Alkeran

Main information

  • Trade name:
  • Alkeran 2 mg Film coated tablet
  • Dosage:
  • 2 mg
  • Pharmaceutical form:
  • Film coated tablet
  • Units in package:
  • Bottle, glass, Type III amber glass/PP cap, 25 tablets
  • Class:
  • Prescription
  • Prescription type:
  • Prescription
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug
  • Manufactured by:
  • Ampac Fine Chemicals LLC

Documents

Localization

  • Available in:
  • Alkeran 2 mg Film coated tablet
    New Zealand
  • Language:
  • English

Other information

Status

  • Source:
  • Medsafe - Medicines Safety Authority - New Zealand
  • Authorization number:
  • 10081
  • Authorization date:
  • 17-01-2001
  • Last update:
  • 27-09-2017

Summary of Product characteristics: dosage,interactions,side effects

ALKERAN

Melphalan Tablets 2mg_Datasheet_New Zealand

DATA SHEET

1.

PRODUCT NAME (strength pharmaceutical form)

ALKERAN

(Melphalan Tablets 2mg)

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2mg melphalan

3.

PHARMACEUTICAL FORM

Film-coated tablets

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

ALKERAN tablets are indicated in the treatment of:

Multiple myeloma;

Advanced ovarian adenocarcinoma;

ALKERAN tablets may be used in the treatment of:

Breast carcinoma: ALKERAN either alone or in combination with other medicines has

a significant therapeutic effect in a proportion of patients suffering from advanced

breast carcinoma;

Polycythaemia rubra vera: ALKERAN is effective in the treatment of a proportion of

patients suffering from polycythaemia vera.

4.2 Dose and method of administration

General:

ALKERAN is a cytotoxic medicine 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 (see Special

Warnings and Special 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.

ALKERAN

Melphalan Tablets 2mg_Datasheet_New Zealand

Multiple myeloma:

A typical oral dosage schedule is 0.15mg/kg bodyweight/day in divided doses for 4

days repeated at intervals of 6 weeks. Numerous regimens have, however, been

used and the scientific literature should be consulted for details.

The administration of oral ALKERAN and prednisone may be more effective than

ALKERAN alone. The combination is usually given on an intermittent basis.

Prolonging treatment beyond one year in responders does not appear to improve

results.

Advanced ovarian adenocarcinoma:

A typical regimen is 0.2mg/kg bodyweight/day orally for 5 days. This is repeated

every 4 to 8 weeks, or as soon as the peripheral blood count has recovered.

Carcinoma of the breast:

ALKERAN has been given orally at a dose of 0.15mg/kg bodyweight or 6mg/m

body

surface area/day for 5 days and repeated every 6 weeks. The dose was decreased if

bone marrow toxicity was observed.

Polycythaemia rubra vera:

For remission induction, doses of 6 to 10mg daily for 5 to 7 days have been used,

after which 2 to 4mg daily were given until satisfactory disease control was achieved.

A dose of 2 to 6mg once per week has been used for maintenance therapy.

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

careful haematological control.

Use in children:

ALKERAN, within the conventional dosage range, is only rarely indicated in children

and absolute dosage guidelines cannot be provided.

Use in the elderly:

Although ALKERAN is frequently used at conventional dosage in the elderly, there is

no specific information available relating to its administration to this patient sub-

group.

Dosage in renal impairment:

(See also Special Warnings and Special Precautions for Use).

ALKERAN clearance, though variable, is decreased in renal impairment.

Currently available pharmacokinetic data do not justify an absolute recommendation

on dosage reduction when administering ALKERAN tablets to patients with renal

ALKERAN

Melphalan Tablets 2mg_Datasheet_New Zealand

impairment, but it may be prudent to use a reduced dosage initially until tolerance is

established.

4.3 Contraindications

ALKERAN

should

given

patients

have

suffered

previous

hypersensitivity reaction to melphalan.

4.4 Special warnings and precautions for use

ALKERAN

ACTIVE

CYTOTOXIC

AGENT

UNDER

DIRECTION

PHYSICIANS

EXPERIENCED

ADMINISTRATION

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.

4.5 Safe handling of ALKERAN: (Special precautions for disposal).

Monitoring:

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.

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.

ALKERAN should be used with caution in patients who have undergone recent

radiotherapy or chemotherapy in view of increased bone marrow toxicity.

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 Posology and Method of Administration), and these patients should

be closely observed.

Temporary significant elevation of the blood urea has been seen in the early stages

of melphalan therapy in myeloma patients with renal damage.

Mutagenicity:

Chromosome aberrations have been observed in patients being treated with the

medicine.

Carcinogenicity:

Melphalan,

common

with

other

alkylating

agents,

been

reported

to

leukaemogenic in man. There have been reports of acute leukaemia occurring after

ALKERAN

Melphalan Tablets 2mg_Datasheet_New Zealand

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.

4.6 Interaction with other medicines and other forms of interaction

Vaccinations

with

live

organism

vaccines

recommended

immunocompromised individuals (see Special Warnings and Special Precautions for

Use).

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

conditioned

with high-dose

intravenous melphalan

and who

subsequently

received cyclosporin to prevent graft-versus-host disease.

4.7 Fertility, pregnancy and lactation

Teratogenicity:

teratogenic

potential

ALKERAN

been

studied.

In view

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 medicine.

Effects on fertility:

ALKERAN

causes

suppression

ovarian

function

premenopausal

women

resulting in amenorrhoea in a significant number of patients.

There is evidence from some animal studies that ALKERAN can have an adverse

effect on spermatogenesis. Therefore, it is possible that ALKERAN may cause

temporary or permanent sterility in male patients.

Pregnancy:

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be

practised when either partner is receiving ALKERAN.

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.

ALKERAN

Melphalan Tablets 2mg_Datasheet_New Zealand

Lactation:

Mothers receiving ALKERAN should not breast-feed.

4.8 Effects on ability to drive and use machines

No data

4.9 Undesirable effects

The most common side effect is bone marrow depression, leading to leucopenia,

thrombocytopenia and anaemia.

Gastrointestinal effects such as nausea and vomiting have been reported in up to

30% of patients receiving conventional oral doses of ALKERAN. Hepatic disorders

ranging from abnormal liver function tests to clinical manifestations such as hepatitis

and jaundice occur rarely.

Stomatitis occurs rarely following conventional doses of ALKERAN.

Allergic

reactions

ALKERAN

such

urticaria,

oedema,

skin

rashes

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.

Maculopapular rashes and pruritus have occasionally been noted.

There have also been case reports of fatal pulmonary fibrosis and haemolytic

anaemia occurring after melphalan treatment.

Alopecia has been commonly reported at conventional doses and occurs very

commonly at high doses.

Reporting of suspected adverse reactions

Healthcare professionals are asked to report any suspected adverse reactions

https://nzphvc.otago.ac.nz/reporting/

4.10 Overdose

Symptoms and signs:

Gastro-intestinal effects, including nausea, vomiting and diarrhoea are the most likely

early signs of acute oral overdosage.

principal

toxic

effect

bone

marrow

suppression,

leading

leucopenia,

thrombocytopenia and anaemia.

Management:

General

supportive

measures,

together

with

appropriate

blood

platelet

transfusions,

should

instituted

necessary,

consideration

given

ALKERAN

Melphalan Tablets 2mg_Datasheet_New Zealand

hospitalisation, cover with anti-infective agents, and the use of haematological growth

factors.

There is no specific antidote. The blood picture should be closely monitored for at

least 4 weeks following overdosage until there is evidence of recovery.

For advice on the management of overdose please contact the National Poisons

Centre on 0800 POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic Properties

Mode 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.

5.2 Pharmacokinetic Properties

The absorption of melphalan was found to be highly variable in 13 patients given

0.6mg/kg bodyweight orally, with respect to both the time to first appearance of the

medicine in plasma (range 0 to 336 minutes) and peak plasma concentration (range

70 to 630ng/mL). In 5 of the patients who were given an equivalent intravenous dose,

the mean absolute bioavailability of melphalan was found to be 56

27%. The

plasma mean terminal elimination half-life was 90

57 minutes with 11% of the

medicine being recovered in the urine over 24 hours.

In a study of 18 patients administered melphalan 0.2 to 0.25mg/kg bodyweight orally,

a maximum plasma concentration (range 87 to 350ng/mL) was reached within 0.5 to

2.0 hours. The mean elimination half-life was 1.12

0.15 hours.

The administration of ALKERAN 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%.

5.3 Preclinical safety data

Melphalan is mutagenic in animals.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet Core:

Microcrystalline cellulose

Crospovidone

ALKERAN

Melphalan Tablets 2mg_Datasheet_New Zealand

Colloidal anhydrous silica

Magnesium stearate

Tablet Film Coating:

Hypromellose

Titanium dioxide

Macrogol

6.2 Incompatibilities

None known

6.3 Shelf-life

24 months

6.4 Special precautions for storage

Store at 2

C to 8

6.5 Nature and contents of container

ALKERAN are white to off-white film-coated, round, biconvex tablets engraved “GX

EH3” on one side and “A” on the other, supplied in amber glass bottles with a child

resistant closure. Each pack contains 25 tablets.

6.6 Special precautions for disposal

Safe handling of ALKERAN tablets:

The handling of ALKERAN tablets should follow guidelines for the handling of

cytotoxic

medicines

according

prevailing

local

recommendations

and/or

regulations.

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

ALKERAN Tablets.

ALKERAN tablets should not be divided.

Disposal:

ALKERAN tablets should be destroyed in accordance with relevant local regulatory

requirements concerning the disposal of cytotoxic medicines.

7.

MEDICINE SCHEDULE

Prescription Only Medicine

8.

SPONSOR

Pharmacy Retailing Pty Ltd

Trading as Healthcare Logistics

58 Richard Pearse Drive

Airport Oaks

Auckland

New Zealand

ALKERAN

Melphalan Tablets 2mg_Datasheet_New Zealand

9.

DATE OF FIRST APPROVAL

22 December 2006

10. DATE OF REVISION OF THE TEXT

10 March 2017

ALKERAN

TM

is a trade mark of Aspen. All rights reserved.

SUMMARY TABLE OF CHANGES

Section Changed

Summary of New Information

Format of Data sheet

As per new European SmPC style format