Alkeran 2 mg Film-coated Tablets

Inj product information was included in the document, now correcting to tablet product information.

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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.

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.

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

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

5.         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

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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

6.4     Special precautions for storage

Store in a refrigerator ion 2°C to 8°C.

8.       MARKETING AUTHORISATION NUMBER

PA 1691/004/002

10.     DATE OF REVISION OF THE TEXT

December  June 2015

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3.       PHARMACEUTICAL FORM

Film‑coated tablet

White to off white, film-coated, round,  White, film‑coated round tablet  biconvex tabletsengraved 'GXEH3' on one side and an 'A' on the other.

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).

 
Posology

Polycythaemia rubra vera

For remission induction doses of 6 to l0 mg daily for 5 to 7 days have been used, after which 2 to 4 mg daily were given until satisfactory disease control was achieved. A dose of 2 to 6 mg once per week has been used for maintenance therapy. In view of the possibility of severe myelosuppression if Alkeran is given on a continuous basis, it is essential that frequent blood counts are taken throughout therapy, with dosage adjustment or breaks in treatment, as appropriate, to maintain careful haematological control.

Paediatric population

Alkeran is only rarely indicated in the paediatric population and absolute dosage guidelines cannot be provided.

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. However, caution should be taken where there is renal impairment.

Renal impairment

Alkeran clearance, though variable, may be decreased in renal impairment (see section 4.4).

Currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering Alkeran Tablets to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established.

Method of administration

Oral administration in adults: The absorption of Alkeran after oral administration is variable. Dosage may need to be cautiously increased until myelosuppression is seen, in order to ensure that potentially therapeutic levels have been reached.

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

Renal impairment

Alkeran clearance may be reduced in patients with renal impairment, who may also have uraemic bone marrow suppression. Dose reduction may therefore be necessary (see section 4.2), and these patients should be closely observed.

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

Mutagenicity

Chromosome aberrations have been observed in patients being treated with the drug.

Carcinogenicity

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

The evidence is growing that melphalan in common with other alkylating agents may be leukaemogenic in man.

Alkeran, in common with other alkylating agents has been reported to be leukaemogenic, especially in older patients after long combination therapy and radiotherapy. There have been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloidosis, 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.

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.

4.5     Interaction with other medicinal products and other forms of interaction

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see section 4.4).

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

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.

Breast‑feeding

Mothers receiving Alkeran should not breastfeed.

Fertility

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

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.

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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

10. DATE OF REVISION OF THE TEXT

February April 20143

1.0       NAME OF THE MEDICINAL PRODUCT

Alkeran Tablets 2mg Film-coated Tablets

2.0       QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2mg melphalan.

For a full list of excipients, see section 6.1

6.5       Nature and Contents of Container

Alkeran Tablets are supplied in amber glass bottles of 25 or 50 tablets with a child resistant closure.

Not all pack sizes may be marketed

6.6       Instructions for Use and Handling

The handling of Alkeran formulations should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations and or regulations (for example, Royal Pharmaceutical Society of Great Britain Working Party on the Handling of Cytotoxic Drugs)

10.              DATE OF (PARTIAL) REVISION OF THE TEXT