Summary of medicine characteristics - SIMPONI 50 MG SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE
Simponi 50 mg solution for injection in pre-filled syringe.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One 0.5 mL pre-filled syringe contains 50 mg of golimumab.
Human IgG1K monoclonal antibody produced by a murine hybridoma cell line with recombinant DNA technology.
Excipient with known effect
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 syringe (injection)
The solution is clear to slightly opalescent, colourless to light yellow.
4.1 Therapeutic indications
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 to disease-modifying anti-rheumatic drug (DMARD) therapy including MTX has been inadequate.
the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with MTX.
Simponi, in combination with MTX, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function.
Juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritis (pJIA)
Simponi in combination with MTX is indicated for the treatment of polyarticular juvenile idiopathic arthritis in children 2 years of age and older, who have responded inadequately to previous therapy with MTX.
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 DMARD therapy has been inadequate. Simponi has been shown to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease (see section 5.1) and to improve physical function.
Axial spondyloarthritis
Ankylosing spondylitis (AS)
Simponi is indicated for the treatment of severe, active ankylosing spondylitis in adults who have responded inadequately to conventional therapy.
Non-radiographic axial spondyloarthritis (nr-Axial SpA)
Simponi is indicated for the treatment of adults with severe, active non-radiographic axial spondyloarthritis 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 antiinflammatory drugs (NSAIDs).
Ulcerative colitis (UC)
Simponi is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.
4.2 Posology and method of administration
Treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, or ulcerative colitis. Patients treated with Simponi should be given the Patient Reminder Card.
Posology
Rheumatoid arthritis
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 axia 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 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.
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 of 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, taking into account the increased risk of 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 of therapeutic benefit after receiving 3 to 4 additional doses of 100 mg.
Ulcerative colitis
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 an adequate response should receive 50 mg at week 6 and every 4 weeks thereafter. Patients who have an inadequate 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 every 4 weeks, thereafter (see section 5.1).
During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.
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 of therapeutic benefit within this time period.
Missed dose
If 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 the forgotten dose and stay on the original schedule.
if the dose is more than 2 weeks late, the patient should inject the forgotten dose and a new schedule should be established from the date of this injection.
Special populations
Elderly (> 65 years)
No dose adjustment is required in the elderly.
Renal and hepatic impairment
Simponi has not been studied in these patient populations. No dose recommendations can be made.
Paediatric population
The safety and efficacy of Simponi in patients aged less than 18 for indications other than pJIA have not been established.
Polyarticular juvenile idiopathic arthritis
Simponi 50 mg administered once a month, on the same date each month, for children with a body weight of at least 40 kg. A 45 mg/0.45 mL pre-filled pen is available for administration to children with 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 of therapeutic benefit within this time period.
Method of administration
Simponi is for subcutaneous use. After proper training in subcutaneous injection technique, patients may self-inject if their physician determines that this is appropriate, with medical follow-up as necessary. Patients should be instructed to inject the full amount of Simponi according to the comprehensive 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.
4.3 Contraindications
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).
4.4 Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Infections
Patients must be monitored closely for infections including tuberculosis before, during and after treatment 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 be given 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. Caution should be exercised when considering the use of golimumab 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 golimumab. 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 golimumab should be monitored closely and undergo a complete diagnostic evaluation. Administration of golimumab 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 golimumab treatment should be carefully considered before initiation of golimumab therapy. In at-risk patients treated with golimumab, an invasive fungal infection should be suspected if they develop a serious systemic illness. Diagnosis and administration of empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the care of patients with invasive fungal infections, if feasible.
Tuberculosis
There have been reports of tuberculosis in patients receiving golimumab. 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 golimumab, all patients must be evaluated for both active and inactive (‘latent’) tuberculosis. This evaluation 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 Reminder 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, 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 be consulted. In all situations described below, the benefit/risk balance of golimumab 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 golimumab, 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 golimumab. Use of anti-tuberculosis therapy should also be considered before the initiation of golimumab in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.
Cases of active tuberculosis have occurred in patients treated with golimumab during and after treatment for latent tuberculosis. Patients receiving golimumab should be monitored closely for signs and 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 for tuberculosis 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 golimumab treatment.
Hepatitis B virus reactivation
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 fatal outcome.
Patients should be tested for HBV infection before initiating treatment with golimumab. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.
Carriers of HBV who require treatment with golimumab 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, golimumab should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
Malignancies and lymphoproliferative disorders
The potential role of TNF-blocking therapy in the development of malignancies is not known. Based on 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 TNF-blocking therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy.
Paediatric malignancy
Malignancies, 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 leukaemia
In the controlled portions of clinical trials of all the TNF-blocking agents including golimumab, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with control patients. During the Simponi Phase IIb and Phase III clinical trials in RA, PsA and AS, the incidence of lymphoma in golimumab-treated patients was higher than expected in the general population. Cases of leukaemia have been reported in patients treated with golimumab. 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.
Rare post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with other TNF-blocking agents (see section 4.8). This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. The majority of cases have occurred in adolescent and young adult males with nearly all on concomitant treatment with azathioprine (AZA) or 6-mercaptopurine (6MP) 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 for hepatosplenic 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 similar between 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 (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations. In patients with newly diagnosed dysplasia treated with golimumab, the risks and benefits to the individual patient must be carefully reviewed and consideration should be given to whether therapy should be continued.
In an exploratory clinical trial evaluating the use of golimumab in patients with severe persistent asthma, more malignancies were reported in patients treated with golimumab compared with control patients (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 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 an increased risk of malignancy due to heavy smoking.
Skin cancers
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocking agents, 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 TNF blockers, 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 been observed. Golimumab has not been studied in patients with CHF. Golimumab should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored and golimumab must be discontinued in patients who develop new or worsening symptoms of heart failure (see section 4.3).
Neurological events
Use of TNF-blocking agents, including golimumab, has been associated with cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and peripheral demyelinating disorders. In patients with pre-existing or recent onset of demyelinating disorders, the benefits and risks of anti-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).
Surgery
There is limited safety experience of golimumab treatment in patients who have undergone surgical procedures, including arthroplasty. The long half-life should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on golimumab should be closely monitored for infections, and appropriate actions should be taken.
Immunosuppression
The possibility exists for TNF-blocking agents, including golimumab, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses.
Autoimmune processes
The relative deficiency of TNFa 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 golimumab and is positive for antibodies against double-stranded DNA, treatment with golimumab should be discontinued (see section 4.8).
Haematologic reactions
There have been reports of pancytopenia, leukopenia, neutropenia, agranulocytosis, aplastic anaemia, and thrombocytopenia in patients receiving TNF-blockers, including golimumab. 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 golimumab therapy 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 and another TNF-blocking agent, etanercept, with no added clinical benefit. Because of the nature of the adverse events seen with this combination therapy, similar toxicities may also result from the combination of anakinra and other TNF-blocking agents. The combination of golimumab and anakinra is not recommended.
Concurrent administration of TNF-antagonists and abatacept
In 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 golimumab and abatacept is not recommended.
Concurrent administration with other biological therapeutics
There is insufficient information regarding the concomitant use of golimumab with other biological therapeutics used to treat the same conditions as golimumab. The concomitant use of golimumab with these biologics is not recommended because of the possibility of an increased risk of infection, and other potential pharmacological interactions.
Switching between biological DMARDs
Care should be taken and patients should continue to be monitored when switching from one biologic to 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 (see sections 4.5 and 4.6). In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections.
Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g. BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with golimumab.
Allergic reactions
In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following golimumab administration. Some of these reactions occurred after the first administration of golimumab. If an anaphylactic reaction or other serious allergic reactions occur, administration of golimumab should be discontinued immediately and appropriate therapy initiated.
Latex sensitivity
The needle cover on the pre-filled syringe is manufactured from dry natural rubber containing latex, and may cause allergic reactions in individuals sensitive to latex.
Special populations
Elderly (> 65 years)
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 received golimumab 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. There were no patients age 45 and over in the nr-Axial SpA study.
Renal and hepatic impairment
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
Vaccinations
If possible, it is recommended that prior to initiating golimumab therapy, paediatric patients be brought up to date with all immunisations in agreement with current immunisation guidelines (see Vaccinations/therapeutic infectious agents above).
Excipients
Simponi contains sorbitol (E420). In patients with rare hereditary problems of fructose intolerance, the additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake 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 important that the right strength is used to administer the correct dose as indicated in the posology (see section 4.2). Care should be taken to provide the right strength to ensure that patients are not underdosed or overdosed.
4.5 Interaction with other medicinal products and other forms of interaction
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 as golimumab, including anakinra and abatacept is not recommended (see section 4.4).
Live vaccines/therapeutic infectious agents
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).
Methotrexate
Although concomitant use of MTX results in higher steady-state trough concentrations of golimumab in patients with RA, PsA or AS, the data do not suggest the need for dose adjustment of either golimumab or MTX (see section 5.2).
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential must use adequate contraception to prevent pregnancy and continue its use for at least 6 months after the last golimumab treatment.
Pregnancy
There are no adequate data on the use of golimumab in pregnant women. Due to its inhibition of TNF, golimumab administered during pregnancy could affect normal immune responses in the newborn. Studies in animals do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The use of golimumab in pregnant women is not recommended; golimumab should be given to a pregnant woman only if clearly needed.
Golimumab crosses the placenta. Following treatment with a TNF-blocking monoclonal antibody during pregnancy, the antibody has been detected for up to 6 months in the serum of the infant born by the treated woman. Consequently, these infants may be at increased risk of infection. Administration of live vaccines to infants exposed to golimumab in utero is not recommended for 6 months following the mother’s last golimumab injection during pregnancy (see sections 4.4 and 4.5).
Breast-feeding
It is not known whether golimumab is excreted in human milk or absorbed systemically after ingestion. Golimumab was shown to pass over to breast milk in monkeys, and because human immunoglobulins are excreted in milk, women must not breast feed during and for at least 6 months after golimumab treatment.
Fertility
No animal fertility studies have been conducted with golimumab. A fertility study in mice, using an analogous antibody that selectively inhibits the functional activity of mouse TNFa, showed no relevant effects on fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
Simponi has minor influence on the ability to drive and use machines. Dizziness may however occur following administration of Simponi (see section 4.8).
4.8 Undesirable effects
Summary of the safety profile
In the controlled period of the pivotal trials in RA, PsA, AS, nr-Axial SpA, and UC, upper respiratory tract infection was the most common adverse reaction (AR) reported in 12.6% of golimumab-treated patients compared with 11.0% of control patients. The most serious ARs that have been reported for golimumab include serious infections (including sepsis, pneumonia, TB, invasive fungal and opportunistic infections), demyelinating disorders, HBV reactivation, CHF, autoimmune processes (lupus-like syndrome), haematologic reactions, serious systemic hypersensitivity (including anaphylactic reaction), vasculitis, lymphoma and leukaemia (see section 4.4).
Tabulated list of adverse reactions
ARs observed in clinical studies and reported from world-wide post-marketing use of golimumab are listed in Table 1. Within the designated system organ classes, the ARs 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1
Tabulated list of ARs
Infections and infestations
Very common: Upper respiratory tract infection (nasopharyngitis, pharyngitis, laryngitis and rhinitis)
Common: Bacterial infections (such as cellulitis), lower respiratory tract infection (such as pneumonia), viral infections (such as influenza and herpes), bronchitis, sinusitis, superficial fungal infections, abscess Uncommon: Sepsis including septic shock, pyelonephritis
Rare: Tuberculosis, opportunistic infections (such as invasive fungal infections [histoplasmosis, coccidioidomycosis, pneumocytosis], bacterial, atypical mycobacterial infection and protozoal), hepatitis B reactivation, _______________________________bacterial arthritis, infective bursitis_______________________ Neoplasms, benign, malignant and unspecified
Uncommon: Neoplasms (such as skin cancer, squamous cell carcinoma and melanocytic naevus)
Rare: Lymphoma, leukaemia, melanoma, Merkel cell carcinoma
____________Not known: Hepatosplenic T-cell lymphoma*, Kaposi’s sarcoma Blood and lymphatic system disorders
Common: Leukopenia (including neutropenia), anaemia Uncommon: Thrombocytopenia, pancytopenia
___________________Rare: Aplastic anaemia, agranulocytosis____________________ Immune system disorders
Common: Allergic reactions (bronchospasm, hypersensitivity, urticaria), autoantibody positive
Rare: Serious systemic hypersensitivity reactions (including anaphylactic reaction), vasculitis (systemic), ____________________________sarcoidosis____________________________________________ Endocrine disorders
Uncommon: Thyroid disorder (such as hypothyroidism, ___________________________hyperthyroidism and goitre)__________________________ Metabolism and nutrition disorders
Uncommon: Blood glucose increased, lipids increased
Psychiatric disorders
______________Common: Depression, insomnia_____________________________ Nervous system
disorders
Common: Dizziness, headache, paraesthesia
Uncommon: Balance disorders
Rare: Demyelinating disorders (central and peripheral), _________________________dysgeusia_________________________________________ Eye disorders
Uncommon: Visual disorders (such as blurred vision and decreased visual acuity), conjunctivitis, eye allergy (such as _______________________________pruritis and irritation)_____________________________________ Cardiac disorders
Uncommon: Arrhythmia, ischemic coronary artery disorders ___________________Rare: Congestive heart failure (new onset or worsening) Vascular disorders
Common: Hypertension
Uncommon: Thrombosis (such as deep venous and aortic), flushing _________________Rare: Raynaud’s phenomenon__________________________ Respiratory, thoracic and
mediastinal disorders______________________________________________________________
Common: Asthma and related symptoms (such as wheezing and bronchial hyperactivity)
_____________Uncommon: Interstitial lung disease______________________________ Gastrointestinal disorders
Common: Dyspepsia, gastrointestinal and abdominal pain, nausea, gastrointestinal inflammatory disorders (such as gastritis and colitis), stomatitis
____________Uncommon: Constipation, gastro-oesophageal reflux disease_______ Hepatobiliary disorders
Common: Alanine aminotransferase increased, aspartate aminotransferase increased
_____________Uncommon: Cholelithiasis, hepatic disorders______________________ Skin and subcutaneous
tissue disorders
Common: Pruritus, rash, alopecia, dermatitis
Uncommon: Bullous skin reactions, psoriasis (new onset or worsening of pre-existing psoriasis, palmar/plantar and pustular), urticaria
Rare: Lichenoid reactions, skin exfoliation, vasculitis (cutaneous)
____________Not known: Worsening of symptoms of dermatomyositis_________ Musculoskeletal and
connective tissue disorders
__________________Rare: Lupus-like syndrome_______________________________ Renal and urinary
disorders
Rare: Bladder disorders, renal disorders
Reproductive system and breast disorders
____________Uncommon: Breast disorders, menstrual disorders_____________
General disorders and administration site conditions
Common: Pyrexia, asthenia, injection site reaction (such as injection site erythema, urticaria, induration, pain, bruising, pruritus, irritation and paraesthesia), chest discomfort
___________________Rare: Impaired healing_________________________________
Injury, poisoning and procedural complications ______________Common: Bone fractures________________________________
* Observed with other TNF-blocking agents.
Throughout this section, median duration of follow-up (approximately 4 years) is generally presented for all golimumab use. Where golimumab use is described by dose, the median duration of follow-up varies (approximately 2 years for 50 mg dose, approximately 3 years for 100 mg dose) as patients may have switched between doses.
Description of selected adverse reactions
Infections
In the controlled period of pivotal trials, upper respiratory tract infection was the most common adverse 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 median follow-up of approximately 4 years, the incidence per 100 subject-years of upper respiratory tract infections 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-treated patients (incidence per 100 subject-years: 132.0; 95% CI: 123.3, 141.1) compared with 20.2% of control patients (incidence per 100 subject-years: 122.3; 95% CI: 109.5, 136.2). In controlled and uncontrolled portions of the trials with a median follow-up of approximately 4 years, the incidence per
100 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 in 1.2% of golimumab-treated patients and 1.2% of control-treated patients. The incidence of serious infections 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 the golimumab 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-treated patients compared with 1.5% of control-treated patients. Serious infections observed in golimumab-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 to 3 years, there was a greater incidence of serious infections, including opportunistic infections and TB in patients receiving golimumab 100 mg compared with patients receiving golimumab 50 mg. The incidence per 100 subject-years of all serious infections was 4.1; 95% CI: 3.6, 4.5, in patients receiving golimumab 100 mg and 2.5; 95% CI: 2.0, 3.1, in patients receiving golimumab 50 mg.
Malignancies
Lymphoma
The incidence of lymphoma in golimumab-treated patients during the pivotal trials was higher than expected in the general population. In the controlled and uncontrolled portions of these trials with a median follow-up of up to 3 years, a greater incidence of lymphoma was observed in patients receiving golimumab 100 mg compared with patients receiving golimumab 50 mg. Lymphoma was diagnosed in 11 subjects (1 in the golimumab 50 mg treatment groups and 10 in the golimumab 100 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, which enrolled patients previously exposed to anti-TNF agents who had longer disease duration and more refractory disease (see section 4.4).
Malignancies other than lymphoma
In the controlled periods of pivotal trials and through approximately 4 years of follow-up, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar between the golimumab and the control groups. Through approximately 4 years of follow-up, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar to the general population.
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 31 golimumab 100 mg-treated subjects with an incidence (95% CI) per 100 subject-years of follow-up of 0.36 (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 5 placebo-treated, 21 golimumab 50 mg-treated and 34 golimumab 100 mg-treated subjects with an incidence (95% CI) per 100 subject-years of follow-up of 0.48 (0.36, 0.62) for combined golimumab and 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 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) were reported. 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.
Neurological events
In the controlled and uncontrolled periods of the pivotal trials with a median follow-up of up to 3 years, a greater incidence of demyelination was observed in patients receiving golimumab 100 mg compared 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 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 and nr-Axial SpA studies, more golimumab-treated patients (26.9%) than control patients (10.6%) had mild ALT elevations. In the controlled and uncontrolled periods of the RA and PsA pivotal trials, with a median follow-up of approximately 5 years, the incidence of mild ALT elevations was similar in golimumab-treated and control patients in RA and PsA studies. In the controlled period of the UC pivotal trials of golimumab induction, mild ALT elevations (> 1 and < 3 x ULN) occurred in similar proportions of golimumab-treated and control patients (8.0% to 6.9%, respectively). In controlled and uncontrolled periods of the UC pivotal trials with a median followup of approximately 2 years, the proportion of patients with mild ALT elevations was 24.7% in patients receiving golimumab during the maintenance portion of the UC study.
In the controlled period of RA and AS pivotal trials, ALT elevations > 5 x ULN were uncommon and seen in more golimumab-treated patients (0.4% to 0.9%) than control patients (0.0%). This trend was not observed in the PsA population. In the controlled and uncontrolled periods of RA, PsA and AS pivotal trials, with a median follow-up of 5 years, the incidence of ALT elevations > 5 x ULN was similar in both golimumab-treated and control patients. In general these elevations were asymptomatic and the abnormalities decreased or resolved with either continuation or discontinuation of golimumab or modification of concomitant medicinal products. No cases were reported in the controlled and uncontrolled 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 of golimumab-treated patients compared to placebo-treated patients (0.3% to 1.0%, respectively). In the controlled and uncontrolled periods of the pivotal UC trials with a median follow-up of approximately 2 years, the proportion of patients with ALT elevations > 5 x ULN was 0.8% in patients receiving golimumab 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-existing liver abnormalities and confounding medicinal products 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 the controlled periods of pivotal trials, 5.4% of golimumab-treated patients had injection site reactions compared with 2.0% 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 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 followup, 3.5% of golimumab-treated patients and 2.3% of control patients were newly ANA-positive (at titres 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 1.1%.
Paediatric population
Polyarticular juvenile idiopathic arthritis
The safety of golimumab has been studied in a phase III study of 173 pJIA patients from 2 to 17 years of age. The average follow-up was approximately two years. In this study, the type and frequency of adverse events reported were generally similar to those seen in adult RA studies.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
Absorption
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. A subcutaneous injection of 50 mg golimumab to healthy subjects produced a mean ± standard deviation maximum serum concentration (Cmax) of 3.1 ± 1.4 Ug/mL
Following a single subcutaneous injection of 100 mg, the absorption of golimumab was similar in the upper arm, abdomen, and thigh, with a mean absolute bioavailability of 51%. Since golimumab exhibited approximately dose proportional PK following a subcutaneous administration, the absolute bioavailability of a golimumab 50 mg or 200 mg dose is expected to be similar.
Distribution
Following a single IV administration, the mean volume of distribution was 115 ± 19 mL/kg.
Elimination
The systemic clearance of golimumab was estimated to be 6.9 ± 2.0 mL/day/kg. Terminal half-life value was estimated to be approximately 12 ± 3 days in healthy subjects and similar values were observed in patients with RA, PsA, AS, or UC.
When 50 mg golimumab was administered subcutaneously to patients with RA, PsA or AS every 4 weeks, serum concentrations reached steady state by week 12. With concomitant use of MTX, treatment with 50 mg golimumab subcutaneously every 4 weeks resulted in a mean (± standard deviation) steady-state trough serum concentration of approximately 0.6 ± 0.4 ^g/mL in RA patients with active RA despite MTX therapy, and approximately 0.5 ± 0.4 ^g/mL in patients with active PsA and approximately 0.8 ± 0.4 ^g/mL in patients with AS. Steady-state trough mean serum golimumab concentrations in patients with nr-Axial SpA were similar to those observed in patients with AS following subcutaneous administration of 50 mg golimumab every 4 weeks.
Patients with RA, PsA or AS who did not receive concomitant MTX had approximately 30% lower steady-state trough concentrations of golimumab than those who received golimumab with MTX. In a limited 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, oral corticosteroids 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, and maintenance doses of 50 mg or 100 mg golimumab subcutaneously every 4 weeks thereafter to patients with UC, serum golimumab concentrations reached steady state approximately 14 weeks after the start of therapy. Treatment with 50 mg or 100 mg golimumab subcutaneous every 4 weeks during maintenance resulted in a mean steady-state trough serum concentration of approximately 0.9 ± 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, concomitant use of immunomodulators did not have a substantial effect on steady-state trough levels of golimumab.
Patients who developed anti-golimumab antibodies generally had low trough steady-state serum concentrations of golimumab (see section 5.1).
Linearity
Golimumab exhibited approximately dose-proportional pharmacokinetics in patients with RA over the dose range of 0.1 to 10.0 mg/kg following a single intravenous dose. Following a single SC dose in healthy subjects, approximately doseproportional pharmacokinetics were also observed over a dose range 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).
Paediatric population
The pharmacokinetics of golimumab were determined in 173 children with pJIA with an age range from 2 to 17 years of age. In the pJIA study, children who received golimumab 30 mg/m2 (maximum 50 mg) subcutaneously every 4 weeks, had median steady-state trough golimumab concentrations which were similar across different age groups, and which were also similar to or slightly higher than those seen in adult RA patients who received 50 mg golimumab every 4 weeks.
Population pharmacokinetic/pharmacodynamic modelling and simulation in children with pJIA confirmed the relationship between golimumab serum exposures and clinical efficacy and supports that the dosing regimen of golimumab 50 mg every 4 weeks in children with pJIA of at least 40 kg achieves similar exposures to those shown to be efficacious in adults.
5.3 Preclinical safety data
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sorbitol (E420)
Histidine
Histidine hydrochloride monohydrate
Polysorbate 80
Water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
24 months
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the 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 written on 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.
6.5 Nature and contents of container
0.5 mL solution in a pre-filled syringe (Type 1 glass) with a fixed needle (stainless steel) and a needle cover (rubber containing latex). Simponi is available in packs containing 1 pre-filled syringe and multipacks containing 3 (3 packs of 1) pre-filled syringes.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalSimponi is supplied in a single use as a single use pre-filled syringe. Each pack is provided with instructions for use that fully describe the use of the syringe. After removing the pre-filled syringe from the refrigerator it should be allowed to reach room temperature by waiting for 30 minutes, before injecting Simponi. The syringe should not be shaken.
The solution is clear to slightly opalescent, colourless to light yellow and may contain a few small translucent or white particles of protein. This appearance is not unusual for solutions containing protein. Simponi should not be used if the solution is discoloured, cloudy or containing visible foreign particles.
Comprehensive instructions for the preparation and administration of Simponi in a pre-filled syringe are given in the package leaflet.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Janssen Biologics B.V.
Einsteinweg 101
2333 CB Leiden
The Netherlands
8 MARKETING AUTHORISATION NUMBER(S)
PLGB 08563/0029
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
01/01/2021