Side Effects of Enbrel (etanercept)

Enbrel (etanercept) is a tumor necrosis factor inhibitor used to treat rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis.

Enbrel works by blocking tumor necrosis factor alpha (TNF alpha). TNF alpha is a protein that the body produces during when there is inflammation, the body's reaction to injury. TNF alpha promotes inflammation and its associated fever and signs (pain, tenderness, and swelling) in several inflammatory conditions including rheumatoid arthritis and ankylosing spondylitis.

Enbrel is a synthetic (man-made) protein that binds to TNF alpha. It thereby acts like a sponge to remove most of the TNF alpha from the joints and blood. This prevents TNF alpha from promoting inflammation and the fever, pain, tenderness, and swelling of joints in patients with rheumatoid or psoriatic arthritis and ankylosing spondylitis.

Enbrel prevents the progressive destruction of the joints in patients with rheumatoid arthritis and the arthritis of psoriasis. 

Common side effects of Enbrel include

• mild to moderate itching, pain, swelling and redness at the site of injection,
• headache,
• dizziness, and
• nasal and throat irritation.

Serious side effects of Enbrel include

• worsening or increasing occurrence of infections, cancer, multiple sclerosis, myelitis, optic neuritis, seriously low blood counts (pancytopenia), and
• new cases or worsening of congestive heart failure.

Drug interactions of Enbrel include live vaccines, because Enbrel may reduce the response of the immune system. Combining Enbrel with anakinra or abatacept, drugs that also reduce the response of the immune system, may increase the risk of serious infections.

Studies have not been conducted with Enbrel in pregnant women. Enbrel is only used in pregnant women when there is a clear need.

It is unknown if Enbrel is excreted in breast milk. Because of the risk of serious effects in the infant, a decision should be made whether to discontinue breastfeeding or Enbrel.

The most common side effects are:

• mild to moderate itching,
• pain,
• swelling and redness at the site of injection,
• headache,
• dizziness,
• nasal and throat.

TNF alpha has an important role in the responses of the immune system to infections. Thus, blocking the action of TNF alpha with etanercept may worsen or increase the occurrence of infections such as

• tuberculosis,
• bacterial sepsis,
• invasive fungal infections (such as histoplasmosis), and
• other opportunistic infections (infections that occur primarily in patients with suppressed immune systems).

Patients with serious infections should not receive etanercept, and etanercept should be discontinued if a patient develops a serious infection. Etanercept should be used with caution in patients prone to infection, such as those with advanced or poorly controlled diabetes. Children should receive their recommended immunizations before treatment with etanercept.

Some reported associated conditions may or may not be related to etanercept.

Other important side effects include:

• cancer,
• multiple sclerosis,
• myelitis, and
• optic neuritis.

For this reason, etanercept is not recommended for persons with preexisting disease of the central nervous system (brain and/or spinal cord) or for those with multiple sclerosis, myelitis, or optic neuritis. Additionally, rare cases of seriously low blood counts (pancytopenia) have been reported in patients using etanercept. New cases or worsening of congestive heart failure may occur.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Serious Infections
• Neurologic Reactions
• Malignancies
• Patients with Heart Failure
• Hematologic Reactions
• Hepatitis B Reactivation
• Allergic Reactions
• Autoimmunity
• Immunosuppression

Clinical Trials Experience

• Across clinical studies and postmarketing experience, the most serious adverse reactions with Enbrel were infections, neurologic events, CHF, and hematologic events.
• The most common adverse reactions with Enbrel were infections and injection site reactions.
• Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in clinical practice.

Adverse Reactions In Adult Patients With Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Or Plaque Psoriasis

• The data described below reflect exposure to Enbrel in 2219 adult patients with RA followed for up to 80 months, in 182 patients with PsA for up to 24 months, in 138 patients with AS for up to 6 months, and in 1204 adult patients with PsO for up to 18 months.
• In controlled trials, the proportion of Enbrel-treated patients who discontinued treatment due to adverse events was approximately 4% in the indications studied.

Adverse Reactions In Pediatric Patients

• In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients.
• In a 48-week clinical study in 211 children aged 4 to 17 years with pediatric PsO, the adverse reactions reported were similar to those seen in previous studies in adults with PsO. Long-term safety profile for up to 264 additional weeks was assessed in an open-label extension study and no new safety signals were identified.
• In open-label clinical studies of children with JIA, adverse reactions reported in those ages 2 to 4 years were similar to adverse reactions reported in older children.

Infections

• Infections, including viral, bacterial, and fungal infections, have been observed in adult and pediatric patients. Infections have been noted in all body systems and have been reported in patients receiving Enbrel alone or in combination with other immunosuppressive agents.
• In controlled portions of trials, the types and severity of infection were similar between Enbrel and the respective control group (placebo or MTX for RA and PsA patients) in RA, PsA, AS and PsO patients.
• Rates of infections in RA and adult PsO patients are provided in Table 3 and Table 4, respectively. Infections consisted primarily of upper respiratory tract infection, sinusitis and influenza.
• In controlled portions of trials in RA, PsA, AS and PsO, the rates of serious infection were similar (0.8% in placebo, 3.6% in MTX, and 1.4% in Enbrel/Enbrel + MTX-treated groups).
• In clinical trials in rheumatologic indications, serious infections experienced by patients have included, but are not limited to,
  • pneumonia,
  • cellulitis,
  •  septic arthritis,
  • bronchitis,
  • gastroenteritis,
  • pyelonephritis,
  • sepsis,
  • abscess and osteomyelitis.
• In clinical trials in adult PsO patients, serious infections experienced by patients have included, but are not limited to,
  • pneumonia,
  • cellulitis,
  • gastroenteritis,
  • abscess and osteomyelitis.
• The rate of serious infections was not increased in open-label extension trials and was similar to that observed in Enbrel- and placebo-treated patients from controlled trials.
• In 66 global clinical trials of 17,505 patients (21,015 patient-years of therapy), tuberculosis was observed in approximately 0.02% of patients. In 17,696 patients (27,169 patient-years of therapy) from 38 clinical trials and 4 cohort studies in the U.S. and Canada, tuberculosis was observed in approximately 0.006% of patients. These studies include reports of pulmonary and extrapulmonary tuberculosis.
• The types of infections reported in pediatric patients with PsO and JIA were generally mild and consistent with those commonly seen in the general pediatric population. Two JIA patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae.

Injection Site Reactions

• In placebo-controlled trials in rheumatologic indications, approximately 37% of patients treated with Enbrel developed injection site reactions. In controlled trials in patients with PsO, 15% of adult patients and 7% of pediatric patients treated with Enbrel developed injection site reactions during the first 3 months of treatment.
• All injection site reactions were described as mild to moderate (erythema, itching, pain, swelling, bleeding, bruising) and generally did not necessitate drug discontinuation.
• Injection site reactions generally occurred in the first month and subsequently decreased in frequency.
• The mean duration of injection site reactions was 3 to 5 days. Seven percent of patients experienced redness at a previous injection site when subsequent injections were given.

Other Adverse Reactions

Table 3 summarizes adverse reactions reported in adult RA patients. The types of adverse reactions seen in patients with PsA or AS were similar to the types of adverse reactions seen in patients with RA.

Table 3: Percent of Adult RA Patients Experiencing Adverse Reactions in Controlled Clinical Trials

In placebo-controlled adult PsO trials, the percentages of patients reporting adverse reactions in the 50 mg twice a week dose group were similar to those observed in the 25 mg twice a week dose group or placebo group.

Table 4 summarizes adverse reactions reported in adult PsO patients from Studies I and II.

Table 4: Percent of Adult PsO Patients Experiencing Adverse Reactions in Placebo-Controlled Portions of Clinical Trials (Studies I & II)

Immunogenicity

• As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
• Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
• For these reasons, comparison of the incidence of antibodies to etanercept in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Immunogenicity

• Patients with RA, PsA, AS or PsO were tested at multiple time points for antibodies to etanercept.
• Antibodies to the TNF receptor portion or other protein components of the Enbrel drug product were detected at least once in sera of approximately 6% of adult patients with RA, PsA, AS or PsO.
• These antibodies were all non-neutralizing. Results from JIA patients were similar to those seen in adult RA patients treated with Enbrel.
• In adult PsO studies that evaluated the exposure of etanercept for up to 120 weeks, the percentage of patients testing positive at the assessed time points of 24, 48, 72 and 96 weeks ranged from 3.6%-8.7% and were all non-neutralizing.
• The percentage of patients testing positive increased with an increase in the duration of study; however, the clinical significance of this finding is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed.
• The immunogenicity data of Enbrel beyond 120 weeks of exposure are unknown.
• In pediatric PsO studies, approximately 10% of subjects developed antibodies to etanercept by Week 48 and approximately 16% of subjects developed antibodies to etanercept by Week 264.
• All of these antibodies were non-neutralizing. However, because of the limitations of the immunogenicity assays, the incidence of binding and neutralizing antibodies may not have been reliably determined.
• The data reflect the percentage of patients whose test results were considered positive for antibodies to etanercept in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay.

Autoantibodies

• Patients with RA had serum samples tested for autoantibodies at multiple time points.
• In RA Studies I and II, the percentage of patients evaluated for antinuclear antibodies (ANA) who developed new positive ANA (titer ≥ 1:40) was higher in patients treated with Enbrel (11%) than in placebo-treated patients (5%).
• The percentage of patients who developed new positive anti-double-stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with Enbrel compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with Enbrel compared to none of placebo-treated patients).
• The proportion of patients treated with Enbrel who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients.
• In RA Study III, no pattern of increased autoantibody development was seen in Enbrel patients compared to MTX patients.

Postmarketing Experience

Adverse reactions have been reported during post approval use of Enbrel in adults and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Enbrel exposure.

Adverse reactions are listed by body system below:

• Blood and lymphatic system disorders: pancytopenia, anemia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, aplastic anemia
• Cardiac disorders: congestive heart failure
• Gastrointestinal disorders: inflammatory bowel disease (IBD)
• General disorders: angioedema, chest pain
• Hepatobiliary disorders: autoimmune hepatitis, elevated transaminases, hepatitis B reactivation
• Immune disorders: macrophage activation syndrome, systemic vasculitis, sarcoidosis
• Musculoskeletal and connective tissue disorders: lupus-like syndrome
• Neoplasms benign, malignant, and unspecified: melanoma and non-melanoma skin cancers, Merkel cell carcinoma
• Nervous system disorders: convulsions, multiple sclerosis, demyelination, optic neuritis, transverse myelitis, paresthesias
• Ocular disorders: uveitis, scleritis
• Respiratory, thoracic and mediastinal disorders: interstitial lung disease
• Skin and subcutaneous tissue disorders: cutaneous lupus erythematosus, cutaneous vasculitis (including leukocytoclastic vasculitis), erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, subcutaneous nodule, new or worsening psoriasis (all sub-types including pustular and palmoplantar)

Opportunistic infections, including atypical mycobacterial infection, herpes zoster, aspergillosis and Pneumocystis jiroveci pneumonia, and protozoal infections have also been reported in postmarketing use.

Rare (< 0.1%) cases of IBD have been reported in JIA patients receiving Enbrel, which is not effective for the treatment of IBD.

Specific drug interaction studies have not been conducted with Enbrel.

Vaccines

• Most PsA patients receiving Enbrel were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and fewer patients had 2-fold rises in titers compared to patients not receiving Enbrel.
• The clinical significance of this is unknown. Patients receiving Enbrel may receive concurrent vaccinations, except for live vaccines.
• No data are available on the secondary transmission of infection by live vaccines in patients receiving Enbrel.
• Patients with a significant exposure to varicella virus should temporarily discontinue Enbrel therapy and be considered for prophylactic treatment with varicella zoster immune globulin.

Immune-Modulating Biologic Products

• In a study in which patients with active RA were treated for up to 24 weeks with concurrent Enbrel and anakinra therapy, a 7% rate of serious infections was observed, which was higher than that observed with Enbrel alone (0%) and did not result in higher ACR response rates compared to Enbrel alone.
• The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases).
• One patient with pulmonary fibrosis and pneumonia died due to respiratory failure.
• Two percent of patients treated concurrently with Enbrel and anakinra developed neutropenia (ANC < 1 x 10⁹/L).
• In clinical studies, concurrent administration of abatacept and Enbrel resulted in increased incidences of serious adverse events, including infections, and did not demonstrate increased clinical benefit.

Cyclophosphamide

• The use of Enbrel in patients receiving concurrent cyclophosphamide therapy is not recommended.

Sulfasalazine

• Patients in a clinical study who were on established therapy with sulfasalazine, to which Enbrel was added, were noted to develop a mild decrease in mean neutrophil counts in comparison to groups treated with either Enbrel or sulfasalazine alone.
• The clinical significance of this observation is unknown.