Rotop - Dmsa
FDA Label NDC 71647-001

This Package Leaflet and Summary of Product Characteristics was translated by the manufacturer based on the original German document (Vs. 4), authorized by the German Federal Institute for Drugs and Medicinal Services in November 2014.

Package Leaflet and Summary of Product Characteristics

ROTOP - DMSA, 1.0 mg
Kit for radiopharmaceutical preparation
Succimer

In this leaflet:

1. What ROTOP – DMSA is and what it is used for
2. Before you use ROTOP – DMSA
3. How to use ROTOP – DMSA
4. Possible side effects
5. How to store ROTOP – DMSA
6. Further information

ROTOP - DMSA is a radiodiagnostic pharmaceutical. The kit contains the non-radioactive powder for reconstitution of the [^99mTc]technetium succimer injection solution ([^99mTc]-DMSA). The sodium [^99mT]pertechnetat which is needed for the preparation is not part of this kit.

After labelling with sodium [^99mTc]technetium pertechnetat solution, ROTOP - DMSA is used for static renal scintigraphy when adequate diagnostics are not possible using other diagnostic procedures (such as ultrasound):

• to identify focal renal parenchymal changes (e.g. in the case of renal infarction)
• to identify norm variants such as atypical double kidney, small kidney, dysplastic kidney, horseshoe kidney, as well as to identify ectopic kidneys
• to confirm absence of renal function in multicystic kidneys.

Take special care with ROTOP – DMSA

ROTOP - DMSA is not suitable for determining global renal function from the DMSA accumulation. In the case of proximal tubulopathies [^99mTc]DMSA does not lead to a sufficient diagnostic renal accumulation.

The patient must be well hydrated before and after administration. In order to keep radiation exposure to a minimum, patients must be encouraged to empty their bladders as often as possible during the first hours after the examination.

For each patient it should be carefully considered whether the expected diagnostic benefits outweigh the risk linked to radiation exposure. In order to keep the radiation dose as low as possible, the administered activity may not be higher than that required for eliciting the diagnostic information.

Radiopharmaceuticals may be received, used and administered only by authorised persons in areas specially designated for this purpose. The manipulation and use of these products is subject to the regulations of the local supervisory authority and/or requires appropriate permission.

Using other medicines

Chemotherapeutic agents such as methotrexate, cyclophosphamide and vincristine can alter the biodistribution of [^99mTc]DMSA.

Shifting the acid/base balance, e.g. through ammonium chloride or sodium hydrogen carbonate, effects in vivo a change in the valence of the [99mTc]DMSA complex and in turn a lower accumulation in the renal cortex with simultaneous strong accumulation in the liver and rapid urine excretion. Mannitol leads to dehydration and in turn to a reduction in the extraction of [^99mTc]DMSA.

In the case of renal artery stenosis, ACE inhibitors can lead to a reversible insufficiency of the tubular function and in turn to a reduced accumulation of [^99mTc]DMSA as a result of the reduction in filtration pressure in the affected kidney.

If high doses of other chelating agents are injected at the same time, the stability of the [^99mTc]DMSA DMSA may be influenced, thus effecting a change in kinetics.

Pregnancy and lactation

Pregnancy: No data on the clinical use of [^99mTc]DMSA with pregnant women is available. If it is necessary to administer a radiopharmaceutical product to a woman of child-bearing age, she must have a pregnancy test first.

If a woman has missed a period, it must be assumed that she is pregnant. In case of doubt, radiation exposure must be reduced to the minimum amount required to acquire the needed clinical information. In this case, alternative investigative methods must be considered that do not use ionising radiation. Radiopharmaceutical examinations of pregnant women also expose the foetus to radiation. For this reason, [^99mTc]DMSA may only be used if there is a vital indication and if the expected benefit outweighs the risk to mother and child.

Lactation: Before administering [^99mTc]DMSA to a breast-feeding mother, it must be considered whether the investigation could also be delayed until the mother has ceased breast-feeding and as to whether using a radiopharmaceutical is the most appropriate examination method, bearing in mind the secretion of activity into breast milk. If administering [^99mTc]DMSA is deemed necessary, breast-feeding must be interrupted for at least 12 hours, and the expressed breast milk discarded.

Driving and using machines

Effects on the ability to drive or use machines have not been described.

Precautions for avoiding hazards for the environment

Radiopharmaceuticals must be prepared and used by the user under precautions for the protection from ionizing radiation and taking pharmaceutical quality standards into account. In accordance with the guidelines for Good Pharmaceutical Manufacturing Practice, work must be done under aseptic conditions.

Patients treated with radiopharmaceuticals pose a risk for other persons based on external radiation exposure or contamination due to spilling urine, vomiting, etc. For this reason, the precautionary measures provided by the national radiation protection regulations must be observed. Contamination brought about by radioactivity that has been excreted by the patient must be avoided.

Single intravenous use after preparation with sodium [^99mTc]pertechnetate solution.

Adults are given 0.3 to 1.0 mg succimer and activities of 70 MBq.

Scintigraphic examinations should not be carried out until at least 1 hour after application; waiting 3 hours is preferable. In the case of very poor renal function, waiting periods of up to 6 hours should be observed. The patient must be well hydrated.

Children

The recommendation of the Paediatric Task Group of the European Association of Nuclear Medicine (EANM) of 1990 lists the paediatric dose scaled to body weight as a fraction of the adult dose:

Activity of less than 20 % (15 MBq) of the adult dose generally does not allow a satisfactory assessment to be derived from the examination.

If you use more ROTOP – DMSA than you should

Due to the low amounts of substances used, overdosage in the pharmacological sense is not expected. Exposure to radiation resulting from an overdosage of radioactivity can be reduced by forced diuresis.

As all medicinal products, ROTOP - DMSA can cause side effects, although not everybody gets them.

For assessing the side effects the frequency is classified as follows:

In very rare cases (< 0.01 %) after intravenous injection of the ready-to-use solution, hypersensitivity reactions have occurred such as locally confined or general rashes, itching, drop in blood pressure, headache, dizziness, nausea and vomiting. Reactions can occur up to 24 hours after the injection.

Although such reactions are very rare and usually very minor, appropriate instruments and medications for immediate treatment of allergic reactions (adrenaline, corticosteroids and antihistamines) should be within reach for possible emergency treatment at all times.

Since the administered amounts of active substances are very low, the risks of use are mainly related to radiation exposure. Ionising radiation can cause cancer and genetic mutations.

Since most radiopharmaceutical examinations are conducted with low effective radiation doses of less than 20 mSv, the probability of such effects occurring is expected to be low.

The effective radiation dose is 0.62 mSv when the maximum recommended activity of this medicinal product is applied.

Reporting of side effects

If you notice any side effects please contact your nuclear physician responsible for supervising the administration. This also applies to any side effects not listed in this leaflet.

You can also report any side effects directly to: Bundesinstitut für Arzneimittel und Medizinprodukte, Abt. Pharmakovigilanz, Kurt-Georg-Kiesinger Allee 3, D-53175 Bonn, website: http://www.bfarm.de.

By reporting side effects you can help provide more information on the safety of this medicine.

Keep out of the reach and sight of children.

Do not use this medicinal product after the expiry date stated on the label.

Storage conditions

Store refrigerated (2 to 8 °C) in the original package. Radiopharmaceuticals must be stored in accordance with the regulations for radioactive protection and in particular be kept from unauthorised access.

Shelf life after opening and reconstitution

The product labelled with [99mTc]technetium  can be injected within 4 hours after reconstitution and has to be stored at room temperature (15–25 °C) during this time.

What ROTOP – DMSA contains

One vial contains 1.74 mg powder with the active substance:
1.0 mg succimer

The other ingredients are:
Stannous chloride dihydrate
Ascorbic  acid
Sodium hydroxide
Hydrochloric acid 36%
Nitrogen

What ROTOP – DMSA looks like and contents of the pack:

The package consists of a carton with 5 vials.

Marketing Authorisation Holder and Manufacturer
ROTOP Pharmaka GmbH,
Bautzner Landstr. 400,
01328 Dresden,
Germany
Tel:  0049 + (0) 351 – 26 310 210
Fax: 0049 + (0) 351 – 26 310 313
e-mail: [email protected]

This medicinal product is authorised in the Member States of the EEA under the following names:
Germany: ROTOP - DMSA

This leaflet was last approved in November 2014.

The following information is intended for medical or healthcare professionals only:

Pharmacodynamic properties
Pharmacotherapeutic group: Diagnostic radiopharmaceutical for renal diagnostics (ATC: V09CA02). Based on current research, for the low amounts of substances used for imaging techniques no clinically relevant pharmacodynamic effects of [^99mTc]DMSA are expected.

Pharmacokinetic properties
After intravenous injection, within 5 minutes over 70% of the [^99mTc]DMSA is bound to theα-2 microglobulin fraction in blood plas ma. Binding to erythrocytes may be disregarded. One hour post injection, 25% of the radiopharmaceutical is already located in the renal cortex and only 30% remains in the plasma. Approx. 10% appears in the urine.

In healthy persons, the plasma clearance of [^99mTc]DMSA amounts to approx. 10 ml/min. (scaled to 1.73 sqm body surface). After approx. 3 hours, the maximum renal accumulation is reached. In healthy persons, at this point approx. 50% of the radiopharmaceutical is located in the renal cortex, approx. 20% remains in the plasma and just under 10% in the liver and muscles. Within 24 hours, approx. 30% is excreted with the urine.

[^99mTc]DMSA accumulates in the pars recta and convoluta of the proximal renal tubules – most likely due to peritubular reabsorption. On an intracellular level, the majority of the [^99mTc]DMSA is bound to a soluble protein in the cytosol. This mechanism, which has not yet been explained in detail, is disrupted in the case of proximal tubulopathies (such as nephritides or the Fanconi syndrome), which can be recognised by the increased plasma clearance of [^99mTc]DMSA and low renal accumulation.

Toxicological properties
Due to the low amounts of DMSA and stannous chloride contained in the kit, toxic effects brought about by the substances are not expected if used according to directions. Data on investigations on reproduction toxicity as well as on mutagenicity and cancerogenity are not available.

Special precautions for disposal and further directions for handling
The empty package is considered to be regular waste if the permitted level for [^99mTc]technetium is not exceeded (≤ 0.5 Bq/g or 0.5 Bq/cm²). Particulars indicating radioactivity must be removed prior to disposing of the non-radioactive waste and must be destroyed separately. Radioactive waste must be disposed of as provided by law.

MARKETING AUTHORISATION NUMBER
3003663.00.00

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
24/11/2005

Radiation exposure

According ICRP publication 80 (Table 1) the following radiation doses will be absorbed:

In an adult (70 kg), after intravenous injection of 70 MBq (maximum dose) [^99mTc]DMSA, the effective dose is approx. 0.62 mSv. The absorbed dose in the target organ kidney is approx. 12.6 mGy and in the critical organ bladder wall 1.26 mGy.

Radiophysical Properties

[^99mTc]technetium is produced using a [⁹⁹Mo/^99mTc] sterile generator and decays releasing gamma radiation with an energy of 140/142 keV with a half-life of 6.02 hours to [⁹⁹Tc]technetium, which in turn decays to stable [⁹⁹Ru]ruthenium; However, due to a long half-life of 214,000 years, ⁹⁹Tc itself is considered to be stable.

Instruction for labelling

[^99mTc]technetium succimer injection solution is prepared under sterile conditions with a sodium [^99mTc]pertechnetate injection solution (European Pharmacopoeia quality 4.00/0124 or 4.00/0283) directly before use. Oxygenation must be avoided.

Place the vial with powder in sufficient lead shielding with ample space and disinfect the stopper (allow disinfectant to dry). Use a syringe with the smallest possible cannula lumen to transfer 5 mL sodium [^99mTc]technetium pertechnetate solution with a maximum of 3 GBq to the vial. Use the same syringe to withdraw the appropriate gas volume from the vial for pressure compensation.

Lightly shake the vial in order to completely dissolve the powder. The stopper should be well moistened as well. After 10 minutes reaction time, measure the overall activity. If needed, the finished injection solution can be diluted with sterile isotonic sodium chloride to a total volume

of up to 10 mL.

Quality Control

Prior to use in the patient, the radiochemical purity of the [^99mTc]technetium succimer injection solution must be tested using the method described below:

Preparation:

Type of test:               Thin layer chromatography
Plates used:                Silica gel on a glass fibre plate, heated for 10 min.
                                   at 110°C prior to testing
Starting point:            1.5 cm from lower end of the plate
Migration distance:    10 to 15 cm (in approx. 15 minutes)

Execution:

Use a capillary tube or pipette to extract a volume of approx. 5 μl and apply it to the plate. Chromatography begins immediately with a solution of sodium chloride (9 g/L) over a migration distance of 10 to 15 cm. Allow the plate to air-dry, and use a detector to determine the distribution of radioactivity.

Evaluation:

[^99mTc]technetium in colloidal form remains at the starting point, and the [^99mTc]technetium succimer complex migrates to nearly the middle of the chromatogram.

Target value: ≤ 2.0% [^99mTc]pertechnetate

CLASSIFICATION FOR SUPPLY

Pharmacy-only medicine