SIMPONI 50mg / 0.5ml injectible solution medication leaflet

Simponi 50 mg solution for injection in pre-filled pen.

Simponi 50 mg solution for injection in pre-filled syringe.

Simponi 50 mg solution for injection in pre-filled pen

One 0.5 mL pre-filled pen contains 50 mg of golimumab*.

Simponi 50 mg solution for injection in pre-filled syringe

One 0.5 mL pre-filled syringe contains 50 mg of golimumab*.

* Human IgG1κ monoclonal antibody produced by a murine hybridoma cell line with recombinant

DNA technology.

Each pre-filled pen contains 20.5 mg sorbitol per 50 mg dose.

Each pre-filled syringe contains 20.5 mg sorbitol per 50 mg dose.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled pen (injection), SmartJect

Solution for injection in pre-filled syringe (injection)

The solution is clear to slightly opalescent, colourless to light yellow.

Rheumatoid arthritis (RA)

Simponi, in combination with methotrexate (MTX), is indicated for:

- the treatment of moderate to severe, active rheumatoid arthritis in adults when the response todisease-modifying anti-rheumatic drug (DMARD) therapy including MTX has been inadequate.

- the treatment of severe, active and progressive rheumatoid arthritis in adults not previouslytreated with MTX.

Simponi, in combination with MTX, has been shown to reduce the rate of progression of joint damageas measured by X-ray and to improve physical function.

Simponi in combination with MTX is indicated for the treatment of polyarticular juvenile idiopathicarthritis in children 2 years of age and older, who have responded inadequately to previous therapywith MTX.

Psoriatic arthritis (PsA)

Simponi, alone or in combination with MTX, is indicated for the treatment of active and progressivepsoriatic arthritis in adult patients when the response to previous DMARD therapy has beeninadequate. Simponi has been shown to reduce the rate of progression of peripheral joint damage asmeasured by X-ray in patients with polyarticular symmetrical subtypes of the disease (see section 5.1)and to improve physical function.

Simponi is indicated for the treatment of severe, active ankylosing spondylitis in adults who haveresponded inadequately to conventional therapy.

Non-radiographic axial spondyloarthritis (nr-Axial SpA)

Simponi is indicated for the treatment of adults with severe, active non-radiographic axialspondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein(CRP) and/or magnetic resonance imaging (MRI) evidence, who have had an inadequate response to,or are intolerant to nonsteroidal anti-inflammatory drugs (NSAIDs).

Ulcerative colitis (UC)

Simponi is indicated for treatment of moderately to severely active ulcerative colitis in adult patientswho have had an inadequate response to conventional therapy including corticosteroids and6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medicalcontraindications for such therapies.

Treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis andtreatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis,ankylosing spondylitis, non-radiographic axial spondyloarthritis, or ulcerative colitis. Patients treatedwith Simponi should be given the Patient Reminder Card.

Simponi 50 mg given once a month, on the same date each month.

Simponi should be given concomitantly with MTX.

Psoriatic arthritis, ankylosing spondylitis, or non-radiographic axial spondyloarthritis

Simponi 50 mg given once a month, on the same date each month.

For all of the above indications, available data suggest that clinical response is usually achieved within12 to 14 weeks of treatment (after 3-4 doses). Continued therapy should be reconsidered in patientswho show no evidence of therapeutic benefit within this time period.

Patients with body weight greater than 100 kg

For all of the above indications, in patients with RA, PsA, AS, or nr-Axial SpA with a body weight ofmore than 100 kg who do not achieve an adequate clinical response after 3 or 4 doses, increasing thedose of golimumab to 100 mg once a month may be considered, taking into account the increased riskof certain serious adverse reactions with the 100 mg dose compared with the 50 mg dose(see section 4.8). Continued therapy should be reconsidered in patients who show no evidence oftherapeutic benefit after receiving 3 to 4 additional doses of 100 mg.

Patients with body weight less than 80 kg

Simponi given as an initial dose of 200 mg, followed by 100 mg at week 2. Patients who have anadequate response should receive 50 mg at week 6 and every 4 weeks thereafter. Patients who have aninadequate response may benefit from continuing with 100 mg at week 6 and every 4 weeks thereafter(see section 5.1).

Patients with body weight greater than or equal to 80 kg

Simponi given as an initial dose of 200 mg, followed by 100 mg at week 2, then 100 mg every4 weeks, thereafter (see section 5.1).

During maintenance treatment, corticosteroids may be tapered in accordance with clinical practiceguidelines.

Available data suggest that clinical response is usually achieved within 12-14 weeks of treatment(after 4 doses). Continued therapy should be reconsidered in patients who show no evidence oftherapeutic benefit within this time period.

If a patient forgets to inject Simponi on the planned date, the forgotten dose should be injected as soonas the patient remembers. Patients should be instructed not to inject a double dose to make up for theforgotten dose.

The next dose should be administered based on the following guidance:

- if the dose is less than 2 weeks late, the patient should inject the forgotten dose and stay on theoriginal schedule.

- if the dose is more than 2 weeks late, the patient should inject the forgotten dose and a newschedule should be established from the date of this injection.

No dose adjustment is required in the elderly.

Simponi has not been studied in these patient populations. No dose recommendations can be made.

The safety and efficacy of Simponi in patients aged less than 18 for indications other than pJIA havenot been established.

Simponi 50 mg administered once a month, on the same date each month, for children with a bodyweight of at least 40 kg. A 45 mg/0.45 mL pre-filled pen is available for administration to childrenwith polyarticular juvenile idiopathic arthritis weighing less than 40 kg.

Available data suggest that clinical response is usually achieved within 12 to 14 weeks of treatment(after 3-4 doses). Continued therapy should be reconsidered in children who show no evidence oftherapeutic benefit within this time period.

Simponi is for subcutaneous use. After proper training in subcutaneous injection technique, patientsmay self-inject if their physician determines that this is appropriate, with medical follow-up asnecessary. Patients should be instructed to inject the full amount of Simponi according to thecomprehensive instructions for use provided in the package leaflet. If multiple injections are required,the injections should be administered at different sites on the body.

For administration instructions, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active tuberculosis (TB) or other severe infections such as sepsis, and opportunistic infections(see section 4.4).

Moderate or severe heart failure (NYHA class III/IV) (see section 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Patients must be monitored closely for infections including tuberculosis before, during and aftertreatment with golimumab. Because the elimination of golimumab may take up to 5 months,monitoring should be continued throughout this period. Further treatment with golimumab must not begiven if a patient develops a serious infection or sepsis (see section 4.3).

Golimumab should not be given to patients with a clinically important, active infection. Cautionshould be exercised when considering the use of golimumab in patients with a chronic infection or ahistory of recurrent infection. Patients should be advised of, and avoid exposure to, potential riskfactors for infection as appropriate.

Patients taking TNF-blockers are more susceptible to serious infections.

Bacterial (including sepsis and pneumonia), mycobacterial (including TB), invasive fungal andopportunistic infections, including fatalities, have been reported in patients receiving golimumab.

Some of these serious infections have occurred in patients on concomitant immunosuppressive therapythat, in addition to their underlying disease, could predispose them to infections. Patients who developa new infection while undergoing treatment with golimumab should be monitored closely and undergoa complete diagnostic evaluation. Administration of golimumab should be discontinued if a patientdevelops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy shouldbe initiated until the infection is controlled.

For patients who have resided in or travelled to regions where invasive fungal infections such ashistoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks ofgolimumab treatment should be carefully considered before initiation of golimumab therapy. In at-riskpatients treated with golimumab, an invasive fungal infection should be suspected if they develop aserious systemic illness. Diagnosis and administration of empiric antifungal therapy in these patientsshould be made in consultation with a physician with expertise in the care of patients with invasivefungal infections, if feasible.

There have been reports of tuberculosis in patients receiving golimumab. It should be noted that in themajority of these reports, tuberculosis was extrapulmonary presenting as either local or disseminateddisease.

Before starting treatment with golimumab, all patients must be evaluated for both active and inactive(‘latent’) tuberculosis. This evaluation should include a detailed medical history with personal historyof tuberculosis or possible previous contact with tuberculosis and previous and/or currentimmunosuppressive therapy. Appropriate screening tests, i.e. tuberculin skin or blood test and chest

X-ray, should be performed in all patients (local recommendations may apply). It is recommended thatthe conduct of these tests should be recorded in the Patient Reminder Card. Prescribers are remindedof the risk of false negative tuberculin skin test results, especially in patients who are severely ill orimmunocompromised.

If active tuberculosis is diagnosed, golimumab therapy must not be initiated (see section 4.3).

If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should beconsulted. In all situations described below, the benefit/risk balance of golimumab therapy should bevery carefully considered.

If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started withanti-tuberculosis therapy before the initiation of golimumab, and in accordance with localrecommendations.

In patients who have several or significant risk factors for tuberculosis and have a negative test forlatent tuberculosis, anti-tuberculosis therapy should be considered before the initiation of golimumab.

Use of anti-tuberculosis therapy should also be considered before the initiation of golimumab inpatients with a past history of latent or active tuberculosis in whom an adequate course of treatmentcannot be confirmed.

Cases of active tuberculosis have occurred in patients treated with golimumab during and aftertreatment for latent tuberculosis. Patients receiving golimumab should be monitored closely for signsand symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis,patients who are on treatment for latent tuberculosis, or patients who were previously treated fortuberculosis infection.

All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis(e.g. persistent cough, wasting/weight loss, low-grade fever) appear during or after golimumabtreatment.

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including golimumab,who are chronic carriers of this virus (i.e. surface antigen positive). Some cases have had fataloutcome.

Patients should be tested for HBV infection before initiating treatment with golimumab. For patientswho test positive for HBV infection, consultation with a physician with expertise in the treatment ofhepatitis B is recommended.

Carriers of HBV who require treatment with golimumab should be closely monitored for signs andsymptoms of active HBV infection throughout therapy and for several months following terminationof therapy. Adequate data of treating patients who are carriers of HBV with anti-viral therapy inconjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patientswho develop HBV reactivation, golimumab should be stopped and effective anti-viral therapy withappropriate supportive treatment should be initiated.

The potential role of TNF-blocking therapy in the development of malignancies is not known. Basedon the current knowledge, a possible risk for the development of lymphomas, leukaemia or othermalignancies in patients treated with a TNF-antagonist cannot be excluded. Caution should beexercised when considering TNF-blocking therapy for patients with a history of malignancy or whenconsidering continuing treatment in patients who develop malignancy.

Paediatric malignancy

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to22 years of age) treated with TNF-blocking agents (initiation of therapy ≤ 18 years of age) in the postmarketing setting. Approximately half the cases were lymphomas. The other cases represented avariety of different malignancies and included rare malignancies usually associated withimmunosuppression. A risk for the development of malignancies in children and adolescents treatedwith TNF-blockers cannot be excluded.

Lymphoma and leukaemia

In the controlled portions of clinical trials of all the TNF-blocking agents including golimumab, morecases of lymphoma have been observed among patients receiving anti-TNF treatment compared withcontrol patients. During the Simponi Phase IIb and Phase III clinical trials in RA, PsA and AS, theincidence of lymphoma in golimumab-treated patients was higher than expected in the generalpopulation. Cases of leukaemia have been reported in patients treated with golimumab. There is anincreased background risk for lymphoma and leukaemia in rheumatoid arthritis patients withlong-standing, highly active, inflammatory disease, which complicates risk estimation.

Rare post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patientstreated with other TNF-blocking agents (see section 4.8). This rare type of T-cell lymphoma has a veryaggressive disease course and is usually fatal. The majority of cases have occurred in adolescent andyoung adult males with nearly all on concomitant treatment with azathioprine (AZA) or6-mercaptopurine (6-MP) for inflammatory bowel disease. The potential risk with the combination of

AZA or 6-MP and golimumab should be carefully considered. A risk for the development forhepatosplenic T-cell lymphoma in patients treated with TNF-blockers cannot be excluded.

Malignancies other than lymphoma

In the controlled portions of the Simponi Phase IIb and Phase III clinical trials in RA, PsA, AS, and

UC, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similarbetween the golimumab and the control groups.

Colon dysplasia/carcinoma

It is not known if golimumab treatment influences the risk for developing dysplasia or colon cancer.

All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (forexample, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had aprior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervalsbefore therapy and throughout their disease course. This evaluation should include colonoscopy andbiopsies per local recommendations. In patients with newly diagnosed dysplasia treated withgolimumab, the risks and benefits to the individual patient must be carefully reviewed andconsideration should be given to whether therapy should be continued.

In an exploratory clinical trial evaluating the use of golimumab in patients with severe persistentasthma, more malignancies were reported in patients treated with golimumab compared with controlpatients (see section 4.8). The significance of this finding is unknown.

In an exploratory clinical trial evaluating the use of another anti-TNF agent, infliximab, in patientswith moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly inthe lung or head and neck, were reported in infliximab-treated patients compared with control patients.

All patients had a history of heavy smoking. Therefore, caution should be exercised when using any

TNF-antagonist in COPD patients, as well as in patients with an increased risk of malignancy due toheavy smoking.

Skin cancers

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blockingagents, including golimumab (see section 4.8). Periodic skin examination is recommended,particularly for patients with risk factors for skin cancer.

Congestive heart failure (CHF)

Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNFblockers, including golimumab. Some cases had a fatal outcome. In a clinical trial with another

TNF-antagonist worsening congestive heart failure and increased mortality due to CHF have beenobserved. Golimumab has not been studied in patients with CHF. Golimumab should be used withcaution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored andgolimumab must be discontinued in patients who develop new or worsening symptoms of heart failure(see section 4.3).

Use of TNF-blocking agents, including golimumab, has been associated with cases of new onset orexacerbation of clinical symptoms and/or radiographic evidence of central nervous systemdemyelinating disorders, including multiple sclerosis and peripheral demyelinating disorders. Inpatients with pre-existing or recent onset of demyelinating disorders, the benefits and risks ofanti-TNF treatment should be carefully considered before initiation of golimumab therapy.

Discontinuation of golimumab should be considered if these disorders develop (see section 4.8).

There is limited safety experience of golimumab treatment in patients who have undergone surgicalprocedures, including arthroplasty. The long half-life should be taken into consideration if a surgicalprocedure is planned. A patient who requires surgery while on golimumab should be closelymonitored for infections, and appropriate actions should be taken.

The possibility exists for TNF-blocking agents, including golimumab, to affect host defences againstinfections and malignancies since TNF mediates inflammation and modulates cellular immuneresponses.

The relative deficiency of TNF caused by anti-TNF therapy may result in the initiation of anautoimmune process. If a patient develops symptoms suggestive of a lupus-like syndrome followingtreatment with golimumab and is positive for antibodies against double-stranded DNA, treatment withgolimumab should be discontinued (see section 4.8).

There have been reports of pancytopenia, leukopenia, neutropenia, agranulocytosis, aplastic anaemia,and thrombocytopenia in patients receiving TNF-blockers, including golimumab. All patients shouldbe advised to seek immediate medical attention if they develop signs and symptoms suggestive ofblood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor). Discontinuation of golimumabtherapy should be considered in patients with confirmed significant haematologic abnormalities.

Concurrent administration of TNF-antagonists and anakinra

Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra andanother TNF-blocking agent, etanercept, with no added clinical benefit. Because of the nature of theadverse events seen with this combination therapy, similar toxicities may also result from thecombination of anakinra and other TNF-blocking agents. The combination of golimumab and anakinrais not recommended.

Concurrent administration of TNF-antagonists and abatacept

In clinical studies concurrent administration of TNF-antagonists and abatacept has been associatedwith an increased risk of infections including serious infections compared to TNF-antagonists alone,without increased clinical benefit. The combination of golimumab and abatacept is not recommended.

There is insufficient information regarding the concomitant use of golimumab with other biologicaltherapeutics used to treat the same conditions as golimumab. The concomitant use of golimumab withthese biologics is not recommended because of the possibility of an increased risk of infection, andother potential pharmacological interactions.

Care should be taken and patients should continue to be monitored when switching from one biologicto another, since overlapping biological activity may further increase the risk for adverse events,including infection.

Vaccinations/therapeutic infectious agents

Patients treated with golimumab may receive concurrent vaccinations, except for live vaccines (seesections 4.5 and 4.6). In patients receiving anti-TNF therapy, limited data are available on the responseto vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Useof live vaccines could result in clinical infections, including disseminated infections.

Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g. BCG bladderinstillation for the treatment of cancer) could result in clinical infections, including disseminatedinfections. It is recommended that therapeutic infectious agents not be given concurrently withgolimumab.

In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylacticreaction) have been reported following golimumab administration. Some of these reactions occurredafter the first administration of golimumab. If an anaphylactic reaction or other serious allergicreactions occur, administration of golimumab should be discontinued immediately and appropriatetherapy initiated.

Latex sensitivity

The needle cover on the pre-filled pen or the pre-filled syringe is manufactured from dry naturalrubber containing latex, and may cause allergic reactions in individuals sensitive to latex.

In the Phase III studies in RA, PsA, AS, and UC, no overall differences in adverse events (AEs),serious adverse events (SAEs), and serious infections in patients age 65 or older who receivedgolimumab were observed compared with younger patients. However, caution should be exercisedwhen treating the elderly and particular attention paid with respect to occurrence of infections. Therewere no patients age 45 and over in the nr-Axial SpA study.

Specific studies of golimumab have not been conducted in patients with renal or hepatic impairment.

Golimumab should be used with caution in subjects with impaired hepatic function (see section 4.2).

Paediatrics

If possible, it is recommended that prior to initiating golimumab therapy, paediatric patients bebrought up to date with all immunisations in agreement with current immunisation guidelines (see

Vaccinations/therapeutic infectious agents above).

Simponi contains sorbitol (E420). In patients with rare hereditary problems of fructose intolerance, theadditive effect of concomitantly administered products containing sorbitol (or fructose) and dietaryintake of sorbitol (or fructose) should be taken into account (see section 2).

Potential for medication errors

Simponi is registered in 50 mg and 100 mg strengths for subcutaneous administration. It is importantthat the right strength is used to administer the correct dose as indicated in the posology (seesection 4.2). Care should be taken to provide the right strength to ensure that patients are notunderdosed or overdosed.

No interaction studies have been performed.

Concurrent use with other biological therapeutics

The combination of golimumab with other biological therapeutics used to treat the same conditions asgolimumab, including anakinra and abatacept is not recommended (see section 4.4).

Live vaccines should not be given concurrently with golimumab (see sections 4.4 and 4.6).

Therapeutic infectious agents should not be given concurrently with golimumab (see section 4.4).

Although concomitant use of MTX results in higher steady-state trough concentrations of golimumabin patients with RA, PsA or AS, the data do not suggest the need for dose adjustment of eithergolimumab or MTX (see section 5.2).

Women of childbearing potential must use adequate contraception to prevent pregnancy and continueits use for at least 6 months after the last golimumab treatment.

There is a moderate amount (approximately 400) of prospectively collected pregnancies exposed togolimumab resulting in live birth with known outcomes, including 220 pregnancies exposed during thefirst trimester. In a population-based study from Northern Europe including 131 pregnancies (and134 infants), there were 6/134 (4.5%) events of major congenital anomalies following in uteroexposure to Simponi vs 599/10,823 (5.5%) events for non-biologic systemic therapy compared to4.6% in the general population of the study. Confounder-adjusted odds ratios were OR 0.79 (95% CI0.35-1.81) for Simponi vs. non-biologic systemic therapy and OR 0.95 (95% CI 0.42-2.16) for

Simponi vs. the general population, respectively.

Due to its inhibition of TNF, golimumab administered during pregnancy could affect normal immuneresponses in the newborn. Studies in animals do not indicate direct or indirect harmful effects withrespect to pregnancy, embryonal/foetal development, parturition or postnatal development(see section 5.3). The available clinical experience is limited. Golimumab should only be used duringpregnancy if clearly needed.

Golimumab crosses the placenta. Following treatment with a TNF-blocking monoclonal antibodyduring pregnancy, the antibody has been detected for up to 6 months in the serum of the infant born bythe treated woman. Consequently, these infants may be at increased risk of infection. Administrationof live vaccines to infants exposed to golimumab in utero is not recommended for 6 months followingthe mother’s last golimumab injection during pregnancy (see sections 4.4 and 4.5).

It is not known whether golimumab is excreted in human milk or absorbed systemically afteringestion. Golimumab was shown to pass over to breast milk in monkeys, and because humanimmunoglobulins are excreted in milk, women must not breast feed during and for at least 6 monthsafter golimumab treatment.

No animal fertility studies have been conducted with golimumab. A fertility study in mice, using ananalogous antibody that selectively inhibits the functional activity of mouse TNFα, showed norelevant effects on fertility (see section 5.3).

Simponi has minor influence on the ability to drive and use machines. Dizziness may however occurfollowing administration of Simponi (see section 4.8).

In the controlled period of the pivotal trials in RA, PsA, AS, nr-Axial SpA, and UC, upper respiratorytract infection was the most common adverse reaction (AR) reported in 12.6% of golimumab-treatedpatients compared with 11.0% of control patients. The most serious ARs that have been reported forgolimumab include serious infections (including sepsis, pneumonia, TB, invasive fungal andopportunistic infections), demyelinating disorders, HBV reactivation, CHF, autoimmune processes(lupus-like syndrome), haematologic reactions, serious systemic hypersensitivity (includinganaphylactic reaction), vasculitis, lymphoma and leukaemia (see section 4.4).

ARs observed in clinical studies and reported from world-wide post-marketing use of golimumab arelisted in Table 1. Within the designated system organ classes, the ARs are listed under headings offrequency and 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); very rare (< 1/10,000); not known(cannot be estimated from the available data). Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

Table 1

Tabulated list of ARs

Very common: Upper respiratory tract infection (nasopharyngitis,pharyngitis, laryngitis and rhinitis)

Common: Bacterial infections (such as cellulitis), lower respiratory tractinfection (such as pneumonia), viral infections (such asinfluenza and herpes), bronchitis, sinusitis, superficial fungalinfections, abscess

Uncommon: Sepsis including septic shock, pyelonephritis

Rare: Tuberculosis, opportunistic infections (such as invasivefungal infections [histoplasmosis, coccidioidomycosis,pneumocytosis], bacterial, atypical mycobacterial infectionand protozoal), hepatitis B reactivation, bacterial arthritis,infective bursitis

Neoplasms, benign, malignant andunspecified

Uncommon: Neoplasms (such as skin cancer, squamous cell carcinomaand melanocytic naevus)

Rare: Lymphoma, leukaemia, melanoma, Merkel cell carcinoma

Not known: Hepatosplenic T-cell lymphoma*, Kaposi’s sarcoma

Blood and lymphatic systemdisorders

Common: Leukopenia (including neutropenia), anaemia

Uncommon: Thrombocytopenia, pancytopenia

Rare: Aplastic anaemia, agranulocytosis

Common: Allergic reactions (bronchospasm, hypersensitivity, urticaria),autoantibody positive

Rare: Serious systemic hypersensitivity reactions (includinganaphylactic reaction), vasculitis (systemic), sarcoidosis

Uncommon: Thyroid disorder (such as hypothyroidism, hyperthyroidismand goitre)

Uncommon: Blood glucose increased, lipids increased

Common: Depression, insomnia

Common: Dizziness, headache, paraesthesia

Uncommon: Balance disorders

Rare: Demyelinating disorders (central and peripheral), dysgeusia

Uncommon: Visual disorders (such as blurred vision and decreased visualacuity), conjunctivitis, eye allergy (such as pruritis andirritation)

Uncommon: Arrhythmia, ischemic coronary artery disorders

Rare: Congestive heart failure (new onset or worsening)

Common: Hypertension

Uncommon: Thrombosis (such as deep venous and aortic), flushing

Rare: Raynaud’s phenomenon

Respiratory, thoracic andmediastinal disorders

Common: Asthma and related symptoms (such as wheezing andbronchial hyperactivity)

Uncommon: Interstitial lung disease

Common: Dyspepsia, gastrointestinal and abdominal pain, nausea,gastrointestinal inflammatory disorders (such as gastritis andcolitis), stomatitis

Uncommon: Constipation, gastro-oesophageal reflux disease

Common: Alanine aminotransferase increased, aspartateaminotransferase increased

Uncommon: Cholelithiasis, hepatic disorders

Skin and subcutaneous tissuedisorders

Common: Pruritus, rash, alopecia, dermatitis

Uncommon: Bullous skin reactions, psoriasis (new onset or worsening ofpre-existing psoriasis, palmar/plantar and pustular), urticaria

Rare: Lichenoid reactions, skin exfoliation, vasculitis (cutaneous)

Not known: Worsening of symptoms of dermatomyositis

Musculoskeletal and connectivetissue disorders

Rare: Lupus-like syndrome

Rare: Bladder disorders, renal disorders

Reproductive system and breastdisorders

Uncommon: Breast disorders, menstrual disorders

General disorders andadministration site conditions

Common: Pyrexia, asthenia, injection site reaction (such as injection siteerythema, urticaria, induration, pain, bruising, pruritus,irritation and paraesthesia), chest discomfort

Rare: Impaired healing

Injury, poisoning and proceduralcomplications

Common: Bone fractures

* Observed with other TNF-blocking agents.

Throughout this section, median duration of follow-up (approximately 4 years) is generally presentedfor all golimumab use. Where golimumab use is described by dose, the median duration of follow-upvaries (approximately 2 years for 50 mg dose, approximately 3 years for 100 mg dose) as patients mayhave switched between doses.

In the controlled period of pivotal trials, upper respiratory tract infection was the most commonadverse reaction reported in 12.6% of golimumab-treated patients (incidence per 100 subject-years:60.8; 95% CI: 55.0, 67.1) compared with 11.0% of control patients (incidence per 100 subject-years:54.5; 95% CI: 46.1, 64.0). In controlled and uncontrolled portions of the studies with a medianfollow-up of approximately 4 years, the incidence per 100 subject-years of upper respiratory tractinfections was 34.9 events; 95% CI: 33.8, 36.0 for golimumab treated patients.

In the controlled period of pivotal trials, infections were observed in 23.0% of golimumab-treatedpatients (incidence per 100 subject-years: 132.0; 95% CI: 123.3, 141.1) compared with 20.2% ofcontrol patients (incidence per 100 subject-years: 122.3; 95% CI: 109.5, 136.2). In controlled anduncontrolled portions of the trials with a median follow-up of approximately 4 years, the incidence per100 subject-years of infections was 81.1 events; 95% CI: 79.5, 82.8 for golimumab treated patients.

In the controlled period of RA, PsA, AS, and nr-Axial SpA trials, serious infections were observed in1.2% of golimumab-treated patients and 1.2% of control-treated patients. The incidence of seriousinfections per 100 subject-years of follow-up in the controlled period of RA, PsA, AS, and nr-Axial

SpA trials was 7.3; 95% CI: 4.6, 11.1 for the golimumab 100 mg group, 2.9; 95% CI: 1.2, 6.0 for thegolimumab 50 mg group and 3.6; 95% CI: 1.5, 7.0 for the placebo group. In the controlled period of

UC trials of golimumab induction, serious infections were observed in 0.8% of golimumab-treatedpatients compared with 1.5% of control-treated patients. Serious infections observed ingolimumab-treated patients included tuberculosis, bacterial infections including sepsis and pneumonia,invasive fungal infections and other opportunistic infections. Some of these infections have been fatal.

In the controlled and uncontrolled portions of the pivotal trials with a median follow-up of up to3 years, there was a greater incidence of serious infections, including opportunistic infections and TBin patients receiving golimumab 100 mg compared with patients receiving golimumab 50 mg. Theincidence per 100 subject-years of all serious infections was 4.1; 95% CI: 3.6, 4.5, in patientsreceiving golimumab 100 mg and 2.5; 95% CI: 2.0, 3.1, in patients receiving golimumab 50 mg.

Lymphoma

The incidence of lymphoma in golimumab-treated patients during the pivotal trials was higher thanexpected in the general population. In the controlled and uncontrolled portions of these trials with amedian follow-up of up to 3 years, a greater incidence of lymphoma was observed in patientsreceiving golimumab 100 mg compared with patients receiving golimumab 50 mg. Lymphoma wasdiagnosed in 11 subjects (1 in the golimumab 50 mg treatment groups and 10 in the golimumab100 mg treatment groups) with an incidence (95% CI) per 100 subject-years of follow-up of 0.03(0.00, 0.15) and 0.13 (0.06, 0.24) events for golimumab 50 mg and 100 mg respectively and 0.00(0.00, 0.57) events for the placebo. The majority of lymphomas occurred in study GO-AFTER, whichenrolled patients previously exposed to anti-TNF agents who had longer disease duration and morerefractory disease (see section 4.4).

Malignancies other than lymphoma

In the controlled periods of pivotal trials and through approximately 4 years of follow-up, theincidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar betweenthe golimumab and the control groups. Through approximately 4 years of follow-up, the incidence ofnon-lymphoma malignancies (excluding non-melanoma skin cancer) was similar to the generalpopulation.

In the controlled and uncontrolled periods of pivotal trials with a median follow-up of up to 3 years,non-melanoma skin cancer was diagnosed in 5 placebo-treated, 10 golimumab 50 mg-treated and 31golimumab 100 mg-treated subjects with an incidence (95% CI) per 100 subject-years of follow-up of0.36 (0.26, 0.49) for combined golimumab and 0.87 (0.28, 2.04) for placebo.

In the controlled and uncontrolled period of pivotal trials with a median follow-up of up to 3 years,malignancies besides melanoma, non-melanoma skin cancer and lymphoma were diagnosed in 5placebo-treated, 21 golimumab 50 mg-treated and 34 golimumab 100 mg-treated subjects with anincidence (95% CI) per 100 subject-years of follow-up of 0.48 (0.36, 0.62) for combined golimumaband 0.87 (0.28, 2.04) for placebo (see section 4.4).

Cases reported in clinical studies in asthma

In an exploratory clinical study, patients with severe persistent asthma received a golimumab loadingdose (150% of the assigned treatment dose) subcutaneously at week 0 followed by golimumab200 mg, golimumab 100 mg or golimumab 50 mg every 4 weeks subcutaneously through week 52.

Eight malignancies in the combined golimumab treatment group (n = 230) and none in the placebotreatment group (n = 79) were reported. Lymphoma was reported in 1 patient, non-melanoma skincancer in 2 patients, and other malignancies in 5 patients. There was no specific clustering of any typeof malignancy.

During the placebo-controlled portion of the study, the incidence (95% CI) of all malignancies per100 subject-years of follow-up was 3.19 (1.38, 6.28) in the golimumab group. In this study, theincidence (95% CI) per 100 subject-years of follow-up in golimumab-treated subjects was 0.40 (0.01,2.20) for lymphoma, 0.79 (0.10, 2.86) for non-melanoma skin cancers, and 1.99 (0.64, pct. 4.63) for othermalignancies. For placebo subjects, the incidence (95% CI) per 100 subject-years of follow-up ofthese malignancies was 0.00 (0.00, 2.94). The significance of this finding is unknown.

In the controlled and uncontrolled periods of the pivotal trials with a median follow-up of up to3 years, a greater incidence of demyelination was observed in patients receiving golimumab 100 mgcompared with patients receiving golimumab 50 mg (see section 4.4).

Liver enzyme elevations

In the controlled period of RA and PsA pivotal trials, mild ALT elevations (> 1 and < 3 x upper limitof normal (ULN)) occurred in similar proportions of golimumab and control patients in the RA and

PsA studies (22.1% to 27.4% of patients); in the AS and nr-Axial SpA studies, moregolimumab-treated patients (26.9%) than control patients (10.6%) had mild ALT elevations. In thecontrolled and uncontrolled periods of the RA and PsA pivotal trials, with a median follow-up ofapproximately 5 years, the incidence of mild ALT elevations was similar in golimumab-treated andcontrol patients in RA and PsA studies. In the controlled period of the UC pivotal trials of golimumabinduction, mild ALT elevations (> 1 and < 3 x ULN) occurred in similar proportions ofgolimumab-treated and control patients (8.0% to 6.9%, respectively). In controlled and uncontrolledperiods of the UC pivotal trials with a median follow-up of approximately 2 years, the proportion ofpatients with mild ALT elevations was 24.7% in patients receiving golimumab during the maintenanceportion of the UC study.

In the controlled period of RA and AS pivotal trials, ALT elevations ≥ 5 x ULN were uncommon andseen in more golimumab-treated patients (0.4% to 0.9%) than control patients (0.0%). This trend wasnot observed in the PsA population. In the controlled and uncontrolled periods of RA, PsA and ASpivotal trials, with a median follow-up of 5 years, the incidence of ALT elevations ≥ 5 x ULN wassimilar in both golimumab-treated and control patients. In general these elevations were asymptomaticand the abnormalities decreased or resolved with either continuation or discontinuation of golimumabor modification of concomitant medicinal products. No cases were reported in the controlled anduncontrolled periods of the nr-Axial SpA study (up to 1 year). In the controlled periods of the pivotal

UC trials, of golimumab induction, ALT elevations ≥ 5 x ULN occurred in similar proportions ofgolimumab-treated patients compared to placebo-treated patients (0.3% to 1.0%, respectively). In thecontrolled and uncontrolled periods of the pivotal UC trials with a median follow-up of approximately2 years, the proportion of patients with ALT elevations ≥ 5 x ULN was 0.8% in patients receivinggolimumab during the maintenance portion of the UC study.

Within the RA, PsA, AS, and nr-Axial SpA pivotal trials, one patient in an RA trial with pre-existingliver abnormalities and confounding medicinal products treated with golimumab developednon-infectious fatal hepatitis with jaundice. The role of golimumab as a contributing or aggravationfactor cannot be excluded.

In the controlled periods of pivotal trials, 5.4% of golimumab-treated patients had injection sitereactions compared with 2.0% in control patients. The presence of antibodies to golimumab mayincrease the risk of injection site reactions. The majority of the injection site reactions were mild andmoderate and the most frequent manifestation was injection site erythema. Injection site reactionsgenerally did not necessitate discontinuation of the medicinal product.

In controlled Phase IIb and/or III trials in RA, PsA, AS, nr-Axial SpA, severe persistent asthma, and

Phase II/III trials in UC, no patients treated with golimumab developed anaphylactic reactions.

Autoimmune antibodies

In the controlled and uncontrolled periods of pivotal trials through 1 year of follow-up, 3.5% ofgolimumab-treated patients and 2.3% of control patients were newly ANA-positive (at titres of 1:160or greater). The frequency of anti-dsDNA antibodies at 1 year of follow-up in patients anti-dsDNAnegative at baseline was 1.1%.

The safety of golimumab has been studied in a Phase III study of 173 pJIA patients from 2 to 17 yearsof age. The average follow-up was approximately two years. In this study, the type and frequency ofadverse events reported were generally similar to those seen in adult RA studies.

Reporting 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.

Single doses up to 10 mg/kg intravenously have been administered in a clinical study withoutdose-limiting toxicity. In case of an overdose, it is recommended that the patient be monitored for anysigns or symptoms of adverse effects and appropriate symptomatic treatment be institutedimmediately.

Pharmacotherapeutic group: Immunosuppressants, tumour necrosis factor alpha (TNF-α) inhibitors,

ATC code: L04AB06

Golimumab is a human monoclonal antibody that forms high affinity, stable complexes with both thesoluble and transmembrane bioactive forms of human TNF-α, which prevents the binding of TNF-α toits receptors.

The binding of human TNF by golimumab was shown to neutralise TNF-α-induced cell-surfaceexpression of the adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 andintercellular adhesion molecule (ICAM)-1 by human endothelial cells. In vitro, TNF-induced secretionof interleukin (IL)-6, IL-8 and granulocyte-macrophage colony stimulating factor (GM-CSF) byhuman endothelial cells was also inhibited by golimumab.

Improvement in C-reactive protein (CRP) levels were observed relative to placebo groups andtreatment with Simponi resulted in significant reductions from baseline in serum levels of IL-6,

ICAM-1, matrix-metalloproteinase (MMP)-3 and vascular endothelial growth factor (VEGF)compared to control treatment. In addition, levels of TNF- were reduced in RA and AS patients andlevels of IL-8 were reduced in PsA patients. These changes were observed at the first assessment(week 4) after the initial Simponi administration and were generally maintained through week 24.

The efficacy of Simponi was demonstrated in three multi-centre, randomised, double-blind,placebo-controlled studies in over 1500 patients ≥ 18 years of age with moderately to severely active

RA diagnosed according to American College of Rheumatology (ACR) criteria for at least 3 monthsprior to screening. Patients had at least 4 swollen and 4 tender joints. Simponi or placebo weresubcutaneously administered every 4 weeks.

GO-FORWARD evaluated 444 patients who had active RA despite a stable dose of at least15 mg/week of MTX and who had not been previously treated with an anti-TNF agent. Patients wererandomised to receive placebo + MTX, Simponi 50 mg + MTX, Simponi 100 mg + MTX or Simponi100 mg + placebo. Patients receiving placebo + MTX were switched to Simponi 50 mg + MTX afterweek 24. At week 52, patients entered an open label long-term extension.

GO-AFTER evaluated 445 patients who were previously treated with one or more of the anti-TNFagents adalimumab, etanercept, or infliximab. Patients were randomised to receive placebo, Simponi50 mg, or Simponi 100 mg. Patients were allowed to continue concomitant DMARD therapy with

MTX, sulfasalazine (SSZ), and/or hydroxychloroquine (HCQ) during the study. The stated reasons fordiscontinuation of prior anti TNF therapies were lack of efficacy (58%), intolerance (13%), and/orreasons other than safety or efficacy (29%, mostly for financial reasons).

GO-BEFORE evaluated 637 patients with active RA who were MTX-naïve and had not previouslybeen treated with an anti-TNF agent. Patients were randomised to receive placebo + MTX, Simponi50 mg + MTX, Simponi 100 mg + MTX or Simponi 100 mg + placebo. At week 52, patients enteredan open label long-term extension in which patients receiving placebo + MTX who had at least 1tender or swollen joint were switched to Simponi 50 mg + MTX.

In GO-FORWARD, the (co-)primary endpoints were the percentage of patients achieving an ACR 20response at week 14 and the improvement from baseline in Health Assessment Questionnaire (HAQ)at week 24. In GO-AFTER, the primary endpoint was the percentage of patients achieving an ACR 20response at week 14. In GO-BEFORE, the co-primary endpoints were the percentage of patientsachieving ACR 50 response at week 24 and the change from baseline in the van der Heijde-modified

Sharp (vdH-S) score at week 52. In addition to the primary endpoint(s), additional assessments of theimpact of Simponi treatment on the signs and symptoms of arthritis, radiographic response, physicalfunction and health-related quality of life were performed.

In general, no clinically meaningful differences in measures of efficacy were observed between the

Simponi 50 mg and 100 mg dosing regimens with concomitant MTX, through week 104 in

GO-FORWARD and GO-BEFORE and through week 24 in GO-AFTER. In each of the RA studies bystudy design, patients in the long-term extension may have switched between the 50 mg and 100 mg

Simponi doses at the discretion of the study physician.

Signs and symptoms

Key ACR results for the Simponi 50 mg dose at weeks 14, 24 and 52 for GO-FORWARD,

GO-AFTER and GO-BEFORE are shown in Table 2 and are described below. Responses wereobserved at the first assessment (week 4) after the initial Simponi administration.

In GO-FORWARD, among 89 subjects randomised to Simponi 50 mg + MTX, 48 were still on thistreatment at week 104. Among those, 40, 33 and 24 patients had ACR 20/50/70 response, respectivelyat week 104. Among patients remaining in the study and treated with Simponi, similar rates of

ACR 20/50/70 response was observed from week 104 through week 256.

In GO-AFTER, the percentage of patients achieving an ACR 20 response was greater for patientsreceiving Simponi than for patients receiving placebo regardless of the reason reported fordiscontinuation of one or more prior anti-TNF therapies.

Table 2

Key efficacy outcomes from the controlled portions of GO-FORWARD, GO-AFTER and

GO-BEFORE.

GO-FORWARD GO-AFTER GO-BEFORE

Active RA despite MTX Active RA, previously Active RA, MTX Naïvetreated with one or moreanti-TNF agent(s)

Simponi Simponi

Placebo 50 mg Placebo 50 mg+ + Simponi + +

MTX MTX Placebo 50 mg MTX MTXna 133 89 150 147 160 159

Responders, % of patients

ACR 20

Week 14 33% 55%* 18% 35%* NA NA

Week 24 28% 60%* 16% 31% p = 0.002 49% 62%

Week 52 NA NA NA NA 52% 60%

ACR 50

Week 14 10% 35%* 7% 15% p = 0.021 NA NA

Week 24 14% 37%* 4% 16%* 29% 40%

Week 52 NA NA NA NA 36% 42%

ACR 70

Week 14 4% 14% 2% 10% NA NAp = 0.008 p = 0.005

Week 24 5% 20%* 2% 9% p = 0.009 16% 24%

Week 52 NA NA NA NA 22% 28%a n reflects randomised patients; actual number of patients evaluable for each endpoint may vary by timepoint.

* p ≤ 0.001

NA: Not Applicable

In GO-BEFORE the primary analysis in patients with moderate to severe rheumatoid arthritis(combined Simponi 50 and 100 mg + MTX groups vs MTX alone for ACR50) was not statisticallysignificant at week 24 (p = 0.053). At week 52 in the overall population, the percentage of patients inthe Simponi 50 mg + MTX group who achieved an ACR response was generally higher but notsignificantly different when compared with MTX alone (see Table 2). Additional analyses wereperformed in subsets representative of the indicated population of patients with severe, active andprogressive RA. A generally greater effect of Simponi 50 mg + MTX versus MTX alone wasdemonstrated in the indicated population compared with the overall population.

In GO-FORWARD and GO-AFTER, clinically meaningful and statistically significant responses in

Disease Activity Scale (DAS)28 were observed at each prespecified time point, at week 14 and atweek 24 (p ≤ 0.001). Among patients who remained on the Simponi treatment to which they wererandomised at study start, DAS28 responses were maintained through week 104. Among patientsremaining in the study and treated with Simponi, DAS28 responses were similar from week 104through week 256.

In GO-BEFORE, major clinical response, defined as the maintenance of an ACR 70 response over acontinuous 6-month period, was measured. At week 52, 15% of patients in the Simponi 50 mg + MTXgroup achieved a major clinical response compared with 7% of patients in the placebo + MTX group(p = 0.018). Among 159 subjects randomised to Simponi 50 mg + MTX, 96 were still on thistreatment at week 104. Among those, 85, 66 and 53 patients had ACR 20/50/70 response, respectively,at week 104. Among patients remaining in the study and treated with Simponi, similar rates of

ACR 20/50/70 response were observed from week 104 through week 256.

In GO-BEFORE the change from baseline in the vdH-S score, a composite score of structural damagethat radiographically measures the number and size of joint erosions and the degree of joint spacenarrowing in hands/wrists and feet, was used to assess the degree of structural damage. Key results forthe Simponi 50 mg dose at week 52 are presented in Table 3.

The number of patients with no new erosions or a change from baseline in total vdH-S Score ≤ 0 wassignificantly higher in the Simponi treatment group than in the control group (p = 0.003). Theradiographic effects observed at week 52 were maintained through week 104. Among patientsremaining in the study and treated with Simponi, radiographic effects were similar from week 104through week 256.

Table 3

Radiographic mean (SD) changes from baseline in total vdH-S score at week 52 in the overallpopulation of GO-BEFORE

Placebo + MTX Simponi 50 mg + MTXna 160 159

Total Score

Baseline 19.7 (35.4) 18.7 (32.4)

Change from baseline 1.4 (4.6) 0.7 (5.2)*

Erosion Score

Baseline 11.3 (18.6) 10.8 (17.4)

Change from baseline 0.7 (2.8) 0.5 (2.1)

JSN Score

Baseline 8.4 (17.8) 7.9 (16.1)

Change from baseline 0.6 (2.3) 0.2 (2.0)**a n reflects randomised patients

* p = 0.015

** p = 0.044

Physical function and disability were assessed as a separate endpoint in GO-FORWARD and

GO-AFTER using the disability index of the HAQ DI. In these studies, Simponi demonstratedclinically meaningful and statistically significant improvement in HAQ DI from baseline versuscontrol at week 24. Among patients who remained on the Simponi treatment to which they wererandomised at study start, improvement in HAQ DI was maintained through week 104. Amongpatients remaining in the study and treated with Simponi, improvement in HAQ DI was similar fromweek 104 through week 256.

In GO-FORWARD clinically meaningful and statistically significant improvements weredemonstrated in health-related quality of life as measured by the physical component score of the

SF-36 in patients treated with Simponi versus placebo at week 24. Among patients who remained onthe Simponi treatment to which they were randomised at study start, improvement of the SF-36physical component was maintained through week 104. Among patients remaining in the study andtreated with Simponi, improvement of the SF-36 physical component was similar from week 104through week 256. In GO-FORWARD and GO-AFTER, statistically significant improvements wereobserved in fatigue as measured by functional assessment of chronic illness therapy-fatigue scale(FACIT-F).

The safety and efficacy of Simponi were evaluated in a multi-centre, randomised, double-blind,placebo-controlled study (GO-REVEAL) in 405 adult patients with active PsA (≥ 3 swollen joints and≥ 3 tender joints) despite non-steroidal anti-inflammatory (NSAID) or DMARD therapy. Patients inthis study had a diagnosis of PsA for at least 6 months and had at least mild psoriatic disease. Patientswith each sub-type of psoriatic arthritis were enrolled, including polyarticular arthritis with norheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal (DIP) jointarthritis (15%), spondylitis with peripheral arthritis (11%), and arthritis mutilans (1%). Previoustreatment with an anti-TNF agent was not allowed. Simponi or placebo were administeredsubcutaneously every 4 weeks. Patients were randomly assigned to placebo, Simponi 50 mg, or

Simponi 100 mg. Patients receiving placebo were switched to Simponi 50 mg after week 24. Patientsentered an open label long-term extension at week 52. Approximately forty-eight percent of patientscontinued on stable doses of methotrexate (≤ 25 mg/week). The co-primary endpoints were thepercentage of patients achieving ACR 20 response at week 14 and change from baseline in total PsAmodified vdH-S score at week 24.

In general, no clinically meaningful differences in measures of efficacy were observed between the

Simponi 50 mg and 100 mg dosing regimens through week 104. By study design, patients in thelong-term extension may have switched between the 50 mg and 100 mg Simponi doses at thediscretion of the study physician.

Signs and symptoms

Key results for the 50 mg dose at weeks 14 and 24 are shown in table 4 and described below.

Table 4

Key efficacy outcomes from GO-REVEAL

Simponi

Placebo 50 mg*na 113 146

Responders, % of patients

ACR 20

Week 14 9% 51%

Week 24 12% 52%

ACR 50

Week 14 2% 30%

Week 24 4% 32%

ACR 70

Week 14 1% 12%

Week 24 1% 19%

PASIb 75c

Week 14 3% 40%

Week 24 1% 56%

* p < 0.05 for all comparisons;a n reflects randomised patients; actual number of patients evaluable for each endpoint may vary by timepointb Psoriasis Area and Severity Indexc Based on the subset of patients with ≥ 3% BSA involvement at baseline, 79 patients (69.9%) in the placebo group and109 (74.3%) in the Simponi 50 mg group.

Responses were observed at the first assessment (week 4) after the initial Simponi administration.

Similar ACR 20 responses at week 14 were observed in patients with polyarticular arthritis with norheumatoid nodules and asymmetric peripheral arthritis PsA subtypes. The number of patients withother PsA subtypes was too small to allow meaningful assessment. Responses observed in the Simponitreated groups were similar in patients receiving and not receiving concomitant MTX. Among146 patients randomised to Simponi 50 mg, 70 were still on this treatment at week 104. Of these70 patients, 64, 46 and 31 patients had an ACR 20/50/70 response, respectively. Among patientsremaining in the study and treated with Simponi, similar rates of ACR 20/50/70 response wasobserved from week 104 through week 256.

Statistically significant responses in DAS28 were also observed at weeks 14 and 24 (p < 0.05).

At week 24 improvements in parameters of peripheral activity characteristic of psoriatic arthritis (e.g.number of swollen joints, number of painful/tender joints, dactylitis and enthesitis) were seen in the

Simponi-treated patients. Simponi treatment resulted in significant improvement in physical functionas assessed by HAQ DI, as well as significant improvements in health-related quality of life asmeasured by the physical and mental component summary scores of the SF-36. Among patients whoremained on the Simponi treatment to which they were randomised at study start, DAS28 and HAQ DIresponses were maintained through week 104. Among patients remaining in the study and treated with

Simponi, DAS28 and HAQ DI responses were similar from week 104 through week 256.

Structural damage in both hands and feet was assessed radiographically by the change from baseline inthe vdH-S score, modified for PsA by addition of hand distal interphalangeal (DIP) joints.

Simponi 50 mg treatment reduced the rate of progression of peripheral joint damage compared withplacebo treatment at week 24 as measured by change from baseline in total modified vdH-S Score(mean ± SD score was 0.27 ± 1.3 in the placebo group compared with -0.16 ± 1.3 in the Simponigroup; p = 0.011). Out of 146 patients who were randomised to Simponi 50 mg, 52 week X-ray datawere available for 126 patients, of whom 77% showed no progression compared to baseline. Atweek 104, X-ray data were available for 114 patients, and 77% showed no progression from baseline.

Among patients remaining in the study and treated with Simponi, similar rates of patients showed noprogression from baseline from week 104 through week 256.

The safety and efficacy of Simponi were evaluated in a multi-centre, randomised, double-blind,placebo-controlled study (GO-RAISE) in 356 adult patients with active ankylosing spondylitis(defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4 and a VAS for totalback pain of ≥ 4, on a scale of 0 to 10 cm). Patients enrolled in this study had active disease despitecurrent or previous NSAID or DMARD therapy and had not previously been treated with anti-TNFtherapy. Simponi or placebo were administered subcutaneously every 4 weeks. Patients wererandomly assigned to placebo, Simponi 50 mg and Simponi 100 mg and were allowed to continueconcomitant DMARD therapy (MTX, SSZ and/or HCQ). The primary endpoint was the percentage ofpatients achieving Ankylosing Spondylitis Assessment Study Group (ASAS) 20 response at week 14.

Placebo-controlled efficacy data were collected and analysed through week 24.

Key results for the 50 mg dose are shown in Table 5 and described below. In general, no clinicallymeaningful differences in measures of efficacy were observed between the Simponi 50 mg and100 mg dosing regimens through week 24. By study design, patients in the long-term extension mayhave switched between the 50 mg and 100 mg Simponi doses at the discretion of the study physician.

Table 5

Key efficacy outcomes from GO-RAISE.

Simponi

Placebo 50 mg*na 78 138

Responders, % of patients

ASAS 20

Week 14 22% 59%

Week 24 23% 56%

ASAS 40

Week 14 15% 45%

Week 24 15% 44%

ASAS 5/6

Week 14 8% 50%

Week 24 13% 49%

* p ≤ 0.001 for all comparisonsa n reflects randomised patients; actual number of patients evaluable for each endpoint may vary by timepoint

Among patients remaining in the study and treated with Simponi, the proportion of patients with an

ASAS 20 and ASAS 40 response were similar from week 24 through week 256.

Statistically significant responses in BASDAI 50, 70 and 90 (p ≤ 0.017) were also seen at weeks 14and 24. Improvements in key measures of disease activity were observed at the first assessment(week 4) after the initial Simponi administration and were maintained through week 24. Amongpatients remaining in the study and treated with Simponi, similar rates of change from baseline in

BASDAI were observed from week 24 through week 256. Consistent efficacy was seen in patientsregardless of use of DMARDs (MTX, sulfasalazine and/or hydroxychloroquine), HLA-B27 antigenstatus or baseline CRP levels as assessed by ASAS 20 responses at week 14.

Simponi treatment resulted in significant improvements in physical function as assessed by changesfrom baseline in BASFI at weeks 14 and 24. Health-related quality of life as measured by the physicalcomponent score of the SF-36 was also improved significantly at weeks 14 and 24. Among patientsremaining in the study and treated with Simponi, improvements in physical function and health-relatedquality of life were similar from week 24 through week 256.

Non-radiographic axial spondyloarthritis

GO-AHEAD

The safety and efficacy of Simponi were evaluated in a multi-centre, randomised, double-blind,placebo-controlled study (GO-AHEAD) in 197 adult patients with severe active nr-Axial SpA (definedas those patients meeting the ASAS classification criteria of axial spondyloarthritis but did not meetthe modified New York criteria for AS). Patients enrolled in this study had active disease (defined as a

BASDAI ≥ 4 and a Visual Analogue Scale (VAS) for total back pain of ≥ 4, each on a scale of0-10 cm) despite current or previous NSAID therapy and had not previously been treated with anybiological agents including anti-TNF therapy. Patients were randomly assigned to placebo or Simponi50 mg administered subcutaneously every 4 weeks. At week 16, patients entered an open label periodin which all patients received Simponi 50 mg administered subcutaneously every 4 weeks throughweek 48 with efficacy assessments performed through week 52 and safety follow-up through week 60.

Approximately 93% of patients who were receiving Simponi at the beginning of the open-labelextension (week 16) remained on treatment through the end of the study (week 52). Analyses wereperformed on both the All Treated (AT, N = 197) and Objective Signs of Inflammation (OSI, N = 158,defined by elevated CRP and/or evidence of sacroiliitis on MRI at baseline) populations.

Placebo-controlled efficacy data were collected and analysed through week 16. The primary endpointwas the proportion of patients achieving ASAS 20 response at week 16. Key results are shown in

Table 6 and described below.

Table 6

Key efficacy outcomes from GO-AHEAD at week 16

Improvements in signs and symptoms

Objective signs of inflammation

All treated population (AT) population (OSI)

Placebo Simponi 50 mg Placebo Simponi 50 mgna 100 97 80 78

Responders, % of patients

ASAS 20 40% 71%** 38% 77%**

ASAS 40 23% 57%** 23% 60%**

ASAS 5/6 23% 54%** 23% 63%**

ASAS Partial Remission 18% 33%* 19% 35%*

ASDAS-C b < 1.3 13% 33%* 16% 35%*

BASDAI 50 30% 58%** 29% 59%**

Inhibition of inflammation in sacroiliac (SI) joints as measured by MRI

Placebo Simponi 50 mg Placebo Simponi 50 mgnc 87 74 69 61

Mean change in

SPARCCd MRIsacroiliac joint score -0.9 -5.3** -1.2 -6.4**a n reflects randomised and treated patientsb Ankylosing Spondylitis Disease Activity Score C-Reactive Protein (AT-Placebo, N = 90; AT-Simponi 50 mg, N = 88;

OSI-Placebo, N = 71; OSI-Simponi 50 mg, N = 71)c n reflects number of patients with baseline and week 16 MRI datad SPARCC (Spondyloarthritis Research Consortium of Canada)

** p < 0.0001 for Simponi vs placebo comparisons

* p < 0.05 for Simponi vs placebo comparisons

Statistically significant improvements in signs and symptoms of severe active nr-Axial SpA weredemonstrated in patients treated with Simponi 50 mg compared to placebo at week 16 (Table 6).

Improvements were observed at the first assessment (week 4) after the initial Simponi administration.

SPARCC score as measured by MRI showed statistically significant reductions in SI jointinflammation at week 16 in patients treated with Simponi 50 mg compared to placebo (Table 6). Painas assessed by the Total Back Pain and Nocturnal Back Pain VAS, and disease activity as measured by

ASDAS-C also showed statistically significant improvement from baseline to week 16 in patientstreated with Simponi 50 mg compared to placebo (p < 0.0001).

Statistically significant improvements in spinal mobility as assessed by BASMI (Bath Ankylosing

Spondylitis Metrology Index) and in physical function as assessed by the BASFI were demonstrated in

Simponi 50 mg-treated patients as compared to placebo-treated patients (p < 0.0001). Patients treatedwith Simponi experienced significantly more improvements in health-related quality of life as assessedby ASQoL, EQ-5D, and physical and mental components of SF-36, and experienced significantlymore improvements in productivity as assessed by greater reductions in overall work impairment andin activity impairment as assessed by the WPAI questionnaire than patients receiving placebo.

For all of the endpoints described above, statistically significant results were also demonstrated in the

OSI population at week 16.

In both the AT and OSI populations, the improvements in signs and symptoms, spinal mobility,physical function, quality of life, and productivity observed at week 16 among patients treated with

Simponi 50 mg continued in those remaining in the study at week 52.

GO-BACK

The efficacy and safety of continued golimumab treatment (full or reduced dosing frequency)compared with treatment withdrawal was assessed in adult patients (18-45 years of age) with activenr-axSpA who demonstrated sustained remission during 10 months of monthly treatment withopen-label Simponi (GO-BACK). Eligible patients (who achieved a clinical response by Month 4 andan inactive disease status (ASDAS < 1.3) at both Months 7 and 10) entering the double-blindwithdrawal phase were randomised to continued monthly treatment with Simponi (full-treatmentregimen, N = 63), every 2-month treatment with Simponi (reduced treatment regimen, N = 63) ormonthly placebo treatment (treatment withdrawal, N = 62) for up to approximately 12 months.

The primary efficacy endpoint was the proportion of patients without a flare of disease activity.

Patients who experienced a flare, i.e., had an ASDAS collected at 2 consecutive assessments that bothshowed either an absolute score of ≥ 2.1 or post-withdrawal increase of ≥ 1.1 relative to Month 10(end of open-label period), reinitiated monthly Simponi in an open-label retreatment phase tocharacterise clinical response.

Clinical response after double-blind treatment withdrawal

Among the 188 patients with inactive disease who received at least one dose of double-blindtreatment, a significantly (p < 0.001) greater proportion of patients did not experience a disease flarewhen continuing Simponi with either the full-treatment (84.1%), or reduced treatment (68.3%)regimens compared with treatment withdrawal (33.9%) (Table 7).

Table 7

Analysis of the proportion of participants without a flarea

Full analysis set population (Period 2 - Double-blind)

Difference in % vs Placebo

Treatment n/N % Estimate (95% CI)b p-Valueb

GLM SC QMT 53/63 84.1 50.2 (34.1, 63.6) < 0.001

GLM SC Q2MT 43/63 68.3 34.4 (17.0, 49.7) < 0.001

Placebo 21/62 33.9

Full Analysis Set includes all randomised participants who attained inactive disease in period 1 and received at leastone dose of blinded study treatment.a Defined as ASDAS at 2 consecutive visits that both show either absolute score ≥ 2.1 or post-withdrawal increaseof ≥ 1.1 relative to Month 10 (Visit 23).b Type I error rate over the multiple treatment comparisons (GLM SC QMT vs Placebo and GLM SC Q2MT vs

Placebo) was controlled using a sequential (step-down) testing procedure. Derived based on the stratified

Miettinen and Nurminen method with CRP level (> 6 mg/L or ≤ 6 mg/L) as stratification factor.

Participants who discontinued period 2 prematurely and prior to a ‘flare’ will be counted as having a ‘flare’.

N = Total number of participants; n = number of participants without a flare; GLM = golimumab;

SC = subcutaneous, QMT = monthly dosing; Q2MT = every other month dosing.

The difference in time-to-first flare between the treatment withdrawal group and either of the Simponi

Treatment groups is shown in Figure 1 (log-rank p < 0.0001 for each comparison). In the placebogroup, flares started approximately 2 months after Simponi was withdrawn, with the majority of flaresoccurring within 4 months of treatment withdrawal (Figure 1).

Figure 1: Kaplan-Meier Analysis of Time-to-First Flare

Clinical response to retreatment for a disease flare

Clinical response was defined as a BASDAI improvement of ≥ 2 or ≥ 50% relative to the mean of the2 consecutive BASDAI scores ascribed to the disease flare. Of the 53 participants in the reduceddosing or treatment withdrawal regimens who had a confirmed disease flare, 51 (96.2%) attained aclinical response to Simponi within the first 3 months of retreatment, although fewer patients (71.7%)were able to sustain it for all 3 months.

The efficacy of Simponi was evaluated in two randomised, double-blind, placebo-controlled clinicalstudies in adult patients.

The induction study (PURSUIT-Induction) evaluated patients with moderately to severely activeulcerative colitis (Mayo score 6 to 12; Endoscopy subscore ≥ 2) who had an inadequate response to orfailed to tolerate conventional therapies, or were corticosteroid dependent. In the dose confirmingportion of the study, 761 patients were randomised to receive either 400 mg Simponi SC at week 0 and200 mg at week 2, 200 mg Simponi SC at week 0 and 100 mg at week 2, or placebo SC at weeks 0 and2. Concomitant stable doses of oral aminosalicylates, corticosteroids, and/or immunomodulatoryagents were permitted. The efficacy of Simponi through week 6 was assessed in this study.

The results of the maintenance study (PURSUIT-Maintenance) were based on evaluation of456 patients who achieved clinical response from previous induction with Simponi. Patients wererandomised to receive Simponi 50 mg, Simponi 100 mg or placebo administered subcutaneously every4 weeks. Concomitant stable doses of oral aminosalicylates, and/or immunomodulatory agents werepermitted. Corticosteroids were to be tapered at the start of the maintenance study. The efficacy of

Simponi through week 54 was assessed in this study. Patients who completed the maintenance studythrough week 54 continued treatment in a study-extension, with efficacy evaluated through week 216.

Efficacy evaluation in the study extension was based on changes in corticosteroid use, Physician’s

Global Assessment (PGA) of disease activity, and improvement in quality of life as measured by

Inflammatory Bowel Disease Questionnaire (IBDQ).

Table 8

Key efficacy outcomes from PURSUIT - Induction and PURSUIT - Maintenance

PURSUIT-Induction

Simponi

Placebo 200/100 mg

N = 251 N = 253

Percentage of patients

Patients in clinical response at week 6a 30% 51%**

Patients in clinical remission at week 6b 6% 18%**

Patients with mucosal healing at 29% 42%*week 6c

PURSUIT-Maintenance

Simponi Simponi

Placebod 50 mg 100 mg

N = 154 N = 151 N = 151

Percentage of patients

Maintenance of response (Patients in31% 47%* 50%**clinical response through week 54)e

Sustained remission (Patients in clinicalremission at both week 30 and 16% 23%g 28%*week 54)f

N = number of patients

** p ≤ 0.001

* p ≤ 0.01a defined as a decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, accompanied by a decrease in therectal bleeding subscore of ≥ 1 or a rectal bleeding subscore of 0 or 1.b Defined as a Mayo score ≤ 2 points, with no individual subscore > 1c Defined as 0 or 1 on the endoscopy subscore of the Mayo score.d Simponi induction only.e Patients were assessed for UC disease activity by partial Mayo score every 4 weeks (loss of response was confirmedby endoscopy). Therefore, a patient who maintained response was in a state of continuous clinical response at eachevaluation through week 54.

f A patient had to be in remission at both weeks 30 and 54 (without demonstrating a loss of response at any time pointthrough week 54) to achieve durable remission.

g In patients weighing less than 80 kg, a greater proportion of patients who received 50 mg maintenance therapy showedsustained clinical remission compared with those who received placebo.

More Simponi-treated patients demonstrated sustained mucosal healing (patients with mucosal healingat both week 30 and week 54) in the 50 mg group (42%, nominal p < 0.05) and 100 mg group (42%,p < 0.005) compared with patients in the placebo group (27%).

Among the 54% of patients (247/456) who were receiving concomitant corticosteroids at the start of

PURSUIT-Maintenance, the proportion of patients who maintained clinical response through week 54and were not receiving concomitant corticosteroids at week 54 was greater in the 50 mg group (38%,30/78) and 100 mg group (30%, 25/82) compared with the placebo group (21%, 18/87). Theproportion of patients who eliminated corticosteroids by week 54 was greater in the 50 mg group(41%, 32/78) and 100 mg group (33%, 27/82) compared with the placebo group (22%, 19/87). Amongpatients who entered the study extension, the proportion of subjects who remained corticosteroid freewas generally maintained through week 216.

Patients who did not achieve clinical response at week 6 in the PURSUIT-Induction studies weredosed Simponi 100 mg every 4 weeks in the PURSUIT-Maintenance study. At week 14, 28% of thesepatients achieved response defined by partial Mayo score (decreased by ≥ 3 points compared with startof induction). At week 54, the clinical outcomes observed in these patients were similar to the clinicaloutcomes reported for the patients achieving clinical response at week 6.

At week 6, Simponi significantly improved quality of life as measured by change from baseline in adisease specific measure, IBDQ (inflammatory bowel disease questionnaire). Among patients whoreceived Simponi maintenance treatment, the improvement in quality of life as measured by IBDQwas maintained through week 54.

Approximately 63% of patients who were receiving Simponi at the beginning of the study extension(week 56), remained on treatment through the end of the study (last golimumab administration atweek 212).

Across the Phase III RA, PsA and AS studies through week 52, antibodies to golimumab weredetected by the enzyme immunoassay (EIA) method in 5% (105/2062) of golimumab treated patientsand, where tested, nearly all antibodies were neutralising in vitro. Similar rates were shown acrossrheumatologic indications. Treatment with concomitant MTX resulted in a lower proportion ofpatients with antibodies to golimumab than patients receiving golimumab without MTX(approximately 3% [41/1235] versus 8% [64/827], respectively).

In nr-Axial SpA, antibodies to golimumab were detected in 7% (14/193) of golimumab treatedpatients through week 52 by the EIA method.

In the Phase II and III UC studies through week 54, antibodies to golimumab were detected by the

EIA method in 3% (26/946) of golimumab treated patients. Sixty-eight percent (21/31) ofantibody-positive patients had neutralising antibodies in vitro. Treatment with concomitantimmunomodulators (azathioprine, 6-mercaptopurine and MTX) resulted in a lower proportion ofpatients with antibodies to golimumab than patients receiving golimumab without immunomodulators(1% (4/308) versus 3% (22/638), respectively). Of patients that continued in the study extension andhad evaluable samples through week 228, antibodies to golimumab were detected in 4% (23/604) ofgolimumab treated patients. Eighty-two percent (18/22) of antibody-positive patients had neutralisingantibodies in vitro.

A drug-tolerant EIA method was used in the pJIA study for the detection of antibodies to golimumab.

Due to the higher sensitivity and the improved drug tolerance, a higher incidence of antibodies togolimumab was expected to be detected with the drug-tolerant EIA method compared to the EIAmethod. In the Phase III pJIA study through week 48, antibodies to golimumab were detected by thedrug-tolerant EIA method in 40% (69/172) of golimumab treated children of which a majority had atitre lower than 1:1000. An effect on serum golimumab concentrations was seen at titres of > 1:100while an effect on efficacy was not seen until titres of > 1:1000, though the numbers of children withtitres of > 1:1000 were low (N = 8). Among the children who tested positive for antibodies togolimumab, 39% (25/65) had neutralising antibodies. The higher incidence of antibodies with thedrug-tolerant EIA method, because they were mainly low titre antibodies, did not have an apparentimpact on drug levels, efficacy and safety and therefore does not represent any new safety signal.

The presence of antibodies to golimumab may increase the risk of injection site reactions(see section 4.4). The small number of patients positive for antibodies to golimumab limits the abilityto draw definitive conclusions regarding the relationship between antibodies to golimumab andclinical efficacy or safety measures.

Because immunogenicity analyses are product- and assay-specific, comparison of antibody rates withthose from other products is not appropriate.

The safety and efficacy of Simponi was evaluated in a randomised, double-blind, placebo-controlled,withdrawal study (GO-KIDS) in 173 children (2 to 17 years of age) with active pJIA with at least5 active joints and an inadequate response to MTX. Children with polyarticular course JIA(rheumatoid factor positive or negative polyarthritis, extended oligoarthritis, juvenile psoriatic arthritisor systemic JIA with no current systemic symptoms) were included in the study. The baseline mediannumber of active joints was 12, and median CRP was 0.17 mg/dL.

Part 1 of the study consisted of a 16-week open-label phase in which 173 enrolled children received

Simponi 30 mg/m2 (maximum 50 mg) subcutaneously every 4 weeks and MTX. The 154 children whoachieved an ACR Ped 30 response at week 16 entered Part 2 of the study, the randomised withdrawalphase, and received Simponi 30 mg/m2 (maximum 50 mg) + MTX or placebo + MTX every 4 weeks.

After disease flare, children received Simponi 30 mg/m2 (maximum 50 mg) + MTX. At week 48,children entered a long-term extension.

Children in this study demonstrated ACR Ped 30, 50, 70, and 90 responses from week 4.

At week 16, 87% of children were ACR Ped 30 responders, and 79%, 66%, and 36% of children were

ACR Ped 50, ACR Ped 70, and ACR Ped 90 responders, respectively. At week 16, 34% of childrenhad inactive disease defined as having the presence of all of the following: no joints with activearthritis; no fever, rash, serositis, splenomegaly, hepatomegaly, or generalised lymphadenopathyattributable to JIA; no active uveitis; normal ESR (< 20 mm/hour) or CRP (< 1.0 mg/dL); physicianglobal assessment of disease activity (≤ 5 mm on the VAS); duration of morning stiffness< 15 minutes.

At week 16, all ACR Ped components demonstrated clinically relevant improvement from baseline(see Table 9).

Table 9

Improvements from baseline in ACR Ped components at week 16a

Median percent improvement

Simponi 30 mg/m2nb = 173

Physicians global assessment of disease (VASc 0-10 cm) 88%

Subject/parent global assessment of overall well-being 67%(VAS 0-10 cm)

Number of active joints 92%

Number of joints with limited range of motion 80%

Physical function by CHAQd 50%

ESR (mm/h)e 33%a baseline = week 0b “n” reflects enrolled patientsc VAS: Visual Analogue Scaled CHAQ: Child Health Assessment Questionnairee ESR (mm/h): erythrocyte sedimentation rate (millimetres per hour)

The primary endpoint, the proportion of children who were ACR Ped 30 responders at week 16 andwho did not experience a flare between week 16 and week 48, was not achieved. The majority ofchildren did not experience a flare between week 16 and week 48 (59% in the Simponi + MTX and53% in the placebo + MTX groups, respectively; p = 0.41).

Pre-specified subgroup analyses of the primary endpoint by baseline CRP (≥ 1 mg/dL vs < 1 mg/dL)demonstrated higher flare rates in placebo + MTX vs Simponi + MTX treated subjects among subjectswith baseline CRP ≥ 1 mg/dL (87% vs 40% p = 0.0068).

At week 48, 53% and 55% of children in the Simponi + MTX group and placebo + MTX group,respectively, were ACR Ped 30 responders, and 40% and 28% of children in the Simponi + MTXgroup and placebo + MTX group, respectively, achieved inactive disease.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Simponi in one or more subsets of the paediatric population in ulcerative colitis (see section 4.2 forinformation on paediatric use).

Following a single subcutaneous administration of golimumab to healthy subjects or patients with RA,the median time to reach maximum serum concentrations (Tmax) ranged from 2 to 6 days. Asubcutaneous injection of 50 mg golimumab to healthy subjects produced a mean  standard deviationmaximum serum concentration (Cmax) of 3.1  1.4 g/mL.

Following a single subcutaneous injection of 100 mg, the absorption of golimumab was similar in theupper arm, abdomen, and thigh, with a mean absolute bioavailability of 51%. Since golimumabexhibited approximately dose proportional PK following a subcutaneous administration, the absolutebioavailability of a golimumab 50 mg or 200 mg dose is expected to be similar.

Following a single IV administration, the mean volume of distribution was 115  19 mL/kg.

The systemic clearance of golimumab was estimated to be 6.9  2.0 mL/day/kg. Terminal half-lifevalue was estimated to be approximately 12  3 days in healthy subjects and similar values wereobserved in patients with RA, PsA, AS, or UC.

When 50 mg golimumab was administered subcutaneously to patients with RA, PsA or AS every4 weeks, serum concentrations reached steady state by week 12. With concomitant use of MTX,treatment with 50 mg golimumab subcutaneously every 4 weeks resulted in a mean ( standarddeviation) steady-state trough serum concentration of approximately 0.6  0.4 g/mL in RA patientswith active RA despite MTX therapy, and approximately 0.5  0.4 g/mL in patients with active PsAand approximately 0.8  0.4 g/mL in patients with AS. Steady-state trough mean serum golimumabconcentrations in patients with nr-Axial SpA were similar to those observed in patients with ASfollowing subcutaneous administration of 50 mg golimumab every 4 weeks.

Patients with RA, PsA or AS who did not receive concomitant MTX had approximately 30% lowersteady-state trough concentrations of golimumab than those who received golimumab with MTX. In alimited number of RA patients treated with subcutaneous golimumab over a 6-month period,concomitant use of MTX reduced the apparent clearance of golimumab by approximately 36%.

However, population pharmacokinetic analysis indicated that concomitant use of NSAIDs, oralcorticosteroids or sulfasalazine did not influence the apparent clearance of golimumab.

Following induction doses of 200 mg and 100 mg golimumab at week 0 and 2, respectively, andmaintenance doses of 50 mg or 100 mg golimumab subcutaneously every 4 weeks thereafter topatients with UC, serum golimumab concentrations reached steady state approximately 14 weeks afterthe start of therapy. Treatment with 50 mg or 100 mg golimumab subcutaneous every 4 weeks duringmaintenance resulted in a mean steady-state trough serum concentration of approximately0.9 ± 0.5 g/mL and 1.8 ± 1.1 g/mL, respectively.

In UC patients treated with 50 mg or 100 mg golimumab subcutaneously every 4 weeks, concomitantuse of immunomodulators did not have a substantial effect on steady-state trough levels ofgolimumab.

Patients who developed antibodies to golimumab generally had low trough steady-state serumconcentrations of golimumab (see section 5.1).

Golimumab exhibited approximately dose-proportional pharmacokinetics in patients with RA over thedose range of 0.1 to 10.0 mg/kg following a single intravenous dose. Following a single SC dose inhealthy subjects, approximately dose-proportional pharmacokinetics were also observed over a doserange of 50 mg to 400 mg.

Effect of weight on pharmacokinetics

There was a trend toward higher apparent clearance of golimumab with increasing weight(see section 4.2).

The pharmacokinetics of golimumab were determined in 173 children with pJIA with an age rangefrom 2 to 17 years of age. In the pJIA study, children who received golimumab 30 mg/m2 (maximum50 mg) subcutaneously every 4 weeks, had median steady-state trough golimumab concentrationswhich were similar across different age groups, and which were also similar to or slightly higher thanthose seen in adult RA patients who received 50 mg golimumab every 4 weeks.

Population pharmacokinetic/pharmacodynamic modelling and simulation in children with pJIAconfirmed the relationship between golimumab serum exposures and clinical efficacy and supportsthat the dosing regimen of golimumab 50 mg every 4 weeks in children with pJIA of at least 40 kgachieves similar exposures to those shown to be efficacious in adults.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, toxicity to reproduction and development.

No mutagenicity studies, animal fertility studies nor long-term carcinogenic studies have beenconducted with golimumab.

In a fertility and general reproductive function study in mouse, using an analogous antibody thatselectively inhibits the functional activity of mouse TNFα, the number of pregnant mice was reduced.

It is not known whether this finding was due to effects on the males and/or the females. In adevelopmental toxicity study conducted in mice following administration of the same analogousantibody, and in cynomolgus monkeys using golimumab, there was no indication of maternal toxicity,embryotoxicity or teratogenicity.

Histidine

Histidine hydrochloride monohydrate

Polysorbate 80

Water for injections.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

2 years

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the pre-filled pen or pre-filled syringe in the outer carton in order to protect it from light.

Simponi may be stored at temperatures up to a maximum of 25°C for a single period of up to 30 days,but not exceeding the original expiry date printed on the carton. The new expiry date must be writtenon the carton (up to 30 days from the date removed from the refrigerator).

Once Simponi has been stored at room temperature, it should not be returned to refrigerated storage.

Simponi must be discarded if not used within the 30 days of room temperature storage.

Simponi 50 mg solution for injection in pre-filled pen0.5 mL solution in a pre-filled syringe (Type 1 glass) with a fixed needle (stainless steel) and a needlecover (rubber containing latex) in a pre-filled pen. Simponi is available in packs containing 1 pre-filledpen and multipacks containing 3 (3 packs of 1) pre-filled pens.

Simponi 50 mg solution for injection in pre-filled syringe0.5 mL solution in a pre-filled syringe (Type 1 glass) with a fixed needle (stainless steel) and a needlecover (rubber containing latex). Simponi is available in packs containing 1 pre-filled syringe andmultipacks containing 3 (3 packs of 1) pre-filled syringes.

Not all pack sizes may be marketed.

Simponi is supplied in a single use pre-filled pen called SmartJect or as a single use pre-filled syringe.

Each pack is provided with instructions for use that fully describe the use of the pen or the syringe.

After removing the pre-filled pen or the pre-filled syringe from the refrigerator it should be allowed toreach room temperature by waiting for 30 minutes, before injecting Simponi. The pen or the syringeshould not be shaken.

The solution is clear to slightly opalescent, colourless to light yellow and may contain a few smalltranslucent or white particles of protein. This appearance is not unusual for solutions containingprotein. Simponi should not be used if the solution is discoloured, cloudy or containing visible foreignparticles.

Comprehensive instructions for the preparation and administration of Simponi in a pre-filled pen orthe pre-filled syringe are given in the package leaflet.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Janssen Biologics B.V.

Einsteinweg 1012333 CB Leiden

The Netherlands

EU/1/09/546/001 1 pre-filled pen

EU/1/09/546/002 3 pre-filled pens

EU/1/09/546/003 1 pre-filled syringe

EU/1/09/546/004 3 pre-filled syringes

Date of first authorisation: 1 October 2009

Date of latest renewal: 19 June 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.