Quadramet - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Quadramet 1.3 GBq/mL solution for injection.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 1.3 GBq Samarium (153Sm) lexidronam pentasodium at the reference date (corresponding to 20 to 80 ^g/ml of samarium per vial)

Samarium specific activity is approximately 16 – 65 MBq/^g of samarium.

Each vial contains 2–4 GBq at the reference date.

Samarium-153 emits both medium-energy beta particles and an imageable gamma photon, and has a period of 46.3 hours (1.93 days). The primary radiation emissions of samarium-153 are shown in Table 1.

TABLE 1 : SAMARIUM-153 PRINCIPAL RADIATION EMISSION DATA

Maximum energies are listed for the beta emissions, the average beta particle energy is 233 keV.

Excipient with known effect: sodium 8.1 mg/mL.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear, colourless to light amber solution with pH ranging between 7.0 and 8.5.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Quadramet is indicated for the relief of bone pain in patients with multiple painful osteoblastic skeletal metastases which take up technetium (99mTc)-labelled biphosphonates on bone scan.

The presence of osteoblastic metastases which take up technetium (99mTc)-labelled biphosphonates should be confirmed prior to therapy.

4.2 Posology and method of administration

Quadramet should only be administered by physicians experienced in the use of radiopharmace­uticals and after full oncological evaluation of the patient by qualified physicians.

Posology

The recommended dose of Quadramet is 37 MBq per kg body weight.

Paediatric population

Quadramet is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.

Method of administration

Quadramet is to be administered by slow intravenous route through an established intravenous line over a period of one minute. Quadramet should not be diluted before use.

Patients who respond to Quadramet generally experience the onset of pain relief within 1 week after treatment. Relief of pain may persist for 4 weeks up to 4 months. Patients who experience a reduction in pain may be encouraged to decrease their use of opioid analgesics.

Repeat administration of Quadramet should be based on an individual patient's response to prior treatment and on clinical symptoms. A minimum interval of 8 weeks should be respected, subject to recovery of adequate bone marrow function.

The data on the safety of repeated dosing are limited and based on compassionate use of the product.

For instructions on preparation of the medicinal product before administration, see section 12.

4.3 Contraindications

• • Hypersensitivity to the active substance (ethylenediami­netetramethyle­nephosphonate (EDTMP) or similar phosphonates) or to any of the excipients excipients listed in section 6.1.
• • in pregnant women (See section 4.6).
• • in patients having received chemotherapy or hemi-body external radiation therapy in a preceding period of 6 weeks.

Quadramet is used only as a palliative agent and should not be used concurrently with myelotoxic chemotherapy as this may enhance myelotoxicity.

It should not be used concurrently with other biphosphonates if an interference is shown on the technetium (99mTc)-labelled biphosphonate bone scans.

4.4 Special warnings and precautions for use

In absence of clinical data, the injected activity should be adapted to the renal function.

Use of Quadramet in patients with evidence of compromised bone marrow reserve from previous therapy or disease involvement is not recommended unless the potential benefit of the treatment outweighs its risks.

Because of potential bone marrow suppression after administration, blood counts should be monitored weekly for at least 8 weeks, beginning 2 weeks after administration of Quadramet, or until recovery of adequate bone marrow function.

The patient should be encouraged to ingest (or receive by intravenous administration) a minimum of 500 ml of fluids prior to injection and should be encouraged to void as often as possible after injection to minimise radiation exposure to the bladder.

The clearance of Quadramet being rapid, the precautions relating to the excreted urinary radioactivity need not be taken after 6–12 hours following administration.

Special precautions, such as bladder catheterisation, should be taken during six hours following administration to incontinent patients to minimise the risk of radioactive contamination of clothing, bed linen, and the patient's envi­ronment. For the other patients the urine should be collected for at least six (6) hours.

Bladder catheterisation should be undertaken in patients with urinary obstruction.

Radiopharmace­uticals may be received, used and administered only by authorised persons in designated clinical settings. Its receipt, storage, use, transfer and disposal are subject to the regulations and the appropriate licences of the local competent official organisations.

Radiopharmace­uticals should be prepared by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken, complying with the requirements of Good Manufacturing Practice for pharmaceuticals.

4.5 Interaction with other medicinal products and other forms of interaction

Because of the potential for additive effects on bone marrow, the treatment should not be given concurrently with chemotherapy or external beam radiation therapy. Quadramet may be given subsequent to either of these treatments after allowing for adequate marrow recovery.

4.6 Fertility, pregnancy and lactation

Pregnancy

Quadramet is contra-indicated (see 4.3) in pregnancy. The possibility of pregnancy must strictly be ruled out. Women of childbearing potential have to use effective contraception during the treatment and the whole period of follow-up.

Breast-feeding

There are no available clinical data relating to the excretion of Quadramet in human milk. If therefore Quadramet administration is deemed necessary, formula feeding should be substituted for breastfeeding and the expressed feeds discarded.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

Decreases in white blood cell and platelet counts and anaemia were observed in patients receiving Quadramet.

In clinical trials white blood cell and platelet counts decreased to a nadir of approximately 40 % to 50 % of baseline 3 to 5 weeks after a dose, and generally returned to pre-treatment levels by 8 weeks post treatment.

The few patients who experienced Grade 3 or 4 hematopoietic toxicity usually either had a history of recent external beam radiation therapy or chemotherapy or had rapidly progressive disease with probable bone marrow involvement.

Postmarketing reports of thrombocytopenia have included isolated reports of intracranial haemorrhage, and cases in which the outcome was fatal.

A small number of patients have reported a transient increase in bone pain shortly after injection (flare reaction). This is usually mild and self-limiting and occurs within 72 hours of injection. Such reactions are usually responsive to analgesics.

Adverse drug reactions such as nausea, vomiting, diarrhoea and sweating were reported.

Hypersensitivity reactions including rare cases of anaphylactic reaction have been reported after Quadramet administration.

A few patients experienced cord/root compressions, disseminated intravascular coagulation and cerebrovascular accidents. The occurrence of these events may be linked to the patients’ disease evolution. When there are spinal metastases at the cervico-dorsal level, an increased risk of spinal cord compression cannot be excluded.

The radiation dose resulting from therapeutic exposure may result in higher incidence of cancer and mutations. In all cases, it is necessary to ensure that the risks of the radiation are less than from the disease itself.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

4.9 Overdose

The product should only be administered by qualified personnel in authorised settings. The possibility of pharmacological overdose is therefore remote.

The risks to be expected are associated with the inadvertent administration of excess radioactivity. Radiation dose to the body can be limited by promoting a diuresis and frequent voiding of urine.

5. PHARMACOLOGIC PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Various pain palliation radiopharmace­uticals.

ATC Code: V10BX02

Mechanism of action

Quadramet has an affinity for skeletal tissue and concentrates in areas of bone turnover in intimate association with hydroxyapatite.

Pharmacodynamic effects

Studies in rats have demonstrated that Quadramet is cleared rapidly from the blood and localises to growing areas of bone matrix, specifically the layer of osteoid undergoing mineralisation.

Clinical efficacy and safety

In clinical studies employing planar imaging techniques, Quadramet accumulates with a lesion-to-normal bone ratio of approximately 5 and a lesion-to-soft tissue ratio of approximately 6. Thus, areas of metastatic involvement can accumulate significantly greater amounts of Quadramet than surrounding normal bone.

5.2 Pharmacokinetic properties

Absorption

Total skeletal uptake of Quadramet in studies of 453 patients with a variety of primary malignancies was 65.5 ± 15.5 % of the administered activity. A positive correlation was found between skeletal uptake and the number of metastatic sites. In contrast, skeletal uptake was inversely proportional to plasma radioactivity at 30 minutes.

Elimination

In patients, Quadramet is rapidly cleared from the blood. Thirty minutes after injection of the agent to 22 patients, only 9.6 ± 2.8 % of the administered activity remained in plasma. At 4 and 24 hours, plasma radioactivity had decreased from 1.3 ± 0.7 % to 0.05 ± 0.03 %.

Urinary excretion occurred predominantly during the first 4 hours (30.3 ± 13.5 %). At 12 hours, 35.3 ± 13.6 % of the administered activity had been excreted into the urine. Less urinary excretion occurred in patients who had extensive bony metastases, regardless of the amount of radiopharmaceutical administered.

Biotransformation

Analysis of urine samples found the radioactivity to be present as the intact complex

5.3 Preclinical safety data

The radiolysis products of Sm-EDTMP showed a renal toxicity in rats and dogs with a no effect level of 2.5 mg/kg.

Repeated dose administration of samarium (153Sm)-EDTMP to dogs indicated a slightly longer time for depressed bone marrow and peripheral haematological parameters to recover when compared to recovery following only single dose administration.

Radioactive Sm-EDTMP has not been tested for mutagenicity/car­cinogenicity but due to the radiation dose resulting from therapeutic exposure it should be regarded as presenting a genotoxic/car­cinogenic ris­k.

Non-radioactive Sm-EDTMP showed no mutagenic potential in a battery of in vivo and in vitro tests. The same results were observed for Sm-EDTMP enriched with radiolysis degradants.

In a carcinogenic potential study of EDTMP, osteosarcomas occurred in rats at high doses. In the absence of genotoxic properties, these effects can be assigned to the EDTMP chelatant properties leading to osseous metabolism disturbances.

No studies have been performed to assess the effect of Quadramet on reproduction.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Total EDTMP (as EDTMP.H2O)

Calcium-EDTMP sodium salt (as Ca)

Total sodium (as Na)

Water for Injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with the other medicinal products.

• 6.3 Shelf-life

• 1 day from the activity reference time stated on the label.

Use within 6 hours of thawing. After thawing, do not freeze again.

6.4 Special precautions for storage

Quadramet is delivered frozen in dry ice.

Store in a freezer at –10°C to –20°C in the original package.

Storage procedures should be in accordance with local regulations for radioactive substances.

6.5 Nature and contents of container

15 ml colourless European Pharmacopoeia Type I drawn glass vial closed with Teflon-coated chlorobutyl/natural rubber stopper and aluminium flip-off overseal.

Each vial contains 1.5 ml (2 GBq at calibration) to 3.1 ml (4 GBq at calibration) of solution for injection.

6.6 Special precautions for disposal and other handling

The administration of radiopharmace­uticals creates risks for other persons from external radiation or contamination from spills of urine, vomiting etc. Radiation protection precautions in accordance with national regulations must therefore be taken.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

(See section 12, for detailed instructions of product preparation)

7. MARKETING AUTHORISATION HOLDER

CIS bio international

Boîte Postale 32

F-91192 GIF-SUR-YVETTE Cedex

FRANCE

8. MARKETING AUTHORISATION NUMBER

EU/1/97/057/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

Date of first authorisation: 05 February 1998

Date of latest renewal: 12 December 2007