- Name of the medicinal product
Melphalan 2 mg Tablets USP Taj Pharma
Melphalan 5 mg Tablets USP Taj Pharm
- Qualitative and quantitative composition
a) Each film-coated tablet contains:
Melphalan USP 2 mg
Color: TitaniumDioxide USP
b) Each film-coated tablet contains:
Melphalan USP 5 mg
Color: TitaniumDioxide USP
- Pharmaceutical form
- Clinical particulars
4.1 Therapeutic indications
Melphalan Tablets are indicated in the treatment of multiple myeloma and advanced ovarian adenocarcinoma.
Melphalan either alone or in combination with other drugs has a significant therapeutic effect in a proportion of patients suffering from advanced breast carcinoma.
Melphalan is effective in the treatment of a proportion of patients suffering from polycythaemia vera.
4.2 Posology and method of administration
Since Melphalan is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary (see Special Warnings and Precautions for Use).
Oral administration in Adults: The absorption of Melphalan after oral administration is variable. Dosage may need to be cautiously increased until myelosuppresion is seen, in order to ensure that potentially therapeutic levels have been reached.
Numerous regimes have been used and the scientific literature should be consulted for details. The administration of Melphalan and prednisone is more effective than Melphalan alone. The combination is usually given on an intermittent basis, although the superiority of this technique over continuous therapy is not established. A typical oral dosage schedule is 0.15 mg/kg bodyweight/day in divided doses for 4 days repeated at intervals of six weeks. Prolonging treatment beyond one year in responders does not appear to improve results.
A typical regimen is 0.2 mg/kg bodyweight/day orally for 5 days. This is repeated every 4-8 weeks, or as soon as the bone marrow has recovered. Melphalan has also been used intravenously in the treatment of ovarian carcinoma.
Advanced carcinoma of the breast:
Melphalan has been given orally at a dose of 0.15 mg/kg bodyweight or 6 mg/m2 body surface area/day for 5 days and repeated every 6 weeks. The dose was decreased if bone marrow toxicity was observed.
For remission induction the usual dose is 6-10 mg daily for 5-7 days, after which 2-4 mg daily is given until satisfactory disease control is achieved. Therapy is maintained with a dose of 2-6 mg per week. During maintenance therapy, careful haematological control is essential with dosage adjustment according to the results of frequent blood counts.
Melphalan is very rarely indicated in children and dosage guidelines cannot be stated.
Use in the elderly:
There is no specific information available on the use of Melphalan in elderly patients.
Dosage in renal impairment:
In patients with moderate to severe renal impairment currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering the oral preparation to these patients, but it may be prudent to use a reduced dose initially.
Melphalan should not be given to patients who have suffered a previous hypersensitivity reaction to melphalan.
4.4 Special warnings and precautions for use
Melphalan 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.
Safe Handling of MELPHALAN tablets:
See 6.6 Instructions for use/handling
Since Melphalan is a potent myelosuppresive 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. 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. Melphalan should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity.
Patients with renal impairment should be closely observed as they may have uraemic marrow suppression. (See undesirable effects for elevation of blood urea Section 4.8)
Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.
The evidence is growing that 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 amyloid, malignant melanoma, 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.
Melphalan causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients.
4.5 Interaction with other medicinal products and other forms of interaction
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Warnings and Precautions).
Nalidixic acid together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis.
Impaired renal function has been described in bone marrow transplant patients who were pre-conditioned with high dose intravenous melphalan and who subsequently received ciclosporin to prevent graft-versus-host disease.
4.6 Pregnancy and lactation
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Melphalan.
The teratogenic potential of Melphalan 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.
The use of melphalan 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.
Mother receiving Melphalan should not breast-feed.
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the indication and dose received and also when given in combination with other therapeutic agents.
The following convention has been utilised for the classification of frequency:- Very common ≥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.
|Blood and Lymphatic System Disorders|
|Very common:||bone marrow depression leading to leucopenia, thrombocytopenia and anaemia|
|Immune System Disorders|
|Rare:||allergic reactions (see Skin and Subcutaneous Tissue Disorders)|
Allergic reactions to melphalan such as urticaria, oedema, skin rashes and anaphylactic shock have been reported uncommonly following initial or subsequent dosing, particularly after intravenous administration. Cardiac arrest has also been reported rarely in association with such events.
|Respiratory, Thoracic and Mediastinal Disorders|
|Rare:||interstitial pneumonitis and pulmonary fibrosis (including fatal reports)|
|Very common:||nausea, vomiting and diarrhoea; stomatitis at high dose|
|Rare:||stomatitis at conventional dose|
|Gastrointestinal effects such as nausea and vomiting have been reported in up to 30% of patients receiving conventional oral doses of melphalan.|
|Rare:||hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice|
|Skin and Subcutaneous Tissue Disorders|
|Very common:||alopecia at high dose|
|Common:||alopecia at conventional dose|
|Rare:||maculopapular rashes and pruritus (see Immune System Disorders)|
|Renal and Urinary Disorders|
|Common:||temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage|
Symptoms and signs:
Gastro-intestinal effects, including nausea, vomiting and diarrhoea are the most likely signs of acute oral overdosage. Diarrhoea, sometimes haemorrhagic, has been reported after intravenous overdosage. The principal toxic effect is bone marrow aplasia, leading to leucopoenia, thrombocytopenia and anaemia.
There is no specific antidote. The blood picture should be closely monitored for at least four weeks following overdosage until there is evidence of recovery.
General supportive measures, together with appropriate blood transfusion, should be instituted if necessary.
- Pharmacological properties
5.1 Pharmacodynamic properties
Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-2-chlorethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking two DNA strands and thereby preventing cell replication.
5.2 Pharmacokinetic properties
The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the drug in plasma and peak plasma concentration.
In studies of the absolute bioavailability of melphalan the mean absolute bioavailability ranged from 56 to 85%.
Intravenous administration can be used to avoid variability in absorption associated with myeloablative treatment.
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 nanograms/ml) was reached within 0.5 to 2.0 h.
The administration of melphalan tablets immediately after food delayed the time to achieving peak plasma concentrations and reduced the area under the plasma concentration-time curves by between 39 and 45%.
Melphalan displays limited penetration of the blood-brain barrier. Several investigators have sampled cerebrospinal fluid and found no measurable drug. Low concentrations (~10% of that in plasma) were observed in a single high-dose study in children.
In 13 patients given oral melphalan at 0.6 mg/kg bodyweight, the plasma mean terminal elimination half-life was 90 ± 57 min with 11% of the drug being recovered in the urine over 24 h.
In 18 patients administered melphalan 0.2 to 0.25 mg/kg bodyweight orally, the mean elimination half-life was 1.12 ± 0.15 h.
Special Patient Populations
- Renal impairment
Melphalan clearance may be decreased in renal impairment (see Dosage and Administration – Renal impairment and Warnings and Precautions – Renal impairment).
No correlation has been shown between age and melphalan clearance or with melphalan terminal elimination half-life (see Dosage and Administration).
5.3 Preclinical safety data
There are no preclinical data of relevance to the prescriber, which are additional to that in other sections of the SmPC.
- Pharmaceutical particulars
6.1 List of excipients
Tablet Core: Microcrystalline cellulose, Crospovidone, Colloidal anhydrous silica, Magnesium stearate
Tablet Film Coating: Hypromellose, Titanium dioxide, Macrogol.
6.3 Shelf life
6.4 Special precautions for storage
Store at 2°C to 8°C.
6.5 Nature and contents of container
Supplied in amber glass bottles with a child resistant closure containing 25 or 50 tablets.
6.6 Special precautions for disposal and other handling
Safe handling of MELPHALAN tablets:
The handling of Melphalan tablets should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations and/or regulations (for example Royal Pharmaceutical Society of Great Britain Working Party on the Handling of Cytotoxic Drugs).
Provided the outer coating of the tablet is intact, there is no risk in handling Melphalan tablets.
Melphalan tablets should not be divided.
Melphalan tablets should be destroyed in accordance with relevant local regulatory requirements concerning the disposal of cytotoxic drugs.
7. Manufactured BY:
Taj Pharmaceuticals Limited.
at Survey No.188/1 to, 190/1 to 4,
Athiyawad, Dabhel, Daman 396210
Melphalan 2 mg Tablets USP Taj Pharma
Package Leaflet: Information for the User
Read all of this leaflet carefully before you start taking this medicine.
- Keep this leaflet. You may need to read it again.
- If you have any further questions about your illness or your medicine, ask your doctor, nurse or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
- If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.
In this leaflet:
- What Melphalan is and what it is used for
2. Before you take Melphalan
3. How to take Melphalan
4. Possible side effects
5. How to store Melphalan
6. Further information
1 What Melphalan is and what it is used for
Melphalan tablets contain a medicine called melphalan. This belongs to a group of medicines called cytotoxics (also called chemotherapy). Melphalan is used to treat cancer. It works by reducing the number of abnormal cells your body makes.
Melphalan is used for:
- Multiple myeloma – a type of cancer that develops from cells in the bone marrow called plasma cells. Plasma cells help to fight infection and disease by producing antibodies
- Advanced cancer of the ovaries
- Advanced breast cancer
- Polycythaemia vera – a disease which increases the number of red cells in your blood. This makes the blood thicken and causes blood clots. This leads to headaches, dizziness and shortness of breath
Ask your doctor if you would like more explanation about these diseases.
2 Before you take Melphalan
Do not take Melphalan if:
- You are allergic (hypersensitive) to melphalan or any of the other ingredients of Melphalan tablets (See section 6: Further information)
Do not take if the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking Melphalan.
Take special care with Melphalan
Before you take Melphalan, tell your doctor or pharmacist if:
- you have had radiotherapy or chemotherapy, now or recently
- you have a kidney problem.
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Melphalan.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This includes herbal medicines.
In particular, you must tell your doctor if you are taking any of the following:
- other cytotoxic drugs (chemotherapy)
- nalidixic acid (an antibiotic used to treat urinary tract infections)
- ciclosporin (used to prevent rejection of organs or tissues following a transplant or to treat certain skin conditions like psoriasis and eczema or to treat rheumatoid arthritis).
Having vaccines while you are taking Melphalan
If you are going to have a vaccination speak to your doctor or nurse before you have it. This is because some vaccines (like polio, measles, mumps and rubella) may give you an infection if you have them whilst you are taking Melphalan.
Pregnancy and breast-feeding
Do not take Melphalan if you are planning to have a baby. This applies to both men and women. Melphalan may harm your sperm or eggs. Reliable contraceptive precautions must be taken to avoid pregnancy whilst you or your partner is taking these tablets. Ask your doctor for advice.
If you are already pregnant, it is important to talk to your doctor before taking Melphalan.
Do not breast-feed while taking Melphalan. Ask your doctor or midwife for advice.
3 How to take Melphalan
Melphalan should only be given to you by a specialist doctor who is experienced in treating blood problems or cancer.
Always take Melphalan exactly as your doctor has told you. It is important to take your medicine at the right times. The label on your pack will tell you how many tablets to take and how often to take them. If the label doesn’t say or if you are not sure, ask your doctor, nurse or pharmacist.
- Swallow your tablets whole with a glass of water.
- Do not break, crush or chew the tablets.
The dose of Melphalan depends on your blood problem or cancer (see section 1).
- Your doctor may also change your dose during your treatment, depending on your needs.
- The dose can sometimes be changed if you are elderly or have a kidney problem.
- When you take Melphalan, your doctor will take regular blood tests. This is to check the number of cells in your blood. Your doctor may sometimes change your dose as a result.
- The usual dose is 0.15 mg per kilogram of your body weight each day for 4 days. This is repeated every 6 weeks.
Advanced ovarian adenocarcinoma
- The usual dose is 0.2 mg per kilogram of your body weight each day for 5 days. This is repeated every 4 to 8 weeks.
Advanced breast carcinoma
- The usual dose is 0.15 mg per kilogram of your body weight each day for 5 days. This is repeated every 6 weeks.
- Initially 6 to 10 mg each day for 5 to 7 days. The dose will then be reduced to 2 to 4 mg each day.
If you take more Melphalan than you should
If you take more Melphalan than you should, tell your doctor immediately or go to a hospital straight away. Take the medicine pack with you.
If you forget to take Melphalan
Tell your doctor. Do not take a double dose to make up for a forgotten dose.
4 Possible side effects
Like all medicines, Melphalan can cause side effects, although not everybody gets them.
If you get any of the following, talk to your specialist doctor or go to hospital straight away:
- allergic reaction, the signs may include:
- a rash, lumps or hives on the skin
- swollen face, eyelids or lips
- sudden wheeziness and tightness of the chest
- collapse (due to cardiac arrest)
- any signs of fever or infection (sore throat, sore mouth or urinary problems)
- any unexpected bruising or bleeding or feeling extremely tired, dizzy or breathless, as this could mean that too few blood cells of a particular type are being produced
- if you suddenly feel unwell (even with a normal temperature).
Talk to your doctor if you have any of the following side effects which may also happen with this medicine:
Very common (affects more than 1 in 10 people)
- a drop in the number of blood cells and platelets
- feeling sick (nausea), being sick (vomiting) and diarrhoea
- mouth ulcers – with high doses of Melphalan
- hair loss – with high doses of Melphalan
Common (affects less than 1 in 10 people)
- hair loss – with usual doses of Melphalan
- high levels of a chemical called urea in your blood – in people with kidney problems who are being treated for myeloma
Rare (affects less than 1 in 1,000 people)
- an illness where you have a low number of red blood cells as they are being destroyed prematurely – this can make you feel very tired, breathless and dizzy and can give you headaches or make your skin or eyes yellow
- lung problems which may make you cough or wheeze and make it difficult to breathe
- liver problems which may show up in your blood tests or cause jaundice (yellowing of the whites of eyes and skin)
- mouth ulcers – with normal doses of Melphalan
- skin rashes or itching skin
The following side effects also happen with Melphalan:
- leukaemia – cancer of the blood
- in women: your periods stopping
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
5 How to store Melphalan
- Keep out of the reach and sight of children.
- Do not use Melphalan after the expiry date, which is stated on the pack after ‘Exp’.
- Store in a refrigerator between 2 and 8°C.
- If your doctor tells you to stop taking the tablets, it is important to return any which are left over to your pharmacist, who will destroy them according to disposal of dangerous substance guidelines. Only keep the tablets if your doctor tells you to.
6 Further information
What Melphalan contains
The active ingredient is melphalan. Each Melphalan tablet contains 2 mg of melphalan.
The other ingredients are microcrystalline cellulose, crospovidone, colloidal anhydrous silica, magnesium stearate, hypromellose, titanium dioxide and macrogol.
What Melphalan looks like and contents of the pack
Melphalan tablets are white to off-white film-coated, round, biconvex tablets.
7. Manufactured BY:
Taj Pharmaceuticals Limited.
at Survey No.188/1 to, 190/1 to 4,
Athiyawad, Dabhel, Daman 396210