making bone inflammation/infection simpler to detect · osteomyelitis) adequate antibiotics are...

Making bone inflammation/infection

simpler to detectScintimun® 1mg

Monograph

New active ingredient according to Spanish Royal Decree 1344/2007

New product under intensive monitoring in United Kingdom

2 | IBA | Scintimun® Monograph

Scintimun®

Monograph

Scintimun® Monograph


1.1. Definition and pathogenesis

Osteomyelitis is a progressive infectious processinvolving the various components of bone, namelyperiosteum, medullary cavity, and cortical bone.The disease is characterized by progressive,inflammatory destruction of bone, by necrosis, andby new bone apposition(1).The pathogenesis of osteomyelitis has beenexplored in various animal models; these studieshave found that normal bone is highly resistant toinfection, which can only occur as a result of verylarge inocula, trauma or in the presence of foreignbodies.Although many bacteria can cause osteomyelitisthe predominant microorganism is Staphylococcusaureus in up to 50% of cases. In the other casesCoagulase Negative Staphyloccoci, Enteric GramNegative rods, Pseudomonas sp, anaerobes,Mycobacteria, yeasts or mixed infections may beencountered(2,3).

S aureus adheres to bone by expressing receptorsfor components of bone matrix. This bacteria hasthe capacity to grow as a biofilm in a metabolicallyaltered state, on the surface of dead bone orforeign material. It can also penetrate and survivein healthy cells, such as osteoblasts. Thesefeatures may explain how S aureus may escapefrom immune responses and antibiotics, possiblyfor years, and the necessity of prolonged antibiotictherapy and often of surgery to achieve cure(2,3).

During infection, phagocytes attempt to containinvading microorganisms and, in the process,generate toxic oxygen radicals and proteolyticenzymes that lyse surrounding tissues. The formedpus spreads into vascular channels, raising theintraosseus pressure and impairing blood flow. Theischemic necrosis of bone results in the separationof devascularized and dead bone fragments,which are called sequestra.

1. Osteomyelitis

Prof. Daniel P. Lew Geneva University Hospital, Department of Internal Medicine, Infectious Diseases Service 1211 Geneva 14 - Switzerland

Prosthetic Joint InfectionCoagulase Negative StaphylococciStaphylococcus aureusPolymicrobialStreptococcus sp

Vertebral OsteomyelitisStaphylococcus aureusGram negative Aerobic BacilliStreptococcus spMycobacterium tuberculosis

Diabetic Foot InfectionStaphylococcus aureusStreptococcus spEnterococcus spCoagulase Negative StaphylococciGram Negative Aerobic BacilliAnaerobes

Prostraumatic InfectionStaphylococcus aureusGram negative Aerobic BacilliAnaerobes

Various types and microbial causes of osteomyelitis


1.2. Acute versus chronicOsteomyelitis

Acute osteomyelitis evolves over several days toweeks: the term "acute" is used in opposition tochronic osteomyelitis, a disease characterized byclinical symptoms that persist for several weeksfollowed by longstanding infection that evolves overmonths or even years, by the persistence ofmicroorganisms, by low-grade inflammation, by thepresence of necrotic bone (sequestra) and foreignmaterial, and by fistulous tracts. The terms acuteand chronic do not have a sharp demarcation andare often used somewhat loosely. Nevertheless,they are useful clinical concepts in infectiousdisease, as they describe two different patterns oft h e s a m e d i s e a s e , d u e t o t h e s a m emicroorganisms, but with different evolutions(3).

Development of osteomyelitis secondary to a contiguousfocus of infection; inflammatory cells and necrotic bone

Histopathology of osteomyelitis Radiology of chronic tibial osteomyelitis



1.3. Types of osteomyelitis

From a practical point of view, it is useful todistinguish three types of osteomyelitis(1,2,3).

Hematogenous osteomyelitis follows bacteremicspread, is seen mostly in prepubertal children andin elderly patients, and is characterized by localmultiplication of bacteria within bone duringsepticemia. In most cases infection is located inthe metaphyseal area of long bones or in thespine- ver tebral osteomyel i t is. Typical ly inhospitalized patients who develop nosocomialb a c t e r e m i a o r c a n d i d e m i a , u s u a l l y f r o mintravenous devices, secondary osteomyelitis maydevelop.

Osteomyelitis secondary to a contiguous focus ofinfection without vascular insufficiency followstrauma, perforation, or a surgical or thopedicprocedure. It implies a first infection, which bycontinuity gains access to bone. By definition, itcan occur at any age, and can involve any bone.It is useful to distinguish in this group the patientswith a foreign body implant because of its highsuscept ibi l i ty and necessi ty to remove theprosthesis to achieve cure in most cases. With thelarger utilization of prosthetic devices (knee, hip,shoulder and other), prosthetic joint infectionsassociated with osteomyelitis is becoming a verylarge problem, usually in elderly patients.

Osteomyelitis secondary to vascular insufficiencyand neuropathy is the consequence of poor bloodsupply, usually to the lower extremities. Oftenassociated with diabetes, this last disease entityhas several impor tant contr ibut ing factors:diabetes and its metabolic consequences, boneischemia, neuropathy, vascular insufficiency andin fec t ion p robably a l l con t r ibu te to bonedestruction(4).

1.4. Diagnosis

1.4.1 Imaging modalities in the setting ofsuspected osteomelitisImaging is an usefu l too l in the set t ing ofsuspected osteomyelitis, particularly for supportinga presumed clinical diagnosis, delineating theextent of disease, and planning therapy.➤ Conventional radiography is necessary at bothpresentation and follow up but suffers from poorsensitivity and specificity. Plain films show softtissue swelling, narrowing or widening of jointspaces, and signs of chronic infection such asbone destruction and periostal reaction. Howeverbone destruction is not apparent on plain films untilafter 10-21 days of infection.➤ Ultrasound can be useful for early diagnosis orfor detection of a purulent collection in soft tissue.➤ Nuc lear imag ing i s a reasonably ea r lydiagnostic choice and as an alternative for MRI orCT scans. Various radiopharmaceuticals arecurrently used for bone scintigraphy.T h e m o s t c o m m o n l y u s e d m e t h y l e n ediphosphonate binds to sites of increased bonemetabolic activity and is highly sensitivity butsuffers from poor specificity for infection due toother bone diseases such as diabetic (Charcot )arthropathy, gout, trauma and surgery.Leukocyte scanning with radiolabeled blood cellsor specific antibodies are more recent nucleartechniques increasingly used and are reported tohave high sensit iv i ty and especial ly higherspecificity for detecting infections. They have theadvantage of not being influenced by metalhardware but large studies in humans are lacking.➤ Magnetic resonance imaging (MRI) is the bestmoda l i t y fo r ob ta in ing de ta i l ed anatomicdelineation of the extent of bone marrow and softtissue inflammation. It is useful for evaluation ofosteomylitis in the foot (in the setting of diabetes)and in the vertebrae (given its excellent delineationof the spinal cord). However MRI is not specific forinfection and other causes may create bonemarrow edema (such as contusion, post-surgeryand Charcot disease). MRI may also overestimate


the extent of infection in surrounding tissues andremain positive even after successful treatment.Computed tomography (CT) can also providealternative anatomic delineation of infection incases MRI cannot be obtained. However as withMRI, metal hardware may limit the use of CT.The specificity of positron-emission tomographywith fluorodeoxyglucose (FDG)-PET associatedwith CT needs further evaluation.

1.4.2. Microbiological and pathologicalcriteria

If there is one area where adequate sampling forbacteriology is impor tant, this is the case ofosteomyelitis because treatment will be given formany weeks, most often by a parenteral routefollowing the results of the initial culture. Adequatesampling of deep infected tissue is thus extremelyusefu l ( in contrast to specimens obta inedsuperficially from ulcers or from fistula which areoften misleading). Usually this may be done underCT guidance.Results of gram stain and culture, obtained ideallybefore therapy, should be carefully analyzed. Ifclassical bacteria do not grow in suspicious cases,tissue should be available to perform fungal andmycobacterial cultures as well as broad rangeP C R . T i s s u e s p e c i m e n s p r e p a r e d f o rhistopathology are useful for obser ving thepresence of neutrophils and the use of specials ta ins for var ious microorganisms may besometimes useful to confirm diagnosis.

1.4.3. Antimicrobial and Surgical TherapySingle-agent antibiotic therapy is usually adequatefor the treatment of osteomyelitis of any type. As ageneral principle, these antibiotics should be givenintravenously for 4 to 6 weeks, as substantiated byexperimental models and many clinical reports.They should be adapted carefully to the culturedmicroorganisms(5).In recent years, new approaches to antimicrobialtherapy have been developed experimentally andvalidated cl inical ly. Thus, in hematogenouso s t e o m y e l i t i s o f c h i l d h o o d , p a r e n t e r a l

administration of antibiotics may be followed withan equal success rate by oral therapy for severalweeks, provided that the organism is known,clinical signs abate rapidly, patient compliance isgood, and ser um ant ib io t ic leve ls can bemonitored. This approach has now also beenvalidated in small series of adult patients. Anotherapproach that has gained significant acceptancebecause of i ts reduced cost is parentera ladministration of antibiotics, first in hospital, thenon an outpatient basis. Long-term oral therapyextending over months and more rarely years isaimed at palliation of acute flare-ups of chronic,refractory osteomyelitis. Local administration ofantibiotics, either by instillation or by gentamicin-laden beads, has its advocates both in the UnitedStates and in Europe, but it has not been submittedto critical, controlled studies; antibiotics diffusion islimited in time and space, but may be of someadditional benefit in osteomyelitis secondary to ac o n t i g u o u s f o c u s o f i n f e c t i o n . T h e 8 -fluoroquinolones have been one of the mostinteresting developments in this domain and havebeen shown to be quite efficient in experimentalinfections and in several randomized and nonrandomized studies in adults. Whereas theirefficacy in the treatment of osteomyelitis due tomost Enterobacteriaceae seems undisputed, theira dva n t a g e ove r c o nve n t i o n a l t h e r a py i nosteomyelitis due to Pseudomonas or Serratiaspecies as well as gram-positive organisms (inparticular multiresistant S. aureus) remains to bedemonstrated(6).

Finally, considerable progress has been achievedin the development of novel surgical approaches(bone graft, revascularization procedure, muscleflaps) that allow more rapid formation of new bone.

1.4.4. Clinical ResponseBecause of the protracted characteristics ofosteomyelitis, cure is defined as the resolution ofall signs and symptoms of active disease at theend of therapy and after a minimal post treatmentobservation period of 1 year. By contrast, failure is



defined as a lack of apparent response to therapy,as evidenced by one or more of the following: (1)persistence of drainage; (2) recurrence of a sinustract or fai lure of a sinus tract to close; (3)persistence of systemic signs of infection (chills,

fever, weight loss, bone pain); and (4) progressionof bone infection shown by imaging methods (e.g.,radiography, computed tomography, magneticresonance imaging).

The many pathogen ic fac to r s, modes o fcontamination, clinical presentations, and typesof orthopedic procedures related to osteomyelitishave precluded a very scientific approach totherapy, with well-controlled, statistically validstudies; however, experimental models havehelped to understand some basic principles ofan t ib i o t i c t he rapy. Thus, excep t fo r t hefluoroquinolones, which penetrate unusually wellinto bone, bone antibiotic levels 3 to 4 hours afteradministrat ion are usual ly quite low whencompared to serum levels; antibiotic treatmentgiven parenterally has to be given for severalweeks to achieve an acceptable cure rate; andearly antibiotic treatment, given before extensivebone destruction has occurred, produces thebest results.A combined antimicrobial and surgical approachshould always be considered: whereas at one

end of the spectrum (e.g., hematogenous acuteosteomyelitis) adequate antibiotics are sufficientand surgery usually is unnecessary, at the otherend (a consolidated chronically infected fracture)cure may be achieved with minimal antibiotictreatment provided the foreign material andnecrotic bone are removed. In the presence of aforeign body (prosthetic joint infection) bothcareful surgery (early debridement or prosthesisexchange) and prolonged antibiotic therapy areoften required.

Nowadays a mult idisciplinary approach isrequired for success in treating osteomyelitis,involving multiple exper ts in radiology andnuclear medicine, microbiology and infectiousdiseases as well as orthopedic, vascular andplastic surgery.

General conclusion for the Management of Osteomyelitis

1. Waldvogel F A, Medoff G, Swartz M N. Osteomyelitis:a review of clinical features, therapeutic considerationsand unusual aspects. N Engl J Med 282: 198-206, 1970.

2. Lew D.P., Waldvogel FA, Osteomyelitis. N Engl J med1997; 336: 999-1007, 1997.

3. Lew DP, Waldvogel FA, Osteomyelitis. Lancet 364:369-379, 2004.

4. Lipsky BA et al, Diagnosis and treatment of diabeticfoot infections. Clin Inf Dis 39:885-910, 2004.

5. Mader J T, Norden C, Nelson J D, Calandra G B.Evaluation of new anti-infective drugs for the treatment ofosteomyelitis in adults. Infectious Diseases Society ofAmerica and the Food and Drug Administration. ClinInfect Dis 15 Suppl 1: S155-S161, 1992.

6. Lew DP and Waldvogel FA, Use of quinolones fortreatment of osteomyelitis and septic ar thritis. InQuinolone antimicrobial agents. D.C. Hooper and J.S.Wolfson, editors. American Society for Microbiology,Washington, D.C.. 371-379.1993.

References



2.1. Role of granulocytes

Inflammation is a coordinated process induced bymicrobial infection or tissue injury. The mainfunction of inflammation is to resolve the infectionor repair the damage and return to a state ofhomeostasis. Intrinsic to the efficacy of such asystem is the ability to mount a rapid responseappropriate to the particular type of inflammatorytrigger while limiting the damaging aspects ofinflammation as much as possible(1).

The hallmark of inflammation associated withmicrobial infection (i.e., redness, heat, swelling andpain) are initiated by innate immune recognition.These symptoms are mainly due to vasodilatation,increased vascular permeability and leukocyteinfiltration.They are triggered by inflammatory mediatorsinduced by pathogen recogni t ion such ascomplement-der ived pept ides (C3a, C5a);pathogen-derived chemoattractants such as N-formyl pept ides or inf lammator y mediators( leucotr iène B4, Plate let Act ivat ing factor,chemokines, pro and anti-inflammatory cytokines)produced by resident macrophages in theinfection/inflammation context.Phagocy tes, neu t roph i l s and monocy tes /macrophages constitute one of our most potentdefence systems against pathogenic agents such

as bacteria, fungi, parasites, and viruses whichhave crossed the mucocutaneous barrier, andagainst all bodies recognized as foreign, such asaltered endogenous cells and molecules.➤ Neutrophils are highly motile phagocytic cellsthat are the first immune cells to migrate from thecirculating blood to the inflammatory site.➤ Monocyte migration occurs in a secondary step.Mobil izat ion of inf lammator y neutrophi ls iscoordinated by a complex network of inflammatorymediators that are produced in the context of theinflammatory process triggered by infection.Neutrophils are physiologically at rest in thecirculating blood.

But when they are prompted by different stimulifrom the infectious or inflammatory site, theyadhere to endothelial cells, slip between them andare oriented (chemotaxis) to their tissue target(2).The ef fector responses are triggered by therecognition of microbes by “pattern recognitionreceptors”, adherence to and engulfment of thetarget, together with interaction at the membrane ofdifferent molecules derived from the pathogen,such as N-formyl peptides, endotoxins or productsof cellular origin such as the cytokines(3).These responses include the production andrelease of killer and degrading substances suchas reactive oxygen species, the contents of

2. Inflammation / infection andneutrophils

Prof. Marie-Anne Gougerot-PocidaloProfesseur in ImmunologyDepartment of Haematology and ImmunologyGroupe Hospitalier Bichat-Claude Bernard46 Rue Henri Huchard75018, Paris.


granules and cytokines(4). Furthermore, neutrophilsare clearly involved in the regulation of the othercells present at the inflammatory site and in theregulation of the adaptative immune responsenamely v ia the regulat ion of dendr i t ic cel lmaturation. If the inflammatory response is able tocontain microbial infection, then the overallr e s p o n s e i s s h i f t e d t o w a r d r e s o l u t i o n o finflammation. However, excessive, inapropriate or

prolonged neutrophil stimulation can lead to severecollateral damages that are observed in certainchronic infection or inflammatory disorders. Thishighlights the need for fine tuning of activation ofn e u t r o p h i l s , w h i ch a r e n e c e s s a r y t o t h emaintenance of the host’s biological integrity butare also the source of diseases when they areexcessively or inappropriately activated(5).

References

1-Barton GM A calculated response: control of inflammation bythe innate immune system. J. Clin. Invest. 2008. 118: 413-420.

2-Witko-Sarsat V, Rieu Ph, Descamps-latscha B, lesavre P,Halwachs-mecarelli L. Lab. Invest. 2000. 80: 617-653

3-El-Benna J, Dang PMC, Gougerot-Pocidalo MA. Sem.Immunopathol. 2008. 30: 279-289.

4-Segal AW. How neutrophils kill microbes. Annu Rev Immunol2005. 23: 197-223.

5-Dang PM, Stensballe A, Boussetta T, Raad H, Dewas C,Kroviarski Y, Hayem G, Jensen ON, Gougerot-Pocidalo MA, El-Benna J. A specific p47phox -serine phosphorylated byconvergent MAPKs mediates neutrophil NADPH oxidasep r i m i n g a t i n f l a m m at o r y s i t e s. J C l i n I nve s t . 2 0 0 6Jul;116(7):2033-43.

Bloodstream

Tissue

Enhancement ofvascular permeability

Upregulationof resident

Macrophageresponse

ComplementC3a C5a N-Formyl peptides

Endotoxins

Neutrophil

Pathogen

ResidentMacrophage

Monocyte

Dendritic cellNatural killer cell

Adaptiveimmunity

Ag

Neutrophil recruitement

Inflammatorymediators:

Enzymes, chemokines,pro and anti-inflammatory

cytokines

Amplification ofphagocyte

recruitement

Regulation ofimmune responses

The innate immune response function is the first line of defense against infection


3.1. Clinical indication

“Scintigraphic imaging, in conjunction with otherappropriate imaging modalities, for determining thelocation of inflammation/infection in peripheralbone in adults with suspected osteomyelitis.Scintimun® should not be used for the diagnosis ofdiabetic foot infection”.

3.2. Presentation

Besilesomab is a murine immunoglobulin of IgG1isotype that specifically binds to NCA-95 (nonspecific cross-reacting antigen 95), an epitopeexpressed at the cell membrane of granulocytesand granulocyte precursors. Besilesomab cross-reacts with tumours expressing carcinoembryonica n t i g e n ( C E A ) . B e s i l e s o m a b h a s b e e ndemonstrated to have no ef fect nei ther onactivation of complement, nor on granulocytesfunction and platelets(1).Besilesomab has an affinity for NCA-95 antigen of2 x 109 L/mol(2).


3. Scintimun®

Scintimun®: murine monoclonal antibody BW 250/183(besilesomab) labelled with 99mTc

99mTc

NCA-95 antigenover expressed

in activated granulocyte.

High affinity binding2.109 L/mol

Labelingto alreadymigrated

granulocyte(passive)

Direct labelingin blood stream

(active)


3.3. Pharmacodynamics profile

Mechanism of actionAlthough the mechanism of accumulation ofbesilesomab at the site of infection/inflammationhas not been fully elucidated, it is postulated that itis mainly passive (increased vascular permeability)and partly active (migration of human granulocytescarrying besilesomab to the infection/inflammationsite) because only 10% to 20% of the injected(3)

radiolabelled antibody bind in vivo to humancirculating granulocytes. Specific binding ofbesilesomab to already migrated and activatedgranulocytes may be the major par t of thedetection signal.

Granulocytes and granulocytic functionBesilesomab binds to 99.6% of mature humangranulocytes in whole blood samples analysed byf low cytometr y but does not b ind to ear lygranulocyte precursors in human bone marrowCD34+ cells(4).

D e s p i t e i t s b i n d i n g c a p a c i t y t o h u m a ngranulocytes, besilesomab does not significantlyinfluence granulocyte-mediated functions➤ ( e n z y m e r e l e a s e , p i n o c y t o s i s ,

chemiluminescence)(5) and➤ does not induce any lytic effects to epitope

positive cells via complement-dependent orantibody-dependent cell-mediated cytotoxicity(CDC or ADCC)(6).

➤ I t d o e s n o t i m p a i r b o n e m a r r o w c e l lproliferation(7).

Interaction with other blood cellsNo significant binding of besilesomab to otherhuman peripheral blood cells was observed:erythrocytes (0.1% to 1.3%), platelets (0% to0.9%), lymphocytes (0.2% to 5%) and monocytes(0.4% to 3.5%). Another study confirmed the noncross-reactivity of besilesomab with humanplatelets (<3%)(1).

Cross-reactivity with CEATissue specificity of besilesomab was evaluatedon a broad panel of human cryopreserved normalas well as cancer tissues derived from variousind i v idua l s us ing immunoh is tochemis t r y.Besilesomab showed strong binding to coloncarcinomas and granulocytic cells in normaltissues (i.e. normal liver, lung and bone marrow(8)).Furthermore, besilesomab binds to pancreatic,some lung and some breast carcinomas but doesnot bind to blood vessels and connective tissue.Finally, CD66 expression on bone marrow cells ofpatients with multiple myeloma was shown ex vivoby flow cytometry using besilesomab as anti CD66.Therefore, false positive images are possible inc a s e o f C E A e x p r e s s i n g t u m o u r s o rhaematological malignancies such as myeloma(9).

3.4. Pharmacokinetic profile

Whole blood concentration-time radioactivitycurves show a two-phase course, which can besubdivided into an early phase (0-2 h) and a latephase (5-24 h). After correcting for the decay ofradionuclide, the calculated half-life of the earlyphase is 0.5 h whereas the late phase shows ahalf-life of elimination of 16 h. In plasma the datashow comparable pharmacokinetics, with an earlyphase with a half-life of 0.5 h and a late phase witha half-life of 16 h.


➤ Six hours after injection, about 1.5% of thewhole body radioactivity is found in the liverwhereas about 3.0% is found in the spleen.

➤ Twenty- four hour s a f te r in jec t ion , thepercentages of radioactivity are 1.6% in theliver and 2.3% in the spleen.

➤ Measurement of radioactivity levels in urineshows that up to 14% of the administeredactivity is excreted via the bladder during the24 h post-injection.

➤ The low renal clearance of activity (0.2 l/h fora glomerular filtration rate around 7 l/h)indicates that the kidney is not the major routeof besilesomab elimination(10).

Non pathological unusual accumulations may beobserved in the spleen (up to 6% of the patients),in the bowel (up to 4% of the patients), in the liverand bone marrow (up to 3% of the patients), and inthe thyroid and kidneys (up to 2% of patients).

References

1) Mimouni “Cross reactivity of besilesomab with humanplatelets and granulocytes from doses – Report 348 44EP.

2) Steinsträsser A et al. Binding of the monoclonal antibody BW250/183 to human granulocytes. Nucl Med 1992; 31: 57-63.

3) Clinical trial ref 7 MN-302SZ-A.

4) Hir t. Orpegen Pharma repor t 9-14-02. Flow cytometricanalysis of human bone marrow CD34+ cells labelled with MAbBW 250/183. February 13, 2008.

5) Bosslet “ Influence of MAb BW 250/183 on grabulocytesfunctions” Studu n0 MAb 250.183-BS-12, Sep. 6, 1988.

6) Bosslet “ Immunological characteristics of MAb 250/183”Study n0 MAb 250/183-BS-11, Sep.6, 1988.

7) Krumwieh “ influence of Anti-Granulocyte MonoclonalAntibody (MAb 250/183) on human marrow cell proliferation “Study n° M 258/1998-4-12W, Aug 18, 1988.

8) Bosslet “ Specificity of MAb BW 250/183 on cryopreservedtissues”n° BS-10, Sep.7, 1988.

9) Satoch “Expression of CD66 antigen in multiple myeloma: JClin Lab anal 2002, 16(2) 79-95.

10) Clinical trial ref 7D-101 SZ-A, 7MN-302 SZ-A, 306340.

PK blood

0

2

4

6

8

10

12

0 5 10 15 20 25 30

Time (hr)



3.5. Overview on efficacy

3.5.1. Pivotal trialStudy AG-PH3 was a prospective, open label,randomized, cross-over, confirmatory clinicalphase I I I t r ia l according to today’s qual i tystandards. I t compared blinded reading ofScintimun® and 99mTc-White Blood Cells (WBCs)i m a g e s i n 1 1 9 p a t i e n t s w i t h s u s p e c t e dosteomyelitis. The population consisted of 120patients. All of them had a history of previousdisease or surgery and presented with eitherclinical symptoms and/or biological signs and/orimaging findings of osteomyelitis at study entry.Sixty-two (62) patients were suspected of infectedjoint prosthesis, and 58 were suspected ofosteomyelitis (including 25 patients with infecteddiabetic foot).

The agreement rate between the two methods in119 patients evaluable for efficacy was 83% (lower95% confidence interval limit: 80%). On the basisof 1-month follow-up by the investigator, Scintimun®

had a sensitivity of 75% [95% CI 67%-84%], aspecificity of 72% [95% CI 59%-84%] and anaccuracy of 74% [95% CI 67%-81%]. It showed astatistically significant higher sensitivity than thatachieved by 99mTc-WBCs scanning (75% versus59% p < 0.0001) wi th a s l ight decrease inspecificity as compared to 99mTc-WBCs imaging(72% versus 79% NS). Accuracy was found to besignificantly higher compared to 99mTc-WBCsimaging (74% versus 66% p = 0.0346).

The clinical results of subgroup analyses indicatethat among different presentations of osteomyelitis,Scintimun® can show different results. The productshows a trend being more sensitive (75% versus57%) and equally specific (80% versus 78%) indiagnosing osteomyelitis in patients with prosthesisthan in patients with other sites of long boneosteomyelitis. The clinical results also demonstratethat Scintimun® shows a trend to be more sensitive(84% versus 73%) and equally specific (70%

versus 73%) in acute osteomyelitis than in chronicosteomyelitis.

In a post-hoc analysis based on a surrogate, whichwas an evaluation by an expert panel of all dataavailable from the study CRFs plus all additionaldata available from the investigators, the overalldiagnostic performance of technetium (99mTc)besilesomab in this analysis, sensitivity (76%) andspecificity (69%) appeared similar to that of theprevious analysis based on the investigatordiagnosis at 1 month, 75% and 72%, respectively.

Image quality was assessed by three independentreaders and was compared to that of 99mTc-WBCs.Frequency distribution of image quality was infavour of Scintimun®. The difference between the 2tracers was statistically significant (74.9% ofexcellent and good images with Scintimun® versus55.4% with 99mTc-WBCs).

3.5.2. Impact on patient managementAn evaluation of potential impact of Scintimun® bythe investigators demonstrated that Scintimun®

could change clinical management in 59% orimprove clinical outcome in 55% of 198 patientswith suspected osteomyelitis (study 7MN-301 SZ-A). In 43% of these patients Scintimun® waspresumed to provide clinical benefit not achievableby other available diagnostic imaging methods.

3.5.3. Data on diagnostic efficacy frompeer-reviewed literature

On the basis of a meta-analysis of publishedliterature including 14 publications, Scintimun®

demonstrated a weighted sensitivity of 89% [95%CI 74%-87%] and a weighted specificity of 81%[95% CI 84%-95%].

For comparison, additional meta-analysis weredone for competitors such as 99mTc-WBCs, MRIand 99mTc-sulesomab. Weighted sensitivities andspecificities are reported in the table below.

Source / Year[Appendix]

Enrollmentcriteria

N° of patients Study designMeanage of

patients

99mTc-activity

Scantime

Interpre-tation type

Blindingused

Referencestandard

Se%

Sp%

Acc%

PPV%

NPV%

Lind 1990[37]

Osteomyelitis= 10

10 patients Prospective NR555

(0.5 mg Ab)4-6 h and24 h p.i.

Qualitative NR SU / FU1004/4

835/6

90 80 100

Reuland 1991[45]

Infection inearly post-operativestage in

orthopaedicpatients

106 patients Prospective NR300-400(0.3 – 0.4mg Ab)

2 – 4 hp.i.

Qualitative YesSU / MI / HI

/ FU82

54/6693

37/4086

91/10695

54/5776

37/49

Hotze 1992[26]

Suspicion ofperipheral

osteomyelitis20 patients Prospective 47 500

4 and 20-24 h p.i.

Qualitative Yes MI / HI / IM898/9

647/11

7515/20

678/12

887/8

Sciuk 1992[46]

Suspectedinfection ofprostheses

(hip andknees)

43 patients(48 prosthesis)

Prospective 61 400-5004 and 24

h p.i.Qualitative Yes

SU / MI / HI/ FU

8916/18

8421/25

8637/43

8016/20

9121/23

Dominguez-Gadea 1993

[18]

Diabetic footinfection

25 patients(38 lesions)

Prospective 58 5554-6 and24 h p.i.

Qualitativeand semi-

quantitativeNR

SU in 10,FU in 28

9314/15

7818/23

8432/38

7414/19

9518/19

Boubaker 1995[10]

Suspectedinfection of hip

prostheses

57 patients(78 prostheses)

Prospective 73 490 - 14001, 6, 24 h

p.iQualitative No

SU (48)/FU (30)

647/11*

6623/35*

6530/46*

377/19*

8523/27*

Kaim 1997[27]

Suspicion ofchronic

osteomyelitisof

appendicularskeleton

24 patients Prospective 47555

(0.5 mg Ab)17 h p.i. Qualitative Yes

SU / MI= 19

FU / IM= 5

8411/13**

503/6**

7414/19**

7911/14**

603/5**

Guhlmann1998[22]

Chronicperipheral

osteomyelitis

42 patients(only 38

evaluable)Prospective 48

420(0.3 – 0.5mg Ab)

4 and 24h p.i

Qualitative YesSU***

MI / HI***

9212/13

715/7

909/101008/8

9121/23

8713/15

9212/131005/5

909/1080

8/10

Kaim 2000[28]

Post-traumaticosteomyelitis

18 patients(19 lesions)

Retrospective 45555

(0.5 mg Ab)17 h p.i. Qualitative Yes

SU / MI / HI/ FU

777/9

505/10

6112/19

587/12

715/7

Klett 2001[30]

Hip prosthesis 28 patients Prospective 70600-800(0.33 mg

Ab)

4-6 h p.i.23-25 h

p.i.

QualitativeQuantitative

Yes HI / MI86

12/14100

7911/14

93(13/14)

8223/28

9627/28

8012/15

93(14/15)

8511/13100

Gallowitsch2002[21]

Peripheralosteomyelitis

10 patients Retrospective 56 7404 – 6 and24 h p.i


quantitativeNR MI

1005/5

1005/5

10010/10

Klett 2003[29]

Complicationof knee

prosthesis withhistological

findings

26 patients(28 prostheses)

Retrospective 69600-800(0.33 mg

Ab)

4-6 h p.i.23-25 h

p.i.Quantitative Yes HI / MI 100

8012/15

8925/28

8113/16

100

Horger 2003[25]

Bone infectionafter trauma

27 patients(29 sites)

Prospective 48750

(0.5 mg Ab)1, 3-4, 24

h p.i.

Qualitativeand

quantitativeYes SU

9520/21

756/8

9026/29

9120/22

866/7

Kordelle 2004[31]

Infection onknee

prosthesis32 patients Retrospective 70

600-800(0.33 mg

Ab)

4-6 and23-25 h

p.i.


quantitativeYes HI / MI / SU

10015/15

8214/17

9129/32

8315/18

10014/14



NR: not reported. *: results are reported for 46 evaluable patients with objective proof of infection (microbiology); ** resultsin 19 patients with surgical confirmation and exclusion of patients with clinical follow-up confirmation (5 negative cases)***: sub-analysis in patients with surgery or in patients with microbiology or histology. Reference standard: HI: histologicexamination; SU: surgery; MI : microbiological cultures; IM : imaging including X-ray, ultrasonography, CT, and MRI., FU :follow-up (being either uncomplicated or leading to delayed surgical intervention).

Table 2: Diagnostic performance of 99mTc-besilesomab (in literature)

More details are provided in the following respective meta-analysis tables.

Table 1: Weighted results (BN model)

0

20%

40%

60%

80%

100%

99mTc-besilesomab

99mTc-WBCs

99mTc-sulesomab

MRIWeightedsensitivity

Weightedspecificity

Proportion of studieswith blinded read


Enrollmentcriteria

N° ofexaminations

Study designMeanage of

patients

99mTc-activity

Scantime

Interpre-tation type

Blindingused

Referencestandard

Se%

Sp%

Acc%

PPV%

NPV%

Moragas 1991[39]

Clinical suspicionof bone infection

includingprostheses (35),osteomyelitis (17)


prospective NR 37030-60

min and4-6 h p.i.

qualitative NRMI / HI in

18FU in all

80.917/21

93.730/32

88.7 89.5 88.2

Devillers 1995[14]

Suspectedosteoarticular

infections


retrospective NR 200 4h p.i. qualitative NoMI / HI / SU

/ IM / FU95

60/6390

72/8092

132/14388

60/6896

72/75

Devillers 1998[15]

Diabetic patientswith single or

multiple infectiousfoot lesions

42 patients (56 lesions)

prospective 63 200 4 h p.i. qualitative YesMI / HI / IM

/ FU88.4

23/2696.6

29/3092.9 95.8 90

Harwood 1999[24]

Diabetic patientwith foot ulcer and

suspicion ofosteomyelitis

111 sites prospective 58 NR NR qualitative NR H / MI79

59/7567

24/3675 83 60

Vesco 1999[52]

Diabetic patientwith suspicion of

osteomyelitis24 patients prospective 59 450

4 and24 h p.i

NR NR IM77

10/1382

9/1179 83 75

Devillers 2000[16]

Suspected boneor joint infection

including diabeticfoot (11),

prosthesis (8),joint (4) andothers (9)


prospective 67 2001 and

4–5 h p.i.qualitative No MI / HI / IM

9313/14

10018/18

97 100 95

Wolf 2001 [55] Bone infection 324 patients retrospective 55 11-1852.5 to 5 h

p.i.qualitative NR

HI/MI/SU/IM/FU

97.7216/221

96.8100/103

NR NR NR

van Acker2001 [51]

Painful kneearthroplasty

20 patients prospzctive 66 1854 – 24 h

p.i.

qualitativeand semi-

quantitativeNR

HI / MI in15 pats

FU

1005/5

538/15

6513/20

425/12

1008/8

Ertugrul 2006[20]

Diabetic patientwith foot lesions

26 patients prospective NR 400 - 500 NR qualitative NR MI / HI / SU91

21/23672/3

88 95 50

Simonsen2007 [47]

Suspicion ofinfection ofprosthesis

66 (76 sites)51 scintigraphieswith 99mTc WBCs

(other 25scintigraphies

done with 111In-WBCs)Global

performances

retrospective 73 630 NR qualitative YesMI/ HI / SU

/ FU81.5

22/2793.8

46/4989.5 88 90.2

Liberatore2007 [36]

Osteomyelitis 18 ( 57 sites) retrospective 45 34020 min4h and20 h p.i.

qualitative No MI/FU/IM94.3

33/35100

22/2296.555/57

10033/33

9222/24


NR: not reported. Reference standard: H: histologic examination; SU: surgery; MI: microbiological cultures; IM: imagingincluding X-ray, ultrasonography, CT, and MRI, FU: follow-up.

Table 3: Diagnostic performance of 99mTc-WBCs (in literature)


Enrollment criteriaN° of

examinationsStudy design

Meanage of

patientsMRI characteristics

Blindingused

Referencestandard

Se%

Sp%

Acc%

PPV%

NPV%

Unger 1988[50]

Acuteosteomyelitis

35 patients Prospective 52T1-weighted spin echo T2- weighted spin echo

Yes SU / FU92

11/1296

22/2394 92 96

Erdman 1991[19]

Suspectedosteomyelitis

110 patients Prospective 37T1-weighted spin echo T2- weighted spin echo

No HI / MI98

53/5475

42/5686

95/11079

53/6798

42/43

Weinstein1993 [53]


47 patients(62 scans)

prospective 49T1-weighted spin echo T2- weighted spin echo

Yes SU / HI / FU100

46/4681

13/1695

59/6294

46/49100

13/13

Morrison 1993[40]

Diabetic foot withsuspicion ofosteomyelitis

59 patients(62 MRIs)

Prospective 51

T1-weighted spin echobefore and after gadolinium

administration in all T2 weighted

Yes MI / HI / FU86

30/3589

24/2787

54/6291

30/3383

24/29

Levine 1994[35]


27 patients(29 scans)

prospective 52T1-weighted spin echo T2- weighted spin echo

HI (18) / SU(7) / FU (4)

7710/13

10016/16

9023/29

10010/10

8113/16

Croll 1996 [13]Diabetic foot

infections27 patients Prospective 66

T1-weighted spin echo T2- weighted spin echo

NR HI / MI /FU898/9

10018/18

9626/27

10095

18/19

Craig 1997[12]

Diabetic footinfections

13 (57 bones) Prospective 57

T1-weighted spin echo T1 weighted fat saturatedimages before and after

gadolinium injectionT2- weighted spin echo and

fast fat –suppressed T2-weighted

No HI90

19/2171

26/3679

45/57NR NR

Morrison 1998[41]

Diabetic foot withsuspicion ofosteomyelitis

62 (71 feet) Retrospective 56


administration in all T2 weighted

YesFU (30)/ SU(34) / MI (9)

80 – 100#

R1 40/42R2 38/42

80 – 91 *#

26/2924/29

NR82 – 94

*74 – 100

*

Vesco 1999[52]

Diabetic patientwith suspicion of

osteomyelitis24 patients prospective 59


administrationT2- weighted spin echo

NR IM 10082

9/1192

22/2487

13/15100

Ledermann2000 [33]

Relapse ofinfection in chronic

posttraumaticosteomyelitis of

lower extremities

15 (17 bodyareas)

Retrospective 41.2


administration in all T2 weighted with fat

saturation technique in 5patients

YesSU (11) / FU

(4)100

10/10292/7

71 67 100

Al Khawari2005 [7]

Diabetic foot 19 sites prospective 61

T1-weighted spin echo satbefore and after gadolinium

administration and fatsuppressed T2 weighted

Yes HI / FU100

11/11635/8

8416/19

7911/14

1005/5

Ertugrul 2006[20]

Diabetic patientwith foot lesions

28 sites prospective NRT1-weighted spin echo andT1 fat sat before and aftergadolinium administration

NR MI / HI / SU78

18/23603/5

7521/28

9018/20

37.53/8



Table 4: Diagnostic performances of Magnetic Resonance Imaging (in literature)

# average of two readers (table 2 of article)NR: not reported. * depending on reader and technique of MRIReference standard: HI : histologic examination ; SU: surgery; MI : microbiological cultures; IM: imaging including X-ray,ultrasonography, CT, and MRI., FU : follow-up ; #: R1 reader 1; R2 reader 2.

Source / YearEnrollment

criteriaN° of

examinationsStudy design

Meanage of

patients

99mTc-activity

Scantime

Interpretation type

Blindingused

Referencestandard

Se%

Sp%

Acc%

PPV%

NPV%

Pakos et al2007

Prosthesisinfection

19 Prospective 67 740 2 Qualitative Yes CC, SU, FU75

9/12866/7

7915/19

909/10

666/9

Iyengar et al2005

Prosthetic jointinfections

38 Retrospective 54-89 650 4-5 NR NR HI, CC, IM91

10/1181

22/2784

32/3867

10/1596

22/23

Delcourt et al,2005

Diabetic foot 31 Prospective 59 555–925 3 4Semiquantit

ative No HI, IM, FU

67 12/18

85 11/13

7423/31

8612/14

6511/17

Vicente et al,2004

OsteomyelitisSeptic prosthesis

loosening

3781

NR 64 740 3–4, 7–8 Qualitative Yes CC, HI,FU

7512/16

8012/15

9520/21

8959/66

8732/37

8771/81

9212/13

6312/19

8320/24

9159/62

Rubello et al,2004

Diabetic footProsthesis

7878

retrospective 47 740 4, 18–24Semiquantit

ativeYes CC, IM, FU

9257/62

8448/57

87.514/1685.7

18/21

9161/7884.666/78

96.657/5994.1

48/51

73.614/1966.6

18/27

Gratz et al,2003

ProsthesisPeripheral

osteomyelitis

2021

Retrospective 555–925 1, 4, 24 Qualitative NR IM

635/8666/9

9211/12

8310/12

8016/20

7616/21

835/6756/8

7911/14

7710/13

VonRothenburg et

al, 2003

Peripheralosteomyelitis

30 Retrospective 57 7401, 2, 6,

24Qualitative NR

CC, HI, IM,FU

9520/21

676/9

8726/30

8720/23

866/7

Devillers et al,2000

Osteomyelitis,prosthesis,

diabetic footinfection

23 (32 sites) Prospective 67 900 1, 4–6 Qualitative NRCC, HI, IM,

FU86

12/1472

13/1878

25/3271

12/1787

13/15

Harwood et al,1999

Diabetic foot 122 Prospective 58 555–925 1–2, 5–8Semiquantit

ativeNo CC, HI

9174/81

5623/41

8097/122

8074/92

7723/30

Becker et al,1996

osteomyelitis 53 (66 lesions) Prospective 740 1–6, 24 Qualitative No CC, HI, IM90

36/4085

22/2688

58/6690

36/4085

22/26

Becker et al,1994

Soft tissueinfection andosteomyelitis

20 NR 60 185–9001, 3–4,

24Qualitative No

CC, HI, IM,FU

88 7/8

759/12

8016/20

707/10

909/10


3.5.4. Conclusion on diagnostic efficacy

The results of the phase III and those from theliterature, suggest that the sensitivity of technetium(99mTc) besilesomab is equivalent to that of 99mTcWBCs but that specificity is likely lower.

This lower specificity is acceptable if technetium(99mTc)-besilesomab is used in conjunction withother imaging modal i t ies to determine theappropriate diagnosis.

Table 5: Diagnostic performances of 99mTc-sulesomab (in literature)

NR: not reported.Study design: PR: prospective; RE: retrospective; UN: unclearReference standard: CC: cell cultures; FU: follow-up; H: histologic examination; SU: surgery; MI: microbiological cultures; IM:imaging including X-ray, ultrasonography, CT, and MRI.

3.6. Overview on main safetyaspects (for completeinformation refer to SPC)

DosimetryTechnetium (99mTc) is produced by means of a99Mo/99mTc generator and decays with the emissionof gamma radiation with a mean energy of 140 keVand a half-life of 6.02 hours to technetium (99Tc)which, in view of its long half-life of 2.13 x 105

years can be regarded as quasi stable.

Values of the absorbed doses calculatedfor the individual male and female ofreference

The effective dose as defined in ICRP 103 wasestimated at 8.63x10-3 mSv per MBq of technetium(99mTc)-besilesomab administered. In an adult, thisexaminat ion would cause low to moderateexposure of a few mSv (6.9 mSv for 800 MBqadministered). This is in the range of otherdiagnostic nuclear medicine techniques, e.g.9 9 mTc–sulesomab (6-9 mSv), but more than99mTc–WBCs (~3 mSv). This exposure is notconsidered to constitute a safety concern except inpregnancy, which is a contraindication.

HAMA (Human Anti-Mouse Antibody)Of the 116 patients who had at least one HAMAassessment after administration of technetium(9 9 mTc) besi lesomab in the phase I I I study,16 patients (14%) showed positive HAMA levels.

Adverse eventsSince its marketing launch more than 15 years ago,around 100,000 patients have been administeredtechnetium (99mTc)-besilesomab without relevantsafety concerns.

The table below repor ts adverse reactions byMedDRA system organ classes. The frequenciesare based on the most recent clinical trial and noninterventional safety survey.

The frequency listed below is defined using thefollowing convention:Very common (≥ 1/10); common (≥ 1/100 to <1/10);uncommon (≥ 1/1,000 to <1/100); rare (≥ 1/10,000to <1/1,000).

MedDRA SystemOrgan Classes

Adverse reactions Frequency

Immune systemdisorders

Hypersensitivity, includingangioedema, urticaria

Uncommon

Anaphylactic/anaphylactoidreaction

Rare

Vascular disorders Hypotension Common

Musculoskeletal andconnective tissuedisorders

Myalgia, arthralgia Rare

InvestigationsHuman anti-mouse antibodypositive

Very common

Organ mSv/MBq

Reference male Reference female

Brain 2.36 E-03 3.12 E-03

Heart 4.95 E-03 5.97 E-03

Colon 4.50 E-03 5.76 E-03

Stomach 4.45 E-03 5.35 E-03

Liver 1.00 E-02 1.26 E-02

Small Intestine 4.80 E-03 5.75 E-03

Bone marrow (red) 2.42 E-02 2.29 E-02

Muscles 3.17 E-03 3.91 E-03

Ovaries 5.94 E-03

Pancreas 6.90 E-03 8.26 E-03

Skin 1.78 E-03 2.16 E-03

Lungs 1.25 E-02 1.60 E-02

Spleen 2.71 E-02 3.24 E-02

Kidney 2.10 E-02 2.34 E-02

Breast 3.01 E-03

Adrenal 7.59 E-03 9.37 E-03

Testis 1.82 E-03

Thymus 3.51 E-03 4.23 E-03

Thyroid 2.79 E-03 3.21 E-03

Bone 1.77 E-02 2.27 E-02

Uterus 5.01 E-03

Gallbladder 5.91 E-03 6.81 E-03

Bladder 3.05 E-03 3.80 E-03

Whole body 4.45 E-03 5.52 E-03

Effective Dose 8.63 E-03mSv / MBq




3.7. Dosage and administration

Posology and method of administrationT h e s i n g l e i n j e c t i o n o f Te c h n e t i u m(9 9 mTc)–besi lesomab must be given str ict lyintravenously.➤ The recommended activity of technetium (99mTc)

besilesomab should be between 400 MBq and800 MBq.This cor responds to the administration of0.25 to 1 mg of besilesomab.

➤ Acquisition of images should start 3 to 6 hoursafter administration. An additional acquisition 24hours after initial injection is recommended.

➤ Acquisition can be performed using planar orSPECT (Single Photon Emission ComputedTomography) imaging.

Contra-indicationsHypersensitivity to the active substance, to othermurine antibodies or to any of the excipients.Positive screening test for human anti-mouseantibody (HAMA).Established or suspected pregnancy or whenpregnancy cannot be excluded.

Special warningsAdministration of mouse monoclonal antibodiescan lead to the development of Human Anti-MouseAntibodies (HAMA). Patients who are HAMApositive may have a greater risk for hypersenstivityreactions. Inquiry on possible previous exposure tomurine monoclonal antibodies and a HAMA testshould be made pr ior to admin is t rat ion ofS c i n t i m u n ® ; a p o s i t i ve r e s p o n s e w o u l dcontraindicate the administration of Scintimun®.Data on repeated dosing of Scintimun® are verylimited. Scintimun® should only be used once in apatient’s lifetime.

Anaphylactic or anaphylactoid reactions may occurafter administration of the medicinal product.Appropriate cardiopulmonary resuscitat ionfacilities and trained personnel should be available

for immediate use in the event of an adversereaction.

Since allergic reactions to the murine proteincannot be excluded, cardiovascular treatment,cor ticosteroids, and antihistamines must beavailable during administration of the product.

Fructose intoleranceScintimun® contains sorbitol therefore patients withrare hereditary problems of fructose intoleranceshould not be administered this product.

InteractionsActive substances which inhibit inflammation oraf fect the haematopoiet ic system (such asantibiotics and corticosteroids) may lead to falsenegative results.

Such substances shou ld there fore not beadministered together with, or a short time beforethe injection of Scintimun®.

Pregnancy and lactationScintimun® is contraindicated in pregnancy.Before administering a radioactive medicinalproduct to a mother who is breast-feeding,consideration should be given as to whether theinvestigation could reasonably be delayed until themother has ceased breast-feeding and as tow h e t h e r t h e m o s t a p p r o p r i a t e ch o i c e o fradiopharmaceutical has been made, bearing inmind the secretion of activity in breast milk. If theadministration is considered necessary, breast-feeding should be interrupted for three days andthe expressed milk discarded. These three dayscorrespond to 10 half-lives of Technetium-99m(60 hours). At that time the remaining activityrepresents about 1/1000 of the initial activity in thebody.A close contact with the child should also beavoided during the first 12 hours after the injection.

3.8. Product description

Kit composed of 1 or 2 multidose vials Scintimun®

Vial Scintimun®

- Besilesomab (1mg)- Sodium dihydrogen phosphate, anhydrous- Disodium monohydrogen phosphate, anhydrous- Sorbitol E240- Under nitrogen atmosphere

Vial Solvent for Scintimun®

- 1 , 1 , 3 , 3 -propane te t raphosphore ac id ,tetrasodium salt, dihydrate (PTP)

- Stannous chloride dihydrate- Sodium hydroxide / Hydrochloric acid (for pH

adjustment)- NitrogenThe vials have to be reconstitued with sodiumpertechnetate (99mTc) solution for injection beforeadministration.

Method of preparation

To ensure the highest labelling efficiency:- Radiolabelling is performed using freshly eluted

sodium pertechnetate (99mTc).- Eluates should only be taken from a technetium

(99mTc)-generator that has been eluted within thepast 24 hours (i.e. with less than 24h in-grow).

- The first eluate taken from a technetium (99mTc)-generator that has not been eluted over theweekend must NOT be used.

Radiopharmaceuticals should be prepared by theuser in a manner which satisfies both radiationsafety and pharmaceutical quality requirements.Appropriate aseptic precautions should be taken,comply ing wi th the requi rements o f GoodManufacturing Practice for pharmaceuticals.

Procedure1. Take a vial Solvent for Scintimun (yellow crimped

aluminium capsule) from the kit. Disinfect theseptum and allow to dry. Using a syringe,introduce through the rubber seal 5 ml of 0.9%sodium chloride solution. Without removing theneedle, withdraw an equivalent volume of air inorder to avoid excess pressure in the vial. Shakesmoothly.

2. After complete dissolution, disinfect the septumand allow to dry. Transfer 1 ml of this solutionwith a hypodermic syringe into a vial Scintimun(green crimped aluminium capsule). Withoutremoving the needle, withdraw an equivalentvolume of air in order to avoid excess pressurein the vial. Swirl carefully, the content of vialScint imun wil l dissolve within one minute(DO NOT shake).

3. After 1 min, check that the contents of vialScintimun have completely dissolved. Place vialScintimun in an appropriate lead shieldingcontainer. Disinfect the septum and allow to dry.Using a hypodermic syringe, introduce throughthe rubber seal 2-7 ml of pertechnetate (99mTc)(the eluate complies with the requirements ofcurrent Eur. Ph.). Without removing the needle,withdraw an equivalent volume of air in order toavoid excess pressure in the vial. Swirl carefullyto mix the whole solution (DO NOT shake). Theactivity must be between 400 and 1800 MBqdepending on the volume of per technetate(99mTc). Total volume in vial Scintimun equals 3 to8 ml.

4. Fi l l in the enclosed label and f ix i t to theradiolabelled solution.

5. 10 min after the addition of pertechnetate (99mTc)the solution is ready for injection.

Notes on the instructions:- Solvent for Scintimun must NEVER be radiolabelled first

and then added to Scintimun.- The final radiolabelled injection solution must be

protected from oxygen.



5 ml ofSodium Chloride

Solution

2 - 7 ml

99mTcO4 - (400-800 MBq)

Vialsolvent

VialScintimun®

Scintimun: 2 steps labelling reaction


Quality control

The radiochemical purity of the final radiolabelledpreparation can be tested according to thefollowing procedure:Method: Instant thin layer chromatographyMaterials and reagents :• Methylethylketone R (MEK).• RBM-1 strips (2.5 x 20 cm), cut so that the mobile

phase runs in the direction of the grain of thepaper.

• Glass tank (as a chromatographic chamber)provided with a device to suspend and lower thechromatographic paper without opening thechamber.

• Forceps, scissors, syringes, needles, appropriatecounting assembly.

Procedures:Do not let air enter the vial to be tested and storeall vials containing radioactive solution in leadshielding.1. Place into the glass tank a layer of 1.5 cm deep

of the mobile phase and allow equilibrating forabout 5-10 minutes.

2. Trace two thin lines parallel to the ends of thestrip: one is called “deposit line” at 2.0 cm fromthe bottom, the other one is called “solvent line”at 10 cm above from the deposit line.

3. Apply a spot of the radiolabelled preparation tothe deposit line of the paper strip using asyringe and needle. Do not let dry the spot.

4. Using forceps, suspend the paper strip into thetank and close the lid. Lower the paper into themobile phase (letting the deposit line above thesolvent surface) and allow the solvent to migrateto the solvent line.

5. Remove the paper strip and dry in the air.6. Cut the strip in two separate parts at Rf = 0.57. Determine distribution of radioactivity with an

appropriate detector. Identify each radioactivespot by calculating the Rf.Radiolabelled forms of bound technetium(including 99mTc-MAb monomer,

99mTc-MAb oligomers, 99mTc-MAb fragments,99mTc- PTP and 99mTc-sorbitol) : Rf : 0.0, freetechnetium (pertechnetate ion) migrates aroundRf 1.0.Measure the radioactivity of each consideredimpurity spot by integration of the peaks.

Calculations8) Calculate the percentage of technetium (99mTc)-

Besilesomab (radiochemical purity) as follows:% technetium (99mTc)-Besilesomab (RCP) =100 % - % Free 99m

The radiochemical purity (the percentage ofbound Technetium (99mTc)) must be more than95% or equal to 95%.

Abbreviations used in the text

Abbreviations Terms

AE Adverse event

CEA Carcinoembryonic antigen

CI Confidence interval

CT Computed tomography

h Hour(s)

HAMA Human anti-mouse antibody

ICRPInternational commission onradiological protection

MAb BW 250/183 Monoclonal antibody BW 250/183

MBq Megabecquerel

mg Milligram(s)

mL milliliter

MRI Magnetic-resonance imaging

mSv Millisievert(s)

SAE Serious adverse event

SD Standard deviation

Sens Sensitivity

Spec Specificity

SPECTSingle-photon emission computedtomography

99mTc Technetium-99m

99mTc MAb BW 250/183Technetium-99m labeled monoclonalantibody BW 250/183

3.9. References

R e f e r e n c e s u s e d f o r m e t a - a n a l y s i s o f99mTc–WBCs efficacy

Moragas M, Lomena F, Herranz R, Garcia A, Piera C, Muxi A, Catafau A,Pavia A, Setoain J. 99Tcm – HMPAO leucocyte scintigraphy in thediagnosis of bone infection. Nucl Med Comm 1991; 12 : 417 – 427.

Devillers A, Moisan A, Jean S, Arvieux C, Bourguet P. Technetium-99mhexamethylpropylene amine oxime leukocyte scintigraphy for thediagnosis of bone and joint infections : a retrospective study in 116patients. Eur J. Nucl Med 1995; 22 : 302-307.

Devillers A, Moisan A, Hennion F, Garin E, Poirier JY, Bourguet P.Contribution of technetium-99m hexamethylpropylene amone oximelabelled leukocyte scintigraphy to the diagnosis of diabetic footinfection. Eur j Nucl Med 1998; 25 : 132 – 138.

Harwood SJ, Valdivia S, Hung GL, Quenzer RW. Use of sulesomab, aradiolabeled antibody fragment, to detect osteomyelitis in diabeticpatient with foot ulcers by leukoscintigraphy.Clin Inf Dis 1999; 28 : 1200 -5.

Vesco L, Boulahdour H, Hamissa S, Kretz S, Montazel JL, Perlemuter L,Meignan M, Rahmouni A. The value of combined radionuclide andmagnetic resonance imaging in the diagnosis and conservativemanagement of minimal or localized osteomyelitis of the foot in diabeticpatients. Metabolism 1999; 48 (7) : 922-927.

Devillers A, Garin E, Polard JL, Poirier JY, Arvieux C, Girault S, Moisan A,Bourguet P. Comparison of Tc-99m-labelled antileukocyte fragment Fab’and Tc-99m-HMPAO leukocyte scintigraphy in the diagnosis of bone andjoint infections : a prospective study. Nucl med Comm 2000; 21 : 747-753.

Wolf G, Aigner RM, Schwartz T. Diagnosis of bone infection using 99mTc-HMPAO labelled leukocytes. Nucl.Med Comm. 2001; 22 : 1201-1206

van Acker F, Nuyts J, Maes A, Vanquickenborne B, Stuyck J, BellemansJ, Vleugels S, Bormans G, Mortelmans L. FDGPET, 99mTc-HMPAO whiteblood cell SPET and bone scintigraphy in the evaluation of painful totalknee arthroplasties. Eur J Nucl Med 2001; 28:1496–1504.

Ertugrul MB, Baktiroglu S, Salmant S, Unal S, Aksoy M, Berberoglu K,Calangu S. The diagnosis of osteomyelitis of the foot in diabetes:microbiological examination vs magnetic resonance imaging andlabelled leucocyte scanning. Diabetic Med 2006; 23 : 649-653.

Simonsen L, Buhl A, Oersnes T, Duus B. White blood cell scintigraphy fordifferentiation of infection and aseptic loosening. Acta Orthopaedica2007; 78(5):640 -647

Liberatore M, Calandri E, Pavoni GL, Baiocchi P, Iurilli AP, Venditti M, Al-Nahhas AA, Rubello D. Reliability of white blood cell scan in the follow-up of osteomyelitis. Biomedicine & Pharmacology 2007; 61 : 272-276.

R e f e r e n c e s u s e d f o r m e t a - a n a l y s i s o f99mTc–besilesomab efficacy

Lind P, Langsteger W, Költringer P, Dimai HP, Passl R, Eber O.Immunoscintigraphy of inflammatory processes with a Tc-99m labelledmonoclonal antigranulocyte antibody (MAb 250/183). J Nucl Med 1990;31 : 417-23.

Reuland P, Winker KH, Heuchert T, Ruck P, Müller-Schauenburg W, WellerS, Feine U. Detection of infection in post-operative orthopaedic patientswith technetium-99m labelled monoclonal antibodies againstgranulocytes. J. Nucl Med 1991; 32 : 2209 – 2214.

Hotze A, Briele B, Overbeck B, Kropp J, Gruenwald F, Mekkawy MA, vonSmekal A, Moeller F, Biersack HJ. Technetium-99m labelled anti-granulocyte antibodies in suspected bone infections. J. Nucl Med 1992;33 : 526-531.

Sciuk J, Puskas C, Greitemann B, Schober O. White blood cellscintigraphy with monoclonal antibodies in the study of the infectedendoprosthesis. Eur J Nucl Med 1992; 19 : 497-502.

Dominguez-Gadea L, Martin-Curto LM, de la Calle H and Crespo A.Diabetic foot infections : scintigraphic evaluation with 99mTc-labelledantigranulocyte antibodies. Nucl Med Comm 1993; 14 : 212-218.

Boubaker A, Bischof-Delaloye A, Blanc CH, Dutoit M, Leyvraz PF,Delaloye B. Immunoscintigraphy with antigranulocyte monoclonalantibodies for the diagnosis of septic loosening of hip prostheses. Eur JNucl Med 1995; 22 : 139 – 147.

Kaim A, Maurer T, Ochsner P, Jundt G, Kirsch E, Mueller-Brand J.Chronic complicated osteomyelitis of the appendicular skeleton:diagnosis with technetium-99m labelled monoclonal antigranulocyteantibody-immunoscintigraphy. Eur J Nucl Med 1997; 24 : 732-738.

Guhlmann A, Brecht-Krauss D, Suger G, Glatting G, Kotzerke J, Kinzl L,Reske SN. Fluorine-18-FDG PET and Technetium-99m AntigranulocyteAntibody Scintigraphy in Chronic Osteomyelitis. J Nucl Med 1998; 39(12): 2145-52

Kaim A, Ledermann HP, Bongartz G, Messmer P, Mueller-Brand J,Steinbrich W. Chronic post-traumatic osteomyelitis of the lower extremity:comparison of MRI and combined bone scintigraphy /immunoscintigraphy with radiolabelled monoclonal antigranulocyteantibodies. Skeletal Radiol 2000; 29 : 378-386.

Klett R, Steiner D, Puille M, Khalisi A, Matter HP, Sturz H, Bauer R.Antigranulocyte scintigraphy of septic loosening of hip prosthesis:influence of different analyzing methods. Nuklearmedizin 2001;40:75–79.

Gallowitsch HJ, Heinisch M, Mikosch P, Kresnik E, Kumnig G, Gomez I,Lind P; Tc-99m ciprofloxacin in clinically selected patients suspected forperipherial osteomyelitis, spondylodiscitis and fever of unknown origin:preliminary results. Nuklearmedizin 2002; 41:30-6.




Klett R, Kordelle J, Stahl U, Khalisi A, Puille M, Steiner D, Bauer R.Immunoscintigraphy of septic loosening of knee endoprosthesis: aretrospective evaluation of the antigranulocyte antibody BW 250/183.Eur J Nucl Med Mol Imaging. 2003 Nov;30(11):1463-6.

Horger M, Eschmann SM, Pfannenberg C, Storek D, Dammann F,Vonthein R, Claussen CD, Bares R. The value of SPET/CT in chronicosteomyelitis. Eur J Nucl Med Mol Imaging. 2003 Dec;30(12):1665-73

Kordelle J, Klett R, Stahl U, Hossain H, schleicher I, Haas H.Infektdiagnostik nach Knie-TEP-Implantation. Z. Orthop. 2004:142:337-343.

References used for meta-analysis of MRIefficacy

Unger E, Moldofsky, Gatenby, Hartz W, Broder G. Diagnosis ofosteomyelitis by MR Imaging. AJR 1988; 150 : 605-610

Erdman WA, Tamburro F, Jayson HT, Weatherall PT, Ferry KB, PeshockRM. Osteomyelitis: characteristics and pitfalls of diagnosis with MRimaging. Radiology 1991; 180 : 533-39.

Weinstein D, Wang A, Chambers R, Stewart CA, Motz HA. Evaluation ofMRI in the diagnosis of osteomyelitis in diabetic foot infections. FootAnkle 1993; 14 : 18-22.

Morrison WB, Schweitzer ME, Bock GW, Mitchell DG, Hume EL, pathriaMN, Resnick D. Diagnosis of osteomyelitis: utility of fat-suppressedcontrast-enhanced MR imaging. Radiology 1993; 189 : 251 -257.

Levine SE, Neagle CE, Esterhai JL, Wright DG, Dalinka MK. Magneticresonance imaging for the diagnosis of osteomyelitis in the diabeticpatient with a foot ulcer. Foot Ankle 1994; 15 : 151 – 156.

Croll SD, Nicholas GG, Osborne MA, Wasser TE, Jones S. Role ofmagnetic resonance imaging in the diagnosis of osteomyelitis indiabetic foot ifections. J Vasc Surg 1996; 24 : 266-70.

Craig JG, Amin MB, Wu K, Eyler WR, van Holsbeeck MT, Bouffard JA,Shirazi K. Osteomyelitis of the diabetic foot: MR imaging – pathologiccorrelation. Radiology 1997; 203:849-855

Morrisson WB, Schweitzer ME, Granville Batte W, Radack DP, Russel KM.Osteomyelitis of the foot: relative importance of primary and secondaryMR imaging signs. Radiology 1998; 207 : 625-632.

Vesco L, Boulahdour H, Hamissa S, Kretz S, Montazel JL, Perlemuter L,Meignan M, Rahmouni A. The value of combined radionuclide andmagnetic resonance imaging in the diagnosis and conservativemanagement of minimal or localized osteomyelitis of the foot in diabeticpatients. Metabolism 1999; 48 (7) : 922-927.

Ledermann HP, Haim A, Bongartz G, Steinbrich W. Pitfalls and limitationsof magnetic resonance imaging in chronic posttraumatic osteomyelitis.Eur Radiol 2000; 10: 1815-1823.

Al Khawari H, Al Saeed OM, Jumaa TH, Chishti F. Evaluating diabeticfoot infection with magnetic resonance imaging : Kuwait experience.Med Princ Pract 2005; 14 : 165-172.

Ertugrul MB, Baktiroglu S, Salmant S, Unal S, Aksoy M, Berberoglu K,Calangu S. The diagnosis of osteomyelitis of the foot in diabetes:microbiological examination vs magnetic resonance imaging andlabelled leucocyte scanning. Diabetic Med 2006; 23 : 649-653.

R e f e r e n c e s u s e d f o r m e t a - a n a l y s i s o f99mTc–sulesomab efficacy

Pakos EE, Koumoulis HD, Fotopoulos AD, Ioannidis JPA. Osteomyelitis:Antigranulocyte Scintigraphy with 99mTc Radiolabeled MonoclonalAntibodies for Diagnosis -Meta-Analysis 1. Radiology 2007; 245 (3) :732-741.

Iyengar KP, Vinjamuri S. Role of 99mTc Sulesomab in the diagnosis ofprosthetic joint infections. Nucl Med Comm 2005; 26: 489-496.

Delcourt A, Huglo D, Prangere T, Benticha H, Devemy F, Tsirtsikoulou D,Lepeut M, FontaineL, Steinling M. Comparison between Leukoscan®

(Sulesomab) and Gallium-67 for the diagnosis of osteomyelitis in thediabetic foot. Diabetes Metab 2005, 31:125-133.

Vicente AG, Almoguera M, Alonso JC, et al. Diagnosis of orthopedicinfection in clinical practice using Tc-99m sulesomab (antigranulocytemonoclonal antibody fragment Fab’2). Clin Nucl Med 2004; 29:781–785.

Rubello D, Casara D, Maran A, Avogaro A, Tiengo A, Muzzio PC. Role ofanti-granulocyte Fab’ fragment antibody scintigraphy (LeukoScan) inevaluating bone infection: acquisition protocol, interpretation criteria andclinical results. Nucl Med Commun 2004; 25:39–47.

Gratz S, Schipper ML, Dorner J, et al. LeukoScan for imaging infection indifferent clinical settings: a retrospective evaluation and extended reviewof the literature. Clin Nucl Med 2003;28:267–276.

Von Rothenburg T, Schaffstein J, Ludwig J,Vehling D, Koster O, SchmidG. Imaging osteomyelitiswith Tc-99m-labeled antigranulocyte antibodyFab’ fragments. Clin Nucl Med 2003; 28:643–647.

Devillers A, Garin E, Polard JL, et al. Comparison of Tc-99m-labelledantileukocyte fragment Fab’ and Tc-99m-HMPAO leukocyte scintigraphyin the diagnosis of bone and joint infections: a prospective study. NuclMed Commun 2000; 21:747–753.

Harwood SJ, Valdivia S, Hung GL, Quenzer RW. Use of Sulesomab, aradiolabeled antibody fragment, to detect osteomyelitis in diabeticpatients with foot ulcers by leukoscintigraphy. Clin Infect Dis 1999;28:1200– 1205.

Becker W, Palestro CJ, Winship J, et al. Rapid imaging of infections witha monoclonal antibody fragment (LeukoScan). Clin Orthop Relat Res1996; 329:263–272.

Becker W, Bair J, Behr T, et al. Detection of soft-tissue infections andosteomyelitis usinga technetium-99m-labeled anti-granulocytemonoclonal antibody fragment. J Nucl Med 1994; 35:1436–1443.



Summary of Product Characteristics

1. NAME OF THE MEDICINAL PRODUCTScintimun1 mg kit for radiopharmaceutical preparation

2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial of Scintimun contains 1 mg of besilesomab.

Besilesomab is an anti-granulocyte monoclonal antibody (BW 250/183), produced in murine cells.

The radionuclide is not part of the kit.

Excipients:

Each vial of Scintimun contains 2 mg of sorbitol.

One ml of the labelled solution contains less than 4 mg of sodium.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORMKit for radiopharmaceutical preparation

Scintimun: white powder

Solvent for Scintimun: white powder

4. CLINICAL PARTICULARS4.1 Therapeutic indicationsThis medicinal product is for diagnostic use only.

Scintigraphic imaging, in conjunction with other appropriate imaging modalities, for determining the location of inflammation/infection inperipheral bone in adults with suspected osteomyelitis.

Scintimun should not be used for the diagnosis of diabetic foot infection.

4.2 Posology and method of administrationThis medicinal product is for use in designated nuclear medicine facilities only, and should only be handled by authorised personnel.

Posology

Adults

The recommended activity of technetium (99mTc) besilesomab should be between 400 MBq and 800 MBq.

This corresponds to the administration of 0.25 to 1 mg of besilesomab.

For repeated use, see section 4.4.

Elderly

No dose adjustment is required.

Renal and hepatic impairment

Formal studies have not been performed in patients with renal or hepatic impairment. However, due to the nature of the molecule andthe short half-life of technetium (99mTc) besilesomab, dose adjustment is not necessary in such patients.

Paediatric population

Scintimun is not recommended for use in children below the age of 18 years due to insufficient data on safety and efficacy (see section5.1 and 5.2).

Method of administration and scintigraphic examination

Before administration to the patient, this medicinal product should be reconstituted with the solvent provided and then radiolabelled withsodium pertechnetate (99mTc) injection to obtain a clear and colourless technetium (99mTc) besilesomab injection.

The radiolabelled solution should be administered intravenously as a single dose only.

For instructions for preparation of the radiopharmaceutical, see section 12.

For disposal and other handling, see section 6.6.

Patient preparation

Scintimun should be given to sufficiently hydrated patients. In order to obtain images of best quality and to reduce the radiationexposure of the bladder, patients should be encouraged to drink sufficient amounts and to empty their bladder prior to and after the


scintigraphic examination.

Images acquisition should start 3 to 6 hours after administration. An additional acquisition 24 hours after initial injection isrecommended. Acquisition can be performed using planar imaging.

4.3 Contra-indicationsHypersensitivity to the active substance, to other murine antibodies or to any of the excipients.

Positive screening test for human anti-mouse antibody (HAMA).

Pregnancy (see section 4.6).

4.4 Special warnings and precautions for useIndication of the examination

For all patients, the radiation exposure must be justifiable by the expected diagnostic achieved with the lowest possible radiation dose.

An interval of at least 2 days must be observed between any previous scintigraphy with other technetium (99mTc)-labelled agents andadministration of Scintimun.

Interpretation of the Scintimun images

There are currently no criteria to distinguish infection and inflammation by means of Scintimun imaging. Scintimun images should beinterpreted in the context of other appropriate anatomical and/or functional imaging examinations.

Only limited data is available about binding of technetium (99mTc) besilesomab to CarcinoEmbryonic Antigen (CEA) expressing tumours invivo. In vitro, besilesomab cross-reacts with CEA. False positive findings in patients with CEA expressing tumours cannot be excluded.

False results may be obtained in patients with diseases involving neutrophil defects and to patients with haematological malignanciesincluding myeloma.

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 the appropriate authorisations of the competent authorities.

Warnings related to excipients

Fructose intolerance

Scintimun contains sorbitol therefore patients with rare hereditary problems of fructose intolerance should not be administered this product.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose administered, i.e. is essentially ‘sodium- free’.

Other important warnings

Human Anti-Mouse Antibodies (HAMA)

Administration of murine monoclonal antibodies can lead to the development of Human Anti-Mouse Antibodies (HAMA). Patients who areHAMA positive may have a greater risk for hypersensitivity reactions. Inquiry on possible previous exposure to murine monoclonal antibodiesand a HAMA test should be made prior to administration of Scintimun; a positive response would contraindicate the administration ofScintimun (see section 4.3).

Repeated use

Data on repeated dosing of Scintimun are very limited. Scintimun should only be used once in a patient’s lifetime.

Hypersensitivity reactions

Anaphylactic or anaphylactoid reactions may occur after administration of the medicinal product. Appropriate cardiopulmonaryresuscitation facilities and trained personnel should be available for immediate use in the event of an adverse reaction.

Since allergic reactions to the murine protein cannot be excluded, cardiovascular treatment, corticosteroids, and antihistamines must beavailable during administration of the product.

4.5 Interaction with other medicinal products and other forms of interaction

Active substances which inhibit inflammation or affect the haematopoietic system (such as antibiotics and corticosteroids) may lead tofalse negative results.

Such substances should therefore not be administered together with, or a short time before the injection of Scintimun.

4.6 Fertility, pregnancy and lactationWomen of childbearing potential

When it is necessary to administer radioactive medicinal products to women of childbearing potential, information should always be soughtabout pregnancy. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. Where uncertainty exists,it is important that radiation exposure should be the minimum consistent with achieving the desired clinical information. Alternativetechniques which do not involve ionising radiation should be considered.

Pregnancy

Scintimun is contraindicated in pregnancy (see section 4.3).



Available data is insufficient to address the effects of the product during pregnancy. No reproductive studies have been carried out inanimals. Radionuclide procedures carried out on pregnant women also involve radiation doses to the foetus.

The dose delivered to foetus varies with the stage of pregnancy and is reported in the following table:

Breast-feeding

It is not known if the product is excreted in human milk. A risk to a breast-fed child cannot be excluded.

Before administering a radioactive medicinal product to a mother who is breast-feeding, consideration should be given as to whether theinvestigation could reasonably be delayed until the mother has ceased breast-feeding and as to whether the most appropriate choice ofradiopharmaceutical has been made, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary,breast-feeding should be interrupted for three days and the expressed milk discarded. These three days correspond to 10 half-lives oftechnetium (99mTc) (60 hours). At that time the remaining activity represents about 1/1000 of the initial activity in the body.

A close contact with the child should also be avoided during the first 12 hours after the injection.

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.

At the recommended activity for diagnostic procedures, Scintimun is not likely to have any influence on the ability to drive and usemachines.

4.8 Undesirable effectsIn the most recent clinical study in which 123 patients were administered Scintimun, the most commonly reported adverse reaction was thedevelopment of anti-mouse antibodies (HAMA) in 14% of the patients, after a single administration (16 positive over 116 assayed one and/orthree months after the administration).

The table below reports adverse reactions by MedDRA system organ classes. The frequencies are based on the most recent clinical trialand non interventional safety survey.

The frequency listed below is defined using the following convention:

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)

For all patients, the radiation exposure must be justifiable by the expected diagnostic achieved with the lowest possible radiation dose.Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. For diagnostic nuclearmedicine investigations the frequency of these adverse reactions is not known. After administration of the maximum recommended activityof technetium (99mTc) besilesomab of 800 MBq, the effective dose is about 6.9 mSv.

4.9 OverdoseNo case of overdose has been reported.

If an overdose of technetium (99mTc) besilesomab has been administered, the radiation dose delivered to the patient must be reduced byincreasing as much as possible the elimination of the radionuclide by forced diuresis and frequent micturitions, and by the use of laxativesto promote faecal excretion.

5. PHARMACOLOGIC PROPERTIES5.1 Pharmacodynamic propertiesPharmacotherapeutic group: Diagnostic Radiopharmaceuticals ATC code: V09HA03

Besilesomab is a murine immunoglobulin of IgG1 isotype that specifically binds to NCA-95 (non specific cross-reacting antigen 95), anepitope expressed at the cell membrane of granulocytes and granulocyte precursors. Besilesomab cross-reacts with tumours expressingcarcinoembryonic antigen (CEA). Besilesomab has no effect on activation of complement, granulocyte function or platelets. At therecommended activities, it does not exert any clinically relevant pharmacodynamic effects.

In a randomised cross-over trial comparing blinded reading of Scintimun and 99mTc-White Blood Cells (WBCs) images in 119 patients with

MedDRA System Organ Classes Adverse reactions Frequency

Immune system disordersHypersensitivity, including angioedema, urticaria Uncommon

Anaphylactic/anaphylactoid reaction Rare

Vascular disorders Hypotension Common

Musculoskeletal and connective tissue disorders Myalgia, arthralgia Rare

Investigations Human anti-mouse antibody positive Very common

Stage of pregnancy Equivalent dose in mSv/MBq

Three months 0.00379

Six months 0.00335

Nine months 0.00300


suspected osteomyelitis, the agreement rate between the two methods was 83% (lower 95% confidence interval limit: 80%). However,based on the investigator’s diagnosis after one month of follow-up, Scintimun had a slightly lower specificity (71.8%) than 99mTc-WBCs(79.5%).

There are insufficient data on the use of Scintimun for the diagnosis of diabetic foot infection.

5.2 Pharmacokinetic propertiesWhole blood concentration-time radioactivity curves show a two-phase course, which can be subdivided into an early phase (0-2 h) and alate phase (5-24 h). After correcting for the decay of radionuclide, the calculated half-life of the early phase is 0.5 h whereas the late phaseshows a half-life of elimination of 16 h.

Six hours after injection, about 1.5% of the whole body radioactivity is found in the liver whereas about 3.0% is found in the spleen. Twenty-four hours after injection, the percentages of radioactivity are 1.6% in the liver and 2.3% in the spleen.

Measurement of radioactivity levels in urine shows that up to 14% of the administered activity is excreted via the bladder during the 24 hpost-injection. The low renal clearance of activity (0.2 l/h for a glomerular filtration rate around 7 l/h) indicates that the kidney is not the majorroute of besilesomab elimination.

Non pathological unusual accumulations may be observed in the spleen (up to 6% of the patients), in the bowel (up to 4% of the patients),in the liver and bone marrow (up to 3% of the patients), and in the thyroid and kidneys (up to 2% of patients).

5.3 Preclinical safety dataPreclinical toxicity and safety studies were performed using commercial kits reconstituted with decayed technetium and thus the effect ofradiation has not been assessed.

Preclinical data obtained with the non-radioactive compound reveal no special hazard for humans based on conventional studies of safetypharmacology, single-dose and repeated-dose toxicity, although antimurine antibodies were found in all dose groups (including controls)in a repeated-dose study in monkeys. Genotoxicity studies conducted to test for potentially genotoxic impurities were also negative.

No animal studies regarding carcinogenic potential and toxicity to reproduction were performed.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipientsScintimun

Sodium dihydrogen phosphate, anhydrous

Disodium monohydrogen phosphate, anhydrous

Sorbitol E420

Under nitrogen atmosphere

Solvent for Scintimun

1, 1, 3, 3-propane tetraphosphonic acid, tetrasodium salt, dihydrate (PTP)

Stannous chloride dihydrate

Sodium hydroxide / Hydrochloric acid (for pH adjustment)

Nitrogen

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

6.3 Shelf life2 years.

Do not store the reconstituted and radiolabelled product above 25°C and use within 3 hours.

6.4 Special precautions for storageStore in a refrigerator (2°C – 8°C). Keep the vial in the outer carton in order to protect from light.

For storage conditions of the reconstituted and radiolabelled medicinal product, see section 6.3.

This product should be stored in accordance with national regulations concerning radioactive products.

6.5 Nature and contents of containerVial Scintimun 10 ml, colourless, type I glass vial, closed with chlorobutyl rubber stopper and aluminium crimped capsule (green).

Vial Solvent for Scintimun 6 ml, colourless, type I glass vial, closed with chlorobutyl rubber stopper and crimped aluminium capsule (yellow).

Pack sizes:

Kit of one multidose vial Scintimun and one vial Solvent for Scintimun.

Kit of two multidose vials Scintimun and two vials Solvent for Scintimun.

Not all pack sizes may be marketed.


6.6 Special precautions for disposal and other handlingThe administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spills of urine,vomiting, expectoration or other biological fluids. Radiation protection precautions in accordance with national regulations must be taken.

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

7. MARKETING AUTHORISATION HOLDERCIS bio international

B.P.32

F-91192 Gif-sur-Yvette Cedex

France

8. MARKETING AUTHORISATION NUMBER(S)EU/1/09/602/001

EU/1/09/602/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION11/01/2010

10. DATE OF REVISION OF THE TEXT01/2010

11. DOSIMETRYTechnetium (99mTc) is produced by means of a (99Mo/99mTc) generator and decays with the emission of gamma radiation with a mean energyof 140 keV and a half-life of 6.02 hours to technetium (99Tc) which, in view of its long half-life of 2.13 x 105 years can be regarded as quasistable.

For each organ, or group of organs, the absorbed doses have been calculated using the methodology developed by the MIRD (MedicalInternal Radiation Dose).

The effective dose has been calculated by using the absorbed doses determined for each individual organ, taking into account theweighting factors (radiation and tissue) to use according to the recommendations of the ICRP (International Commission of RadiologicalProtection, Publication 103).

Table 1: Values of the absorbed doses calculated for the individual male and female of reference.

For this product, the Effective Doseresulting from an administered activity of800 MBq is 6.9 mSv.

Organ mSv/MBq

Reference male Reference female

Brain 2.36 E-03 3.12 E-03

Heart 4.95 E-03 5.97 E-03

Colon 4.50 E-03 5.76 E-03

Stomach 4.45 E-03 5.35 E-03

Liver 1.00 E-02 1.26 E-02

Small Intestine 4.80 E-03 5.75 E-03

Bone marrow (red) 2.42 E-02 2.29 E-02

Muscles 3.17 E-03 3.91 E-03

Ovaries 5.94 E-03

Pancreas 6.90 E-03 8.26 E-03

Skin 1.78 E-03 2.16 E-03

Lungs 1.25 E-02 1.60 E-02

Spleen 2.71 E-02 3.24 E-02

Kidney 2.10 E-02 2.34 E-02

Breast 3.01 E-03

Adrenal 7.59 E-03 9.37 E-03

Testis 1.82 E-03

Thymus 3.51 E-03 4.23 E-03

Thyroid 2.79 E-03 3.21 E-03

Bone 1.77 E-02 2.27 E-02

Uterus 5.01 E-03

Gallbladder 5.91 E-03 6.81 E-03

Bladder 3.05 E-03 3.80 E-03

Whole body 4.45 E-03 5.52 E-03

Effective Dose 8.63 E-03mSv / MBq



12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALSScintimun is a sterile powder containing 1 mg of besilesomab per vial Scintimun.

After reconstitution with the solvent provided and then radiolabelling with sodium pertechnetate (99mTc) injection, the resulting clear andcolourless solution for injection of technetium (99mTc) besilesomab has a pH of 6.5-7.5.

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

Method of preparation

To ensure the highest labelling efficiency:

- Radiolabelling is performed using freshly eluted sodium pertechnetate (99mTc).

- Eluates should only be taken from a technetium (99mTc)-generator that has been eluted within the past 24 hours (i.e. with less than 24hin-grow).

- The first eluate taken from a technetium (99mTc)-generator that has not been eluted over the weekend must NOT be used.

Procedure:

1. Take a vial Solvent for Scintimun (yellow crimped aluminium capsule) from the kit. Disinfect the septum and allow to dry. Using asyringe, introduce through the rubber seal 5 ml of 0.9% sodium chloride solution. Without removing the needle, withdraw anequivalent volume of air in order to avoid excess pressure in the vial. Shake smoothly.

2. After complete dissolution, disinfect the septum and allow to dry. Transfer 1 ml of this solution with a hypodermic syringe into a vialScintimun (green crimped aluminium capsule). Without removing the needle, withdraw an equivalent volume of air in order to avoidexcess pressure in the vial. Swirl carefully, the content of vial Scintimun will dissolve within one minute (DO NOT shake).

3. After 1 min, check that the content of vial Scintimun have completely dissolved. Place vial Scintimun in an appropriate lead shieldingcontainer. Disinfect the septum and allow to dry. Using a hypodermic syringe, introduce through the rubber seal 2-7 ml ofpertechnetate (99mTc) (the eluate complies with the requirements of current Eur. Ph.). Without removing the needle, withdraw anequivalent volume of air in order to avoid excess pressure in the vial. Swirl carefully to mix the whole solution (DO NOT shake). Theactivity must be between 400 and 1800 MBq depending on the volume of pertechnetate (99mTc). Total volume in vial Scintimun equals3 to 8 ml.

4. Fill in the enclosed label and fix it to the radiolabelled solution.

5. 10 min after the addition of pertechnetate (99mTc) the solution is ready for injection.

Notes on the instructions:

- Solvent for Scintimun must NEVER be radiolabelled first and then added to Scintimun.

- The final radiolabelled injection solution must be protected from oxygen.

Quality control

The radiochemical purity of the final radiolabelled preparation can be tested according to the following procedure:

Method

Instant thin layer chromatography

Materials and reagents

- Adsorbent: strips for thin layer chromatography (2.5 x 20 cm) coated with silica gel. Trace a starting line 2.5 cm from the bottom of thepaper strip.

- Solvent: methyl ethyl ketone (MEK)

- Containers: appropriate containers such as chromatography tank or 1 000 ml Erlenmeyer flasks.

- Miscellaneous: forceps, scissors, syringes, appropriate counting assembly.


Procedure

Do not let air enter the vial to be tested and store all vials containing radioactive solution in lead shielding.

1. Introduce the solvent into the chromatography tank to a depth of approximately 2 cm. Cover the tank and allow to equilibrate for atleast 5 minutes.

2. Apply a spot (2 µl) of the radiolabelled solution to the starting line of the ITLC paper strip using a syringe and a needle.

3. Introduce the ITLC paper strip immediately into the chromatography tank using forceps to avoid formation of pertechnetate (99mTc)due to oxygen.

4. When the solvent has reached the top of the strip (about 10 minutes), use the forceps to remove the strip and dry in the air.

5. Cut the strip in two separate parts at Rf = 0.5.

6. Separately count each cut part of the strip and record the obtained values (use an appropriate detection apparatus with a constantcounting time, and known geometry and background noise).

7. Calculations

The radiochemical purity corresponds to the percentage of bound technetium (99mTc) and is calculated as follows after correctingdata for background noise:

% bound technetium (99mTc) = 100% - % free Technetium (99mTc)

Where, % free technetium (99mTc) = Activity of cut strip from Rf 0.5 to Rf 1.0 x 100Total activity of strip

8. The radiochemical purity (the percentage of bound Technetium (99mTc) must be more than or equal to 95%.

9. The solution should be inspected visually prior to use. Only clear solutions, free of visible particles should be used.

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

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA)http://www.emea.europa.eu/.


CIS bio internationalMember of IBA groupB.P. 32 - 91192 Gif-sur-Yvette CedexFranceTel : +33 1 69 85 75 70Fax : +33 1 69 85 72 09

HeadquartersIBAAvenue Albert Einstein, 41348 Louvain-la-NeuveBelgium

IBA delivers solutions of unprecedentedprecision in the fields of cancer diagnosis andtherapy. The company also offers sterilizationand ionization solutions to improve the hygieneand safety of everyday life.

www.iba-worldwide.com

Scintimun®

Monograph

Prin

ted

in F

RA

NC

E -

DE

LTA

GR

AP

HIQ

UE

SE

RV

ICE

- M

arch

201

1 -

I-S

CIN

TI-

D-1

1-25

8

making bone inflammation/infection simpler to detect · osteomyelitis) adequate antibiotics are...

Documents