Aspen

Alkeran 50mg, Powder and Solvent for Solution for Infusion

Alkeran Injection is supplied as a unit pack comprising of a vial of powder containing 50mg sterile, anhydrous melphalan, with a vial of solvent containing 10ml of solvent.

Where a pack is reconstituted with 10ml of the solvent, the resultant solution contains 5mg/ml anhydrous melphalan.

Excipients: When reconstituted each vial contains 2mmol (46mg) of Sodium and 0.52ml (0.4mg) of Ethanol.

For a full list of excipients, see Section 6.1.

Powder and solvent for solution for infusion.

Powder: A white to off-white freeze-dried powder.

Solvent: A clear, colourless solution (10ml)

The pH of the reconstituted solution is pH 6.5.

Alkeran Injection, administered by regional arterial perfusion, is indicated in the treatment of localised malignant melanoma of the extremities and localised soft tissue sarcoma of the extremities.

Alkeran Injection may be used alone or in combination with other cytotoxic drugs in the therapy of advanced ovarian carcinoma, multiple myeloma and stage IV neuroblastoma.

Alkeran Injection may be used alone or in combination with other cytotoxic drugs in high-dose therapy for patients with multiple myeloma. Where oral melphalan is not appropriate, intravenous melphalan may be used at conventional doses for treatment of multiple myeloma.

General:-

Alkeran 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. In view of the hazards involved and the level of supportive care required, the administration of high-dose Alkeran Injection should be confined to specialist centres, with the appropriate facilities, and only be conducted by experienced clinicians (see 4.4 Special Warnings and Precautions for Use).

Since Alkeran is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary (see 4.4 Special Warnings and Precautions for Use).

Preparation of Alkeran Injection Solution (see Safe Handling of Alkeran in 6.6 Instructions for Use/Handling).

Adults

Intravenous:-

Except in cases where regional arterial perfusion is indicated, Alkeran Injection is for intravenous use only.

For intravenous administration, it is recommended that Alkeran Injection solution is injected slowly into a fast-running infusion solution via a swabbed injection port. If direct injection into a fast-running infusion is not appropriate, Alkeran Injection solution may be administered diluted in an infusion bag.

Alkeran Injection is not compatible with infusion solutions containing dextrose, and it is recommended that ONLY Sodium Chloride Intravenous Infusion 0.9% w/v is used.

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

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

Care should be taken to avoid possible extravasation of Alkeran and in cases of poor peripheral venous access, consideration should be given to use of a central venous line.

If high-dose Alkeran Injection is administered with or without transplantation (autologous bone marrow, allogenic or haematopoietic stem cell), administration via a central venous line is recommended as extravasation and subsequent local tissue damage may occur if peripheral administration is used (see 4.4 Special Warnings and Precautions for Use).

Multiple myeloma:

Conventional dose:

Alkeran Injection has been used on an intermittent basis alone, or in combination with other cytotoxic drugs, at doses varying between 8 mg/m² body surface area and 30 mg/m² body surface area, given at intervals of between 2 to 6 weeks. Additionally, administration of prednisone has been included in a number of regimens. The literature should be consulted for precise details on treatment protocols.

When used as a single agent, a typical intravenous dosage schedule is 0.4 mg/kg bodyweight (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 240 mg/m² body surface area (approximately 2.5 to 6.0 mg/kg bodyweight), but autologous bone marrow rescue becomes essential following doses in excess of 140 mg/m² body surface area. In cases of renal impairment, the dose should be reduced by 50% (see Dosage in Renal Impairment). In view of the severe myelosuppression induced by high-dose Alkeran Injection, treatment should be confined to specialist centres with the appropriate facilities, and only be administered by experienced clinicians (see 4.4 Special Warnings and Special Precautions for Use).

Advanced ovarian carcinoma:

When used intravenously as a single agent, a dose of 1 mg/kg bodyweight (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 bodyweight (12 to 16 mg/m² body surface area) have been used at intervals of 4 to 6 weeks.

Perfusion:

Malignant melanoma:

Hyperthermic regional perfusion with Alkeran has been used as an adjuvant to surgery for early malignant melanoma and as palliative treatment for advanced but localised disease. The scientific literature should be consulted for details of perfusion technique and dosage used.

Soft tissue sarcoma:

Hyperthermic regional perfusion with Alkeran has been used in the management of all stages of localised soft tissue sarcoma, usually in combination with surgery. Alkeran has also been given with actinomycin D, and the scientific literature should be consulted for details of dosage regimens.

Use in children:

Alkeran, within the conventional dosage range, is only rarely indicated in children and dosage guidelines cannot be stated.

Stage IV neuroblastoma in childhood

High Dose: Doses of between 100 and 240 mg/m² body surface area (sometimes divided equally over 3 consecutive days) together with autologous bone marrow rescue, have been used either alone or in combination with radiotherapy and/or other cytotoxic drugs.

Use in the elderly:

Although Alkeran 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 Alkeran in elderly patients is limited. Consideration should therefore be given to ensure adequate performance status and organ function before using high-dose Alkeran Injection in elderly patients. The pharmacokinetics of intravenous Alkeran has not shown a correlation between age and Alkeran clearance or with Alkeran terminal elimination half-life. The limited data available do not support specific dosage adjustment recommendations for elderly patients receiving intravenous Alkeran and suggested that current practice of dosage adjustment based upon the general condition of the geriatric patient and the degree of myelosuppression incurred during therapy should be continued.

Dosage in renal impairment:

(See also 4.4 Special Warnings and Special Precautions for Use)

Alkeran clearance, though variable, may be decreased in renal impairment.

When Alkeran Injection is used at conventional intravenous dosage (8 to 40 mg/m² body surface area), it is recommended that the initial dose should be reduced by 50% in patients with moderate to severe renal impairment and subsequent dosage determined according to the degree of haematological suppression.

For high intravenous doses of Alkeran (100 to 240 mg/m² body surface area), the need for dose reduction depends upon the degree of renal impairment, whether autologous bone marrow stem cells are reinfused, and therapeutic need.

As a guide, for high-dose Alkeran treatment without haematopoietic stem cell rescue in patient with moderate renal impairment (creatinine clearance 30 to 50 ml/min) an initial dose reduction of 50% is usual.

High-dose Alkeran without haematopoietic stem cell rescue is not recommended in patients with more severe renal impairment.

High-dose Alkeran 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.

Alkeran should not be given to patients who have suffered a previous hypersensitivity reaction to melphalan.

MELPHALAN SHOULD ONLY BE ADMINISTERED UNDER THE DIRECTION OF A SPECIALIST ONCOLOGY SERVICE HAVING THE FACILITIES FOR A REGULAR MONITORING OF CLINICAL BIOCHEMICAL AND HAEMATOLOGICAL EFFECTS DURING AND AFTER ADMINISTRATION.

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised individuals. Therefore, immunisations with live organism vaccines are not recommended.

In view of the hazards involved and the level of supportive care required, the administration of high-dose Alkeran Injection should only be conducted by experienced clinicians.

In patients receiving high-dose Alkeran Injection, consideration should be given to the prophylactic administration of anti-infective agents, the administration of blood products as required.

Consideration should be given to ensure adequate performance status and organ function before using high-dose Alkeran Injection.

Bone marrow depression, with leucopenia and thrombocytopenia, is the main side effect. The time of maximum depression is variable, and careful attention should be paid to the monitoring of blood counts, both during and after treatment, to avoid the possibility of excessive myelosuppression and 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.

Alkeran should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity.

Alkeran Injection solution may cause local tissue damage should extravasation occur, and consequently it should not be administered by direct injection into a peripheral vein. It is recommended that Alkeran Injection solution is administered by injecting slowly into a fast-running intravenous infusion via a swabbed injection port, or via a central venous line.

Melphalan has been shown to be mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug. Melphalan has also been shown to be carcinogenic in animals, and the possibility of a similar effect should be borne in mind when designing the long-term management of the patient.

Suppression of ovarian function with resultant amenorrhoea occurs in a significant number of pre-menopausal patients. There is evidence from some animal studies that Alkeran can have an adverse effect on spermatogensis. Therefore, it is possible that Alkeran may cause temporary or permanent sterility in male patients.

In patients with moderate to severe renal impairment the initial dose of the intravenous preparation should be reduced by 50% being determined thereafter according to haematological response. Such patients should be closely observed for uraemic marrow suppression. Temporary significant elevation of blood urea has been seen in the early stages of treatment in myeloma patients with renal damage.

Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic in man.

There have been reports of acute leukaemia occurring after treatment for disease such as amyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and there has been a significant increase in patients with 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.

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Warnings and Precautions).

Nalidixic acid together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis.

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

Teratogenicity:

The teratogenic potential of Alkeran has not been studied. In view of its mutagenic properties and structural similarity to known teratogenic compounds, it is possible that melphalan could cause congenital defects in the offspring of patients treated with the drug.

Effects on fertility:

Alkeran causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of premenopausal patients.

There is evidence from some animal studies that Alkeran can have an adverse effect on spermatogenesis. Therefore, it is possible that Alkeran may cause temporary or permanent sterility in male patients.

Pregnancy:

This product should not be used during pregnancy unless considered absolutely essential by the physician.

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be practised when either partner is receiving Alkeran.

The teratogenic potential of Alkeran has not been studied. In view of its mutagenic properties and structural similarity to known teratogenic compounds, it is possible that Alkeran could cause congenital defects in the offspring of patients treated with the drug.

The use of Alkeran should be avoided whenever possible during pregnancy, particularly during the first trimester. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.

Lactation:

Mothers receiving Alkeran should not breast-feed.

No data.

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 and <1/10, uncommon 1/1000 and <1/100, rare 1/10,000 and <1/1000, very rare <1/10,000not known (cannot be estimated from the available data).

Blood and Lymphatic System Disorders

Very common: bone marrow depression leading to leucopenia, thrombocytopenia and anaemia

Rare: haemolytic anaemia

Immune System Disorders

Rare: allergic reactions (see Skin and Subcutaneous Tissue Disorders)

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.

Respiratory, Thoracic and Mediastinal Disorders

Rare: interstitial pneumonitis and pulmonary fibrosis (including fatal reports)

Gastrointestinal Disorders

Very common: nausea, vomiting and diarrhoea; stomatitis at high dose

Rare: stomatitis at conventional dose

The incidence of diarrhoea, vomiting and stomatitis becomes the dose-limiting toxicity in patients given high intravenous doses of melphalan in association with autologous bone marrow transplantation. Cyclophosphamide pre-treatment appears to reduce the severity of gastro-intestinal damage induced by highdose melphalan and the literature should be consulted for details.

Hepatobiliary Disorders

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

Skin and Subcutaneous Tissue Disorders

Very Common: alopecia at high dose

Common: alopecia at conventional dose

Rare: maculopapular rashes and pruritus (see Immune System Disorders)

Musculoskeletal and Connective Tissue Disorders

Injection, following isolated limb perfusion:

Very common: muscle atrophy, muscle fibrosis, myalgia, blood creatine phosphokinase increased.

Common: compartment syndrome

Not known: muscle necrosis, rhabdomyolysis

Renal and Urinary Disorders

Common: temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage

General Disorders and Administration Site Conditions

Very common: subjective and transient sensation of warmth and/or tingling

Symptoms and signs:

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 hospitalisation, cover with anti-infective agents, and 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.

Mode of Action:

Melphalan is a bifunctional alkylating anti-neoplastic agent with some immunosuppressant properties. Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enables alkylation through covalent bonding with the 7-nitrogen of guanine on DNA, cross-linking 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 α₁-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.

Following hyperthermic (39°C) perfusion of the lower limb with melphalan at 1.75 mg/kg bodyweight in 11 patients with advanced malignant melanoma, mean volumes of distribution at steady state and central compartment were, respectively, 2.87 ± 0.8 litres and 1.01 ± 0.28 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.

Metabolism

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 (see Pharmacokinetics Elimination).

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 Dosage and Administration - Renal impairment and Warnings and Precautions - Renal impairment).

Elderly

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

Melphalan is mutagenic in animals.

Freeze-dried Powder:

Povidone

Hydrochloric acid, (for pH-adjustment)

Solvent:

Propylene glycol

Sodium citrate

Ethanol, (96% per cent)

Water for Injections

Alkeran Injection is not compatible with infusion solutions containing dextrose, and it is recommended that ONLY Sodium Chloride Intravenous Infusion 0.9% w/v is used.

Unopened: 3 years

Once reconstituted the product should be used immediately. 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, type I glass vial with a bromobutyl rubber stopper and aluminium collar with a plastic flip-top cover. Pack Size: 50mg per vial.

Solvent: Clear, type I glass vial with a chlorobutyl rubber stopper and aluminium collar with a plastic flip-top cover. Pack Size: 10ml per vial.

Safe Handling of Alkeran Injection:-

Alkeran Injection should be prepared for administration either by or under the direct supervision of a pharmacist 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.

Alkeran Injection 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 Alkeran Injection 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 Alkeran Injection 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 eyewash 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 are trying to conceive should not handle Alkeran injection.

Disposal:-

Alkeran Injection solution should be disposed of in compliance with relevant local legislation. In the absence of such guidelines, the solution should be disposed of in a manner appropriate for toxic chemicals, for example, high-temperature incineration or deep burial.

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. All disposals must be in accordance with local regulatory requirements.

Preparation of Alkeran Injection Solution:-

(see also above, Safe Handling of Alkeran).

Alkeran Injection should be prepared, AT ROOM TEMPERATURE, by reconstituting the freeze-dried powder with the solvent provided.

10 ml of this vehicle should be added, as a single quantity, and the vial immediately shaken vigorously until solution is complete. The resulting solution contains the equivalent of 5 mg/ml anhydrous melphalan and has a pH of approximately 6.5.

The reconstituted solution should be colourless, clear and practically free from visible particles

Alkeran Injection solution has limited stability and should be prepared immediately before use. Any unused solution should be discarded (see Disposal, above).

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

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

Alkeran injection is not compatible with infusion solutions containing dextrose, and it is recommended that ONLY Sodium Chloride Intravenous Infusion 0.9% w/v is used. (Please refer to Section 4.2).

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

Aspen Pharma Trading Limited

12/13 Exchange Place

I.F.S.C.

Dublin 1, Ireland

PA 1691/4/1

Date of first authorisation: 25 October 2002

Date of last renewal: 25 October 2007

January 2011