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________24/12/2006_________________ ‫תאריך‬
_ ALKERAN Injection__‫שם תכשיר באנגלית‬
_________ 65-79-28146-10 ___________‫מספרי רישום‬
__GlaxoSmithKline (ISRAEL) Ltd. __‫שם בעל הרישום‬
‫השינויים בעלון מסומנים על רקע צהוב‬
‫לרופאא‬
‫בעלון לרופ‬
‫בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
MULTIPLE MYELOMA
High-dose regimens generally employ single i.v.
doses of between 100 and 200 mg/m2 body surface
area (approximately 2.5 to 5.0 mg/kg bodyweight),
but haematopoietic stem cell rescue becomes
essential following doses in excess of 140 mg/m2
body surface area. In cases of renal impairment, the
dose should be reduced by 50% (see Dosage and
Administration - Renal Impairment). In view of the
severe myelosuppression induced by high- dose
Melphalan Injection, treatment should be confined to
specialist centres with the appropriate facilities, and
only be administered by experienced clinicians (see
Warnings and Precautions).
OVARIAN ADENOCARCINOMA
•
Children
In cases of renal impairment, the dose should be
reduced by 50% (see Dosage in Renal
Impairment). In view of the severe
myelosuppression induced by high- dose Alkeran
Injection, treatment should be confined to specialist
centres with the appropriate facilities, and only be
administered by experienced clinicians (see
Precautions).
Melphalan, 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.
• Elderly
Although Melphalan is frequently used at
conventional dosage in the elderly, there is no specific
information available relating to its administration to
this patient sub-group.
Experience in the use of high-dose Alkeran in
elderly patients is limited. Consideration should
therefore be given to ensure adequate performance
status and organ function before using high-dose
Alkeran Injection in elderly patients.
Experience in the use of high-dose Melphalan in
elderly patients is limited. Consideration should
therefore be given to ensure adequate performance
status and organ function before using high-dose
Melphalan Injection in elderly patients.
• Dosage in Renal impairment
For high intravenous doses of Alkeran (100 to 240
mg/m2 body surface area), the need for dose
reduction depends upon the degree of renal
impairment, whether autologous bone marrow stem
cells are reinfused, and therapeutic need. As a
guide, for moderate to severe renal impairment
(EDTA clearance 30 to 50 ml/min) a dose reduction
of 50% is usual. Adequate hydration and forced
diuresis are also necessary. High-dose Alkeran is
not recommended in patients with more severe renal
impairment (EDTA clearance less than 30 ml/min).
The pharmacokinetics of intravenous melphalan has
not shown a correlation between age and melphalan
clearance or with melphalan terminal elimination
half-life. The limited data available do not support
specific dosage adjustment recommendations for
elderly patients receiving intravenous melphalan and
suggested that current practice of dosage adjustment
based upon the general condition of the geriatric
patient and the degree of myelosuppression incurred
during therapy should be continued.
• Renal impairment
For high intravenous doses of Melphalan (100 to 240
mg/m2 body surface area), the need for dose reduction
depends upon the degree of renal impairment, whether
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‫פרק בעלון‬
Page 1 of 4
Dosage and
Administration
haematopoietic stem cells are reinfused, and
therapeutic need. As a guide for high dose melphalan
treatment without haematopoietic stem cell rescue in
patients with moderate renal impairment (creatinine
clearance 30 to 50 ml/min) a dose reduction of 50% is
usual. High-dose Melphalan without haematopoietic
stem cell rescue is not recommended in patients with
more severe renal impairment
High dose melphalan with haematopoietic stem cell
rescue has been used successfully even in dialysis
dependent patients with end-stage renal failure. The
relevant literature should be consulted for details.
The following tests should be performed at the start
of therapy and prior to each subsequent dose of
Alkeran : platelet count, hemoglobin, white blood
cell count, and differential. Thrombocytopenia
and/or leukopenia are indications to withhold
further therapy until the blood counts have
sufficiently recovered.
Immunisation using a live organism vaccine has the
potential to cause infection in immunocompromised
hosts. Therefore, immunisations with live organism
vaccines are not recommended.
Parenteral administation
In patients receiving high-dose Melphalan
Injection, consideration should be given to the
prophylactic administration of anti-infective
agents, the administration of blood products as
required
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Warning and
Precautions
Hypersensitivity reactions including anaphylaxis
have occurred in approximately 2% of patients who
received the intravenous formulation (see Side and
adverse 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, intravenous or
oral melphalan should not be readministered since
hypersensitivity reactions have been reported with
oral melphalan.
Vaccinations with live organism vaccines are not
recommended in immunocompromised individuals
(see Warnings and Precautions).
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).
Blood and Lymphatic System Disorders
Very common: bone marrow depression leading to
Renal impairment
Temporary significant elevation of the blood urea
has been seen in the early stages of melphalan
therapy in myeloma patients with renal damage.
In patients receiving high-dose Alkeran Injection,
consideration should be given to the prophylactic
administration of anti-infective agents, the
administration of blood products as required, and
the maintenance of a high renal output during the
period immediately following the administration of
Alkeran by the use of hydration and forced diuresis.
Hypersensitivity Reaction
Interactions
Side and adverse effects
The most common side-effect is bone marrow
depression, leading to leucopenia and
thrombocytopenia.
White blood cell count and platelet count nadirs
usually occur 2 to 3 weeks after treatment, with
recovery in to 5 weeks after treatment. Irreversible
bone marrow failure has been reported.
Gastro-intestinal effects such as nausea and
vomiting have been reported in up to 30% of
patients receiving conventional oral doses of
Alkeran.
Stomatitis occurs rarely following conventional
doses of Alkeran .
The incidence of diarrhoea, vomiting and stomatitis
Page 2 of 4
Adverse
Reactions
becomes the dose- limiting toxicity in patients
given high intravenous doses of Alkeran in
association with autologous bone marrow
transplantation. Cyclophosphamide pretreatment
appears to reduce the severity of gastro-intestinal
damage induced by high-dose Alkeran and the
literature should be consulted for details.
Allergic reactions to Alkeran 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.
Hepatic toxicity, including veno-occlusive disease,
has been reported.
There have been case reports of interstitial
pneumonitis and pulmonary fibrosis;
fatal reports of pulmonary fibrosis have been
received .
leucopenia, thrombocytopenia and anaemia
Rare: haemolytic anaemia
Immune System Disorders
Rare: allergic reactions (see Adverse Reactions 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 i.v.
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)
Gastrointestinal Disorders
Very common: nausea, vomiting and diarrhoea;
stomatitis at high dose
Rare: stomatitis at conventional dose
The incidence of diarrhoea, vomiting and stomatitis
becomes the dose-limiting toxicity in patients given
high i.v. doses of melphalan in association with
haemopoietic stem cell rescue. Cyclophosphamide
pretreatment appears to reduce the severity of
gastro-intestinal damage induced by high-dose
melphalan and the literature should be consulted for
details.
Maculopapular rashes and pruritus have
occasionally been noted.
There have also been case reports of haemolytic
anaemia occuring after melphalan treatment.
Temporary significant elevation of the blood urea
has been seen in the early stages of melphalan
therapy in myeloma patients with renal damage .
Alopecia has been reported but is uncommon at
conventional doses.
A subjective and transient sensation of warmth
and/or tingling was described in approximately twothirds of patients with haematological malignancies
who were given high-dose Alkeran Injection via a
central line.
Hepatobiliary Disorders
Rare: hepatic disorders ranging from abnormal liver
function tests to clinical manifestations such as
hepatitis and jaundice;
Rare: veno-occlusive disease following high dose
treatment
Skin and Subcutaneous Tissue Disorders
Very common: alopecia at high dose
Common: alopecia at conventional dose
Rare: maculopapular rashes and pruritus (see
Adverse Reactions - Immune System Disorders)
Musculoskeletal and Connective Tissue Disorders
Injection, following isolated limb perfusion:
Very common: muscle atrophy, muscle fibrosis,
myalgia, blood creatine phosphokinase increased.
Common: compartment syndrome
Not known: muscle necrosis, rhabdomyolysis
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
General Disorders and Administration Site
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Page 3 of 4
Conditions
Very common: subjective and transient sensation of
warmth and/or tingling
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