PERTECTOR 2.3 - 57.1 GBQ RADIONUCLIDE GENERATOR - Summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Pertector 2.3 – 57.1 GBq radionuclide generator

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Sodium pertechnetate (99mTc) injection is produced by means of a (99Mo/99mTc) generator. Technetium (99mTc) decays with the emission of gamma radiation with an energy of 140 keV and a half-life of 6.02 hours to technetium (99Tc) which, in view of its long half-life of 2.13 × 105 years, can be regarded as quasi stable.

The radionuclide generator containing the parent isotope 99Mo, adsorbed on a chromatographic column delivers sodium pertechnetate (99mTc) injection in sterile solution.

The 99Mo on the column is in equilibrium with the formed daughter isotope 99mTc. The generators are supplied with the following 99Mo activity amounts at activity reference time which deliver the following technetium (99mTc) amounts, assuming a 100% theoretical yield and 24 hours time from previous elution and taking into account that branching ratio of 99Mo is about 87 %:

The technetium (99mTc) radioactivity available by a single elution contained in the sodium pertechnetate (99mTc) injection depends on the sodium molybdate (99Mo) amount on the column, the volume of the elution solution and the time period from the previous elution.

Excipient(s) with known effect:

Each mL of sodium pertechnetate (99mTc) solution contains 3.6 mg of sodium.

For the full list of excipients, see section 6.1.

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4

4.1

Radionuclide generator

This medicinal product is for diagnostic use only.

The eluate from the radionuclide generator (sodium pertechnetate (99mTc) injection) is indicated for:

labelling of various kits for radiopharmaceutical preparation developed and approved for radiolabelling with such solution

Thyroid scintigraphy: direct imaging and measurement of thyroid uptake to give information on the size, position, nodularity and function of the gland in case of thyroid disease.

Salivary gland scintigraphy: diagnosis of chronic sialadenitis (e.g. (Sjogren's Syndrom) as well as assessment of salivary gland function and duct patency in salivary glands disorders and monitoring of the response to therapeutic interventions (in particular radio iodine therapy).

Location of ectopic gastric mucosa (Meckel's diver­ticulum).

Lacrimal duct scintigraphy: to assess functional disorders of lacrimation and monitoring of the response to therapeutic interventions.

Shunt scintigraphy: after injection of the sterile sodium(99mTc)per­technetate solution into a Rickham reservoir to test the patency of ventricular shunts in hydrocephalus.

4.2 Posology and method of administration

Posology

This medicinal product is for use in designated nuclear medicine facilities only, and should only be handled by authorised personnel

If sodium pertechnetate (99mTc) is administered intravenously, activities may vary widely according to the clinical information required and the equipment employed. The injection of activities greater than local DRLs (Diagnostic Reference Levels) should be justified for certain indications. Recommended activities are as follows:

Adults (70 kg) and elderly population

Thyroid scintigraphy:       20–80 MBq

Salivary gland scintigraphy: 30 to 150 MBq for static images up to 370 MBq for dynamic images

Meckel's diver­ticulum scintigraphy: 300–400 MBq

Lacrimal duct scintigraphy: 2–4 MBq per drop per eye

Shunt scintigraphy: 3–4 MBq

Renal impairment

Careful consideration of the activity to be administered is required since an increased radiation exposure is possible in these patients.

Paediatric population

The use in children and adolescents has to be considered carefully, based upon clinical needs and assessing the risk/benefit ratio in this patient group.

The activity to be administered to children and adolescents must be adapted and may be calculated according to the recommendations of the European Association of Nuclear Medicine (EANM) paediatric dosage card; the activity administered to children and to adolescents may be calculated by multiplying a baseline activity (for calculation purposes) by the weight-dependent correction factor given in the table below (see Table 1).

A[MBq]Admnistere(| = Baseline Activity x Multiple

Thyroid scintigraphy:

Activity administered [MBq] = 5.6 MBq x correction factor (Table 1).

A minimal activity of 10 MBq is necessary for obtaining images of sufficient quality.

Identification/lo­cation of ectopic gastric mucosa:

Activity administered [MBq] = 10.5 MBq x correction factor (Table 1).

A minimal activity of 20 MBq is necessary in order to obtain images of sufficient quality.

Table 1: Thyroid scintigraphy and Identification/lo­cation of ectopic gastric

mucosa:

Weight-dependent correction factors in the paediatric population according to the EANM-May 2008 guidelines

Salivary gland scintigraphy:

The Paediatric Task Group of EANM (1990) recommends that the activity to be administered to a child should be calculated from the body weight according to the table below (see Table 2) with a minimum dose of 10 MBq in order to obtain images of sufficient quality.

Table 2: Salivary gland scintigraphy:

Weight-dependent correction factor in the paediatric population according to EANM 1990 recommen­dations

Lacrimal duct scintigraphy and shunt scintigraphy :

Recommended activities apply as well for adults as for children.

Method of administration

For multidose use.

For intravenous or ocular use.

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

For patient preparation, see section 4.4.

In thyroid scintigraphy, salivary gland scintigraphy and identification/lo­cation of ectopic gastric mucosa, the sodium pertechnetate (99mTc) solution is administered by intravenous injection.

In lacrimal duct scintigraphy, drops are instilled in each eye (ocular use).

In shunt scintigraphy sterile sodium(99mTc)per­technetate solution is injected into a Rickham reservoir.

Image acquisition

Thyroid scintigraphy: 20 minutes after intravenous injection.

Salivary gland scintigraphy: immediately after intravenous injection and at regular intervals for 15 minutes.

Dynamic images performed immediately after injection and at regular intervals up to 30 minutes.

The dynamic acquisition is recommended.

Identification/lo­cation of ectopic gastric mucosa: immediately after intravenous injection and at regular intervals for 30 minutes.

Lacrimal duct scintigraphy: dynamic acquisition within 2 minutes after instillation, followed by static images acquired at regular intervals within 20 minutes.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Information on the contraindications to the use of a kit for a radiopharmaceutical for radiolabelling can be found in the summary of product characteristics and the package leaflet for the kit.

4.4 Special warnings and precautions for use

Potential for hypersensitivity or anaphylactic reactions

If hypersensitivity or anaphylactic reactions occur, the administration of the medicinal product must be discontinued immediately and intravenous treatment initiated, if necessary. To enable immediate action in emergencies, the necessary medicinal products and equipment such as endotracheal tube and ventilator must be immediately available.

Individual benefit/risk justification

For each patient, the radiation exposure must be justifiable by the likely benefit. The activity administered should in every case be as low as reasonably achievable to obtain the required diagnostic information.

Renal impairment

Careful consideration of the benefit/risk ratio in these patients is required since an

increased radiation exposure is possible.

Paediatric population

For information on the use in paediatric population, see section 4.2 and 5.1.

Careful consideration of the indication is required since the effective dose per MBq is higher than in adults (see section 11).

Thyroid blocking is of special importance in the paediatric patient population except for thyroid scintigraphy.

Patient preparation

Pre-treatment of patients with thyroid-blocking medicinal products may be necessary for certain indications.

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.

To avoid false positive results or to minimise irradiation by reduction of pertechnetate[99mTc] accumulation in the thyroid and salivary glands, a thyroid blocking agent should be given prior to lacrimal duct scintigraphy or Meckel’s diver­ticulum scintigraphy.

Conversely a thyroid blocking agent must NOT be used before thyroid, parathyroid or salivary glands scintigraphy.

Before the application of sodium pertechnetate (99mTc) solution for scintigraphy of Meckel’s diver­ticulum the patient should be fasted for 3 to 4 hours to reduce intestinal peristalsis.

After in vivo labelling of erythrocytes using stannous ions for reduction sodium pertechnetate (99mTc) is primarily built into erythrocytes, therefore Meckel’s scin­tigraphy should be performed before or some days after in vivo labelling of erythrocytes.

After previous nuclear medicine studies using a stannous (II)-containing kit for a radiopharmaceutical product a waiting period of at least 8 days is indicated, as otherwise it may cause an undesirable labelling of red blood cells.

After the procedure

Close contact with infants and pregnant women should be restricted for the following 12 hours.

Specific warnings

Sodium pertechnetate (99mTc) solution for injection contains 3.6 mg/mL of sodium. Depending on the time when the injection is administered, the content of sodium given to the patient may in some cases be greater than 1 mmol (23 mg). This should be taken into account in patient on low sodium diet.

In salivary gland scintigraphy a lower specificity of the method should be expected compared to MR sialography.

When sodium pertechnetate (99mTc) solution is used for labelling of a kit, the determination of the overall sodium content must take into account the sodium derived from the eluate and the kit. Please refer to the SmPC and the package leaflet of the kit.

For precautions with respect to environmental hazard, see section 6.6.

4.5 Interaction with other medicinal products and other forms of interaction

Atropine, isoprenaline and analgesics may cause a delay of gastric emptying and thereby cause a redistribution of (99mTc) pertechnetate in abdominal imaging.

Administration of laxatives should be withheld since they irritate the gastrointestinal tract. Contrast-enhanced studies (e.g. barium) and upper gastro-intestinal examination should be avoided within 48 h prior to administration of pertechnetate (99mTc) for Meckel’s diver­ticulum scintigraphy.

Many pharmacological medicinal products are known to modify the thyroid uptake.

antithyroid medicinal products (e.g. carbimazole or other imidazole derivatives such as propylthiouracil), salicylates, steroids, sodium nitroprusside, sodium sulfobromophtalein, perchlorate should be withheld for 1 week prior thyroid scintigraphy;

phenylbutazone and expectorants should be withheld for 2 weeks;

natural or synthetic thyroid preparations (e.g. sodium thyroxine, sodium liothyronine, thyroid extract) should be withheld for 2–3 weeks

amiodarone, benzodiazepines, lithium should be withheld for 4 weeks

intravenous contrast agents should not have been administered within 1–2 months.

Stannous (II) ions and sulfonamides may increase the concentration of sodium [99mTc] pertechnetate in red blood cells, and there may be decreased accumulation in plasma and cerebral lesions. Such medicines should be discontinued at least 8 days before the procedure.

Increased uptake of (99mTc) pertechnetate in the walls of the cerebral ventricles has been reported as a result of methotrexate-induced ventriculitis in cerebral shunt scintigraphy.

Incompatibilities: Radiopharmaceutical preparations labelled with sodium pertechnetate (99mTc) may not be mixed with other medicinal products. After a nuclear medicine examination using a radiopharmaceutical kit containing stannous ions a waiting time of at least 8 days before administration of sodium pertechnetate (99mTc) is recommended.

Information on interactions when using a kit for a radiopharmaceutical for radiolabelling can be found in the manufacturer’s pro­duct information for the relevant kit.

4.6 Fertility, Pregnancy and lactation

Women of childbearing potential

When an administration of radiopharmace­uticals to a woman of childbearing potential is intended, it is important to determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. If in doubt about her potential pregnancy (if the woman has missed a period, if the period is very irregular, etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient.

Pregnancy

Technetium-99m (as free pertechnetate) has been shown to cross the placental barrier. Administration of pertechnetate (99mTc) to a woman who is known to be pregnant should be justified by medical need and a positive individual benefit risk assessment for the mother and the foetus. Alternative non-irradiating diagnostic modalities should be taken into account.

Direct administration of 400 MBq sodium pertechnetate (99mTc) to a patient results in an absorbed dose to the uterus of 3.2 mGy.

Following pretreatment of patients with a blocking agent, administration of 400 MBq sodium pertechnetate (99mTc) results in an absorbed dose to the uterus of 2.4 mGy.

Breastfeeding

Before administering radiopharmace­uticals to a mother who is breastfeeding, consideration should be given to the possibility of delaying the administration of radionuclide until the mother has ceased breastfeeding and to what is the most appropriate choice of radiopharmace­uticals, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary, breastfeeding should be interrupted for 12 hours post administration and the expressed feeds discarded.

Close contact with infants should be restricted during this period.

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

Summary of the safety profile

Information on adverse reactions is available from spontaneous reporting. The reported reaction types are anaphylactoid reactions, vegetative reactions, as well as different kinds of injection site reactions. Sodium pertechnetate (99mTc) from the Pertector radionuclide generator is used for radioactive labelling of a variety of compounds. These medicinal products generally have a higher potential for adverse reactions than compounds than 99mTc, and therefore the reported adverse reactions are rather related to the labelled compounds than to 99mTc. The possible types of adverse reactions following intravenous administration of a 99mTc-labelled pharmaceutical preparation will be dependent on the specific compound being used. Such information can be found in the SmPC of the kit used for radiopharmaceutical preparation.

Tabulated list of adverse reactions

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).

Immune system disorders

Frequency unknown*: Anaphylactoid reactions (e.g. dyspnoea, coma, urticaria, erythema, rash, pruritus, oedema at various location e.g. face oedema)

Nervous system disorders

Frequency unknown*: Vasovagal reactions (e.g. syncope, tachycardia, bradycardia, dizziness, headache, vision blurred, flushing) Gastrointestinal disorders

Frequency unknown*: Vomiting, nausea, diarrhoea

General disorders and administration site conditions

Frequency unknown*: Injection site reactions due to extravasation (e.g. cellulitis, pain, erythema, swelling)

* Adverse reactions derived from spontaneous reporting

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is 5.2 mSv when the maximal recommended activity of 400 MBq is administered these adverse reactions are expected to occur with a low probability.

Description of selected adverse reactions

Anaphylactic reactions (e.g. dyspnoea, coma, urticaria, erythema, rash, pruritus, oedema at various locations [e.g. face oedema])

Anaphylactic reactions have been reported following intravenous injection of sodium perchtechnetate (99mTc) and include various skin or respiratory symptoms like skin irritations, oedema, or dyspnoea.

Vegetative reactions (nervous system and gastrointestinal disorders)

Single cases of severe vegetative reactions have been reported, however, most of the reported vegetative reactions include gastrointestinal reactions like nausea or vomiting. Other reports include vasovagal reactions like headache or dizziness.

Vegetative reactions are rather considered to be related to the examinational setting than to technetium (99mTc), especially in anxious patients.

General disorders and administration site conditions

Other reports describe local injection site reactions. Such reactions are related to extravasation of the radioactive material during the injection, and the reported reactions rank from local swelling up to cellulitis. Depending on the administered radioactivity and the labelled compound, extended extravasation may necessitate surgical treatment.

Reporting of suspected adverse reactions

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

4.9 Overdose

In the event of administration of a radiation overdose with sodium pertechnetate (99mTc), the absorbed dose should be reduced where possible by increasing the elimination of the radionuclide from the body by defaecation, forced diuresis and frequent bladder voiding.

The uptake in the thyroid, salivary glands and the gastric mucosa can be significantly reduced when sodium perchlorate is given immediately after an accidentally high dose of sodium pertechnetate (99mTc) was administered.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diagnostic radiopharmace­uticals, various thyroid diagnostic radiopharmace­uticals, ATC code: V09FX01.

No pharmacological activity has been observed in the range of doses administered for diagnostic purposes.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing sodium pertechnetate (99mTc) in all subsets of the paediatric population in the granted indication (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Distribution

The pertechnetate ion has similar biological distribution to iodide and perchlorate ions, concentrating temporarily in salivary glands, choroid plexus, stomach (gastric mucosa) and in the thyroid gland, from which it is eliminated, unchanged. The pertechnetate ion also tends to concentrate in areas with increased vascularisation or with abnormal vascular permeability, particularly when pre-treatment with blocking agents inhibits uptake in glandular structures. With intact blood brain barrier, sodium pertechnetate (99mTc) does not penetrate into the brain tissue.

Organ uptake

In the blood 70–80% of the intravenously injected sodium pertechnetate (99mTc) is bound to proteins, primarily in an unspecific way to albumin. The unbound fraction (20–30%) accumulates temporarily in thyroid and salivary glands, stomach and nasal mucous membranes as well as in the plexus chorioideus.

Sodium pertechnetate (99mTc) in contrast to iodine, nevertheless, is neither used for the thyroid hormone synthesis (organification), nor absorbed in the small intestine. In the thyroid the maximum accumulation, depending on functional status and iodine saturation (in euthyroidism approx. 0.3–3%, in hyperthyroidism and iodine depletion up to 25%) is reached about 20 min after injection and then decreases quickly. This also applies for the stomach mucous membrane parietal cells and the salivary glands acinar cells.

In contrast to the thyroid which releases sodium pertechnetate (99mTc) in the bloodstream the salivary glands and the stomach secrete sodium pertechnetate (99mTc) in the saliva and gastric juice, respectively. The accumulation by the salivary gland lies in the magnitude of 0.5% of the applied activity with the maximum reached after about 20 minutes. One hour after injection, the concentration in the saliva is about 1030 fold higher than in the plasma. The excretion can be accelerated by lemon juice or by stimulation of the parasympathetic nerve system, the absorption is reduced by perchlorate.

Elimination

Half life in plasma is approximately 3 hours. Sodium pertechnetate (99mTc) is not metabolised in the organism. One fraction is eliminated very quickly renally, the rest more slowly via faeces, salivary and tear liquid. Excretion during the first 24 hours following administration is mainly urinary (approximately 25 %) with faecal excretion occurring over the next 48 hours. Approximately 50 % of the administered activity is excreted within the first 50 hours. When selective uptake of pertechnetate (99mTc) in glandular structures is inhibited by the preadministration of blocking agents, excretion follows the same pathways but there is a higher renal clearance.

The above data are not valid when sodium pertechnetate (99mTc) is used for labelling of another radiopharmace­utical.

5.3 Preclinical safety data

There is no information on acute, subacute and chronic toxicity from single or repeated dose administration. The quantity of sodium pertechnetate (99mTc) administered during clinical diagnostic procedures is very small and, apart from allergic reactions, no other adverse reactions have been reported.

This medicinal product is not intended for regular or continous administration. Mutagenicity studies and long-term carcinogenicity studies have not been carried out.

Reproductive toxicity

Placental transfer of 99mTc from intravenously administered sodium pertechnetate (99mTc) has been studied in mice. The pregnant uterus was found to contain as much as 60% of the injected 99mTc when administered without perchlorate preadministration. Studies performed on pregnant mice during gestation, gestation and lactation, and lactation alone showed changes in progeny which included weight reduction, hairlessness and sterility.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The technetium-99m is generated from sodium [99Mo]molybdate adsorbed onto an aluminium oxide column. The generator column is eluted with sterile sodium chloride solution to produce the eluate, Sodium Pertechnetate (99mTc) Injection, which contains the following excipients:

Sodium chloride

Water for injections

Benzododecinium bromide (bacteriostatic solution)

Nitric acid (pH adjustment)

Sodium hydroxide (pH adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except for those mentioned in section 12.

6.3 Shelf life

Generator: 14 days from date of calibration. The calibration date and the expiry date are stated on the label.

Sodium pertechnetate (99mTc) eluate: After elution, use within 12 hours.

Elution vials with 0.9% NaCl solution and evacuated injection vials: 12 months.

6.4 Special precautions for storage

Generator:

Do not freeze.

Do not store above 30°C.

Sodium pertechnetate (99mTc) eluate:

Do not freeze.

Do not store above 25°C

For storage conditions after elution of the medicinal product, see section 6.3

Storage of radiopharmace­uticals should be in accordance with national regulation on radioactive materials.

6.5 Nature and contents of container

Pertector is composed of (see figure):

Sterile glass column filled with aluminium oxide (1), on which the primary radionuclide 99Mo is adsorbed. The upper end and floor of the column are sealed with a rubber stopper that is secured by a metal cap.

Stainless steel needle set (2) that provide the connection for the generator column with the eluent injection vials and the evacuated injection vials. During transport and intervals between elutions, these needles are protected by two injection vials containing a bacteriostatic solution (0.02% aqueous benzododecinium bromide solution).

Lead shield (3) that is 50 mm thick, in which the generator column and needles are housed.

Sterile filters (4 and 9) for the eluate and the air that is drawn into the eluate injection vial.

Eluate volume control (5) that can be used to set the desired eluate volume (4 to 8 ± 0.5 ml) and, thus, the desired radioactive concentration of the eluate. This is set by turning the upper sleeve according to the scale that is illustrated.

The following material is supplied with the generator:

16 injection vials of elution solution (0.9% NaCl solution) and 16 evacuated injection vials (receptacles for the eluate).

Shielding canister (8) that acts as a holder for the elution injection vial.

The injection vials (sodium chloride solution and vacuum) are 10 ml glass vials with rubber stoppers and a cap.

Elution solution (0.9% NaCl solution) and evacuated injection vials (vials for the eluate) can be ordered separately as accessories.

Figure: Generator construction

Pack sizes

Radionuclide generator with activities of 2.3, 4.6, 5.7, 6.9, 8.5, 9.1, 11.4, 13.7, 14.9, 17.1, 19.4, 21.1, 22.9, 26.3, 28.6, 34.3, 40.0, 45.7 or 57.1 GBq molybdenum-99 and corresponding variable technetium-99m activities at calibration time. The activity of the generator at the point of calibration is indicated on each pack.

6.6 Special precautions for disposal

General warnings

Radiopharmace­uticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the competent official organisation.

Radiopharmace­uticals should be prepared in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

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

If at any time the integrity of the generator or the vial with the eluted solution is compromised, it should not be used.

Administration procedures should be carried out in a way to minimise risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

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

The residual activity of the generator must be estimated before disposal.

Safe handling

The weight of a generator is about 16 kg. When lifting and carrying the generator attention has to be payed to safety. To limit the risk of injuries, the regulations for safe handling currently in force, must be observed.

Disposal of generators after the expiry date

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

Full instructions describing how the return of generators to the manufacturer should be carried out are included with each generator. Users are reminded that all packaging, documentation and methods of transportation used must be in compliance with international transport regulations and all local regulations and codes of practice that relate to such matters.