ALKERAN 50 mg /10 Ml Proszek I Rozpuszczalnik Do Roztworu Do Wstrzykiwań

Treść ulotki

1. ALKERAN 2 mg film-coated tablets
   1. What is ALKERAN and what is it used for
   2. What you need to know before taking ALKERAN
   3. How to take ALKERAN
   4. Possible side effects
   5. How to store ALKERAN
   6. Contents of the pack and other information
2. ALKERAN 50 mg/10 ml powder and solvent for injectable solution
   1. What is ALKERAN and what is it used for
   2. What you need to know before you take ALKERAN
   3. How ALKERAN is administered
   4. Possible side effects
   5. How to store ALKERAN
   6. Content of the pack and other information

ALKERAN 2 mg film-coated tablets

melfalan
Read this leaflet carefully before you start taking this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others, even if their symptoms are the same as yours, as it could be harmful.
• If you get any side effects, even those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

• 1. What ALKERAN is and what it is used for
• 2. What you need to know before you take ALKERAN
• 3. How to take ALKERAN
• 4. Possible side effects
• 5. How to store ALKERAN
• 6. Contents of the pack and other information

1. What is ALKERAN and what is it used for

ALKERAN contains the active substance melfalan which belongs to the category of antineoplastic drugs, used in the treatment of various forms of cancer. Melfalan is an alkylating agent belonging to the nitrogen mustard analogues.
ALKERAN 2 mg film-coated tablets is indicated in the treatment of:

• multiple myeloma (malignant blood tumor, affecting plasma cells, from which antibodies are formed);
• advanced ovarian adenocarcinoma (malignant tumor of the ovary);
• advanced breast carcinoma (malignant tumor of the breast). ALKERAN, alone or in combination with other drugs, has a significant therapeutic effect in a proportion of patients with advanced breast carcinoma;
• true polycythemia (abnormal increase in red blood cells, sometimes also white blood cells and platelets). ALKERAN is effective in the treatment of a proportion of patients with true polycythemia.

2. What you need to know before taking ALKERAN

Do not take ALKERAN

• If you are allergic to melfalan or any of the other ingredients of this medicine (listed in section 6).
• If you are pregnant or breastfeeding (see also the section “Pregnancy, breastfeeding and fertility”).

Warnings and precautions
Talk to your doctor or nurse before taking Alkeran if:

• you have recently undergone radiotherapy or chemotherapy;
• you have kidney problems;
• you are about to have or have recently had a vaccination, as some live attenuated vaccines (such as for polio, measles, mumps and rubella) can cause infection if received during treatment with melfalan;
• you are taking a combined oral contraceptive (the pill), as there is an increased risk of venous thromboembolism (a blood clot that forms in a vein and migrates to another location) in patients with multiple myeloma;
• you are planning a pregnancy. This is due to the risk of genetic toxicity (damage to genetic information) and infertility (see “Pregnancy, breastfeeding and fertility”).

Alkeran may increase the risk of developing other types of cancer (e.g. secondary solid tumors) in a small number of patients, especially when administered in combination with lenalidomide, thalidomide and prednisone. Your doctor will carefully weigh the benefits and risks of treatment with Alkeran.

Thromboembolic events
You should receive prophylaxis for venous thromboembolism, especially if you have additional thrombotic risk factors. Your doctor will decide what measures to take after a careful assessment of your pre-existing risk factors.
If you experience a thromboembolic event, inform your doctor immediately as treatment must be stopped and standard anticoagulant therapy should be started. Your doctor will decide whether to restart treatment with melfalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone once the thromboembolic events have been managed. You should continue anticoagulant therapy during the treatment cycle with melfalan.
Monitoring
Because ALKERAN is a potent myelosuppressive medicine, meaning it blocks the function of the bone marrow, it is essential to carefully monitor blood cells to avoid the possibility of excessive myelosuppression (reduced production of blood cells by the bone marrow) and the risk of irreversible bone marrow aplasia (total and permanent blockage of bone marrow function).
Blood counts (number of blood cells) may continue to decrease even after treatment has been stopped, therefore at the first sign of an abnormal and severe decrease in the number of leukocytes (white blood cells) or platelets (essential for blood clotting), therapy should be temporarily interrupted.
ALKERAN should be used with caution if you have recently undergone radiotherapy or chemotherapy as you are at increased risk of bone marrow toxicity.

Renal insufficiency
The clearance of ALKERAN (the elimination of the medicine through the kidneys) may be reduced if you suffer from renal insufficiency. If you belong to this category of patients, you may also have uremic bone marrow depression (bone marrow blockage due to renal failure). Therefore, a dose reduction is necessary (see the section “How to take ALKERAN”) and careful observation of your health status is required.
Significant transient increases in azotemia have been observed in the early stages of melfalan therapy in patients with myeloma and kidney damage.

Mutagenesis
Chromosome aberrations (alteration of the structure or number of chromosomes) have been observed in patients treated with the medicine.

Carcinogenesis
Melfalan, like other alkylating agents, has been reported to be leukemogenic (causes tumors of the white blood cells). Cases of acute leukemia have been reported following treatment with melfalan for diseases such as amyloidosis (disease due to accumulation of protein material outside cells in various organs), malignant melanoma (malignant skin tumor), multiple myeloma (tumor of plasma cells, which produce antibodies), macroglobulinemia (a type of myeloma that produces IgM antibodies), cold agglutinin disease (antibodies against the same organism, which are activated by the cold and destroy red blood cells) and ovarian cancer.
A comparison between patients with ovarian neoplasms, treated with or without alkylating agents, has shown that the use of these agents, including melfalan, significantly increases the incidence of acute leukemia. When considering the use of melfalan, the leukemogenic risk must be balanced with the potential therapeutic benefits.
Therefore, checks are necessary before and during treatment to ensure early diagnosis of cancer and, if necessary, start the related treatment.
Alkeran may increase the risk of developing other types of cancer (e.g. secondary solid tumors) in a small number of patients, especially when used in association with lenalidomide, thalidomide and prednisone. When Alkeran is prescribed to you, the doctor must carefully evaluate the benefits and risks.

Teratogenesis
The potential teratogenic effect (causing malformations) of ALKERAN has not been studied. Due to its mutagenic properties (ability to bring about alterations and changes in the genetic code) and structural similarities with known teratogenic compounds, it is possible that melfalan may cause congenital defects (already present at birth) in the offspring of patients treated with the medicine.

Children and adolescents
ALKERAN, within the conventional dosage, is only rarely indicated in children and defined guidelines for dosage cannot be provided.

Other medicines and ALKERAN
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
In particular:

• Vaccines. Vaccinations with vaccines derived from live organisms are not recommended in immunocompromised individuals (see the section “Warnings and precautions”).
• Nalidixic acid, used to treat bacterial infections of the urinary tract. The association of nalidixic acid with high doses of melfalan intravenously has caused death from hemorrhagic enterocolitis (inflammation of the intestine with diarrhea and blood) in children.
• Cyclosporines, immunosuppressant medicines. Alterations in renal function have been described in patients undergoing bone marrow transplantation, who had received conditioning treatment with high doses of melfalan intravenously and who were subsequently treated with cyclosporine to prevent graft rejection.

In children, the administration of ALKERAN within 24 hours of the last oral administration of busulfan (antitumor medicine), may determine toxicity.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you are pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
Treatment with Alkeran is contraindicated during pregnancy as it can cause permanent damage to the fetus. Do not take Alkeran if you are planning a pregnancy. This applies to both men and women. Adequate and effective contraceptive measures must be adopted to avoid pregnancies when one of the partners is taking these tablets.
Women of childbearing potential must use adequate and effective contraceptive measures during treatment and for up to six months after treatment.
Men must use adequate and effective contraceptive measures during treatment and for up to three months after treatment.
If you are already pregnant, it is important to consult your doctor before taking Alkeran. The doctor will assess the risks and benefits of treatment with Alkeran for you and your baby.
Breastfeeding
Women treated with Alkeran must not breastfeed. Consult your doctor for further information.
Fertility
Alkeran may affect the ovaries and sperm, causing infertility (inability to have a child).
In women, cessation of menstruation (amenorrhea) may occur and in men, a total absence of viable spermatozoa (azoospermia) may be observed following treatment with Alkeran.
Therefore, men are advised to seek advice on sperm preservation before treatment.

Driving and operating machinery
No data are available.

3. How to take ALKERAN

ALKERAN is a cytotoxic medicine belonging to the class of alkylating agents. It must be
prescribed only by doctors with experience in the treatment of malignant diseases with such agents.
Since ALKERAN is a myelosuppressive agent (blocks bone marrow activity), it is essential to
perform frequent hemocytometric checks (checking red blood cells, white blood cells and
platelets) during therapy and, if necessary, the dose must be modified (see the paragraph
“Warnings and precautions”).

Adults
After oral administration, the absorption of ALKERAN is variable. In order to ensure the
achievement of potentially therapeutic levels, a cautious increase in the
dose may be necessary until myelosuppression is observed.
Multiple myeloma
The recommended dose is 0.15 mg/kg of body weight per day orally in divided doses, for
4 days, with intervals of 6 weeks between cycles.
Numerous therapeutic regimens have been used. To learn more details, it is necessary to consult the
scientific literature.
The administration of ALKERAN and prednisone may be more effective than ALKERAN alone.
The combination is usually administered at intervals, although the superiority of this mode of
treatment over continuous therapy has not been demonstrated. In patients who respond to
treatment, prolonging therapy beyond one year does not appear to lead to an improvement
in outcomes.
Advanced ovarian adenocarcinoma
The recommended dose is 0.2 mg/kg of body weight per day administered orally for 5
days. Treatment is repeated at intervals of 4-8 weeks, or as soon as the bone marrow has
recovered its normal functionality.
Advanced breast cancer
The recommended dose is 0.15 mg/kg of body weight or 6 mg/m of body surface area per day,
for 5 days, with intervals of 6 weeks between cycles. In case of bone marrow toxicity, the dosage
may be reduced.
True polycythemia rubra vera
The recommended dose to induce remission is 6-10 mg per day for 5-7 days and subsequently, of
2-4 mg per day until satisfactory disease control is achieved. Maintenance therapy includes a dosage of 2-6 mg once a week. During maintenance therapy, careful hematological monitoring and dosage adjustment
based on the results of frequent hemocytometric tests are essential.

Use in children
ALKERAN, within the scope of conventional dosage, is only rarely indicated in children and
no definite guidelines can be provided for dosage.

Use in the elderly
Although ALKERAN is frequently used at conventional dosages in the elderly, no
specific information is available regarding administration in this patient group.
Experience with the use of ALKERAN in the elderly is limited.
If you belong to this category of patients, an adequate general and functional state of the organs must be ensured before administering ALKERAN.

Renal impairment
(See the paragraph “Warnings and precautions”)
The clearance of ALKERAN, although variable, is reduced in case of renal impairment.
The pharmacokinetic data currently available do not indicate an absolute need to reduce the
dosage when the medicine is administered orally. However, it is prudent to initially
use a reduced dose.

How to use and handling

Safe handling of ALKERAN Tablets
The use of melfalan preparations must follow the recommendations relating to
cytotoxic medicines in accordance with local regulations.
Provided that the outer coating of the tablet is intact, there are no risks in handling
ALKERAN.
ALKERAN tablets must not be divided.

Disposal
Remaining ALKERAN tablets must be destroyed in accordance with local regulations
for the destruction of cytotoxic medicines.

If you take more ALKERAN than you should
The most frequent signs of acute overdose following oral administration are
represented by gastrointestinal disorders, such as nausea, vomiting, diarrhea.
The main toxic effect is bone marrow depression (blockage of bone marrow function)
which can lead to leukopenia (reduction of white blood cells), thrombocytopenia (reduction of
platelets) and anemia (reduction of red blood cells).
Treatment
If necessary, general supportive measures must be instituted, associated with appropriate blood and platelet transfusions, and hospitalization should be considered, prophylaxis of
infections with anti-infective agents, the use of growth hematological factors, which stimulate the bone
marrow to produce blood cells.
No specific antidotes are known. The blood count must be carefully monitored for
at least 4 weeks after the overdose, until there is evidence of recovery.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Side effects may vary in their incidence depending on the indication and the dose
received, and also if administered in combination with other therapeutic agents.
Other side effects reported with ALKERAN are listed below in order of
frequency:

Very common (may affect more than 1 in 10 people)

• Myelodepression (reduction of bone marrow activity), which manifests with leucopenia (reduction in the number of white blood cells), thrombocytopenia (reduction in the number of platelets) and anaemia (reduction in the number of red blood cells and the amount of haemoglobin, a protein contained in red blood cells that carries oxygen)
• Nausea, vomiting, diarrhoea; stomatitis (inflammation of the oral mucosa) at high doses
• Alopecia (hair and body hair loss) at high doses

Common (may affect up to 1 in 10 people)

• Alopecia at conventional doses
• Temporary significant increases in azotaemia (a blood test that indicates kidney function)

Rare (may affect up to 1 in 1,000 people)

• Haemolytic anaemia (a type of anaemia with destruction of red blood cells)
• Allergic reactions with skin rashes (maculopapular rash) and itching
• Lung diseases such as interstitial pneumonia and pulmonary fibrosis (including fatal cases)
• Stomatitis (inflammation of the oral mucosa) at conventional doses
• Liver disorders with changes in blood tests that assess liver function, hepatitis (inflammation of the liver) and jaundice (yellowing of the skin and eyes)

Not known (frequency cannot be estimated from available data)

• Secondary acute myeloid leukaemia and myelodysplastic syndrome (leukaemia of the white blood cells)
• Azoospermia (absence of spermatozoa)
• Amenorrhoea (absence of menstruation)
• Deep vein thrombosis (formation of a blood clot called a thrombus in a deep vein, predominantly in the legs) and pulmonary embolism (a blockage of the main pulmonary artery or its branches by a blood clot that breaks off and travels to the lung)
• Acute kidney injury - renal failure (a significant reduction in kidney function) that occurs rapidly.

Allergic reactions to melfalan such as urticaria (skin rash),
oedema (swelling due to fluid accumulation), skin rashes (sudden skin redness) and anaphylactic shock (severe allergic reaction with low blood pressure) have been reported rarely, following the
first administration or subsequent administrations, particularly after intravenous administration.
Cardiac arrest has also been reported in association with these events, rarely.
Up to 30% of patients treated with melfalan at conventional oral doses have experienced gastrointestinal effects such as nausea and vomiting.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the national reporting system at:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store ALKERAN

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the packaging after Exp.
The expiry date refers to the product in intact packaging, correctly
stored.
Store at a temperature between 2-8 °C.
Store in a dry place.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

• The active ingredient is melfalan. One film-coated tablet contains 2 mg of melfalan.
• The other ingredients are: Core: microcrystalline cellulose, crospovidone, anhydrous colloidal silicon dioxide, magnesium stearate. Coating: hypromellose, titanium dioxide, macrogol.

Description of the appearance of ALKERAN and contents of the pack
Film-coated tablets.
ALKERAN 2 mg Film-coated tablets, bottle of 25 tablets.

Marketing Authorisation Holder
Aspen Pharma Trading Limited
3016 Lake Drive
Citywest Business Campus
Dublin 24, Ireland
Tel: +39 0687 502 429

Manufacturer
Excella GmbH & Co. KG, Nürnberger Strasse 12, 90537 Feucht, Germany

ALKERAN 50 mg/10 ml powder and solvent for injectable solution

melfalan
Read this leaflet carefully before you are given this medicine because
it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others, even if their symptoms are the same as yours, as it could be harmful.
• If you get any side effects, even those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

• 1. What ALKERAN is and what it is used for
• 2. What you need to know before you are given ALKERAN
• 3. How ALKERAN is given
• 4. Possible side effects
• 5. How to store ALKERAN
• 6. Contents of the pack and other information

1. What is ALKERAN and what is it used for

Alkeran contains the active substance melfalan which belongs to the category of antineoplastic medicinal products, used in the treatment of various forms of cancer. Melfalan is an alkylating substance belonging to the nitrogen mustard analogues.
ALKERAN powder and solvent for injectable solution, administered by regional arterial infusion (through the artery of the diseased organ), is indicated in the treatment of:

• Malignant melanoma (malignant skin tumor) located on the extremities;
• Soft tissue sarcoma (malignant tumor of fatty tissues, muscles, blood vessels or lymphatic vessels, nerves, ligaments, connective tissues) located on the extremities;

ALKERAN, at the conventional dosage by intravenous route, can be used in the treatment of:

• Multiple myeloma (malignant tumor of the blood, affecting plasma cells, cells from which antibodies are formed). ALKERAN, alone or in combination with other cytotoxic medicinal products (anticancer drugs that destroy or damage cells), is as effective in the treatment of multiple myeloma as the formulation to be administered orally;
• Advanced ovarian carcinoma (ovarian cancer). ALKERAN, administered alone or in combination with other cytotoxic medicinal products, results in a direct response in approximately 50% of patients with advanced ovarian adenocarcinoma.

ALKERAN, at high dosage by intravenous route, can be used in the treatment of:

• Multiple myeloma. Complete remissions have been achieved in up to 50% of patients who were administered ALKERAN at high doses, with or without hematopoietic stem cell transplantation

hematopoietic (cells that can transform into blood cells), both as first-line treatment and to consolidate a response to conventional chemotherapy;

• Advanced neuroblastoma in childhood (malignant tumor that originates from cells of a part of the nervous system). High-dose ALKERAN with hematopoietic stem cell transplantation has been used, alone or in combination with radiotherapy and/or other cytotoxic medicinal products, to consolidate the response to conventional treatment. In a prospective randomized study, patients treated with ALKERAN, compared to those not treated, showed a significant increase in disease-free survival duration.

2. What you need to know before you take ALKERAN

Do not take ALKERAN

• If you are allergic to melfalan or any of the other ingredients of this medicine (listed in section 6).
• If you are pregnant or breastfeeding (see also section “Pregnancy, breastfeeding and fertility”).

Warnings and precautions
Before treatment with Alkeran, tell your doctor if any of the following conditions apply to you:

• If you have recently undergone radiotherapy or chemotherapy;
• If you have kidney problems;
• If you are about to receive or have recently received a vaccination, as some live attenuated vaccines (such as for polio, measles, mumps and rubella) can cause infection if received during treatment with melfalan;
• If you are taking a combined oral contraceptive (the pill), as there is an increased risk of venous thromboembolism (a blood clot that forms in a vein and migrates to another location) in patients with multiple myeloma;
• If you are planning a pregnancy. This is due to the risk of genetic toxicity (damage to genetic information) and infertility (see “Pregnancy, breastfeeding and fertility”).

Alkeran may increase the risk of developing other types of cancer (e.g. secondary solid tumors) in a small number of patients, particularly when administered in combination with lenalidomide, thalidomide and prednisone. Your doctor will carefully assess the benefits and risks of treatment with Alkeran.

Thromboembolic events
You should receive prophylaxis for venous thromboembolism, especially if you have additional thrombotic risk factors. Your doctor will decide which measures to take after a careful assessment of your pre-existing risk factors.
If you experience a thromboembolic event, tell your doctor immediately as treatment must be stopped and standard anticoagulant therapy should be started. Your doctor will decide whether to restart treatment with melfalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone once the thromboembolic events have been managed. You should continue anticoagulant therapy during the treatment cycle with melfalan.
Monitoring
Because ALKERAN is a potent myelosuppressive medicine, meaning it blocks the function of the bone marrow, it is essential that particular attention is paid to monitoring blood cell counts to avoid the possibility of excessive myelosuppression (reduced production of blood cells by the bone marrow) and the risk of irreversible bone marrow aplasia (total and permanent blockage of bone marrow function).
Blood cell counts can continue to decrease even after treatment has been stopped, therefore at the first sign of abnormal and severe decrease in the number of leukocytes or platelets, therapy should be temporarily interrupted.
ALKERAN should be used with caution if you have recently undergone radiotherapy or chemotherapy as you are exposed to a greater risk of bone marrow toxicity.
ALKERAN causes suppression of ovarian function in pre-menopausal women, leading to amenorrhea (absence of menstruation) in a significant number of patients.

Renal insufficiency
The clearance of ALKERAN (the elimination of the medicine through the kidneys) may be reduced if you suffer from renal insufficiency, and may also have uremic myelosuppression (bone marrow blockage due to renal insufficiency). Therefore, a dose reduction is necessary (see section “How to take ALKERAN”) and careful observation of your health status is required.
Temporary significant increases in blood urea have been observed in the early stages of melfalan therapy in patients with myeloma with kidney damage.
Mutagenesis
Chromosomal aberrations (alteration of the structure or number of chromosomes) have been observed in patients treated with this medicine.
Carcinogenesis
Melfalan, like other alkylating agents, has been reported to be leukemogenic (causes leukemia, cancers of the white blood cells). Cases of acute leukemia have been reported following treatment with melfalan for diseases such as amyloidosis (deposition of proteins between cells), malignant melanoma (malignant skin tumor), multiple myeloma (tumor of plasma cells, which produce antibodies), macroglobulinemia (a type of myeloma that produces IgM antibodies), cryo-agglutinin disease (antibodies against the same organism, which are activated by the cold and destroy red blood cells) and ovarian cancer.
A comparison between patients with ovarian neoplasms who had or had not received alkylating agents showed that the use of these agents, including melfalan, significantly increases the frequency of acute leukemia.
When considering the use of melfalan, the leukemogenic risk must be balanced with the potential therapeutic benefits.
Therefore, doctors must always examine the patient before and during treatment with the usual measurements to ensure early diagnosis of cancer and, if necessary, start the relevant treatment.
Alkeran may increase the risk of developing other types of cancer (e.g. secondary solid tumors) in a small number of patients, particularly when used in association with lenalidomide, thalidomide and prednisone. When Alkeran is prescribed to you, your doctor must carefully assess the benefits and risks.
Teratogenesis
The potential teratogenic effect (causing malformations) of ALKERAN has not been studied. Due to its mutagenic properties (altering the genetic code) and structural similarities with known teratogenic compounds (substances that cause malformations), it is possible that melfalan may cause congenital defects (already present at birth) in the offspring of patients treated with the medicine.

Children and adolescents
High doses of ALKERAN, in association with bone marrow transplantation, have been used in childhood neuroblastoma, using dosage guidelines based on body surface area (see section “How ALKERAN is administered - Advanced neuroblastoma in childhood”).
ALKERAN, within the conventional dosage, is only rarely indicated in children and defined guidelines for dosage cannot be provided.

Other medicines and ALKERAN
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
In particular:

• Vaccinations. Vaccinations with vaccines derived from live organisms are not recommended in immunocompromised individuals (see “Warnings and precautions”).
• Nalidixic acid, used to treat bacterial urinary tract infections. The association of nalidixic acid with high doses of melfalan intravenously has caused death from hemorrhagic enterocolitis (inflammation of the intestine with diarrhea and blood in the stool) in children.
• Cyclosporines, immunosuppressive medicines. Alterations in renal function have been described in patients undergoing bone marrow transplantation who had received high-dose intravenous melfalan conditioning treatment and who were subsequently treated with cyclosporine to prevent graft rejection.
• In children, the administration of ALKERAN before 24 hours from the last oral administration of busulfan (anticancer medicine), can determine toxicity.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
Treatment with Alkeran is contraindicated during pregnancy as it can cause permanent damage to the fetus. Do not take Alkeran if you are planning a pregnancy. This applies to both men and women. Adequate and effective contraceptive measures should be adopted to avoid pregnancies when one of the partners is administered this medicine.
Women of childbearing potential must use adequate and effective contraceptive measures during treatment and up to six months after treatment.
Men must use adequate and effective contraceptive measures during treatment and up to three months after treatment.
If a pregnancy has already occurred, it is important to consult your doctor before taking Alkeran. The doctor will assess the risks and benefits of treatment with Alkeran for you and your baby.
Breastfeeding
Women treated with ALKERAN must not breastfeed. Consult your doctor for further information.
Fertility
Alkeran can affect the ovaries and sperm, causing infertility (inability to have a child).
In women, absence of the menstrual cycle (amenorrhea) may occur and in men, a total absence of viable spermatozoa (azoospermia) may be observed following treatment with Alkeran.
Therefore, men are advised to seek advice on sperm preservation before treatment.

Driving and operating machinery
No data are available.
This medicine contains 2.32 mmol (53.4 mg) of sodium per vial.
To be taken into consideration in people who are following a low-sodium diet.
This medicine contains 5% ethanol (alcohol) equivalent to 10 ml of beer or 4.2 ml of wine. It may be harmful to alcoholics. To be taken into consideration in pregnant or breastfeeding women, children and high-risk groups, such as people suffering from liver disease or epilepsy.
This medicine contains propylene glycol. It may cause symptoms similar to those caused by alcohol.

3. How ALKERAN is administered

ALKERAN is a cytotoxic medicine that belongs to the general class of alkylating agents. It must
be prescribed only by doctors with experience in the treatment of malignant diseases with such
medicines.
Since ALKERAN causes myelosuppression (bone marrow block), it is essential to perform
frequent hemocytometric tests (red blood cell, white blood cell and
platelet count) during therapy and, if necessary, the dose must be delayed or modified (see the
paragraph “Warnings and precautions”).

Multiple myeloma
ALKERAN has been used intermittently alone, or in combination with other cytotoxic medicines,
at doses ranging from 8 to 30 mg/m of body surface area, administered at intervals
between 2 and 6 weeks.
In addition, the administration of prednisone has been included in some therapeutic regimens. For more
precise details on treatment protocols, consult the published literature.
The recommended dose for intravenous administration, when used alone, provides 0.4 mg/kg of body
weight (16 mg/m of body surface area) repeated at appropriate intervals (for example once
every 4 weeks), provided that during this period there has been recovery of the peripheral blood count.
High-dose regimens generally employ single i.v. doses ranging from 100 to 200 mg/m of
body surface area (approximately 2.5-5.0 mg/kg of body weight), but hematopoietic stem cell transplantation becomes essential following doses greater than 140 mg/m of body surface area.
In case of renal insufficiency, the dose must be reduced by 50% (see paragraph “Renal insufficiency”).
In anticipation of severe myelosuppression (severe bone marrow block) induced by high doses of
ALKERAN, treatment must be carried out only in specialist centers with suitable equipment and
administered only by experienced clinicians (see the paragraph “Warnings and precautions”).

Advanced ovarian adenocarcinoma
If administered intravenously alone, a dose of 1 mg/kg of body
weight (approximately 40 mg/m of body surface area) administered at intervals of 4 weeks has often been used.
If administered in combination with other cytotoxic medicines, doses ranging from
0.3 to 0.4 mg/kg of body weight (12-16 mg/m of body surface area) at intervals of 4-6
weeks have been used.

Malignant melanoma
Regional perfusion with ALKERAN associated with hyperthermia (increased body
temperature) has been used as an adjunct (in combination) to surgery for early-stage malignant melanomas
and as palliative treatment (i.e. reduces the symptoms of the disease but does not
remove the cause) in advanced but localized forms. For details on the perfusion technique and the
dosage to be used, consult the scientific literature.

Soft tissue sarcoma
Regional perfusion with ALKERAN has been associated with hyperthermia (increased body
temperature) in the treatment of all stages of soft tissue sarcoma, localized, generally in
association with surgery.
ALKERAN has also been administered with actinomycin D; consult the scientific literature for
dosage schedules.

Advanced neuroblastoma in childhood
High doses of ALKERAN, ranging from 100 to 240 mg/m of body surface area (sometimes divided
evenly over 3 consecutive days), in association with hematopoietic stem cell transplantation, have been used alone or in combination with radiotherapy and/or other cytotoxic
medicines.

Use in children
High doses of ALKERAN, in association with bone marrow transplantation, have been used in
childhood neuroblastoma, using dosage guidelines based on body surface area
(see paragraph “Advanced neuroblastoma in childhood”).
ALKERAN, within the conventional dosage, is only rarely indicated in children and no
defined guidelines can be provided for dosage.

Use in the elderly
Although ALKERAN is frequently used at conventional dosages in the elderly, there are
no specific information available regarding administration in this group of patients.
Experience in the use of ALKERAN in the elderly is limited. If you belong to this category of
patients, before the administration of ALKERAN, an adequate
general and functional state of the organs must be ensured.
The pharmacokinetics of melphalan via intravenous route has not shown any correlation between age
and the clearance (renal elimination rate) of melphalan or the terminal elimination half-life
(time required to reduce the concentration of the medicine in the blood by 50%) of melphalan.
The limited data available do not support specific recommendations for dosage adjustments
for elderly patients receiving melphalan intravenously and suggest that
the current practice of adjusting the dosage based on the general condition of the elderly patient and the degree of myelosuppression that occurs during therapy should be continued.

Renal insufficiency
(See also the paragraph “Warnings and precautions”).
The clearance of ALKERAN, although variable, may be reduced in case of renal insufficiency.
If ALKERAN is used at conventional doses via intravenous route (8-40 mg/m
of body surface area), it is recommended that the initial dose be reduced by 50% in patients with
moderate-severe renal insufficiency and the subsequent dosage be determined in relation to
the degree of myelosuppression (bone marrow block).
In the case of high doses of ALKERAN via intravenous route (100-240 mg/m of body surface area), the
need for dose reduction depends on the degree of renal insufficiency, whether or not
hematopoietic stem cells are reinfused (transplantation of cells that can transform into blood cells), and the therapeutic need.
Indicatively, in the case of patients with moderate-severe renal insufficiency [(51-Cr)-EDTA
creatinine clearance of 30-50 ml/min] a dose reduction of 50% is usual.
Adequate hydration (administration of fluids) and forced diuresis (increased urine flow) are also necessary.
ALKERAN at high doses is not recommended in patients with more severe renal insufficiency (EDTA
creatinine clearance less than 30 ml/min).

If you take more ALKERAN than you should
The immediate effects of acute overdose via intravenous route are nausea and vomiting. Gastro-intestinal mucosal damage may also
follow, and diarrhea, sometimes hemorrhagic, has also been reported following overdose.
The main toxic effect is bone marrow depression
(reduction of bone marrow activity), which can lead to leukopenia (reduction of white blood cells), thrombocytopenia (reduction of platelets) and anemia (reduction of red blood cells and
hemoglobin).
Treatment
If necessary, general supportive measures should be instituted, associated with appropriate
blood and platelet transfusions, and hospitalization should be considered, the
prophylaxis (prevention) of infections with anti-infective agents, the use of growth factors
hematological (stimulators of the bone marrow to produce blood cells).
There are no specific antidotes. The blood count must be carefully monitored for at least
4 weeks after the overdose until there is evidence of recovery.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
Side effects may vary in their incidence depending on the indication and the dose
received, and also if administered in combination with other therapeutic agents.
Other side effects reported with ALKERAN are classified below in order of frequency.

Very common (may affect more than 1 in 10 people)

• Myelodepression (decreased bone marrow activity), which manifests as leukopenia (decreased number of white blood cells), thrombocytopenia (decreased number of platelets) and anemia (decreased number of red blood cells and amount of hemoglobin, a protein contained in red blood cells that carries oxygen)
• Nausea, vomiting, diarrhea; stomatitis (inflammation of the oral mucosa) at high doses
• Alopecia (hair and body hair loss) at high doses
• Subjective and transient sensation of heat and/or tingling
• Following isolated limb perfusion: muscle atrophy (reduction in muscle volume), muscular fibrosis (replacement of muscle tissue with scar tissue)
• Myalgia (muscle pain), increased blood creatine phosphokinase (blood test that increases when there is muscle or heart damage)

Common (may affect up to 1 in 10 people)

• Alopecia (hair and body hair loss) at conventional doses
• Temporary significant increases in azotemia (a blood test that indicates kidney function).
• Following isolated limb perfusion: compartment syndrome (a set of symptoms affecting the affected limb)

Rare (may affect up to 1 in 1,000 people)

• Hemolytic anemia (a type of anemia with destruction of red blood cells)
• Allergic reactions with skin rashes (maculopapular rash) and itching
• Lung diseases such as interstitial pneumonia and pulmonary fibrosis, including fatal cases
• Stomatitis (inflammation of the oral mucosa), at conventional doses
• Liver disorders with alteration of blood tests evaluating liver function, hepatitis (inflammation of the liver) and jaundice (yellowing of the skin and mucous membranes); veno-occlusive disease (closure of the veins) following treatment with high doses

Not known (frequency cannot be estimated from available data)

• Muscle necrosis (death of muscle fibers), rhabdomyolysis (breakdown of muscle fibers)
• Secondary acute myeloid leukemia and myelodysplastic syndrome (white blood cell cancers)
• Azoospermia (absence of spermatozoa)
• Amenorrhea (absence of menstruation)
• Deep vein thrombosis (formation of a blood clot called a thrombus in a deep vein, predominantly in the legs) and pulmonary embolism (a blockage of the main pulmonary artery or its branches by a blood clot that breaks off and travels to the lung)
• Acute kidney injury - renal failure (significant reduction in kidney function) that occurs rapidly.

Allergic reactions to melphalan such as urticaria (skin rash),
edema (swelling due to fluid accumulation), skin rash (sudden skin redness) and anaphylactic shock (severe allergic reaction with low blood pressure) have been reported rarely, following the
first administration or subsequent ones, particularly after intravenous administration.
Cardiac arrest has also been reported in association with these events, rarely.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, please
tell your doctor or pharmacist. You can also report side effects directly through
the national reporting system at www.agenziafarmaco.gov.it/content/come-
segnalare-una-sospetta-reazione-avversa.
By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store ALKERAN

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the packaging after Scad.
The expiry date refers to the product in intact packaging, correctly
stored.
Vial before opening: do not store at a temperature above 30°C.
Protect the medicine from light.
Reconstituted solution for injection: store at room temperature of approximately 25°C.
Do not refrigerate.
Reconstituted and further diluted solution for infusion: store at room temperature of
approximately 25°C.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Content of the pack and other information

• The active ingredient is melphalan. One vial of powder contains 50 mg of melphalan hydrochloride;
• The other ingredients are: hydrochloric acid, povidone. One vial of solvent-diluent contains: propylene glycol, sodium citrate, ethanol, water for injections.

Description of the appearance of ALKERAN and content of the pack
Powder and solvent for injectable solution.
ALKERAN 50 mg/10 ml Powder and solvent for injectable solution - 1 vial of powder + 1
vial of solvent of 10 ml.

Marketing Authorisation Holder
Aspen Pharma Trading Limited
3016 Lake Drive,
Citywest Business Campus,
Dublin 24,
Ireland
Tel: +39 0687 502 429

Manufacturers
GlaxoSmithKline Manufacturing S.p.A. - Strada Provinciale Asolana n. 90 - S. Polo di Torrile - Parma
(Italy)
Cenexi - Laboratories Thissen S.A., Rue de la Papyree 2-4-6, Braine-L’Alleud, 1420, Belgium
…………………………………………………………………………………………………………………..

The following information is intended exclusively for doctors or healthcare professionals:
Method of administration
Parenteral administration
In case of regional arterial perfusion, consult the literature for details on the methodology of
use.
Unless regional arterial perfusion is indicated, ALKERAN is intended for intravenous use only.
For intravenous administration, it is recommended that the ALKERAN solution be
injected slowly into a rapid infusion solution through a disinfected site.
If direct injection into a rapid infusion is not appropriate, the ALKERAN solution can be
administered diluted in an infusion bag.
Care must be taken to avoid possible extravasation of ALKERAN and, in case of difficult
peripheral venous access, the use of a central venous catheter should be considered.
If high doses of ALKERAN are administered, with or without autologous bone marrow transplantation,
administration via a central venous catheter is recommended.
Incompatibilities
ALKERAN 50 mg/10 ml Powder and solvent for injectable solution is not compatible with solutions
for infusion containing dextrose and it is recommended that ONLY 0.9% w/v sodium chloride in
intravenous infusion be used.
Preparation of the ALKERAN solution
(see also below: Safe handling and disposal of ALKERAN)
The ALKERAN injectable solution must be prepared, AT ROOM TEMPERATURE,
by reconstituting the lyophilized powder with the solvent-diluent.
If the solvent-diluent is used at a low temperature, the lyophilized powder of ALKERAN
may not reconstitute correctly with visible undissolved particles.
10 ml of this solvent-diluent must be added, in a single amount, and the vial
immediately shaken vigorously (for at least 50 seconds), until a clear solution is obtained
without visible particles. If diluents are added slowly and not shaken
immediately, insoluble particles may form. The shaking process creates a
considerable amount of very small air bubbles. These may persist and require another 2 or
3 minutes to disappear. Since the resulting solution is quite viscous, it may be difficult
to assess the clarity of the solution.
The resulting solution contains the equivalent of 5 mg/ml of anhydrous melphalan and has a pH of approximately

• 6.5. The ALKERAN solution has limited stability and must be prepared immediately before use. Unused solutions must be discarded (see below: Disposal). The reconstituted solution should not be refrigerated as this would cause precipitation. When diluted in an infusion solution, the ALKERAN solution has reduced stability and the degradation rate increases rapidly with increasing temperature. If administration takes place at room temperature of about 25°C, the total time between preparation of the reconstituted solution and completion of the infusion must not exceed 1 hour and a half. If any turbidity or crystallization appears in the reconstituted or diluted solutions, the preparation must be discarded.

Safe handling of ALKERAN
ALKERAN 50 mg/10 ml Powder and solvent for injectable solution must be prepared for
administration by, or under the direct supervision of, pharmacists who are familiar with its characteristics
and the methods for safe handling.
ALKERAN must be prepared for use in an aseptic unit of a pharmacy equipped with a suitable
vertical laminar flow cabinet. If this is not available, a dedicated room adjacent to the hospital ward or
outpatient clinic may be used.
Personnel preparing or handling ALKERAN must wear the following protective clothing:

• disposable surgical gloves made of latex or polyvinyl chloride of suitable quality (rubber gloves are not suitable);
• surgical masks of suitable quality;
• protective glasses that must be washed with water after use;
• disposable gown. In an aseptic environment, further suitable clothing will be required. Any spillage of the solution must be treated immediately (by personnel wearing appropriate protective clothing) by cleaning with disposable wet wipes which, after use

are placed in disposable containers for high-risk disposal in accordance with current regulations.
Contaminated surfaces must be washed with plenty of water.
If the ALKERAN solution comes into contact with the skin, wash immediately with
soap and plenty of cold water. In such cases, it is prudent to seek medical advice.
In case of contact with the eyes, wash the eyes IMMEDIATELY with sodium
chloride irrigation and seek medical advice immediately. If sodium chloride solution is not available,
a large amount of water may be used.
Disposal
ALKERAN solutions must be disposed of in accordance with current regulations. In the absence of
regulations, the solution must be disposed of in the appropriate manner for toxic chemicals,
for example, by high-temperature incineration or deep burial.
Disposal of sharps, such as needles, syringes, administration sets and vials, must
take place in rigid containers labeled with appropriate risk seals. Personnel involved
in disposal must take the necessary precautions and the material must be destroyed, if
necessary, by incineration. All disposal operations must be in accordance with
current regulations.