Cardiogen-82 3.3–5.6 GBq radionuclide generator

This medicinal product is for diagnostic use only.

The generator eluate (solution of rubidium-82 (Rb-82) chloride for injection) is used for Positron Emission Tomography (PET) imaging of the myocardium at rest or under pharmacologic stress conditions to evaluate regional myocardial perfusion in adults with suspected or known coronary artery disease (CAD).

Posology

In adults and the elderly

The recommended activity in adults is 1100 to 2220 MBq (this activity must be adjusted according to the patient's body size, PET equipment used, and imaging technique employed). This activity must be administered via intravenous infusion.

Do not exceed a single dose of 2220 MBq.

Renal and hepatic impairment

A reduction in hepatic or renal function is not anticipated to alter clearance of rubidium-82 (Rb-82) chloride solution, because Rb-82 decays to stable krypton-82 (Kr-82) gas with a half-life of 75 seconds, and Kr-82 gas is naturally expelled through the lungs. Therefore, no adjustments are required for renal and hepatic impairment.

Paediatric population

The safety and efficacy of Cardiogen-82 have not been established for children.

It is not expected that children would be a significant population for Rb-82 PET myocardial perfusion imaging (MPI). If Rb-82 PET MPI of a child is being considered under special circumstances, careful consideration of the administration is required, since the effective absorbed dose per MBq is higher than in adults. Alternative techniques which do not involve ionizing radiation should be considered.

Method of administration

Intravenous administration via infusion. Cardiogen-82 should be used with an appropriate infusion system designed specifically for use with the Cardiogen-82 generator, e.g. Cardiogen-82 Infusion System Model 510 or Model 1701.

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

For patient preparation, see section 4.4.

This radiopharmaceutical should be administered at a rate of 50 mL/minute (Model 510 or Model 1701) or 20 mL/minute (Model 1701 only) through a catheter inserted into a large peripheral vein, with the total volume not exceeding 100 mL. The elution rate should never exceed 50 mL/minute, as this could lead to breakthrough of strontium-82 (Sr-82).

Image acquisition

In general, two single doses should be administered in order to carry out both a rest imaging and a pharmacological stress imaging session:

For myocardial perfusion rest imaging:

- Administer a single dose of rubidium (Rb-82) chloride solution.

- Start imaging 60 to 90 seconds after completion of the infusion of the rest dose, and acquire images for 5 minutes.

For myocardial perfusion pharmacological stress imaging:

- In order to avoid the presence of residual activity from the previous infusion, and to allow time for the generator to accumulate a sufficient quantity of Rb-82, wait at least 10 minutes after completion of the previous rubidium (Rb-82) chloride dose infusion before starting the pharmacological stress test.

- Administer the pharmacological stressor in accordance with its prescribing information (using a vasodilator approved for this purpose).

- After the interval recommended in the prescribing information of the pharmacological stressor, administer the second single dose of rubidium (Rb-82) chloride.

- Start imaging 60 to 90 seconds after completion of the infusion of the stress dose, and acquire images for 5 minutes.

Patients with severe heart failure

In patients with a clinically significant reduction in cardiac function (output, LVEF), a longer circulation time may be anticipated. In such case, it may be necessary to increase the interval between infusion and image acquisition, e.g., to 120 seconds. Such patients should be clinically monitored following the infusion (see section 4.4).

Pregnancy

The eluate must not be used if the specified generator eluate limits for strontium-82 (Sr-82) and/or strontium-85 (Sr-85) have been exceeded (see section 4.4).

Cardiogen-82 is contraindicated for use with solutions other than additive-free Sodium Chloride Infusion 9 mg/mL (0.9% w/v) (see section 4.4).

Individual benefit/risk justification

For each patient, the ionising 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.

Heart failure patients

Patients with congestive heart failure should be monitored particularly carefully during infusion because of the transitory increase in blood volume.

The application of vasodilator pharmacologic stress may cause serious adverse reactions such as myocardial infarction, arrhythmia, hypotension, broncho-constriction, and cerebrovascular events. Perform testing only in setting where cardiac resuscitation equipment and trained staff are readily available.

For pharmacological stress imaging, the procedure should be performed at a medical facility where cardiac monitoring and resuscitation equipment are available. Please refer to the Summary of Product Characteristics of the pharmacological stress agent being administered.

Paediatric population

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

Patient preparation

Patients must be fasting for at least 6 hours, and refrain from caffeinated beverages, food and drugs containing caffeine for at least 12 hours prior to the test.

Failure to respond to pharmacological stress may be due to prolonged caffeine effects or longer serum caffeine clearance, which is seen in some individuals.

Medications that may interfere with responses to a pharmacological stress test (e.g., anti-anginal medicines) should be evaluated for modifications prior to the test by the patient's physicians. Dipyridamole should be stopped for 24 hours, and xanthine-containing drugs for 48 hours, prior to the test.

After the PET scan

Due to the very short half-life of rubidium-82 (Rb-82), no special precautions need to be taken with regard to radioactivity.

Specific warnings

Rubidium-82 (Rb-82) chloride solution for injection is intended only for intravenous administration using an appropriate infusion system (see section 12) capable of accurate measurement and administration of doses of rubidium-82 (Rb-82) chloride, with a single dose not exceeding 2220 MBq and a cumulative dose not exceeding 4440 MBq, at a maximum rate of 50 mL/min, with a maximum volume per infusion of 100 mL, and a total volume not exceeding 200 mL.

Strontium-82 (Sr-82) and strontium-85 (Sr-85) impurities are subject to bone sequestration and subsequent accumulation in bone tissue due to their long half-lives (25.35 days for Sr-82 and 64.84 days for Sr-85). Long-term safety implications of exposure to Sr-82 and Sr-85 are unknown; therefore, the eluate must not be used if the specified generator eluate limits have been exceeded (see section 4.3).

Rubidium-82 (Rb-82) chloride solution contains sodium. According to the time of injection, the content of sodium administered may in some cases be greater than 1 mmol. This should be taken into account in patients on strict low sodium diets.

For precautions with respect to environmental hazard, see section 6.6

Rubidium-82 (Rb-82) chloride solution contributes to a cumulative ionising radiation exposure.

Use the lowest dose of rubidium-82 (Rb-82) chloride injection necessary for imaging and ensure safe handling to protect the patient and health care worker.

Encourage patients to void as soon as a study is completed and as often as possible thereafter for at least one hour.

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. However, as the effective dose is 6 mSv when the maximal recommended cumulative radioactivity of 4440 MBq is administered, these adverse reactions are expected to occur with a low probability.

No interaction studies have been performed.

Drugs known to inhibit the activity of myocardial Na+/K+/ATPase pumps, such as cardiac glycosides (e.g., digoxin), may generally reduce Rb-82 myocardial uptake.

Proton pump inhibitor (PPI) use is associated with an increased gastric uptake of Rb-82. Spill over from gastric uptake could impact on the interpretation of adjacent myocardium on Rb-82 PET MPI studies. Withholding PPI > 36 hours prior to Rb-82 PET MPI may reduce the potential spill over from gastric uptake.

Women of childbearing potential

Pregnancy must be ruled out before the procedure is performed.

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.

Pregnancy

The use of this medicinal product is contraindicated in pregnant women (see section 4.3).

No animal studies have been carried out with rubidium-82 (Rb-82) with regard to reproduction. The risks to the foetus when Rb-82 is used in pregnant women are not known. However, radioactivity has the potential to cause genetic abnormalities, although these have not been observed at this activity level.

Breast-feeding

It is unknown whether rubidium-82 (Rb-82) is excreted in human milk. Due to the short half-life of Rb-82 (75 seconds) significant excretion is unlikely, and what is excreted will rapidly decay. However, because many active substances are excreted in human milk, including strontium-82 (Sr-82) and strontium-85 (Sr-85), which are present in the Cardiogen-82 generator, caution should be exercised when rubidium-82 (Rb-82) chloride solution is administered to nursing women. In general, it is sufficient for women to resume breastfeeding no sooner than one hour after the last rubidium-82 (Rb-82) chloride infusion, after having expressed and discarded milk that has accumulated in the interim.

Fertility

No studies have been carried out on fertility.

The effects on the ability to drive and use machines have not been studied.

The patient's cardiovascular status and any undesirable effects should be taken into account when judging this ability.

No undesirable effects associated with Cardiogen-82 have been observed during the clinical study.

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is 6 mSv when the maximal recommended cumulative radioactivity of 4440 MBq is administered, these adverse reactions are expected to occur with a low probability.

High level radiation exposure to the bone marrow has occurred in some patients due to strontium-82 (Sr-82) and strontium-85 (Sr-85) breakthrough in the eluate when an incorrect solution was used to elute the rubidium-82 (Rb-82) generator (see Section 12.2).

Unintended patient exposure to ionising radiation due to contamination with strontium can occur in patients receiving rubidium-82 (Rb-82) chloride from the Cardiogen-82 generator at clinical sites where quality control is not carried out correctly. Strict adherence to the instructions regarding quality control at clinical sites is required (see section 12).

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard, or search for MHRA Yellow Card in the Google Play or Apple App Store.

Due to the nature of the product and its use, a clinically significant overdose of rubidium-82 (Rb-82) is unlikely. In order to avoid administration of a large quantity of strontium-82 (Sr-82) and/or strontium-85 (Sr-85) (breakthrough), the instructions for use should be strictly adhered to and the maximum elution rate should not exceed 50 mL/minute.

Pharmacotherapeutic group: diagnostic radiopharmaceuticals, other diagnostic radiopharmaceuticals for the cardiovascular system, ATC code: V09GX04

Mechanism of action

Rubidium-82 (Rb-82) is analogous to potassium ion (K+) in its biochemical behaviour and is rapidly extracted by the myocardium proportional to the blood flow. Rb-82 participates in the sodium-potassium (Na+/K+) ion exchange pumps that are present in cell membranes. The intracellular uptake of Rb-82 requires maintenance of an ionic gradient across cell membranes. Rb-82 radioactivity is increased in viable myocardium reflecting intracellular retention, while the tracer is cleared rapidly from necrotic or infarcted tissue.

No pharmacological activity has been observed in the dose levels of Rb-82 administered for diagnostic purposes. The use of Cardiogen-82 in medical diagnostics is based on the biodistribution properties of Rb-82.

Pharmacodynamic effects

At the chemical concentrations and activities recommended for diagnostic examinations, rubidium-82 (Rb-82) chloride does not appear to have any pharmacodynamic activity.

In human studies, myocardial activity was noted within the first minute after peripheral intravenous infusion of Rb-82. When areas of infarction or ischaemia are present in the myocardium, these appear as photon-deficient areas within 2-7 minutes after infusion.

In patients with reduced cardiac function (LVEF < 50%), it may take longer for the rubidium (Rb-82) to reach and be taken up by the myocardium, and uptake may also be diminished (see section 4.4).

As the blood flow carries Rb-82 to all parts of the body during the first circulation, uptake of the tracer is also observed in other tissues such as the kidneys, liver, spleen and lungs.

Clinical efficacy and safety

Hyafil et al. (J Nucl Cardiol 2020) conducted a prospective intra-individual comparison in a population of 169 men with BMI ≥ 25 kg/m² and 144 women referred for clinically indicated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), and with an intermediate prevalence of coronary artery disease (CAD) pre-test (> 30% with Diamond and Forrester clinical score or > 3 cardiovascular risk factors). Patients were not eligible if they had known CAD or cardiomyopathy, or had undergone coronary angiography (CA) in the previous 2 years. All individuals underwent Rb-82 positron emission tomography (PET) MPI with 3D PET/CT, and 99mTc-sestamibi SPECT MPI with a cadmium-zinc-telluride (CZT) gamma camera, performed within 90 days of each other. Experienced nuclear cardiologists analysed the MPI studies separately, and were blinded to the results of each other's analyses; automated methods were used to obtain summed stress, rest and difference scores. Myocardial blood flow (MBF) and flow reserve (MFR) were quantified on PET using data from dynamic acquisitions. Subjects who were negative for significant CAD on both scans were followed up for 1 year for the development of coronary events. Subjects who were positive for significant CAD on either or both MPI scans underwent invasive coronary angiography (ICA) with fractional flow reserve (FFR) measurements. Positivity on CA was defined as significant stenosis as follows: coronary stenosis ≥ 50% and FFR ≤ 0.8; coronary stenosis ≥ 50% for the left main artery; coronary stenosis ≥ 70% or occlusion for other vessels. In the absence of CA, positivity was defined as an occurrence of an acute coronary event during the following year. Five patients were excluded (uninterpretable scans / inflammatory arteritis) and 14 declined CA or follow-up, leaving 294 patients. Thirty-seven (37) patients had myocardial ischaemia. Overall, Rb-82 PET MPI was found to have a sensitivity of 83.8% and a specificity of 93.8%, while 99mTc-sestamibi SPECT MPI with a modern CZT camera had a sensitivity of 56.8% and a specificity of 96.1%. Receiver operating characteristic (ROC) curve analysis showed Rb-82 PET MPI to possess the highest area under the curve (AUC, 0.94, vs. 0.86 for 99mTc-sestamibi SPECT MPI). It was suggested that the greater sensitivity of Rb-82 PET MPI was due to more accurate detection of balanced myocardial ischemia, potentiated by the ability with PET to obtain myocardial flow and flow reserve data.

In a systematic review and meta-analysis of 15 published Rb-82 PET MPI clinical studies including 1,344 patients, and 8 published 99mTc SPECT MPI studies including 1,755 patients (McArdle et al. J Am Coll Cardiol 2012), pooled accuracy using weighted averages according to the size of the patient populations was determined for PET and SPECT. Inclusion criteria were publication in peer-reviewed journals, patient populations with ischemic heart disease, MPI performed with either Rb-82 PET or 99mTc SPECT with both ECG gating and attenuation correction (AC) with either CT or transmission sources, the use of ICA as a reference standard for the diagnosis of obstructive CAD, and diagnostic performance being reported on a per-patient basis. For the PET compared to the SPECT studies, a higher proportion of patients were male (63.5% vs. 55%), with a higher baseline CAD prevalence (63% vs 50%), fewer patients with a low likelihood of CAD (13% vs 30%) and more patients with previous MI (30% vs 3.4%) and prior coronary intervention (32% vs. 3.2%). The overall pooled sensitivity and specificity of Rb-82 PET MPI for the detection of obstructive CAD were 90% (95% CI: 0.88 to 0.92) and 88% (95% CI: 0.85 to 0.91), respectively. Comparison of studies where >50% stenosis on ICA was used as a reference with >70% showed no significant difference in diagnostic accuracy (AUC: 0.948 vs. 0.954, respectively). The overall pooled sensitivity and specificity for 99mTc SPECT MPI with ECG-gating and AC were 85% (95% CI: 0.82 to 0.87) and 85% (95% CI: 0.82 to 0.87), respectively. Subgroup analysis showed that accuracy for a >50% stenosis on ICA was superior to >70% (AUC: 0.91 and 0.87, respectively). Analysis of SPECT studies where patients with known CAD or previous myocardial infarction were excluded did not alter diagnostic accuracy significantly. However, when patients with a low likelihood of CAD were excluded, there was a marked decrease in the specificity of SPECT, to 70% (95% CI: 0.66 to 0.75) with an AUC of 0.86. For PET, when patients with a low likelihood of CAD were excluded, diagnostic accuracy was unchanged (AUC 0.94), with a small decrease in specificity to 86% (95% CI: 0.82 to 0.90).

Distribution

After intravenous administration, blood clearance of Rb-82 takes place quickly due to the high rate of diffusion from the capillaries of the myocardium into the interstitial fluid; the extraction fraction of Rb-82 is 65%.

Organ uptake

Rb-82 is taken up by the myocardial cells via Na⁺/K⁺-ATPase pumps. The increase in Rb-82 uptake decreases as myocardial blood flow increases.

Myocardial uptake of Rb-82 is seen in the first minute following injection of Rb-82 chloride. Uptake may be delayed in patients with a clinically significant reduction in cardiac function.

Rb-82 uptake is also observed in the kidneys, liver, spleen and lungs.

Elimination

With a physical half-life of 75 seconds, Rb-82 is converted very rapidly by radioactive decay into a trace amount of stable Kr-82 gas which is expelled naturally by the lungs. Renal and hepatic excretion is not expected to play an essential role in the elimination of Rb-82, although some of the Rb-82 dose may be excreted in the urine before radioactive decay.

A single intravenous injection of rubidium-82 (Rb-82) chloride at the maximum dose (20 mL/kg at a rate of 0.1 mL/5 seconds) did not result in toxicity in mice.

There was no toxicity with repeated administration of 10 mL/kg/day or 3.0 mL/kg/day rubidium-82 (Rb-82) chloride for 14 days in mice and dogs, respectively.

Rubidium-82 (Rb-82) chloride is not intended for regular or continuous administration.

Mutagenicity studies and long-term carcinogenicity studies have not been carried out.

Solution for elution: Sodium Chloride Infusion 9 mg/mL (0.9% w/v)

This medicinal product must not be used with other medicinal products except those mentioned in section 12.2.

Generator: 42 days after the calibration date

The calibration date and expiration date are stated on the generator labelling.

The generator must not be used if any of its expiration limits are reached:

- 42 days have passed since the calibration date,

- A total elution volume of 17 L has passed through the column since first use of the generator,

- Eluate Sr-82 level exceeds 1x10^-5 MBq/MBq of Rb-82 after elution,

- Eluate Sr-85 level exceeds 1x10^-4 MBq/MBq of Rb-82 after elution.

Rubidium-82 (Rb-82) chloride eluate: use immediately upon elution.

Generator: Store below 25°C.

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

Eluate: Do not store. Use immediately upon elution; see section 6.3.

Due to the short half-life of Rb-82, almost all radioactivity in the eluate disappears within 15 minutes following the end of elution.

The generator is supplied in a type A transport container. It is housed in lead shielding surrounded by a labelled plastic container.

The primary packaging is composed of the “immediate” packaging in contact with the drug product which includes the column components.

Figure 1 shows the complete column assembly. The polypropylene column comprises PVC connector tubing with non-sterile protective caps. The polypropylene column includes a glass fibre Millipore filter with an aluminium seal and a polypropylene spacer ring which locks into the polypropylene column.

For more information refer to the Bracco Cardiogen-82 Infusion System, Operator Manual.

Figure 1: Stannic oxide column assembly

General warning

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 when installing the Bracco Cardiogen-82 Generator, infusion system tubing components and eluant sources. Aseptic techniques, including the use of a mask, sterile gloves and protective clothing, should be employed. If at any time in the preparation of this product the integrity of the radionuclide generator, infusion system tubing and/or eluant container is compromised, the product should not be used.

Administration procedures should be carried out in a way to minimise risk of irradiation of the operators. Adequate shielding is mandatory. The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spill of urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must be taken.

The Bracco Cardiogen-82 Generator should only be used with the Cardiogen-82 Infusion System. Follow instructions in the Cardiogen-82 Infusion System Operator's Manual for the set up and intravenous infusion of rubidium (Rb 82) chloride injection dose(s).

The Cardiogen-82 Infusion System features safety features to reduce the potential for excessive radiation dose to patients while maintaining the expected functionality of the infusion system and improve the ease of use. These include improved technology to identify radionuclides in the generator eluate using an integrated onboard dual detector system, including the addition of an integrated Strontium (Sr) gamma detector (CZT crystal) and associated Multi-Channel Analyzer (MCA).

An on-board Panel PC with a graphical user interface (GUI), and software, provides integrated safety controls including Infusion System Calibration, and automated Daily Quality Control procedures. The system software prevents patient infusions if specified QC parameters or limits are not met, and system enforced limits for dose and volume are reached.

Prior to administration, the product should be inspected visually for particulate and signs of discoloration, if the solution and container permit. Do not administer the generator eluate if the presence of foreign matter is suspected.

Rubidium-82 (Rb-82) activity in the eluate should be measured at the start of each day that the generator is used, along with the levels of strontium-82 (Sr-82) and strontium-85 (Sr-85) after Rb-82 decay (the breakthrough test). Elution is carried out exactly the same way whether it is for the purposes of testing or for administering to patients (see section 12).

Disposal

Any unused eluted medicinal product or used accessory waste material (e.g. infusion tubing) should be disposed of in accordance with local requirements. The generator must not be disposed of as normal waste; Bracco UK Ltd will provide the user with instructions and materials for the lawful and safe disposal of an expired generator.