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.

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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

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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

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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.”

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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

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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.

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.

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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

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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.