Drug Description
One 0.5 ml prefilled pen or pre-filled syringe contains 50 mg of golimumab*.* Human IgG1? monoclonal antibody produced by a murine hybridoma cell line with recombinant DNA technology.Excipient: Each pre-filled pen or pre-filled syringe contains 20.5 mg sorbitol per 50mg dose.

Presentation
Solution for injection in prefilled pen (injection), SmartJect Solution for injection in prefilled syringe (injection)The solution is clear to slightly opalescent, colourless to light yellow.

Indications
Rheumatoid arthritis (RA)Simponi, in combination with methotrexate (MTX), is indicated for the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to diseasemodifying antirheumatic drug (DMARD) therapy including MTX has been inadequate.Simponi has also been shown to improve physical function in this patient population.Psoriatic arthritis (PsA)Simponi, alone or in combination with MTX, is indicated for the treatment of active and progressive psoriatic arthritis in adult patients when the response to previous diseasemodifying antirheumatic drug (DMARD) therapy has been inadequate. Simponi has also been shown to improve physical function in this patient population.Ankylosing spondylitis (AS)Simponi is indicated for the treatment of severe, active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy.

Adult Dosage
Simponi treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. Patients treated with Simponi should be given the Patient Alert Card.Simponi should be injected subcutaneously. After proper training in subcutaneous injection technique, patients may selfinject with Simponi if their physician determines that this is appropriate, with medical followup as necessary. Patients should be instructed to inject the full amount of Simponi according to the comprehensive instructions for administration provided in the package leaflet.Rheumatoid arthritisSimponi 50 mg given once a month, on the same date each month.Simponi should be given concomitantly with MTX.Psoriatic arthritisSimponi 50 mg given once a month, on the same date each month.Ankylosing spondylitisSimponi 50 mg given once a month, on the same date each month.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 patients who show no evidence of therapeutic benefit within this time period.In patients weighing more than 100 kg who do not achieve an adequate clinical response after 3 or 4 doses, increasing the dose of golimumab to 100 mg once a month may be considered. Continued therapy should be reconsidered in patients who show no evidence of therapeutic benefit after receiving 3 to 4 additional doses of 100 mg.Elderly patients ( 65 years)No dose adjustment is required in the elderly.Paediatric patients (< 18 years)Simponi is not recommended for use in children and adolescents below age 18 due to a lack of data on efficacy and safety.Renal and hepatic insufficiencySimponi has not been studied in these patient populations. No dose recommendations can be made.Missed doseIf a patient forgets to inject Simponi on the planned date, the forgotten dose should be injected as soon as the patient remembers. Patients should be instructed not to inject a double dose to make up for the forgotten 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 his/her forgotten dose and stay on his/her original monthly schedule.• if the dose is more than 2 weeks late, the patient should inject his/her forgotten dose and a new once-monthly schedule should be established from the date of this injection.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.Active tuberculosis (TB) or other severe infections such as sepsis, and opportunistic infections.Moderate or severe heart failure (NYHA class III/IV).

Special Precautions
InfectionsPatients must be monitored closely for infections including tuberculosis before, during and after treatment with Simponi. Because the elimination of golimumab may take up to 5 months, monitoring should be continued throughout this period. Further treatment with Simponi must not be given if a patient develops a serious infection or sepsis.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.Patients taking TNF-blockers are more susceptible to serious infections.Bacterial (including sepsis and pneumonia), mycobacterial (including TB), invasive fungal and opportunistic infections, including fatalities, have been reported in patients receiving 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. Patients who develop a new infection while undergoing treatment with Simponi, should be monitored closely and undergo a complete diagnostic eva luation. Administration of Simponi should be discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled. 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.TuberculosisThere have been reports of tuberculosis in patients receiving Simponi. It should be noted that in the majority of these reports, tuberculosis was extrapulmonary presenting as either local or disseminated disease.Before starting treatment with Simponi, all patients must be eva luated for both active and inactive ('latent') tuberculosis. This eva luation should include a detailed medical history with personal history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive 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 that the conduct of these tests should be recorded in the patient's alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.If active tuberculosis is diagnosed, Simponi therapy must not be initiated.If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted. In all situations described below, the benefit/risk balance of Simponi therapy should be very carefully considered.If inactive ('latent') tuberculosis is diagnosed, treatment for latent tuberculosis must be started with anti-tuberculosis therapy before the initiation of Simponi, and in accordance with local recommendations.In patients who have several or significant risk factors for tuberculosis and have a negative test for latent tuberculosis, anti-tuberculosis therapy should be considered before the initiation of Simponi. Use of anti-tuberculosis therapy should also be considered before the initiation of Simponi in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.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 Simponi treatment.Hepatitis B virus reactivationReactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including Simponi, who are chronic carriers of this virus (i.e., surface antigen positive). Some cases have had fatal outcome. Patients at risk for HBV infection should be eva luated for prior evidence of HBV infection before initiating Simponi therapy. Carriers of HBV who require treatment with Simponi should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, Simponi should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.Malignancies and lymphoproliferative disordersThe potential role of TNFblocking therapy in the development of malignancies is not known. With the current knowledge, a possible risk for the development of lymphomas, leukaemia or other malignancies in patients treated with a TNF-antagonist cannot be excluded. Caution should be exercised when considering TNFblocking therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy.Paediatric malignancyMalignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-blocking agents (initiation of therapy 18 years of age) in the post marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-blockers cannot be excluded.Lymphoma and leukaemiaIn the controlled portions of clinical trials of all the TNFblocking agents including Simponi, more cases of lymphoma have been observed among patients receiving antiTNF treatment compared with control patients. During the Simponi Phase IIb and Phase III clinical trials, the incidence of lymphoma in Simponitreated patients was higher than expected in the general population. In the post-marketing setting, cases of leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk estimation.Malignancies other than lymphomaIn the controlled portions of the Simponi Phase IIb and Phase III clinical trials in RA, PsA, and AS, the incidence of nonlymphoma malignancies (excluding nonmelanoma skin cancer) was similar between the Simponi and the control groups.In an exploratory clinical trial eva luating the use of Simponi in patients with severe persistent asthma, more malignancies were reported in patients treated with Simponi compared with control patients. The significance of this finding is unknown.In an exploratory clinical trial eva luating the use of another anti-TNF agent, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the 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 increased risk for malignancy due to heavy smoking.Congestive heart failure (CHF)In a clinical trial with another TNF-antagonist worsening congestive heart failure and increased mortality due to CHF have been observed. Simponi has not been studied in patients with CHF. Simponi should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored and Simponi must be discontinued in patients who develop new or worsening symptoms of heart failure.Neurological eventsUse of TNF-blocking agents, including Simponi, has been associated in rare cases with new-onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis. In patients with preexisting or recent onset of demyelinating disorders, the benefits and risks of antiTNF treatment should be carefully considered before initiation of Simponi therapy.SurgeryThere is limited safety experience of Simponi treatment in patients who have undergone surgical procedures, including artheroplasty. The long half-life should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Simponi should be closely monitored for infections, and appropriate actions should be taken.ImmunosuppressionThe possibility exists for TNF-blocking agents, including Simponi, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses.Autoimmune processes The relative deficiency of TNFα caused by anti-TNF therapy may result in the initiation of an autoimmune process. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Simponi and is positive for antibodies against double-stranded DNA, treatment with Simponi should be discontinued.Haematologic reactions There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. Cytopenias including pancytopenia, have been infrequently reported with Simponi in clinical trials. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor). Discontinuation of Simponi therapy should be considered in patients with confirmed significant haematologic abnormalities.Concurrent administration of TNF-antagonists and anakinraSerious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFblocking 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 other TNF-blocking agents. The combination of Simponi and anakinra is not recommended.Concurrent administration of TNF-antagonists and abataceptIn clinical studies concurrent administration of TNF-antagonists and abatacept has been associated with an increased risk of infections including serious infections compared to TNF-antagonists alone, without increased clinical benefit. The combination of Simponi and abatacept is not recommended.Switching between biological DMARDsWhen switching from one biologic to another, patients should be monitored for signs of infection.VaccinationsPatients treated with Simponi may receive concurrent vaccinations, except for live vaccines. No data are available on the response to vaccination, risk of infection or transmission of infection with the administration of live vaccines to patients receiving Simponi.Allergic reactionsSerious allergic adverse reactions have not been reported with subcutaneous administration of Simponi during clinical trials. Non-serious allergic reactions associated with Simponi occurred in clinical trials, and included urticaria, bronchospasm and hypersensitivity. If an anaphylactic reaction or other serious allergic reactions occurs, administration of Simponi should be discontinued immediately and appropriate therapy initiated.Latex sensitivityThe needle cover on the syringe in the prefilled pen is manufactured from dry natural rubber containing latex, and may cause allergic reactions in individuals sensitive to latex.Special populations Elderly patients ( 65 years)In the Phase III studies in RA, PsA, and AS, no overall differences in Adverse events (AEs), Serious Adverse Events (SAEs) , and serious infections in patients age 65 or older (N=155) who received Simponi were observed compared with younger patients. However, caution should be exercised when treating the elderly and particular attention paid with respect to occurrence of infections.Renal and hepatic insufficiency Specific studies of Simponi have not been conducted in patients with renal or hepatic impairment. Simponi should be used with caution in subjects with impaired hepatic function.ExcipientsSimponi contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take Simponi.

Interactions
No interaction studies have been performed.Concurrent use with anakinra and abatacept The combination of Simponi and anakinra or abatacept is not recommended.Live vaccinesLive vaccines should not be given concurrently with Simponi.MethotrexateAlthough concomitant use of MTX results in higher steadystate trough concentrations of Simponi in patients with RA, PsA or AS, the data do not suggest the need for dose adjustment of either Simponi or MTX.

Adverse Reactions
Safety data from Phase IIb and Phase III clinical trials are available from 2578 golimumabtreated patients including 1600 with RA, 394 with PsA, 353 with AS, 231 with severe persistent asthma and 751 patients receiving placebo or active comparator.Adverse drug reactions (ADRs) observed in clinical studies with golimumab are summarised in Table 1. Within the designated system organ classes, the adverse drug reactions are listed under headings of frequency 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.Table 1Summary of ADRs in clinical studiesInfections and infestationsVery common:Upper respiratory tract infection (nasopharyngitis, pharyngitis, laryngitis and rhinitis)Common:Bacterial infections (such as cellulitis), viral infections (such as influenza and herpes), bronchitis, sinusitis, superficial fungal infections,Uncommon:Septic shock, sepsis, tuberculosis, lower respiratory tract infection (such as pneumonia), opportunistic infections (such as invasive fungal infections [histoplasmosis, coccidioidomycosis, pneumocytosis], bacterial, atypical mycobacterial infection and protozoal), pyelonephritis, abscess, arthritis bacterial, bursitis infectiveRare:Hepatitis B reactivationNeoplasms, benign, malignant and unspecifiedUncommon:Neoplasms (such as skin cancer, squamous cell carcinoma and melanocytic naevus)Rare:LymphomaNot known:leukaemia*Blood and lymphatic system disordersCommon:AnemiaUncommon:Leukopenia, thrombocytopenia,Rare:PancytopeniaNot known:Aplastic anemia*Immune system disordersCommon:Allergic reactions (bronchospasm, hypersensitivity, urticaria), autoantibody positiveEndocrine disordersUncommon:Thyroid disorder (such as hypothyroidism, hyperthyroidism and goiter)Metabolism and nutrition disordersUncommon:Blood glucose increased, lipids increasedPsychiatric disordersCommon:Depression, insomniaNervous system disordersCommon:Dizziness, paresthesia, headacheUncommon:Demyelinating disorders, balance disorders, dysguesiaEye disordersUncommon:Visual disorders (such as blurred vision and decreased vision acuity), conjunctivitis, eye allergy (such as pruritis and irritation)Cardiac disordersUncommon:Congestive heart failure (new onset or worsening), arrhythmia, ischemic coronary artery disordersVascular disordersCommon:HypertensionUncommon:Thrombosis (such as deep venous and aortic), Raynaud's phenomenon, flushingRespiratory, thoracic and mediastinal disordersUncommon:Asthma and related symptoms (such as wheezing and bronchial hyperactivity)Rare:Interstitial lung diseaseGastrointestinal disordersCommon:Constipation, dyspepsia, gastrointestinal and abdominal painUncommon:Gastrointestinal inflammatory disorders (such as gastritis and colitis), gastrooesophageal reflux disease, stomatitisHepatobiliary disordersCommon:Alanine aminotransferase increased, aspartate aminotransferase increasedUncommon:Cholelithiasis, hepatic disordersSkin and subcutaneous tissue disordersCommon:Alopecia, dermatitis, pruritus, rashUncommon:Psoriasis (new onset or worsening of pre-existing psoriasis , palmar/plantar and pustular), urticariaMusculoskeletal and connective tissue disordersRare:Lupus-like syndromeRenal and urinary disordersUncommon:Bladder disordersRare:Renal disordersReproductive system and breast disordersUncommon:Breast disorders, menstrual disordersGeneral disorders and administration site conditionsCommon:Pyrexia, asthenia, injection site reaction (such as injection site erythema, urticaria, induration, pain, bruising, pruritus, irritation and paraesthesia), impaired healing, chest discomfortInjury, poisoning and procedural complicationsUncommon:Bone fractures*: Observed with other TNFblocking agents, but not observed in clinical studies with golimumab.Infections Upper respiratory tract infection was the most common adverse reaction reported in the combined Phase III RA, PsA, and AS studies through Week 16, occurring in 7.2% of golimumab-treated patients (incidence per patient-year: 0.26; 95% CI: 0.22, 0.31) as 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 golimumab-treated patients and 0.25 events (0.20, 0.31) for control patients.In controlled Phase III trials through Week 16 in RA, PsA, and AS, infections were observed in 28.3% of golimumab-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 golimumab-treated patients and 1.31 events (1.18, 1.44) for control patients.In controlled Phase III trials through week 16 in RA, PsA, and AS, serious infections were observed in 1.4% of golimumabtreated 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 golimumabtreated patients included tuberculosis, bacterial infections including sepsis and pneumonia, invasive fungal infections and other opportunistic infections. Some of these infections have been fatal. 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 golimumab-treated patients and 0.06 events (0.04, 0.09) for control patients.MalignanciesLymphomaThe incidence of lymphoma in Simponi treated patients with RA, PsA and AS during the controlled portions of phase IIb and III clinical trials and through 1 year of follow up was higher than expected in the general population. Lymphoma was diagnosed in 2 subjects (both in golimumab 100 mg treatment groups) with an incidence (95%, CI) per 100 subject-years of follow up of 0.10 (0.01, 0.37) events for golimumab and 0.00 (0.00, 0.90) events for placebo.Malignancies other than lymphomaIn the controlled portions of the Simponi Phase IIb and Phase III clinical trials in RA, PsA, and AS, and through 1 year of follow up, the incidence of nonlymphoma malignancies (excluding nonmelanoma skin cancer) was similar between the Simponi and the control groups.Through 1 year of follow up,of the Phase IIb and Phase III studies in rheumatologic indications, nonmelanoma skin cancer was diagnosed in 19 subjects (5 in placebo, 6 in golimumab 50 mg and 8 in golimumab 100 mg treatment groups) with an incidence (95% CI) per 100 subject-years of follow up of 0.72 (0.39, 1.20) events for golimumab and 1.51 (0.49, 3.52) events for placebo.Through 1 year of follow up, of the Phase IIb and Phase III studies in rheumatologic indications, malignancies besides nonmelanoma skin cancer and lymphoma were diagnosed in 12 subjects (2 in placebo, 6 in golimumab 50 mg and 4 in golimumab 100 mg treatment groups) with an incidence (95%CI) per 100 subject-years of follow up of 0.51 (0.24, 0.94) events for golimumab and 0.60 (0.07, 2.17) events for placebo.Cases reported in clinical studies in asthmaIn an exploratory clinical study, patients with severe persistent asthma received a golimumab loading dose (150% of the assigned treatment dose) subcutaneously at Week 0 followed by golimumab 200 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 placebo treatment group (n=79). Lymphoma was reported in 1 patient, non-melanoma skin cancer in 2 patients, and other malignancies in 5 patients. There was no specific clustering of any type of malignancy.During the placebo-controlled portion of the study, the incidence (95% CI) of all malignancies per 100 subject-years of follow-up was 3.19 (1.38, 6.28) in the golimumab group. In this study, the incidence (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, 4.63) for other malignancies. For placebo subjects, the incidence (95% CI) per 100 subject-years of follow-up of these malignancies was 0.00 (0.00, 2.94). The significance of this finding is unknown.Liver enzyme elevations In controlled Phase III trials through week 16, mild ALT elevations (> 1 and < 3 x upper limit of 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 study, more golimumabtreated 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 golimumab-treated and control patients in RA and PsA studies. In the AS population, the incidence of mild ALT elevations was higher in golimumab-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 golimumabtreated patients (0.4% to 0.9%) than control patients (0.0%). 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 golimumab-treated and control patients in the Phase III RA, PsA and AS studies. In general these elevations were asymptomatic and the abnormalities decreased or resolved with either continuation or discontinuation of golimumab or modification of concomitant medications.Within the Phase II and Phase III programme in RA, PsA and AS, one patient with pre-existing liver abnormalities and confounding medication treated with golimumab developed non-infectious fatal hepatitis with jaundice. The role of golimumab as a contributing or aggravation factor cannot be excluded.Injection site reactions In controlled Phase III trials through week 16 in RA, PsA and AS, 5.8% of golimumabtreated patients had injection site reactions compared with 2.2% in control patients. The presence of antibodies to golimumab may increase the risk of injection site reactions. The majority of the injection site reactions were mild and moderate and the most frequent manifestation was injection site erythema. Injection site reactions generally did not necessisate discontinuation of the medicinal product.In controlled phase IIb and III trials in RA, PsA, AS and severe persistent asthma, no patients treated with golimumab developed anaphylactic reactions.Autoimmune antibodiesIn Phase III trials in RA, PsA, and AS through 1 year of follow up, 4.0% of golimumab-treated patients and 2.6% of control patients were newly ANA-positive (at titers of 1:160 or greater). The frequency of anti-dsDNA antibodies at 1 year of follow up in patients anti-dsDNA negative at baseline was uncommon.

Manufacturer
Schering-Plough Ltd

Drug Availability
POM-Prescription Only Medicine

Updated
28 September 2010