be discarded.

Do not store above 30° C. Do not refrigerate.

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

Powder

Clear, glass vial with a bromobutyl rubber stopper and aluminium collar with a plastic flip-top cover.

Pack size: one vial containing 50 mg melphalan.

Solvent

Clear, glass vial with a bromobutyl rubber stopper and aluminium collar with a plastic flip-top cover.

Pack size: one vial containing 10 ml of solvent.

Safe Handling of Melphalan:

Melphalan should be prepared for administration by a trained professional who is familiar with its properties and safe handling requirements. Refer to local cytotoxic guidelines before commencing. For instructions on administration, see Section 4.2.

Melphalan should be prepared for use in the aseptic unit of a pharmacy equipped with a suitable vertical laminar flow cabinet. Where such a facility is not available, a specially designated side room of a ward or clinic may be used.

Personnel preparing or handling Melphalan should wear the following protective clothing:

Disposable gloves of surgical latex or polyvinylchloride of a suitable quality (rubber gloves are not adequate);

Surgical facemask of suitable quality;

Protective goggles or glasses which should be washed thoroughly with water after use;

Disposable apron.

In an aseptic facility, other suitable clothing will be required.

Any spillage should be dealt with immediately (by personnel wearing suitable protective clothing), by mopping with damp, disposable paper towels which are placed in a high-risk waste disposal bag after use and disposed of in compliance with relevant local legislation. Contaminated surfaces should be washed with copious quantities of water.

Should Melphalan solution come into contact with the skin, wash immediately and thoroughly with soap and plenty of cold water. In such instances it may be prudent to seek medical advice.

In case of contact with eyes, IMMEDIATE irrigation with sodium chloride eye wash should be carried out and medical attention sought without delay. If sodium chloride solution is not available, large volumes of water may be used.

Staff who are pregnant or trying to conceive should not handle Melphalan.

Preparation of melphalan solution

Melphalan should be prepared at 25° C, by reconstituting the freeze-dried powder/cake with the solvent-diluent provided.

Reconstitution

It is important that both the freeze-dried powder/cake and the solvent provided are at room temperature before starting reconstitution. Warming the diluent in the hand may aid reconstitution. 10 ml of this vehicle should be added quickly, as a single quantity into the vial containing the freeze dried powder, and immediately shaken vigorously (for approximately 1 minute) until a clear solution, without visible particles, is obtained. Each vial must be reconstituted individually in this manner. The resulting solution contains the equivalent of 5 mg per ml anhydrous melphalan and has a pH of approximately 6.5.

Melphalan solution has limited stability and should be prepared immediately before use.

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

Admixture

Immediately withdraw reconstituted solution having concentration of 5 mg/ml of anhydrous melphalan from reconstituted vial and add using 10 ml new syringe into infusion bag containing of 0.9% Sodium Chloride Intravenous Infusion. Mix this diluted solution thoroughly by manual rotation to give nominal concentration of 0.45 mg/ml of anhydrous melphalan.

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 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.

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.

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

Disposal

Any solution unused after one hour should be discarded according to standard guidelines for handling and disposal of cytotoxic drugs.

Disposal of sharp objects, such as needles, syringes, administration sets and ampoules should be in rigid containers labelled with a suitable hazard warning seal. Personnel involved in disposal should be aware of the precautions to be observed, and the material should be destroyed by incineration if appropriate.