Annex I : CSP
METASTRON Strontium [89Sr] chloride
37 MBq/ml solution for injection
Agreed Core Safety Profile (CSP)
Revision dated: September 2011
4.3 Contraindications
Metastron should not be used as a primary treatment for cord compression secondary to spinal
metastases where more rapid treatment may be necessary.
Use of the product in patients with evidence of seriously compromised bone marrow, particularly low
neutrophil and platelet counts, is not recommended unless the potential benefit of the treatment is
considered to outweigh the risk.
4.4 Special warnings and precautions for use
Individual benefit/risk justification:
For each patient, exposure to ionising radiation must be justifiable on the basis of likely benefit. The
activity administered must be such that the resulting radiation dose is as low as reasonably achievable
bearing in mind the need to obtain the intended therapeutic result. 1
Renal impairment:
Careful consideration of the benefit risk ratio in patients with renal impairment is required since an
increased radiation exposure is possible. 2
Paediatric population:
Careful consideration is required since the effective dose per MBq is higher than in adults. 3
Patient preparation:
The patient should be well hydrated before the start of the examination and urged to void as often as
possible during the first hours after the examination in order to reduce radiation. Special precautions,
such as urinary catheterisation, should be taken following administration of Metastron to patients who
are significantly incontinent to minimise risks of radioactive contamination. International guidelines
for disposal of radioactive waste must be followed.
1
Source: Guideline on core SmPC and package leaflet for radiopharmaceuticals, EMA/CHMP/167834/2011,
slightly modified.
2 Source: Guideline on core SmPC and package leaflet for radiopharmaceuticals , EMA/CHMP/167834/2011
Justification: EANM procedure guideline for treatment of refractory metastatic bone pain (DOI
10.1007/s00259-008-0841-y): Poor renal function reduces the plasma clearance of bone-seeking
radiopharmaceuticals, thus leading to a hingher whole-body dose and risk of myelotoxicity. Therefore, patients
with severely reduced renal function: creatinine >180µmol/l and/or GFR <30ml/min should be excluded.
The guideline continues: The safety and toxicity of treatment in patients with renal insufficiency has not been
thoroughly investigated.
However, an increase of myelosuppressive toxicity is expected because of the impairment of renal excretion. It
is, therefore, advised to lower the administered dose by 50% in patients with creatinine clearance <50 ml/min
[…]. Repeated treatment in the case of acceptable toxicity must be considered after 8 weeks.
Society of Nuclear Medicine Procedure Guideline for Palliative Treatment of Painful Bone Metastases (v3.0,
January 25, 2003): Renal failure may require reducing the activity injected.
3 Source: Guideline on core SmPC and package leaflet for radiopharmaceuticals, EMA/CHMP/167834/2011
Justification: There are published case reports of use of strontium-89 in children. Indication of Metastron (as
mentioned in the PSUR assessment report: “Bone scan-proven multifocal osteoplastic [should read: osteoblastic]
metastasis” or “Metastron is indicated for the palliation of pain from bone metastases” is not necessarily limited
to adults and elderly.
Specific warnings:
Use of the product in patients with evidence of seriously compromised bone marrow, particularly low
neutrophil and platelet counts, is not recommended unless the potential benefit of the treatment is
considered to outweigh the risk. The following values can be considered in general: Leukocytes
>3000/μl, platelets >100,000/μl and haemoglobin (Hb) >90 g/l. 4
It is recommended that the haematology of patients should be monitored. In considering repeat
administration of Metastron the patient’s haematological response to his initial dose, current platelet
levels and any other evidence of marrow depletion should all be carefully considered.
A cytotoxic agent may be administered to a patient who has previously received Metastron provided
that haematological parameters are stable and within the normal range. An interval of 12 weeks is
recommended between administrations of the two therapies.
Therapy with Metastron is inappropriate for patients with a life expectancy less than 4 weeks.
Considering the latency in the onset of the palliative effect, is more beneficial in patients with a
relatively long life expectancy. 5
It should be taken into account in patient management that the expected time of onset of pain relief is
10 to 20 days following Metastron administration. 6 Retention of 89Sr in metastatic bone lesions is
probably 90 days or more and thus significantly prolonged compared with retention in normal bone
tissue.7
Care should be exercised in the pre-treatment assessment of the haematological status of patients who,
for the same cause, have previously received extensive bone radiation and/or another injectable boneseeking isotope.
It is important that information concerning this treatment and the associated safety precautions are
given to the patient, relatives and hospital staff.
4
Justification: EANM procedure guideline for treatment of refractory metastatic bone pain (DOI
10.1007/s00259-008-0841-y): Contraindications (relative): Low blood cell count, within certain limits, may
represent a relative contraindication to the use of boneseeking radiopharmaceuticals for the possible
myelotoxicity. Nevertheless, the precise lower limit is not well-defined in literature and the use of granulocyte
CSFs may lower further the limit. Routinely, the following values can be considered [as relative
contraindications]:
1. Haemoglobin <90 gl−1,
2. Total white cell count <3.5×109 l−1,
3. Platelet count <100×109 l−1.
In selected situations, however, lower values can be considered: values of WBC ≥2.4×109 l−1 may be used;
values of PLT, such as ≥60×109 l−1, can be considered, provided that chronic disseminated intravascular
coagulation (DIC) can be excluded by means of coagulation tests.
5 Justification: This requirement is considered to be too restrictive. According to the EANM guideline, Therapy
with 89Sr, 153Sm-lexidronam or 186Re-etidronate is inappropriate for patients with a life expectancy less than 4
weeks and, considering the latency in the onset of the palliative effect, is more beneficial in patients with a
relatively long life expectancy.
6 Justification: EANM procedure guideline for treatment of refractory metastatic bone pain (DOI
10.1007/s00259-008-0841-y): The patient should be told that pain reduction is unlikely within the first week,
more probable in the second week and could occur as late as 4 weeks or longer after injection, particularly for
long-lived isotopes.
7 Justification: According to Blake (Blake GM, Zivanovic MA, McEwan AJ, Ackery DM. Sr-89 therapy:
Strontium kinetics in disseminated carcinoma of the prostate. Eur J Nucl Med 1986;12:447-454), metastatic
uptake of strontium profoundly affected whole body retention, with 90 day retentions that varied from the
normal value of 20% in patients with limited skeletal involvement to 88% in one patient with a prostatic
superscan (i.e., essentially complete skeletal involvement).
Data on a competing compound, Quadramet, suggest 5-6 times as long a bone retention in lesions compared to
normal bone. It is, however, questionable if this can be extrapolated to Metastron, since Quadramet not only uses
a diffent isotope (153Sm) but also uses a bisphosphonate carrier molecule, which in itself is known to have very
long lasting bone retention.
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This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodiumfree.8
4.5 Interaction with other medicinal products and other forms of interaction
Calcium therapy should be discontinued at least two weeks before Metastron administration.
4.6 Fertility, pregnancy and lactation
Not relevant due to indication
4.7 Effects on ability to drive and use machines
No studies on the effects on ability to drive and use machines have been performed.
4.8 Undesirable effects
The frequencies of undesirable effects are defined as follows:
Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000
to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data)
Blood and lymphatic system disorders
Very common: Bone marrow depression, including serious thrombocytopenia, serious leukopenia,
reduced haemoglobin or low red blood cell count (see section 4.4). 9
General disorders and administration site conditions
Very common: Pain exacerbated (transient)
Vascular disorders
Common: Flushing 10
Adverse effects may include an exacerbation of pain within the first few days of administration. In
clinical trials this effect was temporary and controlled with analgesics. 11
Some degree of haematological toxicity, including thrombocytopenia and leucopenia, is to be expected
following administration of Metastron. Typically platelets will be depressed by about 30% (95%
confidence limits 10-55%) compared to pre-administration levels. Because of the natural progress of
their disease, more severe depression of platelet levels may be observed in some patients. 11
4.9 Overdose
Not applicable
8
Source: Guideline on core SmPC and package leaflet for radiopharmaceuticals, EMA/CHMP/167834/2011
Justification: Silberstein EB. Systemic radiopharmaceutical therapy of painful osteoblastic metastases.
Seminars in Radiation Onclogy 2000;10(3):240-249. Myelotoxicity is the primary adverse event, which can
rarely lead to life-threatening thrombocytopenia or leukopenia. In fact, several deaths have been reported from
thrombocytopenic bleeding cause by both 89Sr chloride and 153Sm-lexidronam. There are a number of causes of
thrombocytopenia which must also be considered. Low platelet (and leukocyte) counts may also be produced by
recent or current chemotherapy or radiotherapy, from metastatic disease replacing bone marrow, or from
disseminated intravascular coagulation (platelets only).
10 Justification: Observed in clinical trial MET301 with Metastron. Eight of 90 (8,9%) experienced flush.
11 Justification: Common information in the EU
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