APPROVED PACKAGE INSERT

Transcription

1 SCHEDULING STATUS S4 APPROVED PACKAGE INSERT PROPRIETARY NAME AND DOSAGE FORM SIMPONI Solution for Injection COMPOSITION Each 0,5 ml single use pre-filled syringe or pre-filled pen contains 50 mg of golimumab. Inactive ingredients: Sorbitol, L-histidine, polysorbate and water for injection. PHARMACOLOGICAL CLASSIFICATION A.30.1 Antibodies. PHARMACOLOGICAL ACTION Pharmacodynamic properties Golimumab is a human monoclonal antibody that forms high affinity, stable complexes with both the soluble and transmembrane bioactive forms of human tumour necrosis factor (TNF), which prevents the binding of TNF to its receptors. The binding of human TNF by golimumab was shown to neutralise TNF-induced cell-surface expression of the adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 by human endothelial cells. TNF-induced secretion of interleukin (IL)-6, IL-8 and granulocyte-macrophage colony stimulating factor (GM-CSF) by human endothelial cells was also inhibited by golimumab. Pharmacokinetic properties Following subcutaneous (SC) administration of golimumab to healthy subjects or patients with RA, the median time to reach maximum serum concentrations (T max ) ranged from 2 to 6 days. Original registration August 2013 Page 1 of 34

2 A SC injection of 50 mg golimumab to healthy subjects produced a mean ± standard deviation maximum serum concentration (C max ) of 3,1 ± 1,4 µg/ml. Golimumab exhibited dose-proportional pharmacokinetics in patients with RA over the dose range of 0,1 to 10,0 mg/kg following a single intravenous (IV) dose. Following a single IV administration over the same dose range in patients with RA, mean systemic clearance of golimumab was estimated to be 4,9 to 6,7 ml/day/kg, and mean volume of distribution ranged from 58 to 126 ml/kg, which indicates that golimumab is distributed primarily in the circulatory system with limited extravascular distribution. Median terminal half-life values were estimated to be 12 ± 3 days in healthy subjects and patients with RA, PsA or AS. Following a single SC injection of 100 mg, the absorption of golimumab was similar in the upper arm, abdomen and thigh, with a mean absolute bioavailability of 51 %. Since golimumab exhibited approximately dose proportional PK following a SC administration, the absolute bioavailability of the golimumab 50 mg dose is expected to be similar to the 100 mg dose. When 50 mg golimumab was administered SC to patients with RA, PsA or AS every 4 weeks, serum concentrations reached steady state by Week 12. With concomitant use of MTX, treatment with 50 mg golimumab SC every 4 weeks resulted in a median steady-state trough serum concentration of approximately 0,6 g/ml in RA patients with active RA despite MTX therapy, and approximately 0,5 g/ml in patients with active PsA and approximately 0,6 g/ml in patients with AS. Patients with RA, PsA or AS who did not receive concomitant use of MTX had approximately 30 % lower steady-state trough concentrations of golimumab than those who received golimumab with MTX. Population pharmacokinetic analysis in patients with RA also indicated that concomitant use of MTX could reduce the apparent clearance of golimumab by 17,1 %. However, concomitant use of non-steroidal anti-inflammatory drugs, oral corticosteroids or sulfasalazine, were not found to influence the apparent clearance of golimumab. Original registration August 2013 Page 2 of 34

3 Population pharmacokinetic analyses showed there was a trend toward higher apparent clearance of golimumab with increasing weight. However, subgroup analyses by weight quartiles did not demonstrate a meaningful difference in clinical efficacy between the different dose groups. Therefore, there is no need to adjust the dosage of golimumab based on the patient s weight. Patients who developed anti-golimumab antibodies generally had low trough steady-state serum concentrations of golimumab (see Immunogenicity). Immunogenicity: Antibodies to golimumab, nearly all neutralising in vitro, were detected in 4,3 % (57/1 322) of golimumab treated patients across Phase 3 rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) studies through week 24 and similar rates were shown across rheumatologic indications. Treatment with concomitant methotrexate (MTX) resulted in a lower proportion of patients with antibodies to golimumab than patients receiving golimumab without MTX (approximately 2 % [14/719] versus 7 % [43/603], respectively). The small number of patients positive for antibodies to golimumab limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures. Because immunogenicity analyses are product- and assay-specific, comparison of of antibody rates with those from other products is not appropriate. Clinical studies: In clinical studies golimumab was effective in modulating select markers of inflammation and bone metabolism. Improvement in C-reactive protein (CRP) levels were observed and treatment with golimumab resulted in significant reductions from baseline in serum levels of IL-6, ICAM-1, matrix metalloproteinase-3 (MMP-3) and vascular endothelial Original registration August 2013 Page 3 of 34

4 growth factor (VEGF). In addition, levels of TNF were reduced in RA and AS patients and levels of IL-8 were reduced in PsA patients. INDICATIONS Rheumatoid arthritis (RA): SIMPONI, in combination with methotrexate (MTX) is indicated for: the treatment of active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drug (DMARD) therapy including MTX has been inadequate. the treatment of active rheumatoid arthritis in adult patients not previously treated with MTX. Psoriatic arthritis (PsA): SIMPONI, alone or in combination with MTX, is indicated for the treatment of active psoriatic arthritis in adult patients when the response to previous DMARD therapy has been inadequate. Ankylosing spondylitis (AS): SIMPONI is indicated for the treatment of active ankylosing spondylitis in adult patients when the response to conventional therapy has been inadequate. CONTRA-INDICATIONS SIMPONI is contra-indicated in: Patients with a known hypersensitivity to golimumab or to any of its excipients. Active mycobacterium tuberculosis infection or other severe infections such as sepsis, and opportunistic infections (see WARNINGS AND SPECIAL PRECAUTIONS: Infections). Moderate to severe heart failure (NYHA class III/IV) (see WARNINGS AND SPECIAL PRECAUTIONS: Congestive Heart Failure). Original registration August 2013 Page 4 of 34

5 Patients receiving live vaccines (see Interactions and WARNINGS AND SPECIAL PRECAUTIONS: Vaccinations). Lymphomas. Active demyelating pathology of the nervous system (see WARNINGS AND SPECIAL PRECAUTIONS: Neurological events). Pregnancy and lactation (see PREGNANCY AND LACTATION). WARNINGS and SPECIAL PRECAUTIONS Infections Bacterial (including sepsis and pneumonia), mycobacterial (tuberculosis), invasive fungal and opportunistic infections (such as listeriosis and legionella), including fatalities, have been reported in patients receiving TNF blocking agents, including SIMPONI. Some of these serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infections. For patients who have resided in or travelled to regions where invasive fungal infections such as histoplasmosis, coccidioidomycosis or blastomycosis are endemic, the benefits and risks of SIMPONI treatment should be carefully considered before initiation of SIMPONI therapy. SIMPONI should not be given to patients with a clinically important, active infection. Caution should be exercised when considering the use of SIMPONI in patients with a chronic infection or a history of recurrent infection. Patients should be advised of and avoid exposure to potential risk factors for infection as appropriate. Tuberculosis Patients should be evaluated for tuberculosis risk factors (including close contact with a person with active tuberculosis) and tested for latent tuberculosis infection prior to treatment with SIMPONI. Treatment of latent tuberculosis infection should be initiated prior to therapy with SIMPONI (see CONTRA-INDICATIONS). Original registration August 2013 Page 5 of 34

6 Anti-tuberculosis therapy should be considered prior to initiation of SIMPONI in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Tests for latent tuberculosis may yield false negative results, especially in patients who are immunocompromised or severely ill. Prior to initiating SIMPONI, treatment for latent TB should be considered in patients who have significant risk factors for TB despite a negative test for latent tuberculosis. The decision to initiate anti-tuberculosis therapy in these patients should only be made following consultation with a medical practitioner with expertise in the treatment of tuberculosis and taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy. Patients receiving SIMPONI should be monitored closely for signs and symptoms of active tuberculosis during and after treatment, including patients who tested negative for latent tuberculosis infections. Malignancies The potential role of TNF-blocking therapy in the development of malignancies is not known. Caution should be exercised when considering SIMPONI therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy. Lymphoma In the controlled portions of clinical trials of SIMPONI, more cases of lymphoma have been observed among patients receiving SIMPONI treatment compared with control patients. Malignancies other than lymphoma In the controlled portions of the SIMPONI Phase 2 and Phase 3 clinical trials in RA, PsA and AS, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar between the SIMPONI and the control groups. Original registration August 2013 Page 6 of 34

7 In an exploratory clinical trial evaluating the use of SIMPONI in patients with severe persistent asthma, more malignancies were reported in patients treated with SIMPONI compared with control patients (see SIDE EFFECTS.). The significance of this finding is unknown. Hepatitis B virus reactivation SIMPONI has been associated with reactivation of hepatitis B virus in patients who are chronic carriers of the virus (i.e. surface antigen positive). Chronic carriers of hepatitis B should be appropriately evaluated and monitored prior to the initiation of, during treatment with, and for several months following discontinuation of SIMPONI. Congestive Heart Failure (CHF) Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with SIMPONI. SIMPONI should be used with caution in patients with heart failure. If a decision is made to administer SIMPONI to patients with heart failure, they should be closely monitored during therapy and SIMPONI should be discontinued if new or worsening symptoms of heart failure appear (see CONTRA-INDICATIONS). Neurological events SIMPONI has been associated with an exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis. In patients with pre-existing or recent onset of demyelinating disorders, SIMPONI treatment is contra-indicated (see CONTRA-INDICATIONS). Concurrent administration of SIMPONI with anakinra Serious infections were seen in clinical studies with concurrent use of anakinra and another TNF blocking agent, etanercept, with no added clinical benefit. Because of the nature of the adverse events seen with this combination therapy, similar toxicities may also result from the combination of anakinra and SIMPONI.Therefore, the combination of SIMPONI and anakinra is not recommended. Original registration August 2013 Page 7 of 34

8 Vaccinations Patients treated with SIMPONI may receive concurrent vaccinations, except for live vaccines (see CONTRA-INDICATIONS). Psoriatic arthritis patients treated with SIMPONI in one Phase 3 PsA study were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine. Similar numbers of psoriatic arthritis patients receiving SIMPONI and not receiving SIMPONI had at least a 2- fold increase in antibody titres. The proportions of patients with response to pneumococcal vaccine were lower among SIMPONI and control-treated patients receiving MTX compared with patients not receiving MTX. Overall, the data indicate that SIMPONI does not suppress the humoral immune response to this vaccine. Allergic reactions Latex sensitivity The needle cover on the syringe in the pre-filled pen is manufactured from dry natural rubber containing latex, and may cause allergic reactions in individuals sensitive to latex. Hypersensitivity reactions In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following SIMPONI administration. Some of these reactions occurred after the first administration of SIMPONI. If an anaphylactic or other serious allergic reaction occurs, administration of SIMPONI should be discontinued immediately and appropriate therapy instituted. Special populations Paediatric use Safety and efficacy of SIMPONI in paediatric patients have not been established. Original registration August 2013 Page 8 of 34

9 Geriatric use In the Phase 3 studies in RA, PsA and AS, no overall differences in AEs, SAEs, and serious infections in patients age 65 or older (n=155) who received SIMPONI were observed compared with younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly. Renal and hepatic insufficiency Specific studies of SIMPONI have not been conducted in patients with renal or hepatic impairment. Excipients SIMPONI contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take SIMPONI. Effects on ability to drive and use machines SIMPONI may cause dizziness. Patients should not drive or operate machinery until their individual susceptibility is known. INTERACTIONS No interaction studies have been performed. Anakinra The combination of SIMPONI and anakinra is not recommended (see WARNINGS AND SPECIAL PRECAUTIONS: Concurrent administration of SIMPONI and anakinra). Live vaccines Live vaccines should not be given concurrently with SIMPON (see CONTRA-INDICATIONS and WARNINGS AND SPECIAL PRECAUTIONS: Vaccinations). Original registration August 2013 Page 9 of 34

10 Methotrexate Although concomitant use of methotrexate results in higher steady-state trough concentration of SIMPONI in patients with RA, PsA or AS, the data do not suggest the need for dose adjustment of either SIMPONI or methotrexate. (See Pharmacokinetic properties.) PREGNANCY AND LACTATION Pregnancy SIMPONI should not be used in pregnant women (see CONTRA-INDICATIONS). Women of childbearing potential should be advised not to become pregnant during SIMPONI therapy. Lactation It is not known whether golimumab is excreted in human breast milk. SIMPONI should not be used in mothers who are breast-feeding. DOSAGE AND DIRECTIONS FOR USE SIMPONI treatment is to be initiated and supervised by medical practitioners experienced in the diagnosis and treatment of rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. After proper training in subcutaneous (SC) injection technique, patients may self-inject with SIMPONI if their physician determines that this is appropriate, with medical follow-up as necessary. Dosage: Adults 18 years and older Rheumatoid arthritis 50 mg given as a subcutaneous injection once a month, on the same date each month. Psoriatic arthritis 50 mg given as a subcutaneous injection once a month, on the same date each month. Original registration August 2013 Page 10 of 34

11 Ankylosing spondylitis 50 mg given as a subcutaneous injection once a month, on the same date each month. Use in elderly patients (65 years and older) No dosage adjustment is required. Use in paediatric patients (less than 18 years) Not recommended due to a lack of data on efficacy and safety. Use in patients with renal and/ or hepatic impairment SIMPONI has not been studied in these patient populations. No dose recommendations can be made. Method of administration Patients should be instructed to inject the full amount of SIMPONI according to directions. SIDE EFFECTS Safety data from Phase 2 and 3 clinical trials are available from SIMPONI-treated patients. Adverse Drug Reactions (ADRs) observed in clinical studies with SIMPONI are summarised in the following table. Within the designated system organ classes, the adverse drug reactions are listed under headings of frequency, using the following convention: Very common ( 1/10), Common ( 1/100, < 1/10), Uncommon ( 1/1 000, < 1/100), Rare ( 1/10 000, < 1/1 000), Very rare (< 1/10 000). Summary of ADRs in clinical studies Infections and infestations Very Common: Upper respiratory tract infection (nasopharyngitis, pharyngitis, laryngitis, Common: rhinitis) Original registration August 2013 Page 11 of 34

12 Influenza, bronchitis, cellulitis, sinusitis, oral herpes Uncommon: Septic shock, sepsis, tuberculosis, lower respiratory tract infection (pneumonia), septic arthritis, pyelonephritis, septic bursitis, abscess Rare: Histoplasmosis, coccidioidomycosis, Pneumocystis jiroveci; (carinii) (PCP) infection Nervous system disorders Common: Uncommon: Dizziness, paraesthesia Demyelinating disorders Vascular disorders Common: Hypertension Skin and subcutaneous tissue disorders Uncommon Pustular psoriasis General disorders and administrative site conditions Common: Pyrexia, injection site (injection site erythema, urticaria, induration, pain, bruising, pruritus, irritation, paraesthesia) Investigations Common: Alanine aminotransferase increased, aspartate aminotransferase increased Uncommon: Neutrophil count decreased Infections Upper respiratory tract infection was the most common adverse reaction reported in the combined Phase 3 RA, PsA and AS studies through Week 16, occurring in 7,2 % of SIMPONI-treated patients (incidence per patient-year: 0,26; 95 % CI: 0,17; 0,31) as Original registration August 2013 Page 12 of 34

13 compared with 5,8 % of control patients (incidence per patient-year: 0,23; 95 % CI: 0,17; 0,31). The incidence per patient year (95 % confidence interval; CI) of upper respiratory tract infections through 1 year of follow up was 0,23 events (0,21; 0,25) for SIMPONI-treated patients and 0,25 events (0,20; 0,31) for control patients. In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, infections were observed in 28,3 % of SIMPONI-treated patients (incidence per patient-year: 1,28; 95 % CI: 1,18; 1,38) compared with 24,7 % of control patients (incidence per patient-year: 1,17; 95 % CI: 1,02; 1,33). The incidence per patient year (95 % CI) of infections through 1 year of follow up was 1,32 events (1,27; 1,38) for SIMPONI-treated patients and 1,31 events (1,18; 1,44) for control patients. In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, serious infections were observed in 1,4 % of SIMPONI-treated patients (incidence per patient-year: 0,06; 95 % CI: 0,04; 0,08) and 1,3 % of control patients (incidence per patient-year: 0,04; 95 % CI: 0,02; 0,08). Serious infections observed in SIMPONI-treated patients included sepsis, pneumonia, cellulitis, abscess, and tuberculosis. The incidence per patient year (95 % CI) of serious infections through 1 year of follow up was 0,05 events (0,04; 0,06) for SIMPONI-treated patients and 0,06 events (0,04; 0,09) for control patients. Malignancies Lymphoma The incidence of lymphoma in SIMPONI-treated patients with RA, PsA and AS during the controlled portions of Phase 2 and 3 clinical trials was higher than expected in the general population. Malignancies other than lymphoma The potential role of TNF-blocking therapy in the development of malignancies is unknown. Original registration August 2013 Page 13 of 34

14 Liver enzyme elevations In controlled Phase 3 trials through Week 16, mild ALT elevations (> 1 and < 3 x ULN) occurred in similar proportions of SIMPONI and control patients in the RA and PsA studies (22,1 % to 27,4 % of patients); in the AS study, more SIMPONI-treated patients (25,6 %) than control patients (3,9 %) had mild ALT elevations. Through 1 year of follow up, the incidence of mild ALT elevations was similar in the SIMPONI-treated and control patients in the RA and PsA studies. In the AS study, the incidence of mild ALT elevations was higher in SIMPONI-treated patients than in control patients. In the RA and AS studies through week 16, ALT elevations 5 x ULN were uncommon and seen in more SIMPONI-treated patients (0,4 % to 0,9 %) than control patients (0 %). This trend was not observed in the PsA population. This trend was not observed in the PsA population. Through 1 year of follow up, the incidence of ALT elevations 5 x ULN was similar in both SIMPONI-treated and control patients in the Phase 3 RA, PsA and AS studies. The majority of these elevations were asymptomatic. Injection site reactions In controlled Phase 3 trials through Week 16 in RA, PsA and AS, 5,8 % of SIMPONItreated patients had injection site reactions compared with 2,2 % in control patients. The majority of the injection site reactions were mild and moderate and the most frequent manifestation was injection site erythema. Antinuclear antibodies (ANA)/anti-double-stranded DNA (dsdna) antibodies Use of TNF blocking agents has been associated with the formation of auto-antibodies and rarely, in the development of a lupus-like syndrome. In Phase 3 trials in RA, PsA and AS at 1 year of follow up, 4,0 % of SIMPONI-treated patients and 2,6 % of control patients were newly ANA-positive (at titres of 1:160 or Original registration August 2013 Page 14 of 34

15 greater) compared with baseline. The frequency of anti-dsdna antibodies at 1 year of follow up in patients, anti-dsdna negative at baseline was uncommon. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT Single doses up to 10 mg/ kg intravenously have been administered in a clinical study without dose-limiting toxicity. In case of an overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment be instituted immediately. IDENTIFICATION The solution is clear to slightly opalescent, colourless to light yellow and may contain a few small translucent or white particles of protein. This appearance is not unusual for solution contains protein. PRESENTATION SIMPONI is supplied in Type 1 glass syringes with fixed stainless steel needles as single use pre-filled syringes available in carton packs of 1 or 3 pre-filled syringes. SIMPONI is supplied in a Type 1 glass syringe with a fixed stainless steel needle. This syringe is contained in a single-use pre-filled pen called SmartJect available in carton packs of 1 or 3 pre-filled pens. STORAGE INSTRUCTIONS Store at 2 to 8 C (in a refrigerator). Do not freeze. Do not shake. Keep the pre-filled syringe and the pre-filled pen in the outer carton in order to protect from light. KEEP OUT OF REACH OF CHILDREN. REGISTRATION NUMBER 43/30.1/0808 Original registration August 2013 Page 15 of 34

16 NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION JANSSEN PHARMACEUTICA (Pty) Ltd (Reg. No. 1980/011122/07) Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) DATE OF PUBLICATION 21 May 2015 Original registration August 2013 Page 16 of 34

17 VOUBILJET SKEDULERINGSTATUS S4 EIENDOMSNAAM EN DOSERINGSVORM SIMPONI Oplossing vir inspuiting SAMESTELLING Elke 0,5 ml eenmalige gebruik, reeds gevulde spuit, of reeds gevulde pen, bevat 50 mg golimumab. Onaktiewe bestanddele: Sorbitol, L-histidien, polisorbaat en water vir inspuiting. FARMAKOLOGIESE KLASSIFIKASIE A.30.1 Teenliggaampies FARMAKOLOGIESE WERKING Farmakodinamiese eienskappe Golimumab is n mens monoklonale antiliggaam, wat hoë affiniteit stabiele komplekse vorm met sowel die oplosbare as die transmembraan bioaktiewe vorme van mens tumor nekrose faktor (TNF), wat die binding van TNF aan sy reseptore voorkom. Daar is aangetoon dat die binding van mens TNF deur golimumab die TNF- geïnduseerde seloppervlak ekspressie van die adhesiemolekules E-selektien, vaskulêreseladhesiemolekuul-1(vsam-1) en intrasellulêre adhesiemolekuul-1(isam)-1 deur mens endoteelselle neutraliseer. Die TNF-geïnduseerde afskeiding van interleukien (IL)-6, IL-8 en granulosiet-makrofaag-kolonie-stimulerende faktor (GM-CSF) deur mens endoteelselle, was ook deur golimumab gerem. Original registration August 2013 Page 17 of 34

18 Farmakokinetiese eienskappe Na subkutane (SK) toediening van golimumab aan gesonde proefpersone of pasiënte met RA, het die mediane tyd om die maksimum konsentrasie (T maks ) in die serum te bereik, gestrek van 2 tot 6 dae. Toediening van n SK-inspuiting van 50 mg golimumab aan gesonde proefpersone het gelei tot n gemiddelde ± standaardafwyking maksimum konsentrasie (K maks ) van 3,1 ± 1,4 µg/ml in die serum. Golimumab het dosis-eweredige farmakokinetika getoon by pasiënte met RA oor die dosis-reikwydte van 0,1 tot 10,0 mg/kg na n enkele intraveneuse (IV) dosis. Na n enkele IV toediening binne dieselfde dosis-reikwydte aan pasiënte met RA, was daar beraam dat die gemiddelde sistemiese opklaring van golimumab tussen 4,9 tot 6,7 ml/dag/kg was en die gemiddelde volume van verspreiding het gestrek van 58 tot 126 ml/kg, wat daarop dui dat golimumab hoofsaaklik in die bloedsomloop versprei word, met beperkte ekstravaskulêre verspreiding. Gemiddelde terminale halfleeftydwaardes was na skatting 12 ± 3 dae by gesonde proefpersone en pasiënte met RA, PsA of AS. Na n enkele SK-inspuiting van 100 mg, was die absorpsie van golimumab eenders by die boarm, buik en dy, met n gemiddelde biobeskikbaarheid van 51 %. Aangesien golimumab n ongeveer dosis-eweredige PK na n SK-toediening getoon het, word daar verwag dat die absolute biobeskikbaarheid van die golimumab 50 mg dosis soortgelyk sal wees aan die 100 mg dosis. Toe 50 mg golimumab SK aan pasiënte met RA, PsA of AS elke 4 weke toegedien is, het die serumkonsentrasies bestendige toestand teen week 12 bereik. Met gesamentlike gebruik van MTX het behandeling met 50 mg golimumab SK elke 4 weke gelei tot n gemiddelde bestendige toestand trog-serumkonsentrasie van ongeveer 0,6 g/ml by RA pasiënte met aktiewe RA, ten spyte van MTX behandeling, en ongeveer 0,5 g/ml by pasiënte met aktiewe PsA en ongeveer 0,6 g/ml by pasiënte met AS. Pasiënte met RA, PsA of AS wat nie gesamentlike behandeling met MTX ontvang het nie, het ongeveer 30 % laer bestendige toestand trogkonsentrasies van golimumab gehad as diegene wat golimumab saam met Original registration August 2013 Page 18 of 34

19 MTX ontvang het. Populasie farmakokinetiese analise by pasiënte met RA het ook daarop gedui dat gesamentlike gebruik van MTX die skynbare opklaring van golimumab met 17,1 % verminder het. Daar is egter nie gevind dat gesamentlike gebruik van nie-steroïed antiinflammatoriese middels, orale kortikosteroïed of sulfasalasien die skynbare opklaring van golimumab beïnvloed het nie. Populasie farmakokinetiese analise het getoon dat daar n neiging was tot hoër skynbare opklaring van golimumab met toenemende gewig. Subgroep analise volgens gewig-kwartiel het egter nie op n beduidende verskil tussen die verskillende doseringsgroepe betreffende kliniese doeltreffendheid gedui nie. Daar is gevolglik geen rede waarom die dosis van golimumab op die pasiënt se gewig gebaseer moet word nie. Pasiënte wat anti-golimumab antiliggaampies ontwikkel het, het oor die algemeen by bestendige toestand lae trogkonsentrasies van golimumab in die serum gehad (sien Immunogenisiteit). Immunogenisiteit: Antiliggame teen golimumab was feitlik almal in vitro geneutraliseer by 4,3 % (57/1 322) pasiënte behandel met golimumab by Fase 3 rumatoïede artritis (RA), psoriatiese artritis (PsA) en ankiloserende spondilitis (AS) navorsingstudies tot en met week 24 en soortgelyke voorkomssyfers is aangetoon vir al die rumatologiese indikasies. Gelyktydige behandeling met metotreksaat (MTX) het n kleiner gedeelte pasiënte met antiliggame teen golimumab tot gevolg gehad, as pasiënte wat golimumab sonder MTX (onderskeidelik ongeveer 2 % [14/719] teenoor 7 % [43/603] ontvang het). Die klein hoeveelheid pasiënte wat positief was vir antiliggame teen golimumab beperk die vermoë om definitiewe gevolgtrekkings te maak aangaande die verwantskap tussen antiliggame teen golimumab en kliniese doeltreffendheid of veiligheidsmaatreëls. Original registration August 2013 Page 19 of 34

20 Aangesien immunogenisiteit-analises produk- en gehaltetoets-spesifiek is, is vergelyking van antiliggaam voorkomssyfers met dié van ander produkte nie toepaslik nie. Kliniese navorsingstudies: in kliniese navorsingstudies was golimumab doeltreffend om geselekteerde inflammatoriese merkers en been metabolisme te moduleer. Verbetering in C- reaktiewe proteïen (CRP) vlakke is waargeneem en behandeling met golimumab het gelei tot beduidende verminderings vanaf basislyn in serumvlakke van IL-6, ICAM-1, matriks metalloproteïenase -3 (MMP-3) en vaskulêre endoteel groeifaktor (VEGF). Daarbenewens was die vlakke van TNF by RA en AS pasiënte verminder en die vlakke van IL-8 by PsA pasiënte verminder. INDIKASIES Rumatoïede artritis (RA): SIMPONI, in kombinasie met metotreksaat (MTX), word aangedui vir: die behandeling van aktiewe rumatoïede artritis by volwasse pasiënte wanneer die reaksie op siekte-wysigende anti-rumatiese geneesmiddel (SWARG) terapie, insluitende MTX, onvoldoende was. die behandeling van aktiewe rumatoïede artritis by volwasse pasiënte wat nie voorheen met MTX behandel is nie. Psoriatiese artritis (PsA): SIMPONI alleen, of in kombinasie met MTX, word aangedui vir die behandeling van aktiewe psoriatiese artritis by volwasse pasiënte wanneer die respons op vorige SWARG terapie onvoldoende was. Ankiloserende spondilitis (AS): SIMPONI word aangedui vir die behandeling van aktiewe ankiloserende spondilitis by volwasse pasiënte wanneer die respons op konvensionele terapie onvoldoende was. Original registration August 2013 Page 20 of 34

21 KONTRAÏNDIKASIES SIMPONI word teenaangedui by: Pasiënte met bekende hipersensitiwiteit vir golimumab of vir enige van die bestanddele daarvan. Aktiewe mikobakterium tuberkulose infeksie of ander ernstige infeksies soos sepsis en opportunistiese infeksies ( sien WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS: Infeksies). Matige tot ernstige hartversaking (NYHA klas III/IV) (sien WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS: Kongestiewe hartversaking). Pasiënte wat lewende entstowwe ontvang (sien INTERAKSIES en WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS: Entstowwe). Limfome. Aktiewe demiëliniserende patologie van die senuweestelsel (sien WAARSKUWINGS: EN SPESIALE VOORSORGMAATREËLS: Neurologiese voorvalle). Swangerskap en laktasie (sien SWANGERSKAP EN LAKTASIE). WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS Infeksies Bakteriële (insluitende sepsis en pneumonie), mikobakteriële (tuberkulose), indringende swam- en opportunistiese infeksies (soos listeriose en legionella), insluitende noodlottige gevalle, is aangemeld by pasiënte wat TNF blokkeermiddels, ook SIMPONI, ontvang het. Sommige van hierdie ernstige infeksies het voorgekom by pasiënte op gepaardgaande immuunonderdrukkende terapie, wat bykomend tot hulle onderliggende siekte, hulle vatbaar kon maak vir infeksies. Vir pasiënte wat woonagtig is in, of gereis het na streke waar indringende swaminfeksies soos histoplasmose, kokkidioïdomikose of blastomikose endemies voorkom, moet die voordele en risiko s van SIMPONI behandeling deeglik oorweeg word voordat SIMPONI terapie begin word. Original registration August 2013 Page 21 of 34

22 SIMPONI moet nie aan pasiënte gegee word met n klinies belangrike, aktiewe infeksie nie. Versigtigheid moet uitgeoefen word wanneer die gebruik van SIMPONI oorweeg word by pasiënte met n chroniese infeksie, of n geskiedenis van terugkerende infeksie. Pasiënte moet paslik ingelig word oor infeksie en hoe om die moontlike risikofaktore vir infeksie te vermy. Tuberkulose Pasiënte moet geëvalueer word vir risikofaktore vir tuberkulose (insluitende nabye kontak met n persoon met aktiewe tuberkulose) en getoets word vir latente tuberkulose infeksie voor behandeling met SIMPONI. Behandeling van latente tuberkulose infeksie moet geskied voor behandeling met SIMPONI (sien KONTRAÏNDIKASIES). Anti-tuberkulose behandeling moet oorweeg word voordat SIMPONI begin word by pasiënte met n geskiedenis van latente of aktiewe tuberkulose by wie n volledige behandelingskursus nie bevestig kan word nie. Toetse vir latente tuberkulose kan vals-regatiewe resultate oplewer, veral by pasiënte wat immuungebrekkig of ernstig siek is. Voordat SIMPONI behandeling begin word, moet behandeling vir latente TB oorweeg word by pasiënte wat beduidende risikofaktore het vir TB, ondanks n negatiewe toets vir latente tuberkulose. Die besluit om anti-tuberkulose terapie by hierdie pasiënte te begin moet slegs gedoen word na konsultasie met n mediese praktisyn wat ervare is met die behandeling van tuberkulose en met inagneming van beide die risiko vir latente tuberkulose infeksie en die risiko van anti-tuberkulose terapie. Pasiënte wat SIMPONI ontvang, moet deeglik waargeneem word vir tekens en simptome van aktiewe tuberkulose tydens en na behandeling, insluitende pasiënte wat negatief getoets het vir latente tuberkulose infeksies. Maligniteite Original registration August 2013 Page 22 of 34

23 Die potensiële rol van TNF-blokkerende terapie by die ontwikkeling van maligniteite is nie bekend nie. Versigtigheid moet aan die dag gelê word wanneer behandeling met SIMPONI oorweeg word by pasiënte met n geskiedenis van maligniteit of wanneer volgehoue behandeling oorweeg word by pasiënte wat n maligniteit ontwikkel. Limfoom In die gekontroleerde gedeeltes van kliniese proewe met SIMPONI, is meer gevalle van limfoom waargeneem onder pasiënte wat met SIMPONI behandel is, as by kontrolegroepe. Maligniteite, behalwe limfoom In die gekontroleerde gedeeltes van die SIMPONI Fase 2 en Fase 3 kliniese proewe in RA, PsA en AS, was die insidensie van nie-limfoom maligniteite (behalwe nie-melanoom velkanker) eenders by die SIMPONI en die kontrolegroepe. In n ondersoekende kliniese proef waar die gebruik van SIMPONI by pasiënte met erge volgehoue asma geëvalueer is, is meer maligniteite aangemeld by pasiënte wat met SIMPONI behandel is, as by kontrole pasiënte (sien NEWE-EFFEKTE). Die waarde van hierdie bevinding is onbekend. Hepatitis B virus reaktivering SIMPONI is geassosieer met reaktivering van hepatitis B virus by pasiënte wat chroniese draers is van die virus (i.e. oppervlak-antigeen positief). Chroniese draers van hepatitis B moet paslik geëvalueer en gemoniteer word voordat behandeling plaasvind en ook gedurende behandeling en vir etlike maande nadat SIMPONI gestaak is. Kongestiewe hartversaking (KHV) Gevalle van verslegtende kongestiewe hartversaking (KHV) en nuwe aanvang KHV is met SIMPONI aangemeld. SIMPONI moet met versigtigheid gebruik word by pasiënte met Original registration August 2013 Page 23 of 34

24 hartversaking. Indien n besluit geneem word om SIMPONI aan pasiënte met hartversaking toe te dien, moet hulle deeglik gemoniteer word tydens behandeling en SIMPONI moet gestaak word as nuwe of erger simptome van hartversaking verskyn (sien KONTRAÏNDIKASIES). Neurologiese voorvalle SIMPONI is by seldsame gevalle geassosieer met n opflikkering van kliniese simptome en/of radiografiese bewyse van sentrale senuweestelsel demiëliniserende versteurings, insluitende veelvuldige sklerose. By pasiënte met reeds bestaande of onlangse aanvang van demiëliniserende versteurings is SIMPONI behandeling teenaangedui (sien KONTRAÏNDIKASIES). Gelyktydige toediening van SIMPONI met anakinra Ernstige infeksies is waargeneem tydens kliniese navorsingstudies met die gesamentlike gebruik van anakinra en n ander TNF-blokkeermiddel, etanersept, met geen toegevoegde kliniese voordeel nie. As gevolg van die aard van die newe-effekte waargeneem met hierdie kombinasiebehandeling, kan soortgelyke toksisiteit ook resulteer uit die kombinasie van anakinra en SIMPONI. Die kombinasie van SIMPONI en anakinra word dus nie aanbeveel nie. Entstowwe Pasiënte wat met SIMPONI behandel word, kan gelyktydige inentings ontvang, maar nie met lewende entstowwe nie (sien KONTRAÏNDIKASIES). Psoriatiese artritis pasiënte wat met SIMPONI behandel is in een Fase 3 PsA navorsingstudie kon doeltreffende B-sel immuunreaksie op pneumokokkus polisaggariede entstof hê. Ewe veel psoriatiese artritis pasiënte wat SIMPONI ontvang het as wat nie SIMPONI ontvang het nie, het ten minste n 2-voudige toename in antiliggaam titers gehad. Die verhoudings van pasiënte wat reageer het op pneumokokkus entstof was minder onder die SIMPONI en kontrole behandelde pasiënte wat MTX ontvang het, as by die pasiënte wat Original registration August 2013 Page 24 of 34

25 nie MTX ontvang het nie. Oor die algemeen dui die data daarop dat SIMPONI nie die humorale immuunreaksie op hierdie entstof onderdruk nie. Allergiese reaksies Lateks-gevoeligheid Die skede van die naald op die spuit in die reeds gevulde pen word vervaardig uit droë natuurlike rubber wat lateks bevat en kan allergiese reaksies veroorsaak by individue gevoelig vir lateks. Hipersensitiwiteitsreaksies: Met ervaring na bemarking, is ernstige sistemiese hipersensitiwiteitsreaksies (insluitende anafilaktiese reaksie) aangemeld na SIMPONI toediening. Sommige van hierdie reaksies het na die eerste toediening van SIMPONI voorgekom. Indien n anafilaktiese of ander ernstige allergiese reaksie voorkom, moet toediening van SIMPONI dadelik gestaak word en toepaslike terapie ingestel word. Spesiale populasies Pediatriese gebruik Veiligheid en doeltreffendheid van SIMPONI is nie by pediatriese pasiënte bepaal nie. Geriatriese gebruik In die Fase 3 navorsingstudies by RA, PsA en AS, is daar geen algemene verskille in neweeffekte, ernstige newe-effekte en ernstige infeksies by pasiënte 65 jaar of ouer (n=155) wat SIMPONI ontvang het, vergeleke met jonger pasiënte, waargeneem nie. Omdat daar n hoër insidensie is van infeksies by die bejaarde populasie oor die algemeen, moet versigtigheid aan die dag gelê word by die behandeling van die bejaarde. Nier en lewerinkorting Original registration August 2013 Page 25 of 34

26 Spesifieke navorsingstudies oor SIMPONI is nie uitgevoer op pasiënte met nier- of lewerinkorting nie. Eksipiënte SIMPONI bevat sorbitol. Pasiënte met seldsame oorerflike probleme van fruktose intoleransie moet nie SIMPONI gebruik nie. Effek op vermoë om te bestuur en masjinerie te gebruik SIMPONI kan duiseligheid veroorsaak. Pasiënte moet nie bestuur of masjinerie hanteer totdat hulle individuele gevoeligheid bekend is nie. INTERAKSIES Geen interaksiestudies is uitgevoer nie. Anakinra Die kombinering van SIMPONI en anakinra word nie aanbeveel nie (sien WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS: gelyktydige toediening van SIMPONI en anakinra.) Lewende entstowwe Lewende entstowwe moet nie saam met SIMPONI toegedien word nie (sien KONTRAÏNDIKASIES en WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS: Entstowwe). Metotreksaat Alhoewel meegaande gebruik van metotreksaat lei tot hoër trogkonsentrasie van SIMPONI by bestendige toestand by pasiënte met RA, PsA of AS, dui die data nie daarop dat dit nodig is om n dosisaanpassing van of SIMPONI, of metotreksaat, te maak nie. (sien Farmakokinetiese eienskappe.) Original registration August 2013 Page 26 of 34

27 SWANGERSKAP EN LAKTASIE Swangerskap SIMPONI moet nie by swanger vroue gebruik word nie (sieen KONTRAÏNDIKASIES). Vroue wat moontlik swanger kan raak, moet aangeraai word om nie tydens SIMPONI behandeling swanger te raak nie. Laktasie Dit is nie bekend of golimumab in mens borsmelk uitgeskei word nie. SIMPONI moet nie gebruik word by vroue wat borsvoed nie. DOSIS EN GEBRUIKSAANWYSINGS Behandeling met SIMPONI moet slegs begin word en gemoniteer word deur mediese praktisyns wat ervare is in die diagnose en behandeling van rumatoïede artritis, psoriatiese artritis of ankiloserende spondilitis. Na behoorlike opleiding in die tegniek van subkutane (SK) inspuiting, kan pasiënte hulself inspuit met SIMPONI indien hulle dokter bepaal dat hulle geskik daarvoor is, met mediese opvolging soos nodig. Dosis: Volwassenes 18 jaar en ouer Rumatoïede artritis 50 mg, toegedien as n subkutane inspuiting een keer per maand, elke maand op dieselfde datum. Psoriatiese artritis 50 mg, toegedien as n subkutane inspuiting een keer per maand, elke maand op dieselfde datum. Ankiloserende spondilitis Original registration August 2013 Page 27 of 34

28 50 mg, toegedien as n subkutane inspuiting een keer per maand, elke maand op dieselfde datum. Gebruik by bejaarde pasiënte (65 jaar en ouer) Geen dosis aanpassing word benodig nie. Gebruik by pediatriese pasiënte (minder as 18 jaar) Dit word nie aanbeveel nie, as gevolg van n gebrek aan data oor doeltreffendheid en veiligheid. Gebruik by pasiënte met nier en/of lewerinkorting SIMPONI is nie by hierdie pasiënte populasies ondersoek nie. Geen dosis aanbevelings kan gedoen word nie. Metode van toediening Pasiënte moet aangesê word om die hele inhoud van SIMPONI in te spuit volgens die aanwysings. NEWE-EFFEKTE Veiligheidsdata uit Fase 2 en 3 kliniese proewe is beskikbaar oor SIMPONIbehandelde pasiënte. Ongunstige Geneesmiddelreaksies (OGRs) wat met kliniese navorsingstudies met SIMPONI waargeneem is, word in die volgende tabel opgesom. Die ongunstige geneesmiddelreaksies word volgens die aangewese orgaanstelsel klasse en frekwensie gelys, deur van die volgende konvensie gebruik te maak: Baie algemeen ( 1/10), Algemeen ( 1/100, < 1/10), Ongewoon ( 1/1 000, < 1/100), Seldsaam ( 1/10 000, < 1/1 000), Baie seldsaam (< 1/10 000). Original registration August 2013 Page 28 of 34

29 Opsomming van OGRs by kliniese navorsingstudies Infeksies en infestasies Baie algemeen: Boonste lugweginfeksie (nasofaringitis, faringitis, laringitis, rinitis) Algemeen: Influensa, brongitis, sellulitis, sinusitis, orale herpes Ongewoon: Septiese skok, sepsis, tuberkulose, onderste lugweginfeksie (pneumonie), septiese artritis, piëlonefritis, septiese bursitis, abses Seldsaam: Histoplasmose, kokkidioïdomikose, Pneumocystis jiroveci (carinii) (PCP) infeksie Senuweestelsel siektes Algemeen: Ongewoon: Duiseligheid, parestesie Demiëliniserende siektes Vaatsiektes Algemeen: Hipertensie Vel- en onderhuidse weefselsiektes Ongewoon Pustulêre psoriase Algemene siektes en toestande by die plek van toediening Algemeen: Pireksie, plek van inspuiting (eriteem by plek van inspuiting, urtikarie, verharding, pyn, kneusing, pruritus, irritasie, parestesie) Ondersoeke Algemeen: Alanien aminotransferase verhoog, aspartaat aminotransferase verhoog Ongewoon: Neutrofieltelling verminder Infeksies Original registration August 2013 Page 29 of 34

30 Boonste lugweginfeksie was die mees algemene ongunstige reaksie wat met die gekombineerde Fase 3 RA, PsA en AS navorsingstudies tot en met week 16 aangemeld is; dit het by 7,2 % van die SIMPONI-behandelde pasiënte voorgekom (insidensie per pasiëntjaar: 0,26; 95 % VI: 0,17; 0,31), vergeleke met 5,8 % by kontrole pasiënte (insidensie per pasiënt -jaar: 0,23; 95 % CI: 0,17; 0,31). Die insidensie per pasiënt-jaar (95 % vertrouensinterval; VI) van boonste lugweginfeksies tot en met 1 jaar van opvolg was 0,23 voorvalle (0,21; 0,25) vir SIMPONI-behandelde pasiënte en 0,25 voorvalle (0,20; 0,31) vir kontrole pasiënte. In gekontroleerde Fase 3 proewe, tot en met week 16 by RA, PsA en AS, is infeksies waargeneem by 28,3 % van die SIMPONI-behandelde pasiënte (insidensie per pasiëntjaar: 1,28; 95 % CI: 1,18; 1,38) vergeleke met 24,7 % van die kontrole pasiënte (insidensie per pasiënt-jaar: 1,17; 95 % VI: 1,02; 1,33). Die insidensie per pasiënt-jaar (95 % VI) van infeksies tot en met 1 jaar van opvolg was 1,32 voorvalle (1,27; 1,38) vir SIMPONI-behandelde pasiënte en 1,31 voorvalle (1,18; 1,44) vir kontrole pasiënte. In gekontroleerde Fase 3 proewe, tot en met week 16 by RA, PsA en AS pasiënte, is ernstige infeksies by 1,4 % van die SIMPONI-behandelde pasiënte waargeneem (insidensie per pasiënt -jaar: 0,06; 95 % VI: 0,04; 0,08) en 1,3 % van die kontrole pasiënte (insidensie per pasiënt -jaar: 0,04; 95 % VI: 0,02; 0,08). Ernstige infeksies waargeneem by SIMPONI-behandelde pasiënte het ingesluit: sepsis, pneumonie, sellulitis, abses en tuberkulose. Die insidensie per pasiënt-jaar (95 % VI) van ernstige infeksies tot en met 1 jaar van opvolg, was 0,05 voorvalle (0,04; 0,06) vir SIMPONI-behandelde pasiënte en 0,06 voorvalle (0,04; 0,09) vir kontrole pasiënte. Maligniteite Limfoom Original registration August 2013 Page 30 of 34

31 Die voorkoms van limfoom by pasiënte met RA, PsA en AS wat met SIMPONI behandel is tydens die gekontroleerde gedeeltes van Fase 2- en 3- kliniese toetse was hoër as wat verwag was in die algemene bevolking. Maligniteite, limfoom uitgesluit Die potensiële rol van TNF-blokkerende terapie by die ontwikkeling van maligniteite is nie bekend nie. Verhoogde lewerensieme In gekontroleerde Fase 3 proewe, tot en met week 16, het effense ALT verhogings (> 1 en < 3 x BLN) in gelyke dele voorgekom by SIMPONI en kontrole pasiënte in die RA en PsA navorsingstudies (22,1 % tot 27,4 % van die pasiënte); in die AS navorsingstudie, het meer SIMPONI-behandelde pasiënte (25,6 %) as kontrole pasiënte (3,9 %) geringe ALT verhogings getoon. Regdeur 1 jaar van opvolging was die insidensie van ligte ALT verhogings eenders by die SIMPONI-behandelde en kontrole pasiënte in die RA en PsA navorsingstudies. In die AS navorsingstudie was die insidensie van effense ALT verhogings hoër by SIMPONI-behandelde pasiënte as by die kontrole pasiënte. In die RA en AS navorsingstudies tot en met week 16, was ALT verhogings van 5 x ULN ongewoon en by meer SIMPONI-behandelde pasiënte (0,4 % to 0,9 %) waargeneem as by kontrole pasiënte (0 %). Hierdie neiging was nooit waargeneem by die PsA populasie nie. Regdeur 1 jaar van opvolg, was die insidensie van ALT verhogings 5 x BLN dieselfde by beide SIMPONI-behandelde en gekontroleerde pasiënte by die Fase 3 RA, PsA en AS navorsingstudies. Die meeste van hierdie verhogings was asimptomaties. Reaksies by die plek van inspuiting By gekontroleerde Fase 3 proewe, regdeur week 16 by RA, PsA en AS, het 5,8 % van die SIMPONI-behandelde pasiënte, vergeleke met 2,2 % by kontrole pasiënte, reaksies by Original registration August 2013 Page 31 of 34

32 die plek van inspuiting gehad. Die meeste van die reaksies by die plek van inspuiting was lig en matig en het meestal manifesteer as eriteem by die plek van inspuiting. Antinukleêre antiliggame (ANA)/anti-dubbelstring DNA (dsdna) antiliggame Gebruik van TNF blokkeermiddels is geassosieer met die vorming van outo-antiliggame en selde, met die ontwikkeling van n lupus-agtige sindroom. In Fase 3 proewe by RA, PsA en AS, by die 1-jaar opvolg, was 4,0 % van die SIMPONIbehandelde pasiënte en 2,6 % van die kontrole pasiënte nuut ANA-positief (by titers van 1:160 of meer), vergeleke met basislyn. Die frekwensie van anti-dsdna antiliggame by 1 jaar opvolg by pasiënte wat anti-dsdna negatief was by basislyn, was ongewoon. BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VAN DIE BEHANDELING DAARVAN Enkeldosisse, tot 10 mg/kg intraveneus, is met n kliniese navorsingstudie toegedien, sonder dosis-beperkende toksisiteit. In geval van n oordosering, word daar aanbeveel dat die pasiënt gemoniteer word vir enige tekens of simptome van ongunstige effekte en toepaslike simptomatiese behandeling moet onmiddellik ingestel word. IDENTIFIKASIE Die oplossing is helder tot effens troebel, kleurloos tot liggeel en kan n paar klein deursigtige of wit proteïen deeltjies bevat. Dit is nie ongewoon vir n oplossing wat proteïen bevat nie. AANBIEDING SIMPONI word verskaf in Tipe 1 glas spuite met gefikseerde vlekvrye staal naalde, as eenmalige gebruik, reeds gevulde spuite, beskikbaar in kartonhouers met 1 of 3 reeds gevulde spuite. Original registration August 2013 Page 32 of 34

33 SIMPONI word verskaf in n Tipe 1 glasspuit met n gefikseerde vlekvrye staal naald. Hierdie spuit word bevat in n eenmalige gebruik, reeds gevulde pen, bekend as SmartJect en beskikbaar in kartonhouers met 1 of 3 reeds gevulde penne. BERGINGSINSTRUKSIES Bewaar by 2 tot 8 C (in n yskas). Moenie vries nie. Moenie skud nie. Hou die reeds gevulde spuit en die reeds gevulde pen in die karton omhulsel om dit teen lig te beskerm. HOU BUITE DIE BEREIK VAN KINDERS. REGISTRASIENOMMER 43/30.1/0808 NAAM EN BESIGHEIDSADRES VAN DIE HOUER VAN DIE REGISTRASIESERTIFIKAAT JANSSEN PHARMACEUTICA (Pty) Ltd (Reg. No. 1980/011122/07) Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) DATUM VAN PUBLIKASIE 21 Mei 2015 Original registration August 2013 Page 33 of 34

34 Original registration August 2013 Page 34 of 34