Alkeran 50 mg, Powder and Solvent for Solution for Infusion

  • Name:

    Alkeran 50 mg, Powder and Solvent for Solution for Infusion

  • Company:
    info
  • Active Ingredients:

    Melphalan

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 12 July 2019 SmPC

Reasons for updating

  • File format updated to PDF

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 21 May 2018 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 14 May 2018 SmPC

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  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text
  • Improved presentation of SmPC

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 24 April 2018 PIL

Reasons for updating

  • Change to section 2 - pregnancy, breast feeding and fertility

Updated on 24 April 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 6 - date of revision

Updated on 1 December 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 1 December 2017 SmPC

Reasons for updating

  • Change to section 6.4 - Special precautions for storage

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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 hour.

Updated on 29 November 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 29 November 2017 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text
  • Improved presentation of SPC
  • Change to section 4.4 - Special warnings and precautions for use

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4.4     Special warnings and precautions for use

 

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.

 

 

 

 

Ovulation inhibitory progesterone-only pills (i.e., desogestrel). Because of the Due to an increased risk of venous thromboembolism in patients with multiple myeloma,   undergoing treatment with melphalan in combination with lenalidomide and prednisone or in combination with thalidomide and prednisone or dexamethasone, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception, she should switch to one or the other another reliable contraceptive effective method s listed above  (i.e. ovulation inhibitory progesterone-only pills such as desogestrel, barrier method, etc). The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception.

 

 

 

 

 

 

10.       DATE OF REVISION OF THE TEXT

 

May 2017

Nov 2017

Updated on 29 November 2017 PIL

Reasons for updating

  • Change to section 5 - how to store or dispose

Updated on 28 November 2017 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 6 - date of revision

Updated on 17 May 2017 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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4.2       Posology and method of administration

 

Since melphalan is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary (see section 4.4).

 

Thromboembolic events

Melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone is associated with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism). 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.

 

4.3       Contraindications

 

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

•           Lactation.

 

4.4       Special warnings and precautions for use

 

Venous thromboembolic events

Patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone, have an increased risk of deep vein thrombosis and pulmonary embolism (see section 4.8). The risk appears to be greatest during the first 5 months of therapy, especially in patients with additional thrombotic risk factors (e.g. smoking, hypertension, hyperlipidaemia and history of thrombosis). These patients should be closely monitored and actions to minimize all modifiable risk factors should be undertaken. Thromboprophylaxis and dosing/anticoagulation therapy recommendations are provided in section 4.2.

Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. If a patient experiences any thromboembolic events, discontinue the treatment immediately and initiate the standard anticoagulation therapy. 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 throughout the course of treatment.

Neutropenia and thrombocytopenia

Increased rate of haematological toxicities, particularly, neutropenia and thrombocytopenia, was observed in newly diagnosed elderly multiple myeloma in patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone. Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in patients receiving combination drug regimens described (section 4.8).

 

 

Contraception

 

Ovulation inhibitory progesterone-only pills (i.e., desogestrel). Because of the increased risk of venous thromboembolism in patients with multiple myeloma, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception, she should switch to one of the effective methods listed above. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception.

 

 

Excipients with known effects

 

 

4.5     Interaction with other medicinal products and other forms of interaction

In 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.

 

 

 

 

4.6     Fertility, pregnancy and lactation

 

Breast‑feeding

Mothers receiving Alkeran should not breastfeed (see section 4.3).

 

 

4.8     Undesirable effects

1.       Increased rate of haematological toxicities, particularly, neutropenia and thrombocytopenia, was observed in newly diagnosed elderly multiple myeloma in patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone (see sections 4.4)

2.       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.

3.       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 high‑dose melphalan and the literature should be consulted for details.

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

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

6.       The clinically important adverse reactions associated with the use of melphalan in combination with thalidomide and prednisone or dexamethasone and to a lesser extend melphalan with lenalidomide and prednisone include: deep vein thrombosis and pulmonary embolism (see sections 4.2 and 4.4).

 

 

 

5.3     Preclinical safety data

Fertility Studies

In mice, melphalan administered intraperitoneally at a dose of 7.5 mg/kg, showed reproductive effects attributable to cytotoxicity in specific male germ cell stages and induced dominant lethal mutations and heritable translocations in post-meiotic germ cells, particularly in mid to late stage spermatids.

 

A study was performed to measure the total reproductive capacity of melphalan in female mice. Females received a single intraperitoneal dose of 7.5 mg/kg melphalan and were then housed with an untreated male for most of their reproductive life span (a minimum of 347 days post-treatment). A pronounced reduction in litter size occurred within the first post-treatment interval, followed by an almost complete recovery. Thereafter, a gradual decline in litter size occurred. This was simultaneous with a reduction in the proportion of productive females, a finding associated with an induced reduction in the number of small follicles (see section 4.6).

 

10.     DATE OF REVISION OF THE TEXT

 

May 2017  Dec 2015

 

Updated on 16 May 2017 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 3 - how to take/use
  • Change to section 4 - possible side effects
  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 28 January 2016 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may not be renewed (A)

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6.5     Nature and Contents of Container

Clear, type I glass vial with either a chlorobutyl rubber stopper or a grey fluoro-resin D film, B2 coated stopper and aluminium collar with a plastic flip‑top cover. Pack Size: 10 ml per vial.”

Updated on 9 December 2015 SmPC

Reasons for updating

  • Correction of spelling/typing errors
  • Change to section 10 - Date of revision of the text
  • Change to section 8 - MA number

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HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: medsafety@hpra.ie



8. MARKETING AUTHORISATION NUMBER

 

PA 1691/004/001

10. DATE OF REVISION OF THE TEXT

 

December June 2015


Updated on 4 December 2015 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

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

 

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

 

Excipients: When reconstituted each vial contains 2 mmol (46 mg) of Sodium, 0.52 ml (0.4 mg) of Ethanol and 6.0 ml of Propylene Glycol.


 

4.2     Posology and Method of Administration

 

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 section 4.4).

 

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

 

Preparation of Alkeran Injection Solution (see section 6.6).

Posology

 

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 section 4.4). Special Warnings and Precautions for Use).

 

 

 

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

 

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%. 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 section 4.4).

 

Paediatric population

 

Alkeran, within the conventional dosage range, is only rarely indicated in the paediatric population and dosage guidelines cannot be stated. High dose Alkeran, in association with haematopoietic stem cell rescue, has been used in childhood neuroblastoma and dosage guidelines based on body surface area are used in this situation.

 

Use in the elderly Older people

 

Although Alkeran is frequently used at conventional dosage in the older people, there is no specific information available relating to its administration to this patient sub‑group.

 

 

 

Method of administration

 

Injection / infusion

 

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

 

After reconstitution the appearance of the product should be a clear solution, see section 6.6.

 

 

4.3     Contraindications

 

Alkeran should not be given to patients who have suffered a previous hypersensitivity reaction to melphalan. Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4     Special Warnings and Precautions for Use

 

Monitoring

 

Mutagenicity

 

Renal Impairment

 

Carcinogenicity

 

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS)

 

Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic in man, especially in older patients after long combination therapy and radiotherapy.

 

 

 

 

Before the start of the treatment, the leukaemogenic risk (AML and MDS) must be balanced against the potential therapeutic benefit when considering the use of melphalan and especially if the use of melphalan in combination with thalidomide or lenalidomide and prednisone is considered as it has been shown that these combinations may increase the leukaemogenic risk. [CK1] Before and during treatment doctors must therefore examine the patient at all times by usual measurements to ensure the early detection of cancer and initiate treatment if necessary.

 

This medicinal product contains 2mmol (46 mg)[CK2]  sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

 

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.

 

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

 

 

 

 4.5     Interaction with Other Medicinal Products and Other Forms of Interaction

 

 

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

 (seesection 4.4).

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

 the paediatric population due to haemorrhagic enterocolitis.

4.6     Pregnancy and Lactation

 

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

 

Alkeran should be not be used during pregnancy and particularly during the first trimester, unless considered absolutely essential by the physician. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.

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.[CK1] 

 

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

Breast‑feeding

 

 

Mothers receiving Alkeran should not breast‑feed.

 

 

 

 

 

Fertility

 

Melphalan 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 melphalan can have an adverse effect on spermatogenesis. Therefore, it is possible that melphalan may cause temporary or permanent sterility in male patients.

 

It is recommended that men who are receiving treatment with melphalan not father a child during treatment and up to 6 months afterwards and that they have a consultation on sperm preservation before treatment due to the possibility of irreversible infertility as a result of melphalan treatment

4.7     Effects on Ability to Drive and Use Machines

 

Effects on the ability to drive and operate machinery in patients taking this medicine have not been studied..

 

4.8     Undesirable Effects

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 ³1/10, common ³1/100, <1/10, uncommon ³1/1000 and <1/100, rare ³1/10,000 and <1/1000, very rare <1/10,000. not 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.

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

Hepatobiliary Disorders

Rare: hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice.

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).

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.

 

Body System

Side Effects

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Not known

secondary acute myeloid leukaemia and myelodysplastic syndrome (see section 4.4).

Blood and Lymphatic System Disorders

Very common

bone marrow depression leading to leucopenia, thrombocytopenia and anaemia.

Rare

haemolytic anaemia.

Immune System Disorders

Rare

allergic reactions1 (see Skin and Subcutaneous Tissue Disorders).

Respiratory, Thoracic and Mediastinal Disorders

Rare

interstitial pneumonitis and pulmonary fibrosis (including fatal reports).

Gastrointestinal Disorders

Very common

nausea2, vomiting2 and diarrhoea; stomatitis at high dose.

Rare

stomatitis at conventional dose.

Hepatobiliary Disorders

Rare

hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice.

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).

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.

Reproductive system and breast disorders

Not known

azoospermia, amenorrhoea.

1. Allergic reactions to melphalan such as urticaria, oedema, skin rashes and anaphylactic shock have been reported uncommonly following initial or subsequent dosing, particularly after intravenous administration. Cardiac arrest has also been reported rarely in association with such events.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

5.1     Pharmacodynamic Properties

 

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

 

Mechanism of Action


 

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 the paediatric population.

 

Biotransformation

Special Patient Populations

 

Renal impairment

 

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

 

Older people

 

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

 

5.3     Preclinical Safety Data

 

Mutagenicity

Melphalan is mutagenic in animals.

 

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 Alkeran could cause congenital defects in the offspring of patients treated with the drug (see section 4.6).[CK1] 

 

 

 

 

 

 

 

 

6.6       Special precautions for disposal and other handling

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.

 

If the solvent is used at cold temperature, the freeze-dried powder may not reconstitute properly and undissolved particles may be observed. 

 

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 at least 50 seconds) until a clear colourless solution without visible particles, is obtained. Each vial must be reconstituted individually in this manner. Slow solvent addition and delaying the shaking may lead to the formation of insoluble particles. It should also be noted that the shaking process creates a considerable amount of very small air bubbles. These bubbles may persist and may take a further 2 to 3 minutes to clear, as the resulting solution is quite viscous.

 

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 remaining after one hour[CK1]  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 hour[CK2] .

 

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.

 



 

 

 

 

 

10. DATE OF REVISION OF THE TEXT

June 2015

 

 

 

 

 

 

 

 

 

Updated on 3 December 2015 PIL

Reasons for updating

  • Change to side-effects
  • Change to information about pregnancy or lactation
  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 10 April 2014 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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Text in red = new text
Text strikethrough = deleted text

 

7 MARKETING AUTHORISATION HOLDER

12/13 Exchange Place

I.F.S.C Dublin 1

3016 Lake Drive,

Citywest Business Campus

Dublin 24
This leaflet was last revised in: August April 20143

10 DATE OF REVISION OF THE TEXT

August April 20143

Updated on 8 April 2014 PIL

Reasons for updating

  • Change to date of revision
  • Change to MA holder contact details

Updated on 10 January 2013 SmPC

Reasons for updating

  • Improved electronic presentation

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Improved presentation

Updated on 4 May 2011 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text
  • SPC retired pending re-submission

Legal category: Product subject to medical prescription which may not be renewed (A)

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Product ownership transfered from GSK to Aspen
New PL numbers and revision of text

Updated on 3 May 2011 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 6 December 2010 PIL

Reasons for updating

  • Change of licence holder

Updated on 20 April 2010 SmPC

Reasons for updating

  • Change to section 6.4 - Special precautions for storage

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change to Secrtion 6.4:  sentence 'Store in originla packaging' has been changed to the following 'Keep the vial in the outer carton, in order to protect from light'.

Updated on 16 April 2010 PIL

Reasons for updating

  • Change due to harmonisation of patient information leaflet

Updated on 30 January 2009 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 6.1 - List of excipients
  • Change to section 6.2 - Incompatibilities

Legal category: Product subject to medical prescription which may not be renewed (A)

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New text is highlighted in red:

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

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

 

3.         PHARMACEUTICAL FORM

 

The pH of the reconstituted solution is pH 6.5.

 

6.1       List of Excipients

 

Freeze-dried Powder:

Povidone

Hydrochloric acid, (for pH-adjustment)

 

Solvent:

Propylene glycol

Sodium citrate

Ethanol, (96% per cent)

Water for Injections

 

6.3       Shelf-Life

 

Unopened: 3 years

Once reconstituted the product should be used immediately. Any unused portion should be discarded.

Updated on 10 December 2008 PIL

Reasons for updating

  • Change to improve clarity and readability

Updated on 29 October 2008 SmPC

Reasons for updating

  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 2 April 2007 SmPC

Reasons for updating

  • Improved electronic presentation

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 2 April 2007 PIL

Reasons for updating

  • Change to side-effects

Updated on 4 August 2005 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 25 May 2005 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 18 May 2005 PIL

Reasons for updating

  • New PIL for medicines.ie

Updated on 5 August 2004 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 1 July 2003 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may not be renewed (A)