Consumer medicine information

Alkeran Tablets

Melphalan

BRAND INFORMATION

Brand name

Alkeran

Active ingredient

Melphalan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Alkeran Tablets.

SUMMARY CMI

Alkeran® tablets

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ALKERAN tablets?

ALKERAN tablets contain the active ingredient melphalan. ALKERAN tablets are used to treat some types of cancer and certain blood disorders.

For more information, see Section 1. Why am I using ALKERAN tablets? in the full CMI.

2. What should I know before I use ALKERAN tablets?

Do not use if you have ever had an allergic reaction to ALKERAN or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ALKERAN TABLETS? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ALKERAN TABLETS and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ALKERAN tablets?

  • The dose of ALKERAN tablets varies from patient to patient. Your doctor will decide what dose and for how long you will be taken it, and it may be adjusted throughout your treatment.
  • Swallow each tablet whole with water.
  • Do not break, crush or chew the tablets.

More instructions can be found in Section 4. How do I use ALKERAN tablets? in the full CMI.

5. What should I know while using ALKERAN tablets?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ALKERAN tablets.
  • Tell your doctor if you become pregnant, or plan on becoming pregnant or fathering a child.
  • Take precautions to reduce your risk of infections or bleeding.
Things you should not do
  • Do not have any vaccinations without your doctor's approval
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use ALKERAN tablets to treat any other complaints unless your doctor says to.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ALKERAN tablets affects you.
Looking after your medicine
  • Store ALKERAN tablets in the refrigerator where the temperature is between 2-8°C. Do not freeze.
  • Keep it where young children cannot reach it.
  • Keep your tablets in the bottle until it is time to take them.

For more information, see Section 5. What should I know while using ALKERAN tablets? in the full CMI.

6. Are there any side effects?

Common side effects of ALKERAN tablets include nausea, vomiting, diarrhoea, hair loss, muscle loss or pain, and reduced bone marrow cell production. Serious side effects may also occur when using ALKERAN tablets. Many of these are associated with reduced bone marrow cell production, including more frequent and severe infections (symptoms include fever, sore throat, or mouth ulcers); bruising or bleeding more easily than normal (e.g. nose bleeds); and unusual tiredness; looking pale; and feeling weaker, dizzy or more tired than usual. Other serious side effects include a severe allergic reaction (symptoms of which include: wheezing, swelling of lips/mouth, difficulty breathing, hayfever, lumpy rash (hives) or fainting), a yellowing of the eyes or skin, problems with eyesight, and an unusually fast heartbeat.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Alkeran® tablets

Active ingredient(s): melphalan

Consumer Medicine Information (CMI)

This leaflet provides important information about using ALKERAN tablets. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ALKERAN tablets.

Where to find information in this leaflet:

1. Why am I using ALKERAN tablets?
2. What should I know before I use ALKERAN tablets?
3. What if I am taking other medicines?
4. How do I use ALKERAN tablets?
5. What should I know while using ALKERAN tablets?
6. Are there any side effects?
7. Product details

1. Why am I using ALKERAN tablets?

ALKERAN tablets contains the active ingredient melphalan. ALKERAN belongs to a group of medicines called cytotoxics.

ALKERAN tablets are used to treat some types of cancer and certain blood disorders. It interferes with the growth of cancer cells. ALKERAN may be used in combination with other medicines to treat cancer.

Ask your doctor if you have any questions about why ALKERAN has been prescribed for you.

Your doctor may have prescribed it for another purpose.

2. What should I know before I use ALKERAN tablets?

Warnings

Do not use ALKERAN tablets if:

  • You are allergic to melphalan, or any of the ingredients listed at the end of this leaflet.
    - Some symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue, or any other parts of the body; rash, itching or hives on the skin.
    - Always check the ingredients to make sure you can use this medicine.
  • You have an infection or a high temperature.
    Your doctor may decide to delay your treatment until your infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.
  • Do not take ALKERAN tablets after the expiry date printed on the label.
  • Do not take it if the bottle shows signs of tampering.

Check with your doctor if you:

  • have any other medical conditions, especially the following:
    - you have recently received or are receiving radiotherapy of chemotherapy.
    - you have been vaccinated or are planning to be vaccinated.
    - kidney disease
    - blood disorders
    - you have received ALKERAN treatment previously.
  • take any medicines for any other condition.
  • have had any allergy to any other medicines, or any other substances, such as foods, preservatives, or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

You must not be given this medicine if you are trying to become pregnant or to father a child.
ALKERAN tablets may harm eggs and sperm. Reliable contraceptive methods must be taken to avoid pregnancy whilst you or your partner is being treated with this medicine and for at least 12 weeks after either partner stops being given it

Mothers receiving ALKERAN tablets should not breastfeed. It is not known whether this medicine passes into the breast milk.

You must not be given ALKERAN tablets if you are pregnant or breast feeding unless you and your doctor have discussed the risks and benefits involved.

Use in children

  • The safety and effectiveness of ALKERAN tablets in children has not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by ALKERAN tablets or may affect how well it works. This includes:

  • nalidixic acid
  • cyclosporin
  • cisplatin
  • carmustine
  • other cytotoxic drugs
  • vaccinations with 'live' organism vaccines.

You may need to take different amounts of your medicine, or you may need to take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ALKERAN tablets.

4. How do I use ALKERAN tablets?

How much to take

  • Your doctor will decide what dose and for how long you will be taking ALKERAN TABLETS. This depends on factors such as your weight, any pre-existing conditions and your response to the treatment.
  • Your doctor may change the dose and frequency of your medicine as your condition changes. Your doctor may order regular blood tests while you are taking ALKERAN tablets in order to monitor your blood cell count and to change your dosage if necessary.
  • Take ALKERAN tablets exactly as directed by your doctor.

When to take ALKERAN tablets

  • Your doctor will decide when you should be taking ALKERAN tablets.
  • When to take ALKERAN tablets depends on factors such as the condition being treated.

How to take ALKERAN tablets

  • Swallow each tablet whole with water.
  • Do not break, crush or chew the tablets.

How long to take it for

  • Do not stop taking ALKERAN tablets or change the dose without first checking with your doctor.
  • It is important to take your ALKERAN tablets until your doctor tells you to stop.

If you forget to use ALKERAN tablets

Tell your doctor that you have missed a dose, and they will give you further instruction.

Do not take a double dose to make up for the dose you missed.

If you use too much ALKERAN

If you think that you have used too much ALKERAN, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ALKERAN tablets?

Things you should do

  • Tell your doctor if, for any reason, you have not taken your medicine exactly as directed. Otherwise, your doctor may think that it was not working as it should and change your treatment unnecessarily
  • Visit your doctor regularly so your doctor can check your progress and make sure your medicine is working.
  • Tell your doctor if you become pregnant, are trying to become pregnant, or trying to father a child.
  • If you are about to undergo surgery or an operation, tell your doctor or surgeon that you are taking ALKERAN tablets.
  • Remind any doctor, dentist or pharmacist you visit that you are using ALKERAN tablets. Especially if you are about to be started on any new medicines, immunisations, vaccinations, or radiotherapy.

This medicine can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding.

The following precautions should be taken to reduce your risk of infection or bleeding:

  • Avoid people who have infections.
  • Be careful when using a toothbrush, toothpick, or dental floss.
    - Check with your doctor before having dental work.
    - Your doctor, dentist, nurse, or pharmacist may recommend other ways to clean your teeth and gums.
  • Be careful not to cut yourself when using sharp objects such as a razor or nail cutters.
  • Avoid contact sports or other situations where you may bruise or get injured.

Call your doctor straight away if you:

  • Become pregnant while taking ALKERAN tablets
  • Think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back, or side pain or find it painful or difficult to urinate.

Things you should not do

  • Do not break, crush or chew the tablet
  • Do not have any vaccinations without your doctor's approval. ALKERAN tablets may lower your body's resistance and there is a chance you might get the infection the vaccination is meant to prevent.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use ALKERAN tablets to treat any other complaints unless your doctor says to.

Use in children

  • The safety and effectiveness in children has not been established

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ALKERAN tablets affect you.

Looking after your medicine

  • Store ALKERAN tablets in the refrigerator where the temperature is between 2 and 8 degrees Celsius. Do not freeze.
  • Keep it where young children cannot reach it.
  • Keep your tablets in the bottle until it is time to take them. If you take the medicine out of the bottle it may not keep as well.

Follow the instructions in the carton on how to take care of your medicine properly.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

Tell your doctor as soon as possible if you do not feel well while you are taking ALKERAN tablets.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Hair loss
  • in some women, periods may stop.
  • in some men, sperm production may be reduced or stop.
  • Nausea and vomiting
  • Diarrhoea
  • Mild skin rash or itching
  • Persistent cough or breathlessness
  • Muscle loss and pain
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • wheezing, swelling of the lips or mouth, difficulty in breathing, hayfever, lumpy rash (hives) or fainting
  • signs of infection such as fever, sore throat or mouth ulcers (infections may happen more frequently and at a higher severity due to reduced cell production by your bone marrow)
  • bruising or bleeding more easily than normal, nose bleeds
  • unusual tiredness, looking pale, feeling weaker, dizzy or more tired than usual
  • jaundice, a yellowing of the whites of the eyes or skin
  • problems with your eyesight unusually fast heart beat.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor if you notice anything else that is making you feel unwell, even if you think the problems are not connected with this medicine and are not referred to in this leaflet.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ALKERAN tablets contain

Active ingredient
(main ingredient)
  • melphalan
Other ingredients
(inactive ingredients)
  • cellulose-microcrystalline
  • crospovidone
  • silica colloidal anhydrous
  • magnesium stearate
  • hypromellose
  • titanium dioxide

Do not take this medicine if you are allergic to any of these ingredients.

What ALKERAN tablets look like

ALKERAN tablets are white to off-white, film-coated, round tablets engraved with "GX EH3" on one side and "A" on the other. Available in bottles of 25 tablets

(AUST R 81543)

Who distributes ALKERAN tablets

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St. Leonards NSW 2065
Australia

This leaflet was revised in August 2024

Published by MIMS November 2024

BRAND INFORMATION

Brand name

Alkeran

Active ingredient

Melphalan

Schedule

S4

 

1 Name of Medicine

Melphalan.

2 Qualitative and Quantitative Composition

Alkeran tablets contain 2 mg melphalan.
Melphalan is a white to cream coloured powder. It is practically insoluble in water, chloroform and ether, slightly soluble in methanol and dissolves in dilute mineral acids.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White to off-white, round, biconvex film-coated tablets, with one side engraved "A" and the other side engraved "GX EH3".

4 Clinical Particulars

4.1 Therapeutic Indications

Alkeran is indicated for the palliative treatment of multiple myeloma and advanced ovarian adenocarcinoma.
Alkeran has a significant therapeutic effect in a proportion of patients suffering from advanced breast carcinoma and may be used in the treatment of polycythaemia vera.

4.2 Dose 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.
Since Alkeran is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary. At least one determination should be obtained prior to each course of treatment. Patients should be observed closely for consequences of bone marrow suppression, which include severe infections, bleeding, and symptomatic anaemia (see Section 4.4 Special Warnings and Precautions for Use).
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.

Thromboembolic events.

Melphalan in combination with lenalidomide and prednisone or in combination with thalidomide and prednisone or dexamethasone is associated with an increased risk of venous thromboembolism. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient's underlying risk factors (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Multiple myeloma.

The administration of Alkeran and prednisone is more effective than Alkeran alone. The combination is usually given on an intermittent basis.
A typical oral dosage schedule is 0.15 mg/kg bodyweight/day in divided doses for 4 days together with 40 mg prednisone daily for 4 days, repeated at intervals of six weeks. Numerous regimes have been used and the scientific literature should be consulted for details. Prolonging treatment beyond one year in responders does not appear to improve results.

Advanced ovarian adenocarcinoma.

The usual regime is 0.2 mg/kg bodyweight/day, given orally in divided doses, three times daily, for 5 days. This is repeated every 4-8 weeks, provided the bone marrow has recovered.

Advanced carcinoma of the breast.

Alkeran has been given orally at a dose of 0.15 mg/kg bodyweight daily or 5 mg/m2 body surface area daily for 4-6 days and repeated every 6 weeks.

Polycythaemia vera.

For remission induction the usual dose is 6 to 10 mg daily for 5 to 7 days, after which 2-4 mg daily is given until satisfactory disease control is achieved. The maintenance dose is 2 to 6 mg once per week. 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 haematological control.

Children.

Safety and efficacy in children have not been established.

Elderly.

Although Alkeran is frequently used at conventional dosage in the elderly, there is no specific information available relating to its administration in this patient sub-group. Clinical experience with Alkeran has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal impairment.

Alkeran clearance, though variable, is decreased in renal impairment. Dosage reduction of up to 50% should be considered in patients with moderate to severe renal impairment and subsequent dosage determined according to the degree of haematological suppression. (See Section 4.4 Special Warnings and Precautions for Use.)

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Alkeran is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
Since Alkeran is a potent myelosuppressive agent, it is essential that careful attention should be paid to the monitoring of blood counts to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent course of Alkeran: platelet count, haemoglobin, white blood cell count, and differential. Thrombocytopenia and/or leucopoenia are indications to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity. Dose adjustment on the basis of blood counts at the nadir and day of treatment should be considered. (See Section 4.2 Dose and Method of Administration.)
Although controlled trials comparing intravenous (IV) to oral melphalan have shown more myelosuppression with the IV formulation, severe bone marrow suppression with resulting infection or bleeding may occur.
Alkeran should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy or whose marrow function is recovering from previous cytotoxic therapy.

Contraception.

Due to an increased risk of venous thromboembolism in patients 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 another reliable contraceptive method (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.
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. The recommended duration of contraception in females should be until the end of relevant systemic exposure or 6 months afterwards (See Section 4.6).

Carcinogenicity (second primary malignancy) 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.

Use in renal impairment.

Alkeran clearance may be reduced in patients with renal impairment, who may also have uraemic bone marrow suppression. Dosage reduction may therefore be necessary (see Section 4.2 Dose and Method of Administration), and these patients should be closely observed.
The use of high dose melphalan has the potential to cause acute kidney injury in patients, especially those with underlying renal impairment.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Simultaneous administration of nalidixic acid with melphalan should be avoided if possible. Nalidixic acid together with high dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis.
Ciclosporin and high dose melphalan is a potentially dangerous combination. A deterioration of renal function was associated with simultaneous use of these drugs, but not with melphalan alone.
Cisplatin may affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan clearance. IV melphalan may also reduce the threshold for carmustine lung toxicity.
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special Warnings and Precautions for Use).
In a 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.
Impaired renal function has been described in haemopoietic stem cell rescue patients who were conditioned with high-dose i.v. melphalan and who subsequently received cyclosporin to prevent graft-versus-host disease.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Alkeran causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients. Reversible and irreversible testicular suppression have also been reported.
No fertility studies have been conducted in animals. However, there is evidence from some animal studies that melphalan can have an adverse effect on spermatogenesis. Therefore, it is possible that Alkeran may cause temporary or permanent sterility in male patients.

Women of childbearing potential / contraception in males and females.

As with all cytotoxic treatments, male and female patients who use Melphalan should use effective and reliable contraceptive methods for a period of six months, following the cessation of treatment.
The final decision regarding the additional time period on contraception should be taken by the doctor and/or the patient (See Section 4.4).
(Category D)
As with other cytotoxic agents, Alkeran can produce spontaneous abortion, foetal loss and birth defects. 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.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be practiced when either partner is receiving Alkeran.
The use of Alkeran should be avoided whenever possible during pregnancy, particularly during the first trimester. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.
Melphalan has been shown to be teratogenic and embryogenic in animal studies. A single dose of 5 mg/kg IP (30 mg/m2) given on day 6 or day 9 of gestation in the rat was embryolethal and teratogenic, and a single dose of 3 mg/kg IP (18 mg/m2) was teratogenic when administered on day 6. Malformations resulting from melphalan administration included alterations of the brain (underdevelopment, deformation, meningocele and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, as well as exomphaly (umbilical hernia).
In a repeat-dose embryotoxicity study in rats (0.33, 1 and 3 mg/kg/day PO on gestation days 7-17; total doses: 22, 66 and 198 mg/m2 PO, respectively; cf. clinical dose of 16 mg/m2 IV), all doses were maternotoxic (reduced weight gain and mortality occurred at the high dose). Intrauterine deaths, reduced foetal and pup weights and pup weight gain over the lactation period were seen in the mid and high dose groups but pup survival over the lactation period was reduced at all doses. Melphalan showed a reduction in ossification at ≥ 1 mg/kg/day and an increased incidence of rib anomalies and impairment of pup development (delayed eruption of incisors, significantly different open-field behaviour) at the high dose.
No animal studies have been conducted to investigate the peri- and post-natal effects of melphalan.
 It is not known whether this drug is excreted in human milk. Mothers receiving Alkeran should not breast feed.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (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 ≥ 1/10, common ≥ 1/100, < 1/10, uncommon ≥ 1/1000 and < 1/100, rare ≥ 1/10,000 and < 1/1000, very rare < 1/10,000, not known (cannot be estimated from the available data). See Table 1.

Haematologic.

The most common side-effect is bone marrow depression leading to leucopenia, thrombocytopenia and anemia. White blood cell count and platelet count nadirs usually occur 2 to 3 weeks after treatment, with recovery in 4 to 5 weeks after treatment. Irreversible bone marrow failure has been reported. Acute leukaemia has also been reported (see Section 5.3 Preclinical Safety Data, Carcinogenicity).

Gastrointestinal.

Gastro-intestinal effects such as nausea and vomiting occur in up to 30 per cent of patients receiving conventional oral doses of Alkeran. Diarrhoea is very common. Oral ulceration occurs infrequently.
Stomatitis occurs rarely following conventional doses of Alkeran. At high doses stomatitis is very common.

Hypersensitivity.

Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of 425 patients receiving Alkeran for Injection for myeloma (see Section 4.4 Special Warnings and Precautions for Use). These reactions were characterised by urticaria, pruritus, skin rashes, oedema, and in some patients, tachycardia, bronchospasm, dyspnoea, and hypotension. These patients appeared to respond to antihistamine and corticosteroid therapy. If a hypersensitivity reaction occurs, IV or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan. Cardiac arrest has also been reported rarely in association with such events.

Miscellaneous.

Other reported adverse reactions include skin hypersensitivity, skin necrosis rarely requiring skin grafting, maculopapular rashes, pruritus, vasculitis, allergic reaction, and interstitial pneumonitis.
Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported. Veno-occlusive disease has been reported in association with these cases.
Temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage.
There have been case reports of interstitial pneumonitis and pulmonary fibrosis. There have also been case reports of fatal pulmonary fibrosis and haemolytic anaemia occurring after melphalan treatment.
Alopecia is very common at high doses and common at conventional doses.
Myelodysplastic syndrome.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms and signs.

Overdoses resulting in death have been reported. Overdoses, including doses up to 290 mg/m2, have produced the following symptoms: severe nausea and vomiting, decreased consciousness, convulsions, muscular paralysis, and cholinomimetic effects. Damage to the gastrointestinal lining may also ensue. Severe mucositis, stomatitis, colitis, diarrhoea, and haemorrhage of the gastrointestinal tract occur at high doses (> 100 mg/m2). Elevations in liver enzymes and veno-occlusive disease occur infrequently. Significant hyponatremia caused by an associated inappropriate secretion of antidiuretic hormone (ADH) syndrome has been observed. Nephrotoxicity and adult respiratory distress syndrome have been reported rarely.

Management.

The principal toxic effect is bone marrow suppression, leading to leucopenia, thrombocytopenia and anaemia. Haematologic parameters should be closely followed for at least 4 weeks following overdosage until there is evidence of recovery. An uncontrolled study suggests that administration of autologous bone marrow or haematopoietic growth factors (i.e. filgrastim) may shorten the period of pancytopenia. General supportive measures together with appropriate blood and platelet transfusions and antibiotics should be instituted as deemed necessary by the physician. This drug is not removed from plasma to any significant degree by haemodialysis or haemoperfusion. A paediatric patient survived a 254-mg/m2 overdose treated with standard supportive care.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking two DNA strands and thereby preventing cell replication. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumour cells.

Clinical trials.

A randomised trial compared prednisone plus IV melphalan to prednisone plus oral melphalan in the treatment of myeloma. As discussed below, overall response rates at week 22 were comparable; however, because of changes in trial design, conclusions as to the relative activity of the two formulations after week 22 are impossible to make.
Both arms received oral prednisone starting at 0.8 mg/kg per day with doses tapered over 6 weeks. Melphalan doses in each arm were:
Arm 1 oral melphalan 0.15 mg/kg per day x 7 followed by 0.05 mg/kg per day when WBC began to rise.
Arm 2 IV melphalan 16 mg/m2 once every 2 weeks x 4 (over 6 weeks) followed by the same dose every 4 weeks.
Doses of melphalan were adjusted according to the following criteria (see Table 2):
One hundred and seven patients were randomised to the oral melphalan arm and 203 patients to the IV melphalan arm. More patients had a poor-risk classification (58% versus 44%) and high tumour load (51% versus 34%) on the oral compared to the IV arm (P < 0.04). Response rates at week 22 are shown in Table 3.
Because of changes in protocol design after week 22, other efficacy parameters such as response duration and survival cannot be compared.
Severe myelotoxicity (WBC ≤ 1000 and/or platelets ≤ 25,000) was more common in the IV melphalan arm (28%) than in the oral melphalan arm (11%).
An association was noted between poor renal function and myelosuppression; consequently, an amendment to the protocol required a 50% reduction in IV melphalan dose if the BUN was ≥ 30 mg/dL (≥ 10.71 mmol/L). The rate of severe leucopenia in the IV arm in the patients with BUN over 30 mg/dL (≥ 10.71 mmol/L) decreased from 50% (8/16) before protocol amendment to 11% (3/28) (P = 0.01) after the amendment. Before the dosing amendment, there was a 10% (8/77) incidence of drug-related death in the IV arm. After the dosing amendment, this incidence was 3% (3/108). This compares to an overall 1% (1/100) incidence of drug-related death in the oral arm.

5.2 Pharmacokinetic Properties

Absorption, distribution, metabolism and excretion.

In a study of 18 patients administered melphalan 0.2 to 0.25 mg/kg bodyweight orally, a maximum plasma concentration (range 87 to 350 nanogram/mL) was reached within 0.5 to 2.0 hours. The mean elimination half-life was 1.12 + 0.15 hours.
The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The extent of melphalan binding to plasma proteins ranges from 60% to 90%. Serum albumin is the major binding protein, while α1-acid glycoprotein appears to account for about 20% of the plasma protein binding. Approximately 30% of the drug is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible.
Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low, one study noted an increase in the occurrence of severe leucopoenia in patients with elevated blood urea nitrogen (BUN) after 10 weeks of therapy.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Alkeran is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.
Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic in man. There have been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloid, 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. The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of melphalan.
Secondary malignancies, including acute nonlymphocytic leukaemia, myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer treated with alkylating agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of acute leukaemia, myeloproliferative syndrome, or carcinoma is not possible. Published reports of leukaemia in patients who have received melphalan (and other alkylating agents) suggest that the risk of leukaemogenesis increases with chronicity of treatment and with cumulative dose. The potential benefits from Alkeran therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy.
Although adequate and well-controlled carcinogenicity studies have not been conducted in animals, there is clear evidence from animal studies that melphalan is carcinogenic. Intraperitoneal (IP) administration of melphalan in rats (5.4 or 10.8 mg/m2) and mice (2.25 or 4.5 mg/m2) three times per week for 6 months followed by a 12 months post-dose observation produced peritoneal sarcoma in rats, and lung tumors and lymphosarcomas (males) in mice. Lung tumours were also increased in two other studies in mice (total dose: 144 mg/m2 dermal given as 10 injections over a period of 10 weeks; 3.2-51 mg/m2 IP given as 12 injections over a period of 4 weeks) while in one of these studies (dermal), skin papillomas were increased although non-significantly.
Chromosome aberrations have been observed in patients being treated with melphalan. Melphalan has been shown to cause chromatid and chromosome damage in human lymphocytes at a single dose of 20 mg IV (~ 10.6 mg/m2, comparable to a therapeutic dose of 16 mg/m2) and in rat bone marrow cells at a single intramuscular dose of 6 mg/m2. Melphalan also showed mutagenic effects on germ cells in male mice at 17.1-21.9 mg/m2.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, crospovidone, colloidal anhydrous silica, magnesium stearate, hypromellose, titanium dioxide, macrogol 400.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C. (Refrigerate. Do not freeze.)

6.5 Nature and Contents of Container

Alkeran tablets are supplied in amber glass bottles. Pack sizes of 25 and 50* tablets.
(*Not currently distributed in Australia.)

6.6 Special Precautions for Disposal

Provided the outer coating of the tablet is intact, there is no risk in handling Alkeran tablets. Alkeran tablets should not be divided. Do not break, crush or chew the tablets.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

The chemical name for melphalan, is 4-bis (2-chloroethyl) amino-L-phenylalanine, it has a molecular weight of 305.20, and its molecular formula is C13H18Cl2N2O2.
Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent that is active against selected human neoplastic diseases.

Chemical structure.


CAS number.

148-82-3.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription only medicine).

Summary Table of Changes