Special Warning : אזהרת שימוש

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 (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 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 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 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 Auto-Injector pen/ pre-filled syringe is manufactured from dry natural rubber containing latex, and may cause allergic reactions in individuals sensitive to latex.

Special populations

Eldery (≥ 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).
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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.

Effects on Driving

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).