Summary of medicine characteristics - AMYVID 800 MBQ/ML SOLUTION FOR INJECTION
Amyvid800 MBq/mL solution for injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each mL of solution for injection contains 800 MBq of florbetapir (18F) at the date and time of calibration (ToC).
The activity per vial ranges from 800 MBq to 12,000 MBq at the ToC.
Each dose contains up to 790 mg of ethanol and 37 mg of sodium.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for injection.
Clear, colourless solution.
This medicinal product is for diagnostic use only.
Amyvid is a radiopharmaceutical indicated for Positron Emission Tomography (PET) imaging of P-amyloid neuritic plaque density in the brains of adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) and other causes of cognitive impairment. Amyvid should be used in conjunction with a clinical evaluation.
A negative scan indicates sparse or no plaques, which is not consistent with a diagnosis of AD. For the limitations in the interpretation of a positive scan, see sections 4.4 and 5.1.
4.2 Posology and method of administrationA PET scan with florbetapir (18F) should be requested by physicians skilled in the clinical management of neurodegenerative disorders.
Amyvid images should only be interpreted by readers trained in the interpretation of PET images with florbetapir (18F). A recent co-registered computed tomography (CT) scan or magnetic resonance (MR) imaging of the patient to get a fused PET-CT or PET-MR image is recommended in cases of uncertainty about the location of grey matter and of the grey/white matter border in the PET scan (see section 4.4. Image interpretation).
Posology
The recommended activity for an adult weighing 70 kg is 370 MBq florbetapir (18F). The volume of the injection should not be less than 1 mL and not exceed 10 mL.
Special , populations
Elderly
No dose adjustment is recommended based on age.
Renal and hepatic impairment
Careful consideration of the activity to be administered is required since an increased radiation exposure is possible in these patients (see section 4.4).
Extensive dose-range and adjustment studies with the medicinal product in normal and special populations have not been performed. The pharmacokinetics of florbetapir (18F) in patients with renal or hepatic impairment have not been characterised.
Paediatric population
There is no relevant use of Amyvid in the paediatric population.
Method of administration
Amyvid is for intravenous use and multidose use.
The activity of florbetapir (18F) has to be measured with an activimeter (dose calibrator) immediately prior to injection.
The dose is administered by intravenous bolus injection, followed by a flush of sodium chloride 9 mg/mL (0.9%) solution for injection to ensure full delivery of the dose.
Injection of florbetapir (18F) through a short intravenous catheter (approximately 4 cm or less) minimises the potential for adsorption of the active substance to the catheter.
The injection of florbetapir (18F) must be intravenous in order to avoid irradiation as a result of local extravasation, as well as imaging artefacts.
Image acquisition
A 10 minute PET image should be acquired starting approximately 30 to 50 minutes after intravenous injection of Amyvid. Patients should be supine with the head positioned to centre the brain, including the cerebellum, in the PET scanner field of view. Reducing head movement with tape or other flexible head restraints may be employed. Reconstruction should include attenuation correction with resulting transaxial pixel sizes between 2.0 and 3.0 mm.
4.3 ContraindicationsHypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for useLimitations of use
A positive scan does not independently establish a diagnosis of AD or other cognitive disorder since neuritic plaque deposition in grey matter may be present in asymptomatic elderly and some neurodegenerative dementias (Alzheimer’s disease, Lewy body dementia, Parkinson’s disease dementia).
For the limitations of use in patients with mild cognitive impairment (MCI), see section 5.1.
The efficacy of Amyvid for predicting development of AD or monitoring response to therapy has not been established (see section 5.1).
Some scans may be difficult to interpret due to image noise, atrophy with a thinned cortical ribbon, or image blur, which could lead to interpretation errors. For cases in which there is uncertainty about the location of grey matter and of the grey/white matter border on the PET scan, and a co-registered recent CT or MR image is available, the interpreter should examine the fused PET-CT or PET-MR image to clarify the relationship of the PET radioactivity and the grey matter anatomy.
Increased uptake has been identified in extracerebral structures such as salivary glands, skin, muscles and bone in some cases (see section 5.2). Examination of sagittal images and co-registered CT or MR images could help to distinguish occipital bone from occipital grey matter.
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 and hepatic impairment
Careful consideration of the benefit risk ratio in these patients is required since an increased radiation exposure is possible. Florbetapir (18F) is excreted primarily through the hepatobiliary system and patients with hepatic impairment have the potential of increased radiation exposure (see section 4.2).
Paediatric population
For information on the use in the paediatric population, see sections 4.2 or 5.1.
Interpretation of Amyvid images
Amyvid images should only be interpreted by readers trained in the interpretation of PET images with florbetapir (18F). A negative scan indicates sparse or no density of cortical P-amyloid plaques. A positive scan indicates moderate to frequent density. Image interpretation errors in the estimation of brain P-amyloid neuritic plaque density, including false negatives, have been observed.
Review of images should be primarily in the transaxial orientation with access as needed to the sagittal and coronal planes. It is recommended that review of images include all transaxial slices of the brain using a black-white scale with the maximum intensity of the scale set to the maximum intensity of all brain pixels.
Interpretation of the image as negative or positive is made by visually comparing the activity in cortical grey matter with activity in adjacent white matter (see Figure 1).
Negative scans have more activity in white matter than in grey matter, creating clear grey-white contrast. Positive scans will have either:
a) Two or more brain areas (each larger than a single cortical gyrus) in which there is reduced or absent grey-white contrast. This is the most common appearance of a positive scan; or
b) One or more areas in which grey matter activity is intense and clearly exceeds activity in adjacent white matter.
Figure 1: Amyvid PET cases showing examples of negative scans (top two rows) and positive scans (bottom two rows). Left to right panels show sagittal, coronal, and transverse PET image slices. Final panel to right shows enlarged picture of the brain area in the box. The top two arrows are pointing to normal preserved grey-white contrast with the cortical activity less than the adjacent white matter. The bottom two arrows indicate areas of decreased grey-white contrast with increased cortical activity that is comparable to the activity in the adjacent white matter.
Pharmacotherapeutic group: diagnostic radiopharmaceutical, central nervous system, ATC code: V09AX05
Mechanism of action
Florbetapir (18F) binds to P-amyloid neuritic plaques. Binding studies using traditional neuropathological staining methods in post-mortem AD brains demonstrated statistically significant (p < 0.0001) correlations between in vitro florbetapir (18F) binding and P-amyloid aggregate deposition. In vivo, correlation was assessed in end-of-life patients between florbetapir (18F) uptake in cortical grey matter and the total P-amyloid burden using 4G8 antiamyloid antibody that stains P-amyloid found in both neuritic and diffuse plaques. The in vivo binding of florbetapir (18F) to other P-amyloid structures or other brain structures or receptors remains unknown.
Pharmacodynamic effects
At the low chemical concentrations present in Amyvid, florbetapir (18F) does not have any detectable pharmacological activity.
In completed clinical trials, uptake of florbetapir (18F) in 6 predefined cortical areas of the brain (precuneus, frontal, anterior cingulate, posterior cingulate, parietal and temporal) was measured quantitatively using standardised uptake values (SUV). Cortical average SUV ratios (SUVRs, relative to cerebellum) are higher in AD patients compared with those of healthy volunteer subjects. The average cortical to cerebellar SUVR values in AD patients show continual substantial increases from time zero through 30 minutes post-administration, with only small changes thereafter up to 90 minutes post-injection. No differences in SUVR results were noted in subjects taking common AD treatments relative to those not taking AD treatments.
Clinical efficacy
A pivotal study in 59 end-of-life patients was aimed at establishing the diagnostic performance of Amyvid to detect the cortical neuritic plaque density (no or sparse vs. moderate or frequent). The PET results were compared with the maximal neuritic plaque density measured on sections of frontal, temporal or parietal cortex at the patient’s autopsy within 24 months of PET scan. The cognitive status of the subjects could not be reliably measured. In all 59 subjects, a blinded PET reading by 5 nuclear medicine physicians resulted in a majority read sensitivity of 92% (95% CI: 78–98%) and specificity of 100% (95% CI: 80–100%). In a study of 47 young (<40 years) healthy volunteers, presumed to be free of P-amyloid, all Amyvid PET scans were negative.
Sensitivity and specificity to detect the cortical neuritic plaque density of Amyvid was further investigated in two additional studies, in which different sets of readers interpreted images from some subjects followed to autopsy in the pivotal study. Their results closely paralleled the results obtained in the pivotal trial. Inter-rater agreement using Fleiss’ kappa values ranged from 0.75 to 0.85.
In a longitudinal study, 142 subjects (clinically diagnosed as MCI, AD or cognitively normal) underwent baseline florbetapir (18F) PET scans, and were followed for 3 years to evaluate the relationship between Amyvid imaging and changes in diagnostic status.
Diagnostic performance values of florbetapir (18F) PET are tabulated below:
Agreement with baseline Agreement with baseline diagnosis of MCI diagnosis of clinical AD
N=51 N=31
Sensitivity
Specificity
Positive likelihood ratio
| 19/51 = 37.3% (95% CI: 24.1–51.9%) | 21/31 = 67.7% (95% CI: 51.3–84.2%) |
| Using non-MCI cases (cognitively normal & clinical AD) 69/100 = 69.0% (95% CI: 59.9–78.1%) | Using non-AD cases (cognitively normal & MCI) 91/120 = 75.8% (95% CI: 68.2–83.5%) |
| 1.20 (95% CI: 0.76–1.91) | 2.80 (95% CI: 1.88–4.18) |
Of the patients who had been clinically diagnosed with MCI at study entry, 9 (19%) converted to clinical AD 36 months later. Of the 17 MCI patients who had a positive PET scan, 6 (35%) were diagnosed with clinical probable AD 36 months later compared to 3 (10%) of 30 who had a negative scan. Sensitivity of Amyvid scan to show the MCI conversion rate to AD in 9 converters was 66.7% (95% CI: 35–88%), specificity in 38 non-converters was 71.0% (95% CI: 55–83%) and positive likelihood ratio was 2.31 (95% CI: 1.24.5). The design of this study does not allow estimating the risk of MCI progression to clinical AD.
Adjunctive use of quantitative information for image interpretation
The feasibility and reliability of using CE-marked quantitative software as an adjunct to clinical qualitative interpretation was investigated in two studies using three different commercially available quantitative software packages. Participating readers first evaluated a set of 96 PET scans, including 46 scans with autopsy standard of truth, using the visual qualitative read method to establish a baseline and were subsequently asked to re-evaluate the same set of scans with or without access to quantitative software information. Across all participating readers who had access to quantitative information, average reader accuracy on the scans with autopsy standard of truth improved from 90.1% at baseline to 93.1% (p-value <0.0001), with no observed decrease in either sensitivity or specificity.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Amyvid in all subsets of the paediatric population as there is no intended use in the paediatric population.
5.2 Pharmacokinetic propertiesDistribution
Florbetapir (18F) is distributed throughout the body within several minutes of injection, and then is rapidly metabolised.
Organ uptake
Maximal brain uptake of florbetapir (18F) occurs within several minutes of injection, followed by rapid brain clearance during the first 30 minutes following injection. The organs of greatest exposure are organs of elimination, mainly the gallbladder, liver, and intestines.
Healthy controls show relatively low levels of florbetapir (18F) retention in cortex and cerebellum. Regional analyses show slightly higher levels of retention in the caudate, putamen and hippocampus. The highest level of uptake is in regions mainly composed of white matter (pons and centrum semiovale). In AD subjects, cortical regions and putamen show significantly greater uptake compared to controls. In AD subjects, as in controls, there is low retention in cerebellum and hippocampus and high retention in pons and centrum semiovale.
The biophysical basis of the white matter retention of florbetapir (18F) in the living human brain cannot be definitively explained. It is hypothesised that slower clearance of the radiopharmaceutical may contribute to white matter retention since regional cerebral blood flow in white matter is less than half of that of cortex. Uptake has also been identified in some cases in extracerebral structures such as scalp, salivary glands, muscles and cranial bone. The reason for this uptake is unknown, but may be due to accumulation of florbetapir (18F) or to any of its radioactive metabolites or to blood radioactivity.
Elimination
Elimination occurs primarily by clearance through the liver and excretion into the gallbladder and the intestines. Some accumulation/excretion is also observed in the urinary bladder. Radioactivity in urine is present as polar metabolites of florbetapir (18F).
Half-life
Florbetapir (18F) is very rapidly cleared from circulation post-intravenous injection. Less than 5% of the injected 18F radioactivity remains in blood 20 minutes following administration, and less than 2% is present 45 minutes after administration. The residual 18F in circulation during the 30–90 minute imaging window is principally in the form of polar 18F species. The radioactive half-life of 18F is 110 minutes.
Renal/hepatic impairment
The pharmacokinetics in patients with renal or hepatic impairment have not been characterised.
5.3 Preclinical safety dataAnimal toxicology and safety pharmacology
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and single and repeated dose toxicity, in which florbetapir [the non-radioactive form of florbetapir (18F)] was used. An acute dose study was conducted in rats, and the NOAEL (no observable adverse effect level) was determined to be at least 100 times maximum human dose. The potential toxicity of 28 days of repeated intravenous injections of florbetapir was tested in rats and dogs, and the NOAEL was found to be at least 25 times the maximum human dose.
In an in vitro bacterial reverse mutation assay (Ames test), increases in the number of revertant colonies were observed in 2 of the 5 strains exposed to florbetapir. In a chromosomal aberration in vitro study with cultured human peripheral lymphocyte cells, florbetapir did not increase the percent of cells with structural aberrations with 3 hour exposure with or without activation; however, 22 hour exposure produced an increase in structural aberrations at all tested concentrations. Potential in vivo genotoxicity of florbetapir was
evaluated in a rat micronucleus study. In this assay, florbetapir did not increase the number of micronucleated polychromatic erythrocytes at the highest achievable dose level, 372 gg/kg/day, when given twice daily for
3 consecutive days. This dose is approximately 500 times the maximum human dose, and showed no evidence of mutagenicity.
No studies have been conducted in animals to investigate the potential long term carcinogenicity, fertility, or reproductive effects of florbetapir (18F).
No animal toxicology and safety pharmacology studies have been performed with florbetapir (18F).
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipientsEthanol, anhydrous Sodium ascorbate
Sodium chloride
Water for injections
6.2 IncompatibilitiesIn the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life7.5 hours from the ToC
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Storage of radiopharmaceuticals should be in accordance with national regulation on radioactive materials.
6.5 Nature and contents of containerAmyvid is supplied in 10 mL or 15 mL clear Type I borosilicate glass vials with FluroTec-coated chlorobutyl elastomeric stoppers and aluminium seals.
One multidose vial of 10 mL capacity contains 1 to 10 mL of solution, corresponding to 800 to 8,000 MBq at ToC.
One multidose vial of 15 mL capacity contains 1 to 15 mL of solution, corresponding to 800 to 12,000 MBq at ToC.
As a result of differences in the manufacturing process, it is possible that vials of some product batches are distributed with punctured rubber stoppers.
Each vial is enclosed in a shielded container of appropriate thickness to minimise external radiation exposure.
Pack size: 1 vial.
6.6 Special precautions for disposalGeneral 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.
If the integrity of the vial 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 (including pregnant healthcare professionals) from external radiation or contamination from spill of urine, vomiting etc. Radiation protection precautions in accordance with national regulations must therefore be taken.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Eli Lilly Nederland B.V.
Papendorpseweg 83
3528 BJ Utrecht
The Netherlands
8 MARKETING AUTHORISATION NUMBER(S)
PLGB 14895/0232
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
01/01/2021
10 DATE OF REVISION OF THE TEXT
01/01/2021
11. DOSIMETRY
The estimated absorbed radiation doses to organs and tissues of an average adult patient (70 kg) per 370 MBq of florbetapir (18F) using standard methods for dosimetry calculations (ICRP Volume 30) is tabulated below. No assumptions were made regarding urinary bladder voiding.
| Organ/tissue | Dose absorbed per activity administered (jaGv/MBq) |
| Average | |
| Adrenal | 13.6 |
| Brain | 10.0 |
| Breasts | 6.2 |
| Gallbladder wall | 143.0 |
| Lower large intestine wall | 27.8 |
| Small intestine | 65.5 |
| Stomach wall | 11.7 |
| Upper large intestine wall | 74.4 |
| Heart wall | 12.7 |
| Kidneys | 13.0 |
| Liver | 64.4 |
| Lungs | 8.5 |
| Muscle | 8.6 |
| Ovaries | 17.6 |
| Pancreas | 14.4 |
| Red marrow | 14.3 |
| Osteogenic cells | 27.6 |
| Skin | 5.9 |
| Spleen | 8.9 |
| Testes | 6.8 |
| Thymus | 7.3 |
| Thyroid | 6.8 |
| Urinary bladder wall | 27.1 |
| Uterus | 15.6 |
| Total body | 11.6 |
| Effective Dose [uSv MBq] | 18.6 |
Assumed quality factor (Q) of 1 for conversion of absorbed dose to effective dose for 18F.
The effective dose resulting from the administration of a 370 MBq dose for an adult weighing 70 kg is about 7 mSv. If a CT scan is simultaneously performed as part of the PET procedure, exposure to ionising radiation will increase in an amount dependent on the settings used in the CT acquisition. For an administered activity of 370 MBq the typical radiation dose to the target organ (brain) is 3.7 mGy.
For an administered activity of 370 MBq the typical radiation doses delivered to the critical organs, gallbladder, upper large intestine wall, lower large intestine wall, small intestine and liver are 53 mGy, 27.5 mGy, 10.3 mGy, 24.2 mGy and 23.8 mGy, respectively.