Safety profile

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

Patients should be evaluated for infections before, during, and after treatment with Benepali™, taking into consideration that the mean elimination half-life of etanercept is approximately 70 hours (range 7–300 hours). 

Serious infections, sepsis, tuberculosis, and opportunistic infections, including invasive fungal infections, listeriosis and legionellosis, have been reported with the use of etanercept (see Section 4.8 of the Summary of Product Characteristics). These infections were due to bacteria, mycobacteria, fungi, viruses and parasites (including protozoa). In some cases, particular fungal and other opportunistic infections have not been recognised, resulting in delay of appropriate treatment and sometimes death. In evaluating patients for infections, the patient’s risk for relevant opportunistic infections (e.g. exposure to endemic mycoses) should be considered. 

Patients who develop a new infection while undergoing treatment with Benepali™ should be monitored closely. Administration of Benepali™ should be discontinued if a patient develops a serious infection. The safety and efficacy of etanercept in patients with chronic infections have not been evaluated. Physicians should exercise caution when considering the use of Benepali™ in patients with a history of recurring or chronic infections or with underlying conditions that may predispose patients to infections, such as advanced or poorly controlled diabetes.

Cases of active tuberculosis, including miliary tuberculosis and tuberculosis with extra-pulmonary location, have been reported in patients treated with etanercept. 

Before starting treatment with Benepali™, 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 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, Benepali™ therapy must not be initiated. If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started with anti-tuberculosis therapy before the initiation of Benepali™, and in accordance with local recommendations. In this situation, the benefit/risk balance of Benepali™ therapy should be very carefully considered. 

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 Benepali™ treatment.

Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant TNF-antagonists, including etanercept, has been reported. This includes reports of reactivation of hepatitis B in patients who were anti-HBc positive but HBsAg negative. 

Patients should be tested for HBV infection before initiating treatment with Benepali™. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when administering Benepali™ in patients previously infected with HBV. These patients should be monitored for signs and symptoms of active HBV infection throughout therapy and for several weeks following termination of therapy. Adequate data from treating patients infected with HBV with anti-viral therapy in conjunction with TNF-antagonist therapy are not available. 

In patients who develop HBV infection, Benepali™ should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.

There have been reports of worsening of hepatitis C in patients receiving etanercept. Benepali™ should be used with caution in patients with a history of hepatitis C.

Allergic reactions associated with etanercept administration have been reported commonly. 

Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, Benepali™ therapy should be discontinued immediately and appropriate therapy initiated.

The possibility exists for TNF-antagonists, including etanercept, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 49 adult patients with rheumatoid arthritis treated with etanercept, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations. Two juvenile idiopathic arthritis patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. Patients with a significant exposure to varicella virus should temporarily discontinue Benepali™ therapy and be considered for prophylactic treatment with Varicella Zoster Immune Globulin. 

The safety and efficacy of etanercept in patients with immunosuppression have not been evaluated. 

Solid and haematopoietic malignancies (excluding skin cancers) 

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have been received in the post-marketing period (see Section 4.8 of the Summary of Product Characteristics). 

In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. In the post-marketing setting, cases of leukaemia have been reported in patients treated with TNF-antagonists. 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. 

Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded. Caution should be exercised when considering TNF-antagonist therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy. 

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age), including etanercept, in the post-marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies typically associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF-antagonists, including etanercept. Post-marketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with etanercept. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. 

Combining the results of controlled clinical trials, more cases of NMSC were observed in patients receiving etanercept compared with control patients, particularly in patients with psoriasis.

Live vaccines should not be given concurrently with Benepali™. No data are available on the secondary transmission of infection by live vaccines in patients receiving etanercept. In a double-blind, placebo-controlled, randomised clinical study in adult patients with psoriatic arthritis, 184 patients also received a multivalent pneumococcal polysaccharide vaccine at week 4. In this study, most psoriatic arthritis patients receiving etanercept were able to mount effective B-cell immune response to pneumococcal polysaccharide vaccine, but titres in aggregate were moderately lower, and few patients had two-fold rises in titres compared to patients not receiving etanercept. The clinical significance of this is unknown.

Treatment with Benepali™ may result in the formation of autoimmune antibodies (see Section 4.8 of the Summary of Product Characteristics).

Rare cases of pancytopenia and very rare cases of aplastic anaemia, some with fatal outcome, have been reported in patients treated with etanercept. Caution should be exercised in patients being treated with Benepali™ who have a previous history of blood dyscrasias. All patients and parents/caregivers should be advised that if the patient develops signs and symptoms suggestive of blood dyscrasias or infections (e.g. persistent fever, sore throat, bruising, bleeding, and paleness) whilst on Benepali™, they should seek immediate medical advice. Such patients should be investigated urgently, including full blood count; if blood dyscrasias are confirmed, Benepali™ should be discontinued. 

There have been rare reports of CNS demyelinating disorders in patients treated with etanercept see Section 4.8 of the Summary of Product Characteristics). Additionally, there have been rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy). Although no clinical trials have been performed evaluating etanercept therapy in patients with multiple sclerosis, clinical trials of other TNF-antagonists in patients with multiple sclerosis have shown increases in disease activity. A careful risk/benefit evaluation, including a neurologic assessment, is recommended when prescribing Benepali™ to patients with pre-existing or recent onset of demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease. 

In a controlled clinical trial of two years duration in rheumatoid arthritis patients, the combination of etanercept and methotrexate did not result in unexpected safety findings, and the safety profile of etanercept when given in combination with methotrexate was similar to the profiles reported in studies of etanercept and methotrexate alone. Long-term studies to assess the safety of the combination are ongoing. The long-term safety of etanercept in combination with other disease-modifying antirheumatic drugs (DMARD) has not been established. 

The use of etanercept in combination with other systemic therapies or phototherapy for the treatment of psoriasis has not been studied. 

Physicians should use caution when using Benepali™ in patients who have congestive heart failure (CHF). There have been post-marketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking etanercept. There have also been rare (< 0.1%) reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. Two large clinical trials evaluating the use of etanercept in the treatment of CHF were terminated early due to lack of efficacy. Although not conclusive, data from one of these trials suggest a possible tendency toward worsening CHF in those patients assigned to etanercept treatment.

In a phase II randomised placebo-controlled study of 48 hospitalised patients treated with etanercept or placebo for moderate to severe alcoholic hepatitis, etanercept was not efficacious, and the mortality rate in patients treated with etanercept was significantly higher after 6 months. Consequently, Benepali™ should not be used in patients for the treatment of alcoholic hepatitis. Physicians should use caution when using Benepali™ in patients who also have moderate to severe alcoholic hepatitis.

A placebo-controlled trial, in which 89 adult patients were treated with etanercept in addition to standard therapy (including cyclophosphamide or methotrexate, and glucocorticoids) for a median duration of 25 months, has not shown etanercept to be an effective treatment for Wegener’s granulomatosis. The incidence of non-cutaneous malignancies of various types was significantly higher in patients treated with etanercept than in the control group. Benepali™ is not recommended for the treatment of Wegener’s granulomatosis.

There have been reports of hypoglycaemia following initiation of etanercept in patients receiving medicinal products for diabetes, necessitating a reduction in anti-diabetic medicinal products in some of these patients.

Elderly

In the Phase 3 studies in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, no overall differences in adverse events, serious adverse events, and serious infections in patients age 65 or older who received etanercept 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. 

Paediatric population 

Vaccinations

It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating etanercept therapy (see ‘Vaccinations’ above).

Benepali™ contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

Adult patients treated with etanercept and anakinra were observed to have a higher rate of serious infection when compared with patients treated with either etanercept or anakinra alone (historical data). 

In addition, in a double-blind, placebo-controlled trial in adult patients receiving background methotrexate, patients treated with etanercept and anakinra were observed to have a higher rate of serious infections (7%) and neutropenia than patients treated with etanercept (see Sections 4.4 and 4.8 of the Summary of Product Characteristics). 

The combination of etanercept and anakinra has not demonstrated increased clinical benefit, and is therefore not recommended.

In clinical studies, concurrent administration of abatacept and etanercept resulted in increased incidences of serious adverse events. 

This combination has not demonstrated increased clinical benefit; such use is not recommended (see Section 4.4 of the Summary of Product Characteristics).

In a clinical study of adult patients who were receiving established doses of sulfasalazine, to which etanercept was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with etanercept or sulfasalazine alone. The clinical significance of this interaction is unknown. 

Physicians should use caution when considering combination therapy with sulfasalazine.

In clinical trials, no interactions have been observed when etanercept was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, or methotrexate (see section 4.4 of the SmPC for vaccination advice).

No clinically significant pharmacokinetic drug-drug interactions were observed in studies with methotrexate, digoxin or warfarin.

Women of childbearing potential should consider the use of appropriate contraception to avoid becoming pregnant during Benepali™ therapy and for three weeks after discontinuation of therapy.

Developmental toxicity studies performed in rats and rabbits have revealed no evidence of harm to the foetus or neonatal rat due to etanercept. 

The effects of etanercept on pregnancy outcomes have been investigated in two observational cohort studies. A higher rate of major birth defects was observed in an observational study comparing pregnancies exposed to etanercept (n=370) during the first trimester, with pregnancies not exposed to etanercept or other TNF-antagonists (n=164) (adjusted odds ratio 2.4, 95% CI: 1.0-5.5). The types of major birth defects were consistent with those most commonly reported in the general population and no particular pattern of abnormalities was identified. No change in the rate of spontaneous abortion, stillbirth, or minor malformations was observed. In another observational multi-country registry study comparing the risk of adverse pregnancy outcomes in women exposed to etanercept during the first 90 days of pregnancy (n=425) to those exposed to non-biologic drugs (n=3497), there was no observed increased risk of major birth defects (crude odds ratio [OR]= 1.22, 95% CI: 0.79-1.90; adjusted OR = 0.96, 95% CI: 0.58-1.60 after adjusting for country, maternal disease, parity, maternal age and smoking in early pregnancy). This study also showed no increased risks of minor birth defects, preterm birth, stillbirth, or infections in the first year of life for infants born to women exposed to etanercept during pregnancy. 

Benepali™ should only be used during pregnancy if clearly needed. 

Etanercept crosses the placenta and has been detected in the serum of infants born to female patients treated with etanercept during pregnancy. The clinical impact of this is unknown, however, infants may be at increased risk of infection. 

Administration of live vaccines to infants for 16 weeks after the mother’s last dose of Benepali™ is generally not recommended.

Etanercept has been reported to be excreted in human milk following subcutaneous administration. 

In lactating rats following subcutaneous administration, etanercept was excreted in the milk and detected in the serum of pups. 

Because immunoglobulins, in common with many medicinal products, can be excreted in human milk, a decision must be made whether to discontinue breast-feeding or to discontinue Benepali™ therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. 

Preclinical data about peri- and postnatal toxicity of etanercept and of effects of etanercept on fertility and general reproductive performance are not available.