Leaflet SIILTIBCY (0.5mcg+0.5mcg) / ml solution for injection
Indicated for: diagnosis of tuberculosis infection
Route of administration: injectable
Substance: antigens derived from Mycobacterium tuberculosis (rDESAT-6 and rCFP-10) (diagnostic agent)
ATC: V04CF02 (Various | Other diagnostic agents | Tuberculosis diagnostics)
Mycobacterium tuberculosis-derived antigens, rdESAT-6 and rCFP-10, are used as a skin test to help detect infection with the tuberculosis bacterium in adults and children aged at least 4 weeks. This product is a diagnostic aid, not a vaccine and not a treatment for tuberculosis.
The test contains two laboratory-produced proteins that are specific to the tuberculosis bacterium. If the immune system has previously encountered Mycobacterium tuberculosis, an intradermal injection may trigger a local reaction. The area becomes firm, and the healthcare professional measures the induration 48 to 72 hours later; a result above the defined threshold may suggest infection.
The injection is given into the skin of the forearm by trained staff using the Mantoux technique. It is essential to return for reading within the recommended time window, otherwise the result may be invalid. Tell your doctor if you have had severe reactions to tuberculosis skin tests, important allergies, conditions that reduce immunity, or immunosuppressive treatment.
The most common reactions are itching, pain, bruising, redness, or swelling at the injection site. Rarely, allergic reactions or strong local reactions can occur. The test alone cannot determine whether tuberculosis is active or latent; the result must be interpreted together with symptoms, chest imaging, laboratory tests, and the history of possible exposure.
General data about SIILTIBCY (0.5mcg+0.5mcg) / ml
- Substance: antigens derived from Mycobacterium tuberculosis (rDESAT-6 and rCFP-10)
- Product code: W71433001
- Concentration: (0.5mcg+0.5mcg) / ml
- Pharmaceutical form: solution for injection
- Quantity: 1
- Product type: Generic medicine
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Leaflet SIILTIBCY (0.5mcg+0.5mcg)/ml
Contents of the package leaflet for the medicine SIILTIBCY (0.5mcg+0.5mcg) / ml solution for injection
1. NAME OF THE MEDICINAL PRODUCT
SIILTIBCY (0.5 microgram + 0.5 microgram)/mL solution for injection
Mycobacterium tuberculosis derived antigens (rdESAT-6 and rCFP-10)
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One dose (0.1 mL) contains 0.05 microgram of rdESAT-6* and 0.05 microgram of rCFP-10**.
*Recombinant dimer of Mycobacterium tuberculosis early secretory antigenic target1
**Recombinant culture filtrate protein of Mycobacterium tuberculosis11Produced in Lactococcus lactis cells
Multidose vial.One vial (1 mL) contains 10 doses of 0.1 mL.
Excipient with known effectEach dose (0.1 mL) contains 0.011 mg of polysorbate 20.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection (injection).
Clear, colourless to pale-yellow solution, with a pH of 7.2 - 7.6.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
SIILTIBCY is indicated as a diagnostic aid for detection of Mycobacterium tuberculosis infection,including disease, in adults and children aged 28 days or older.
This medicinal product is for diagnostic use only.
4.2 Posology and method of administration
The dose is 0.1 mL of SIILTIBCY.
Special populationsElderly
There is only limited data on the safety and efficacy for SIILTIBCY in individuals aged 65 years andabove. No dose adjustment is necessary for this population.
Paediatric populationThe safety and efficacy of SIILTIBCY in newborn infants aged under 28 days have not beenestablished. No data are available.
Method of administrationSIILTIBCY should be prepared and administered via intradermal injection by healthcare professionalstrained for the Mantoux technique. The medicinal product should be administered with adequatehygiene of the hands and using aseptic technique, as follows:
* Withdraw 0.1 mL of SIILTIBCY using a 1 mL syringe with a short-bevel needle. Beforedrawing SIILTIBCY from the multidose vial, expel any air from the syringe. If the vial wasalready opened, swab it with an alcohol swab and let it dry before use.
* Administer the 0.1 mL of SIILTIBCY intradermally in the middle-third of the forearm using the
Mantoux technique. Therefore, stretch the skin slightly and hold the needle almost parallel tothe skin surface with the bevel upwards. Insert the tip of the needle into the superficial layer ofthe dermis. Make sure the needle is visible through the epidermis during the injection. Do notapply the test in areas of scars, rashes, burn or tattoos.
* Inject the drawn 0.1 mL solution slowly. A small-blanched papule of 8-10 millimetres (mm) indiameter will appear, which should disappear after about 10 minutes. If the papule does notappear, repeat a new injection of 0.1 mL of SIILTIBCY on the other arm or on the same arm atleast 4 cm away from the first injection site.
Evaluating the reaction
Intradermal injected SIILTIBCY may induce an induration at the site of injection. The induration canbe seen as a raised area with clearly defined margin at and around the injection site. Althougherythema can accompany the induration, only the induration should be measured.
The induration is measured 48 to 72 hours after the injection by a trained healthcare professional.
Measure the diameter of the induration transversely to the long axis of the forearm with a ruler. Toallow ease with measurement, a flexible (or easily bendable) ruler is suggested.
Normally the induration and erythema will decrease after 4 days and disappear within 28 days after theinjection.
Interpretation
An induration of ≥ 5 mm is considered as a positive test result, which indicates infection with
Mycobacterium tuberculosis.
Interpretation of skin test results should consider the specific context of use and risk assessment, andcould be complemented by radiography and other diagnostic evaluations.
Performing a test before 6 to 8 weeks from Mycobacterium tuberculosis exposure might result in afalse-negative result.
The risk of false-positive test results may increase if SIILTIBCY is repeated within 6 weeks.
Therefore, an interval of at least 6 weeks should be observed between repeated tuberculosis skin tests.
This may be relevant for individuals taking part in a screening program such as healthcareprofessionals and contacts to active tuberculosis cases (i.e. index case).
As any diagnostic tool, false-negative results are possible (see section 5.1 for details). If a negative testresult is found, but clinical suspicion is high, further examinations should be performed.
The test results are not influenced by previous vaccination with Bacillus Calmette-Guérin (BCG).
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Hypersensitivity to Lactococcus lactis.
Severe local or systemic reaction to other Mycobacterium tuberculosis derived products.
4.4 Special warnings and precautions for use
In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.
General recommendationsAnaphylaxis
Anaphylactic or other allergic type reactions are possible following administration of SIILTIBCY.
Appropriate equipment for management of such reactions should always be available during theconduct of the test. Close observation for at least 15 minutes is recommended following the test.
Route of administration
Adherence to the Mantoux technique when administering SIILTIBCY is essential for obtainingreliable results, therefore avoid subcutaneous or intramuscular injection.
Special populationsThe reactivity to SIILTIBCY can be lower or give false-negative results in immunocompromisedindividuals, including those receiving immunosuppressant therapy and human immunodeficiency virus(HIV) positive individuals if cluster of differentiation 4 positive (CD4+) thymus cell (T-cell) count is< 100 T-cells/mm3. A positive test result indicates infection with Mycobacterium tuberculosisregardless of the CD4+ T-cell count.
There may be an increased risk of false-negative results in the elderly population due toimmunosenescence with age.
Previous exposure to non-tuberculous mycobacteria
SIILTIBCY does not identify subjects with previous exposure to non-tuberculous mycobacteria aswell as those who received Bacillus Calmette-Guérin vaccine or therapy, and thus use for this purposeis not appropriate.
Diagnosis of active tuberculosis
SIILTIBCY cannot be used as stand-alone tool for diagnosis of active tuberculosis disease. Inaddition, risk assessment, radiography, and other diagnostic evaluations should be considered forsubjects suspected to have active tuberculosis.
ExcipientsThis medicinal product contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially‘potassium-free’.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.
This medicinal product contains 0.011 mg of polysorbate 20 in each dose, which is equivalent to0.11 mg/mL. Polysorbates may cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
Similar to other Mycobacterium tuberculosis skin tests, reactivity to SIILTIBCY may be decreased inpersons who are receiving corticosteroids or immunosuppressive agents.
Reduced reactivity may be observed when SIILTIBCY is used after vaccination with live vaccines(e.g. vaccines against measles, mumps and rubella). This decreased reactivity may result in false-negative reactions. Therefore, SIILTIBCY should be administered either before or at the same time ofthe vaccination or should be postponed for 4 weeks after vaccination.
Regardless of the concomitant use of other medicinal products a positive test result indicates infectionwith Mycobacterium tuberculosis.
4.6 Fertility, pregnancy and lactation
There are no or limited data from the use of SIILTIBCY in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).
No effects during pregnancy are anticipated, since systemic exposure to SIILTIBCY is negligible.
SIILTIBCY can be used during pregnancy.
Breast-feedingNo effects on the breast-fed newborns/infants are anticipated since the systemic exposure of thebreast-feeding mother to SIILTIBCY is negligible. The skin test can be carried out duringbreast-feeding.
FertilityNo animal studies have been conducted on the effects of SIILTIBCY on fertility. Considering thenegligible human systemic exposure to SIILTIBCY, no effects on fertility in male and female subjectsis anticipated.
4.7 Effects on ability to drive and use machines
SIILTIBCY has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
The safety profile presented below is based on data obtained from 7 clinical trials (TESEC-01 to
TESEC-07), where SIILTIBCY was administered to 2 960 subjects (aged 32 days to 76 years)(Table 1).
The most common adverse reactions were injection site pruritus (20%), injection site pain (8%) andinjection site hematoma (6%).
Tabulated list of adverse reactionsAdverse reactions reported are listed according to the following frequency: 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); veryrare (< 1/10 000) and not known (cannot be estimated from the available data). Adverse drug reactions(ADRs) are organised by MedDRA System Organ Class (SOC). Within each frequency grouping,adverse reactions are presented in order of decreasing seriousness.
Table 1: Adverse reactions reported with SIILTIBCY (infants, children, adolescents and adultscombined)
System organ class Frequency Adverse reactionscategory
Infections and infestations Uncommon Gastroenteritis
Blood and lymphatic system disorders Uncommon Lymphadenopathy
Rare Lymphadenitis
Eosinophilia
Nervous system disorders Common Headache
Uncommon Dizziness
Rare Head discomfort
Paraesthesia
Gastrointestinal disorders Uncommon Diarrhoea
Nausea
Rare Vomiting
Hepatobiliary disorders Rare Hepatitis
Jaundice
Transaminases increased
Skin and subcutaneous tissue disorders Uncommon Rash
Pruritus
Rare Night sweats
Urticaria
Musculoskeletal and connective tissue Uncommon Pain in extremitydisorders Rare Myalgia
Arthritis
General disorders and Very common Injection site pruritusadministration site conditions Common Injection site haematoma
Injection site vesicles
Injection site induration#
Injection site swellingInjection site pain
Injection site rash
Injection site erythema
Uncommon Injection site ulcer
System organ class Frequency Adverse reactionscategory
Injection site haemorrhage
PyrexiaMalaise
FatigueInjection sitediscolouration
PainInfluenza-like illness
Rare Axillary pain
Injection site inflammation
Injection site urticaria
Injection site nodule
Injection site papule
Chills
Injection sitehypoaesthesia#: Please refer to “Description of selected adverse reactions” for further details.
Description of selected adverse reactionsInjection site reactions
Mild injection site reactions were common and included pruritus, pain, haematoma, rash, vesicles,induration, erythema and swelling. Induration and erythema are expected reactions in individualsinfected with Mycobacterium tuberculosis. Cases with induration more than 50 mm and erythemamore than 80 mm are uncommon. Injection site reactions were generally transient and normallydecreased in severity within 4 days and disappeared within 28 days.
Special population
Patients with HIV positive status at the time of screening visit were included in the clinical trials with
SIILTIBCY if they were receiving antiretroviral therapy but were excluded if diagnosed with acquiredimmune deficiency syndrome (AIDS). Based on available data, frequency, type and severity ofadverse reactions in the HIV positive status population seemed overall similar as in the general adultpopulation.
Paediatric populationThe safety assessment in children and adolescents is based on data obtained from 2 Phase 3 trials,
TESEC-05 and TESEC-06, in which a total of 723 paediatric subjects aged from 32 days to 17 yearsreceived SIILTIBCY (see section 5.1). Overall, the safety profile in infants, children and adolescentswas similar to that observed in the adult population.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
No case of overdose has been reported.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: not yet assigned, ATC code: not yet assigned.
Mechanism of actionSIILTIBCY contains two recombinant Mycobacterium tuberculosis specific antigens, rdESAT-6 andrCFP-10. In case of infection with Mycobacterium tuberculosis, SIILTIBCY induces a delayed -typehypersensitivity reaction directed by cytokines, which are released by thymus helper cells type 1 afterstimulation by the specific antigens included in SIILTIBCY.
This reaction is seen as an induration at the site of injection. The induration reaches its maximum 48 to72 hours after administration.
Clinical efficacyThe diagnostic performance of SIILTIBCY to identify individuals infected with Mycobacteriumtuberculosis was evaluated in 3 pivotal clinical trials TESEC-05, TESEC-06 and TESEC-07 (Table 2,
Table 3) in comparison to other approved diagnostic immunological tuberculosis tests, i.e. thetuberculin purified protein derivative from the Statens Serum Institut (SSI) (PPD RT 23 SSI, hereinafter referred to as PPD) and QuantiFERON®-TB Gold in-Tube (QFT).
The sensitivity and specificity comparison of SIILTIBCY and other diagnostic tests (QFT and PPD)were evaluated in a post hoc analysis on the full analysis set (FAS) population with confirmedtuberculosis and in the negative control group, respectively (Table 2 and Table 3).
TESEC-05
This Phase 3 trial compared the diagnostic performance of SIILTIBCY vs QFT, in combination with adouble-blind, randomised, split-body assessment of SIILTIBCY vs PPD. The primary trial objectiveswere to evaluate the performance of SIILTIBCY in relation to age, HIV status and CD4+ count, and toevaluate the clinical safety of SIILTIBCY, with an emphasis on children and HIV positive individuals.
The primary endpoint was the test positivity rate for SIILTIBCY; secondary endpoints werecomparisons of SIILTIBCY, PPD and QFT test positivity as well as sensitivity and specificity.
The trial was conducted in South Africa where tuberculosis is endemic, HIV infection prevalence ishigh and BCG vaccination at birth is routine practice.
A total of 1 190 subjects were enrolled of which 1 090 were suspected tuberculosis cases (0 to65 years). Two hundred and ninety-nine subjects (25.1%) were HIV positive and 882 (74.1%) were
BCG-vaccinated. The mean (standard deviation [SD]) age of all subjects was 22.5 (18.3) years with arange from 1 month to 65 years. The gender distribution was close to 50% (females 49.5% vs males50.5%). The negative control population (n = 100) comprised of children aged 5 to 11 years old withno known contact with people infected with Mycobacterium tuberculosis and no signs of symptoms oftuberculosis.
Subjects were randomised to receive dual injections of SIILTIBCY and PPD in either forearm (split-body); blood samples for QFT analysis were collected prior to the administration of the skin tests, andtest positivity rates were compared.
TESEC-06
This double-blind, randomised, split-body, Phase 3 trial conducted across 13 centres in Spaincompared the diagnostic performance of SIILTIBCY with QFT in 4 risk groups (negative control,occasional contacts, close contacts, and positive controls). The primary objective was to assesswhether a trend in SIILTIBCY test positivity would be seen with an increasing risk of Mycobacteriumtuberculosis infection (i.e. from negative controls to the occasional contacts to close contacts).
Secondary outcomes were comparisons of SIILTIBCY, QFT, and PPD test positivity, sensitivity andspecificity.
Nine hundred and seventy-nine eligible subjects (aged 0 to 76 years) were enrolled, comprising 263negative controls, 299 occasional contacts, 316 close contacts and 101 tuberculosis patients. The mean(SD) age of all enrolled subjects was 30.6 (14.5) years. Overall, 53.5% of the subjects were female and46.5% male. Of all the enrolled subjects 366 (37.4%) were BCG-vaccinated. All subjects in theoccasional and close contacts, and positive control groups, received dual injections of SIILTIBCY and
PPD. In the negative control group, 213 subjects received dual injections of SIILTIBCY and PPD indifferent arms and a subgroup of 50 subjects received only SIILTIBCY in order to explore whether
SIILTIBCY responses were affected by the concurrent administration of PPD. QFT testing wasplanned for all subjects aged 5 years and older, prior to the administration of the skin tests in order toavoid possible booster responses.
TESEC-07
This was a double-blind, randomised, controlled, Phase 2/3 clinical trial in adults with newlydiagnosed, active pulmonary tuberculosis (PTB) and in treatment for < 2 weeks, conducted at7 centres in South Africa. The primary trial objectives were to investigate and compare the indurationsizes of SIILTIBCY and PPD when injected alone or concomitantly in different arms, and to assess ifconcomitant injections of SIILTIBCY and PPD influence the tests’ sensitivity. Secondary trialobjective was to compare the test positivity rates (sensitivity) of SIILTIBCY to that of PPD and QFT.
Four hundred and fifty-six eligible adults (aged 18 to 67 years) were enrolled and randomised into 1 of3 treatment groups to receive either SIILTIBCY (n = 1534), PPD (n = 149) or SIILTIBCY and PPD(n = 153) in either forearm. Samples for QFT testing were collected prior to the administration of theskin tests.
In the FAS population, the mean age (SD) was 37.2 (12.7) years in the SIILTIBCY group, 36.3(11.8) years for PPD and 35.3 (11.5) years for the SIILTIBCY and PPD group. Overall, 64.3% of thesubjects were male and 35.7% female.
Table 2: Sensitivity analysis - individual clinical trials TESEC-05/-06/-07 (FAS populations withconfirmed tuberculosis)
SIILTIBCY QFT PPD Difference in sensitivity,%(95% CI)
Clinical n Sensitivity, n Sensitivity, n Sensitivity, SIILTIBCY SIILTIBCYtrial % % % - QFT - PPD(95% CI) (95% CI) (95% CI)
TESEC- 75 72.0 70 58.6 75 77.3 13.4 -5.305 (61.8; 82.2) (47.0; 70.1) (67.9; 86.8) (-3.3; 30.2) (-20.6; 9.9)
TESEC- 100 68.0 101 81.2 100 81.0 -13.2 -13.006 (58.9; 77.1) (73.6; 88.8) (73.3; 88.7) (-26.1; -0.3) (-25.9; -0.1)
TESEC- 305 78.0 446 69.5 303 87.1 8.5 -9.107 (73.4; 82.7) (65.2; 73.8) (83.4; 90.9) (1.9; 15.1) (-15.4; -2.8)
Abbreviations: BCG = Bacillus Calmette-Guérin; CI = confidence interval; FAS = full analysis set;
HIV = human immunodeficiency virus; mm = millimetre; n = number of subjects in the populationwith a test result; PPD = tuberculin purified protein derivative RT 23 SSI; QFT = QuantiFeron®-TB
Gold in-Tube Test. Sensitivity analysis was performed post hoc. Percentages were calculated using nas the denominator. SIILTIBCY test diagnostic outcome used a cut-off point of ≥ 5 mm. PPD testdiagnostic outcome used a test cut-off of ≥ 15 mm for HIV negative and BCG-vaccinated subjects and5 mm otherwise. QFT test diagnostic outcome was based on manufacturer’s algorithm. The QFTindeterminates were incorporated in the analysis as either “not positive” or “not negative” depending ifsensitivity or specificity of QFT was calculated, respectively. Subjects with suspected tuberculosiswere not considered in calculations of sensitivity.
Table 3: Specificity analysis - individual clinical trials TESEC-05/-06 (FAS populations with notuberculosis)
SIILTIBCY QFT PPD Difference in specificity, %(95% CI)
Clinical n Specificity, n Specificity, n Specificity, SIILTIBCY SIILTIBCYtrial % % % - QFT - PPD(95% CI) (95% CI) (95% CI)
TESEC- 100 83.0 98 71.4 100 85.0 11.6 -2.005 (75.6; 90.4) (62.5; 80.4) (78.0; 92.0) (-1.0; 24.2) (-13.2; 9.2)
TESEC- 263 96.6 263 96.2 213 93.4 0.4 3.206 (94.4; 98.8) (93.9; 98.5) (90.1; 96.8) (-3.2; 3.9) (-1.3; 7.6)
Abbreviations: BCG = Bacillus Calmette-Guérin; CI = confidence interval; FAS = full analysis set;
HIV = human immunodeficiency virus; mm = millimetre; n = number of subjects in the populationwith a test result; PPD = tuberculin purified protein derivative RT 23 SSI; QFT = QuantiFeron®-TB
Gold in-Tube Test. Specificity analysis was performed post hoc. Percentages were calculated using nas the denominator. SIILTIBCY test diagnostic outcome used a cut-off of ≥ 5 mm. PPD test diagnosticoutcome used a test cut-off of ≥ 15 mm for HIV negative and BCG-vaccinated subjects and 5 mmotherwise. QFT test diagnostic outcome was based on manufacturer’s algorithm. The QFTindeterminates were incorporated in the analysis as either “not positive” or “not negative” depending ifsensitivity or specificity of QFT was calculated, respectively. Suspected tuberculosis subjects are notconsidered in the calculation for specificity. Specificity was not evaluated in the TESEC-07 clinicaltrial as the trial was conducted in patients recently diagnosed with active tuberculosis.
Supportive analysis
A post hoc analysis of data pooled from the 3 pivotal clinical trials (TESEC-05, TESEC-06 and
TESEC-07) was performed to assess SIILTIBCY’s diagnostic performance. The QFT indeterminateswere incorporated in the analysis as either “not positive” or “not negative” depending if sensitivity orspecificity of QFT was calculated, respectively. Suspected tuberculosis subjects were not consideredin the calculation for sensitivity or specificity.
Sensitivity
Sensitivity was evaluated in subjects with culture-confirmed active tuberculosis disease of TESEC-05and TESEC-07 studies. The sensitivity of SIILTIBCY (n = 380) was 76.8% (95% CI: 72.6; 81.1)compared to 68.0% (95% CI: 64.0; 72.0) for QFT (n = 516) and 85.2% (95% CI: 81.6; 88.8) for PPD(n = 378). The percentage difference in sensitivity was 8.8% (95% CI: 2.7; 14.9) in comparison to
QFT and -8.3% (95% CI: -14.2; -2.5) compared to PPD.
Special populationsPaediatric population
A total of 723 paediatric subjects (32 days to 2 years: 115 subjects; 2 to 4 years: 156 subjects; 5 to11 years: 312 subjects; 12 to17 years: 140 subjects) were included in 2 Phase 3 trials, TESEC-05 and
TESEC-06, with the aim to evaluate the diagnostic performance and the safety of SIILTIBCY in thepaediatric population. The paediatric group received the same dose of SIILTIBCY as the adult group.
The induration was measured 2 to 3 days after SIILTIBCY administration and cut-off for a positivetest was ≥ 5 mm.
The sensitivity and specificity of SIILTIBCY in different age groups were evaluated in a post hocpooled analysis of the 3 pivotal clinical trials (TESEC-05, TESEC-06 and TESEC-07).
In children of 0 to 10 years of age, sensitivity of SIILTIBCY (n = 5) was 80.0% (95% CI: 44.9; 100.0)compared to 66.7% (95% CI: 13.3; 100.0) for QFT (n = 3) and 60.0% (95% CI: 17.1; 100.0) for PPD(n = 5). In individuals of 11 to 25 years of age, sensitivity of SIILTIBCY (n = 108) was 81.5%(95% CI: 74.2; 88.8) compared to 76.3% (95% CI: 69.1; 83.5) for QFT (n = 135) and 90% (95% CI:84.1; 95.9) for PPD (n = 100).
In children of 0 to 10 years, specificity of SIILTIBCY (n = 85) was 81.2% (95% CI: 72.9; 89.5)compared to 72.3% (95% CI: 62.7; 81.9) for QFT (n = 83) and 84.7% (95% CI: 77.1; 92.4) for PPD(n = 85). In individuals of 11 to 25 years of age, specificity of SIILTIBCY (n = 241) was 98.3%(95% CI: 96.7; 100.0) compared to 95.9% (95% CI: 93.3; 98.4) for QFT (n = 241) and 97.4%(95% CI: 95.1; 99.6) for PPD (n = 191).
5.2 Pharmacokinetic properties
No pharmacokinetic study has been performed. Since SIILTIBCY is administered intradermally, theexposure is mostly local and very little systemic effect is expected.
5.3 Preclinical safety data
Non-clinical data on rdESAT-6 (administered subcutaneously to rat and dog) and the combinationrdESAT-6 + rCFP-10 (administered subcutaneously to rat) reveal no special hazard for humans basedon conventional studies of acute and repeated dose toxicity.
An embryo-foetal development study on the combination rdESAT-6 + rCFP-10 and vehicle phenol0.5% (included in the commercial formulation) administered subcutaneously to rat, reveal no maternaltoxicity nor embryo-foetal abnormalities. The estimated human equivalent dose at which no effectswere observed in rats was 4.64 mcg/kg rdESAT-6 + rCFP-10 (more than 2 700-fold higher than thehuman dose) in the repeated dose toxicity studies, and 6.08 mcg/kg for rdESAT-6 + CFP-10 in theembryo-foetal development study (more than 3 500-fold higher than the human dose).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Disodium hydrogen phosphate dihydrate (E339)
Potassium dihydrogen orthophosphate (E340)
Potassium chloride (E508)
Sodium chloride
Polysorbate 20 (E432)
Phenol
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other products.
6.3 Shelf life
Unopened vial3 years.
After first openingChemical and physical in-use stability has been demonstrated for 28 days at 2 °C to 8 °C.
From a microbiological point of view, once opened, the product may be stored for a maximum of28 days at 2 °C to 8 °C. Other in-use storage times and conditions are responsibility of the user.
6.4 Special precautions for storage
Store in a refrigerator (2 °C - 8 °C).
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions after first opening of the medicinal product, see section 6.3.
6.5 Nature and contents of container
1 mL solution in a clear multidose glass vial with stopper (bromobutyl rubber) and a plastic flip-offcap with aluminium over-seal. Each vial contains 10 doses of 0.1 mL.
Pack sizes* 1 multidose vial
* Multipack containing 10 (10 packs of 1) multidose vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Upon discharge, patients should be instructed to keep the injection site clean. The scratching of theinjection site should be avoided but in case of itching a cold compress can be applied.
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
The solution is to be discarded if visible particulate matter is observed.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.