Consumer medicine information

Alkeran Injection

Melphalan

BRAND INFORMATION

Brand name

Alkeran Injection

Active ingredient

Melphalan

Schedule

What is in this leaflet

This leaflet answers some common questions about ALKERAN injection. It does not contain all of the available information.

It does not take the place of talking to your doctor.

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

If you have any concerns about being given this medicine, ask your doctor.

Keep this leaflet while being treated. You may need to read it again.

What ALKERAN injection is used for

ALKERAN injection contains melphalan as the active ingredient. It belongs to a group of medicines called cytotoxics.

ALKERAN injection is used to treat multiple myeloma, a cancer of the blood.

It is thought to work by stopping cancer cells from growing and multiplying.

This medicine may be used in combination with other medicines to treat cancer.

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

Your doctor may have prescribed it for another purpose.

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

There is no evidence that it is addictive.

Before you are given it

When you must not be given it

You must not be given ALKERAN injection if you have an allergy to:

melphalan
any of the 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.

You must not be given ALKERAN injection 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.

You must not be given this medicine if you are trying to become pregnant or to father a child.

ALKERAN injection 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.

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

You must not be given this medicine after the expiry date has passed or if the packaging is torn or shows signs of tampering.

Use in Children

The safety and effectiveness in children has not been established.

If you are not sure if you should be given this medicine, talk to your doctor.

Before you are given it

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

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 are given ALKERAN injection.

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 injection 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 has more information on medicines to be careful with or avoid while being given this medicine.

How it is given

How much is given

Your doctor will decide what dose and for how long you will be given ALKERAN injection.

Your doctor may order regular blood tests while you are being given ALKERAN injection in order to monitor your blood cell count and to change your dosage if necessary.

How it is given

ALKERAN injection will be given to you under the supervision of a doctor.

It is a sterile powder which is dissolved and then further diluted before intravenous infusion or 'drip' into a vein.

If you take too much (overdose)

As ALKERAN injection is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you experience any side effects after being given ALKERAN injection, tell your doctor immediately.

Symptoms of overdose may include severe nausea and vomiting, convulsions and stomach pain.

While you are receiving it

Things you must do

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 doctor, dentist or pharmacist that you are being given ALKERAN injection, especially if you are about to be started on any new medicines or radiotherapy.

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.

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 being given ALKERAN injection.

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

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.

Things to be careful of

Be careful driving or operating machinery until you know how ALKERAN injection affects you.

Side effects

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

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 injection:

production of bone marrow cells may be reduced.

Your doctor will frequently test your blood count, but you should tell him at once if you notice any signs of fever, infection, unexpected bruising, bleeding or signs of blood in your urine.

hair loss
in some women, periods may stop
in some men, sperm production may be reduced or stop.

Tell your doctor if you notice any of the following and they worry you:

nausea and vomiting
diarrhoea
mild skin rash or itching
tingling sensation
persistent cough or breathlessness
pain or swelling at the injection site.

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
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
problems with your eyesight
unusually fast heart beat.

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 using it

Things to be aware of

Because of the way this medicine works there is a chance it might cause other unwanted effects that may not occur until months or years after the medicine is used. These delayed effects may include certain types of cancer, such as leukaemia.

Discuss these possible effects with your doctor.

Storage

Keep ALKERAN injection in a cool, dry place where it stays below 30°C, protected from light.

Keep this medicine where children cannot reach it, such as in a locked cupboard.

Return any unused or expired medicine to your pharmacist.

Product description

What it looks like

ALKERAN injection is supplied in a carton containing:

one clear glass vial containing sterile, white or off white powder for injection
one 10 mL clear glass vial containing a sterile, clear, colourless solution of diluent.

The diluent is used to dissolve the powder.

Ingredients

Each vial of sterile powder for injection contains 50 mg melphalan and povidone.

Each vial of sterile diluent contains sodium citrate, propylene glycol, ethanol and water for injections.

Sponsor

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

Australian registration number:
AUST R 79834

This leaflet was prepared in August 2010.

Published by MIMS November 2010

BRAND INFORMATION

Brand name

Alkeran Injection

Active ingredient

Melphalan

Schedule

1 Name of Medicine

Melphalan.

2 Qualitative and Quantitative Composition

Alkeran Injection is a composite pack containing 2 components, a single use vial containing melphalan hydrochloride equivalent to 50 mg melphalan and a vial of sterile diluent.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Component 1: powder for injection.

A clear, glass vial containing white or off-white powder, practically free of visible particles when dissolved.

Component 2: sterile diluent.

A clear, glass vial containing a clear colourless solution, practically free of visible particles.
Alkeran Injection is reconstituted using the sterile diluent provided.

4 Clinical Particulars

4.1 Therapeutic Indications

Alkeran Injection is indicated for the treatment of patients with multiple myeloma for whom oral therapy is not appropriate.

4.2 Dose and Method of Administration

Alkeran Injection is administered intravenously.

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)).

Laboratory tests.

Periodic complete blood counts with differentials should be performed during the course of treatment with Alkeran Injection. At least one determination should be obtained prior to each dose. 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).

Dosage.

The usual IV dose is 16 mg/m². The drug is administered as a single infusion over 15 to 20 minutes. Alkeran Injection is administered at 2-week intervals for four doses, then, after adequate recovery from toxicity, at 4-week intervals. Available evidence suggests about one-third to one-half of the patients with multiple myeloma show a favourable response to the drug. Experience with oral melphalan suggests that repeated courses should be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned prematurely. Dose adjustment on the basis of blood cell counts at the nadir and day of treatment should be considered.

Use in the elderly.

Clinical experience with Alkeran Injection 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.

Use in children.

Safety and efficacy in children have not been established.

Patients with renal impairment.

Alkeran Injection 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).
Alkeran Injection is not compatible with infusion solutions containing dextrose and it is recommended that only sodium chloride intravenous infusion 0.9% w/v be used.

Administration precautions.

As with other toxic compounds, caution should be exercised in handling and preparing the solution of Alkeran Injection. Appropriate guidelines for the handling of cytotoxic compounds should be consulted. Skin reactions associated with accidental exposure may occur. The use of disposable latex or PVC gloves, facemask, protective goggles and a disposable apron is recommended. If the solution of Alkeran Injection contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and cold water. In such instances it may be prudent to seek medical advice.
In case of contact with eyes, immediate irrigation with sodium chloride eyewash should be carried out and medical attention sought without delay. If sodium chloride solution is not available, large volumes of water may be used.
Any spillage should be dealt with immediately (by personnel wearing suitable protective clothing), by mopping with damp, disposable paper towels which are placed in a high risk waste disposal bag. Contaminated surfaces should be washed with copious quantities of water.

Preparation for administration/stability.

1. Alkeran Injection must be reconstituted at room temperature by rapidly injecting 10 mL of the supplied diluent directly into the vial of lyophilised powder using a sterile needle (20-gauge or larger needle diameter) and syringe. Immediately shake vial vigorously until a clear solution is obtained. This provides a 5 mg/mL solution of melphalan and has a pH of approximately 6.5. Rapid addition of the diluent, as a single quantity, followed by immediate vigorous shaking is important for proper dissolution.
2. Immediately dilute the dose to be administered in 0.9% sodium chloride injection to a concentration not greater than 0.45 mg/mL.
3. Administer the diluted product over a minimum of 15 minutes.
4. Complete administration within 60 minutes of reconstitution.
Parenteral drug products should be visually inspected for particulate matter and discolouration prior to administration whenever solution and container permit. If either occurs, do not use this product.
The time between reconstitution/dilution and administration of Alkeran Injection should be kept to a minimum because reconstituted and diluted solutions of Alkeran Injection are unstable. Over as short a time as 30 minutes, a citrate derivative of melphalan has been detected in reconstituted material from the reaction of Alkeran Injection with Sterile Diluent for Alkeran Injection. Upon further dilution with saline, nearly 1% label strength of melphalan hydrolyses every 10 minutes.
A precipitate forms if the reconstituted solution is stored at 5°C. Do not refrigerate the reconstituted product. Alkeran Injection contains no antimicrobial agent. It is for single use in one patient only. Any unused solution should be discarded (see Section 6.6 Special Precautions for Disposal).

4.3 Contraindications

Melphalan should not be used in patients whose disease has demonstrated prior resistance to this agent. Patients who have demonstrated hypersensitivity to melphalan should not be given the drug.
Lactation.

4.4 Special Warnings and Precautions for Use

Alkeran Injection should be administered in carefully adjusted dosage under the direction of physicians experienced in the use of cytotoxic 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.
Severe bone marrow suppression with resulting infection or bleeding may occur. Since Alkeran Injection 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 dose of Alkeran Injection: 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).
Blood counts may continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in leucocyte or platelet counts, treatment should be temporarily interrupted.
Controlled trials comparing intravenous (IV) to oral melphalan have shown more myelosuppression with the IV formulation.
Alkeran Injection 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.
Hypersensitivity reactions including anaphylaxis have occurred in approximately 2% of patients who received the IV formulation (see Section 4.8 Adverse Effects (Undesirable Effects)). These reactions usually occur after multiple courses of treatment. Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of volume expanders, pressor agents, corticosteroids or antihistamines at the discretion of the physician. If a hypersensitivity reaction occurs, IV or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan.
Alkeran Injection solution may cause local tissue damage should extravasation occur and, consequently, it should not be administered by direct injection into a peripheral vein.
In all instances where the use of Alkeran Injection is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse events.

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.

Melphalan 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. In one trial, increased bone marrow suppression was observed in patients with BUN levels ≥ 30 mg/dL (≥ 10.71 mmol/L). A 50% reduction in the IV melphalan dose decreased the incidence of severe bone marrow suppression in the latter portion of this study.

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

Ciclosporin.

Impaired renal function has been described in bone marrow transplant patients who were conditioned with high dose intravenous melphalan and who subsequently received ciclosporin to prevent graft versus host disease.

Cisplatin/carmustine.

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.

Nalidixic acid.

When nalidixic acid and IV melphalan are given simultaneously, the incidence of severe haemorrhagic necrotic enterocolitis has been reported to increase in paediatric patients.

Vaccines.

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.

Melphalan 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 Injection may cause temporary or permanent sterility in male patients.
(Category D)
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.
Melphalan may cause foetal harm when administered to a pregnant woman.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be practised when either partner is receiving Alkeran Injection.
The use of Alkeran Injection 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.
Although adequate animal studies have not been conducted with IV melphalan, oral and IV melphalan have 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 postnatal effects of melphalan.
It is not known whether this drug is excreted in human milk. Mothers receiving Alkeran Injection should not breastfeed.

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.
The following information on adverse reactions is based on data from both oral and IV administration of melphalan as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.

Haematologic.

The most common side effect is bone marrow suppression, leading to leucopenia, thrombocytopenia and anaemia. 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).

Gastrointestinal.

Gastrointestinal disturbances such as nausea, vomiting and diarrhoea are very common. At high doses of Alkeran Injection, stomatitis is very common, and rare at conventional doses. The incidence of diarrhoea, vomiting and stomatitis becomes the dose limiting toxicity in patients given high IV doses of Alkeran Injection in association with haemopoietic stem cell rescue. Cyclophosphamide pretreatment appears to reduce the severity of gastrointestinal damage induced by high dose Alkeran Injection and the literature should be consulted for details. Oral ulceration occurs infrequently. Hepatic toxicity, including veno-occlusive disease, has been reported.

Hypersensitivity.

Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of 425 patients receiving Alkeran 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 ulceration at injection site, skin necrosis rarely requiring skin grafting, maculopapular rashes, pruritus, vasculitis, allergic reaction, and interstitial pneumonitis. A subjective and transient sensation of warmth and/or tingling is very common.
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.
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.
Temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage.
Muscular atrophy, muscle fibrosis, myalgia and increases in blood creatine phosphokinase are very commonly observed following isolated limb perfusion, while compartment syndrome is commonly observed. The incidence of muscle necrosis and rhabdomyolysis is not known in this setting.
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.

Treatment.

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 haemopoietic 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.

Cytotoxic and alkylating agent.
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/day with doses tapered over 6 weeks. Melphalan doses in each arm were:
Arm 1. Oral melphalan 0.15 mg/kg/day x 7 followed by 0.05 mg/kg/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 ≤ 1,000 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.

The pharmacokinetics of melphalan after IV administration has been extensively studied in adult patients. Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 and 75 minutes, respectively. Estimates of average total body clearance varied among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m²) were observed. One study has reported that on repeat dosing of 0.5 mg/kg every 6 weeks, the clearance of melphalan decreased from 8.1 mL/min/kg after the first course, to 5.5 mL/min/kg after the third course, but did not decrease appreciably after the third course. Mean (± SD) peak melphalan plasma concentrations in myeloma patients given IV melphalan at doses of 10 or 20 mg/m² were 1.2 ± 0.4 and 2.8 ± 1.9 microgram/mL, respectively.
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.

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 myeloproliferative syndrome or carcinoma is not possible. Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic. There have been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloidosis, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer. 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.
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 potential benefits from Alkeran Injection therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy.
Before the start of the treatment, the leukaemogenic risk (AML and MDS) must be balanced against the potential therapeutic benefit, especially if the use of melphalan in combination with thalidomide or lenalidomide and prednisone is considered, as it has been shown that these combinations increase the leukaemogenic risk. Before, and during and after treatment doctors must therefore examine the patient at all times by usual measurements to ensure the early detection of cancer and initiate treatment if necessary.
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 postdose observation produced peritoneal sarcoma in rats, and lung tumours 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 nonsignificantly.
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

Excipients - powder for injection.

Hydrochloric acid, povidone.

Excipients - sterile diluent.

Ethanol, propylene glycol, sodium citrate dihydrate, water for injections.

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 below 30°C. Protect from light.

6.5 Nature and Contents of Container

Alkeran Injection is supplied in a carton containing one single-use clear glass vial of freeze-dried melphalan hydrochloride equivalent to 50 mg melphalan and one 10 mL clear glass vial of sterile diluent.

6.6 Special Precautions for Disposal

Alkeran Injection solution should be disposed in a manner appropriate for toxic chemicals, for example, high-temperature incineration.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

It is known chemically as 4-[bis (2-chloroethyl) amino]- L-phenylalanine. The molecular formula is C₁₃H₁₈Cl₂N₂O₂ and the molecular weight is 305.20. Melphalan is the active L-isomer of the compound and was first synthesised in 1953. Melphalan is practically insoluble in water and has a pKa₁ of ~ 2.5.
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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