Consumer medicine information

ALKERAN tablets

Melphalan

BRAND INFORMATION

Brand name

Alkeran

Active ingredient

Melphalan

Schedule

What is in this leaflet

This leaflet answers some common questions about ALKERAN tablets. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ALKERAN against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What ALKERAN is used for

ALKERAN contains melphalan as the active ingredient.

ALKERAN belongs to a group of medicines called cytotoxics and is 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.

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

There is no evidence that it is addictive.

Before you take it

When you must not take it

Do not take ALKERAN if you have ever had an allergic reaction to:

melphalan
any of the tablet ingredients listed at the end of this leaflet.

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.

Do not take it if you have an infection or a high temperature.

Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

Do not take ALKERAN if you are planning to become pregnant or father a child.

ALKERAN may harm eggs and sperm. Reliable contraceptive methods must be taken to avoid pregnancy whilst you or your partner is taking this medicine and for at least 12 weeks after either partner stops using it.

Do not take ALKERAN if you are pregnant or breast feeding unless you and your doctor have discussed the risks and benefits involved.

Do not take ALKERAN after the expiry date (EXP) printed on the bottle label.

Do not take it if the bottle shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines or any other foods, dyes or preservatives.

Tell your doctor if you have or have had any of the following conditions:

you have recently received or are receiving radiotherapy or chemotherapy
you have recently been vaccinated or are planning to be vaccinated
kidney disease
blood disorders
you have received ALKERAN treatment previously.

If you have not told your doctor about any of the above, tell them before you start taking ALKERAN.

Taking other medicines

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

Some medicines may be affected by ALKERAN or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines. These include:

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

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking this medicine.

How to take it

How much to take

Take ALKERAN tablets exactly as directed by your doctor.

Your doctor will decide what dose and for how long you will be taking ALKERAN. 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 in order to monitor your blood cell count and to change your dosage if necessary.

How to take it

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.

Use in Children

The safety and effectiveness in children has not been established.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much ALKERAN. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are taking it

Things you must 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.

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

It is important that you visit your doctor regularly so your doctor can check your progress and make sure your medicine is working.

Tell any other specialist, doctor, dentist or pharmacist that you are on ALKERAN, especially if you are about to be started on any new medicines, immunisations, vaccinations or radiotherapy.

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.

Things you must not do

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.

Things to be careful of

Do not break, crush or chew the tablet.

Provided the outer coating of the tablet is intact, there is no risk in handling ALKERAN tablets.

Be careful driving or operating machinery until you know how ALKERAN tablets affect you.

Do not have any vaccinations without your doctor's approval.

ALKERAN may lower your body's resistance and there is a chance you might get the infection the vaccination is meant to prevent.

ALKERAN tablets 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

Check with your doctor immediately if you 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.

be careful when using a toothbrush, tooth pick 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.

Side effects

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

The following side-effects have been reported with ALKERAN:

production of bone marrow cells may be reduced. You may notice an increase in infections. Your doctor will do regular blood tests, but you should tell him at once if you notice any signs of fever or infection or any unexpected bruising, bleeding or signs of blood in your urine.
in women, periods may stop
in men, sperm production may be reduced or stopped.

Tell your doctor if you notice any of the following:

nausea and vomiting
diarrhoea
skin rash or itching
frequent infections such as fever, sore throat or mouth ulcers
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
persistent cough or breathlessness
hair loss
unusually fast heart beat.

Tell your doctor immediately if you notice any of the following:

wheezing, swelling of the lips or mouth, difficulty in breathing, hayfever, lumpy rash (hives) or fainting.

These could be a symptom of an allergic reaction.

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 above may also occur in some people.

Do not be alarmed by this list of side effects.

You may not experience any of them.

After taking it

Storage

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.

Product description

What it looks 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.

Ingredients

Active ingredient:
Each ALKERAN tablet contains 2 mg melphalan.

Inactive ingredients:

cellulose-microcrystalline
crospovidone
silica colloidal anhydrous
magnesium stearate
hypromellose
titanium dioxide
macrogol 400.

ALKERAN tablets do not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Aspen Pharmacare Australia Pty Limited
34-36 Chandos Street
St Leonards NSW 2065 Australia

Australian registration number: AUST R 81543

This leaflet was prepared in August 2010.

Published by MIMS November 2010

BRAND INFORMATION

Brand name

Alkeran

Active ingredient

Melphalan

Schedule

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.

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.

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.
(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.

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BRAND INFORMATION

Alkeran 2 mg