Enbrel Side Effects

Generic Name: etanercept

Note: This page contains information about the side effects of etanercept. Some of the dosage forms included on this document may not apply to the brand name Enbrel.

Not all side effects for Enbrel may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to etanercept: subcutaneous powder for solution, subcutaneous solution

Along with its needed effects, etanercept (the active ingredient contained in Enbrel) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking etanercept:

More common
  • Chills
  • cough
  • fever
  • sneezing
  • sore throat
Less common
  • Congestion in the chest
  • depression
  • fast heartbeat
  • frequent or painful urination
  • itching, pain, redness, or swelling on the skin
  • joint or muscle stiffness, tightness, or rigidity
  • shortness of breath
  • stomach discomfort or pain
Incidence not known
  • bladder pain
  • blistering, peeling, or loosening of the skin
  • bloody, black, or tarry stools
  • blue-yellow color blindness
  • blurred vision
  • chest discomfort or pain
  • cloudy or bloody urine
  • confusion
  • convulsions
  • darkened urine
  • decreased urine output
  • decreased vision
  • diarrhea
  • difficult, irregular, troubled, or labored breathing (or difficulty in breathing gets worse)
  • difficulty with moving
  • dilated neck veins
  • double vision
  • extreme fatigue
  • eye pain
  • feeling sad or empty
  • fruit-like breath odor
  • general feeling of discomfort, illness, or weakness
  • generalized pain
  • heartburn or indigestion
  • high blood pressure
  • inability to move the arms, legs, or facial muscles
  • irregular heartbeat
  • joint or muscle pain
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • lightheadedness
  • loss of consciousness
  • muscle tenderness
  • pain or discomfort in the arms, jaw, back, or neck
  • pain, redness, or swelling in the arm or leg
  • problems with bowel or bladder function
  • red skin lesions, often with a purple center
  • red, scaling, or crusted skin
  • severe and continuing nausea
  • severe numbness, especially on one side of the face or body
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swelling of the face, fingers, feet, or lower legs
  • tenderness
  • tightness in the chest
  • trouble concentrating
  • trouble sleeping
  • unexplained weight loss
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • vomiting of blood or material that looks like coffee grounds
  • weight loss
  • wheezing
  • yellow eyes or skin

Some side effects of etanercept may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Abdominal or stomach pain
  • loss of energy or weakness
  • nausea and vomiting
  • pain or burning in the throat
  • redness or itching, pain, or swelling at the site of injection (under the skin)
  • runny or stuffy nose
Less common
  • Bumps below the skin
  • depression
  • dry eyes
  • dry mouth
  • hair loss or thinning
  • heartburn
  • irritation or soreness of the mouth
  • itching, redness, or tearing of the eye
  • skin rash
Incidence not known
  • Altered sense of taste
  • burning, crawling, itching, numb, prickling, “pins and needles”, or tingling feelings
  • feeling faint, dizzy, or lightheaded
  • feeling of warmth or heat
  • flushing or redness of the skin, especially on the face and neck
  • loss of appetite
  • sweating
  • weight gain

For Healthcare Professionals

Applies to etanercept: subcutaneous kit, subcutaneous solution

Respiratory

A 38-year-old man with rheumatoid arthritis developed disseminated histoplasmosis after 11 months of treatment with etanercept (the active ingredient contained in Enbrel) He recovered following itraconazole therapy.

A 50-year-old male with rheumatoid arthritis experienced pulmonary nodulosis coincident with etanercept therapy. On presentation, he was taking leflunomide (20 mg/day for 3 years) and etanercept (25 mg twice weekly for 2 years). Clinical examination showed multiple densities in the apical part of the left lung. Chest radiography and high resolution computed tomography showed disseminated bilateral, partly confluating nodules, some pleural thickening, and pleural effusion. Both etanercept and leflunomide were stopped and therapy with prednisolone and azathioprine was initiated. Three months later, the pulmonary nodules had largely disappeared.

A 40-year-old male with a history of severe psoriatic arthritis experienced pulmonary sarcoidosis coincident with etanercept therapy. He was admitted to the hospital with dyspnea and subfebrile illness several months after initiating treatment with etanercept 25 mg subcutaneously twice weekly. His diagnosis was consistent exclusively with sarcoidosis. The patient's symptoms improved when etanercept therapy was discontinued, but they did not resolve completely. Therapy with prednisone 40 mg led to complete improvement of his pulmonary disease.

A 37-year-old male with a greater than 10-year history of psoriatic arthritis experienced lung granulomas coincident with etanercept therapy. He started therapy with etanercept 25 mg subcutaneously twice weekly for psoriatic arthritis. Approximately a year and one-half later, he developed respiratory symptoms with fever, productive cough, and dyspnea. Chest radiograph indicated a bilateral reticulonodular interstitial pattern which was worse in the upper lobes, but with no hilar lymphadenopathy. Etanercept therapy was discontinued and he was initially treated with amoxicillin and then, when he did not improve, with clarithromycin. His symptoms improved and his chest radiograph showed improvement.

Respiratory side effects have included the development of respiratory infections (29% to 38%), upper respiratory tract infection (20.89%), rhinitis (12% to 18.42%), pharyngitis (2% to 7%), cough (3% to 6%), unexplained respiratory disorder (5%,) sinusitis (3%), dyspnea, worsening of prior lung disorder, coccidioidomycosis, pneumocystis, increased cough, bronchitis, pneumonia, lung abscess, pleural infection, and tonsillitis. Histoplasmosis and tuberculosis have been reported rarely. Cases of pulmonary cavitation and vasculitis, interstitial lung disease, viral pneumonia, and pulmonary disease have been reported. At least one case of pulmonary nodulosis has been reported, in addition to a case of pulmonary sarcoidosis. At least three cases of lung granulomas have also been reported.

Immunologic

Immunologic side effects have included serious infections and sepsis, including fatalities. Cases of systemic lupus erythematosus have also been reported. Postmarketing immunologic side effects have included macrophage activation syndrome, systemic vasculitis, and sarcoidosis.

Infections have been reported with various pathogens including viral, bacterial, fungal, and protozoal organisms.

Many of the serious events have been reported in patients with underlying diseases in addition to their rheumatoid arthritis which could have predisposed them to infections.

Four cases of systemic lupus erythematosus (SLE) have been reported to occur between 6 weeks and 14 months after initiation of therapy. All SLE related symptoms resolved between 2 to 6 weeks after discontinuation of therapy.

Nervous system

Nervous system side effects have included headache (17% to 20%) and dizziness (7% to 10%). Stroke, paresthesias, seizures, and central nervous system events suggestive of multiple sclerosis or isolated demyelinating conditions such as transverse myelitis or optic neuritis have been reported.

Postmarketing nervous system side effects have included neurologic events suggestive of demyelination including paresthesias, visual disturbances secondary to optic neuritis, confusion, gait disturbance, apraxia, facial palsy, and Guillain-Barré syndrome. Additionally, herpes zoster, demyelination, peripheral mononeuropathy, convulsions, multiple sclerosis, optic neuritis, and transverse myelitis have been reported during postmarketing surveillance.

Although neurological events suggestive of demyelination reported during postmarketing experience did not show causal relationship between adverse events and etanercept, the neurologic side effects resolved, partially or completely, on discontinuation of therapy.

A patient with a history of Takayasu arteritis experienced herpes zoster coincident with etanercept therapy. Etanercept was temporarily discontinued in this patient, and treatment with valacyclovir led to full clinical recovery.

An 18-year-old female with severe psoriasis of 14 years duration experienced demyelinating disease coincident with etanercept therapy. Her history was significant for previous flares of psoriatic erythroderma and pustular psoriasis. She had been recently treated with 25 mg etanercept of subcutaneously twice per week for 1 year, with excellent control of her psoriasis. At presentation, she reported the gradual resolution during the week just past of left-sided tingling and numbness in the upper and lower extremities and scalp, as well as blurry vision in the left eye, lasting about 4 weeks. She was still taking etanercept. A neurological examination revealed hyperreflexia throughout. Magnetic resonance imaging results of the brain were consistent with demyelinating disease. Etanercept was discontinued at presentation and alternative therapy was initiated. She has had no recurrence of neurologic symptoms during 7 months of follow-up and has had stable findings on neurological examination.

A 43-year-old male with a history of psoriatic arthritis experienced peripheral neuropathy coincident with etanercept therapy. Eight weeks after reinitiating therapy with etanercept and leflunomide for the fourth time, the patient presented with acute-onset numbness in the ulnar aspect of his left hand, fourth and fifth digits. His neurological examination showed mildly decreased left hand intrinsic motor strength (4/5) and diminished pinprick sensation on his fifth digit. Given his distribution of findings, he was diagnosed with ulnar neuropathy. However, based on symptom improvement after the drug was discontinued and a lack of other possible causes, drug-induced peripheral neuropathy seemed like the most plausible diagnosis. The patient's neuropathy improved 6 weeks after etanercept was discontinued, although he continued taking leflunomide, which had been started 6 months before the neuropathy.

Gastrointestinal

Gastrointestinal (GI) side effects have included diarrhea (18.4%), nausea (10% to 20.86%), vomiting (5%), mouth ulcers (3%), abdominal pain, dyspepsia, altered sense of taste, oral mycosis, GI infection, and bacterial peritonitis. Uncommon cases of dry mouth have been reported, in addition to rare cases of anorexia. Pancreatitis, esophagitis, and gastroenteritis have been reported. Cases of intestinal perforation have been reported. At least one case of cacogeusia has also been reported, in addition to a case of Crohn's disease. Postmarketing gastrointestinal side effects have included inflammatory bowel disease.

A 21-year-old male with a 10 year history of psoriatic arthritis was in clinical remission after beginning etanercept 25 mg twice weekly 3 years prior. He presented with right upper quadrant and bilateral lower quadrant pain of 3 weeks duration. Although histological features were nonspecific, the diagnosis suggested CD due to the involvement of the terminal ileum, colon, and rectum. He continued taking etanercept for his arthritis and started mesalamine therapy for his CD, with good control.

Cardiovascular

Cardiovascular side effects have included hypertension (7%), heart failure, chest pain, vasodilation (flushing), and angioedema. During postmarketing experience, new-onset heart failure, with or without documented risk factors, was the most frequently reported event followed by heart failure exacerbation. Arteriosclerosis and leukocytoclastic vasculitis have been reported. At least one case of giant cell arteritis has been reported.

Cases of heart failure (n=29) reported during postmarketing experience developed on average 6 months after initiation of etanercept therapy.

A 22-year-old female with juvenile rheumatoid arthritis (JRA) experienced leukocytoclastic vasculitis coincident with etanercept therapy. The patient presented with purpuric rash and lower extremity edema. Four years prior to the current admission, she was started on etanercept for JRA and responded immediately. Skin biopsy showed leukocytoclastic vasculitis. Rapid resolution of the clinical features and accompanying improvements were observed following discontinuation of etanercept.

A 79-year-old female with rheumatoid arthritis experienced giant cell arteritis (GCA) coincident with etanercept therapy. She presented with left jaw pain, so severe that she would not open her mouth to eat. The patient had associated ear pain and a sore throat. She had been prescribed etanercept 25 mg twice weekly and methotrexate 7.5 mg weekly for two years. A biopsy of the left temporal artery showed GCA.

Dermatologic

A 49-year-old male with alopecia areata and rheumatoid arthritis experienced recurrence of alopecia areata coincident with etanercept (the active ingredient contained in Enbrel) therapy. Three years prior, he had begun a twice weekly subcutaneous course of 25 mg etanercept injections. After more than 2 years of etanercept treatment, the alopecia areata recurred, with extensive, confluent 4- to 6-cm patches on the occipital and parietal regions of the scalp. He is currently being treated with clobetasol foam twice daily on weekends and topical 5% minoxidil twice daily, along with intralesional triamcinolone injections to a few affected areas. Only slight improvement has been observed.

A 38-year-old female with rheumatoid arthritis experienced lichen planus coincident with etanercept therapy. She received etanercept 25 mg twice weekly and methotrexate 15 mg weekly. Four months starting etanercept therapy, a pruriginous cutaneous eruption appeared on the right lower limb, consisting of numerous erythematous to violaceous polygonal flat-topped papules in a zosteriform distribution. Etanercept was suspected, and the therapy was withdrawn. After discontinuation, progressive healing was observed, with further complete remission over a period of 4 months, secondarily helped by topical betamethasone propionate once daily for 8 weeks. Continuation of the patients other medications without relapse of the skin eruption excluded the drugs as causal.

A patient presented with an abscess of the right gluteal area within 6 weeks after discontinuing etanercept; it was treated by surgical incision and oral administration of amoxicillin-clavulanate 1 g every 6 hours for 10 days, and resolved.

A 56-year-old female with psoriatic arthritis experienced lichen planopilaris (LPP) coincident with etanercept therapy. She was prescribed etanercept 50 mg weekly initially and after 12 weeks, the patient showed improvement of both skin lesions and joint tenderness. At week 32 of therapy, the patient attended the routine follow-up evaluation complaining about remarkable hair loss, and severe pain and itch affecting the whole scalp. Two areas of cicatricial alopecia with erythema and follicular hyperkeratosis with peripheral distribution were noted. The histology of a biopsy specimen revealed atrophy of the follicular epithelium and perifollicular fibrosis, with moderate inflammatory infiltrate and evolution to cicatricial alopecia. The picture was suggestive of LPP. Because of the onset of alopecia and pain, the patient wanted to stop etanercept therapy. After 3 months, the patient's erythema and follicular hyperkeratosis disappeared, with local pain and itch remarkably reduced.

Dermatologic side effects have included rash (5%), urticaria, and pruritus. Cutaneous vasculitis and subcutaneous nodules have rarely been reported. A necrotic lesion on the lower extremity, not at the injection site, has been reported to occur after the first injection. Psoriasis, interstitial granulomatous dermatitis, fungal skin infection, bacterial skin infection, paronychia, furuncle/folliculitis, erysipelas, recurrence of alopecia areata, lichen planus, lichen planopilaris, gluteal abscess, and cellulitis have been reported.

Postmarketing dermatologic side effects have included cutaneous lupus erythematosus, cutaneous vasculitis (including leukocytoclastic vasculitis), erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, subcutaneous nodule, and new or worsening psoriasis (all sub-types including pustular and palmoplantar).

Musculoskeletal

Musculoskeletal side effects have included bone fracture (3.2%). Joint pain and accelerated nodulosis have been reported uncommonly. Back pain and infective arthritis have also been reported. At least one case of septic arthritis due to Listeria monocytogenes has been reported. Postmarketing reports have included chest pain and lupus-like syndrome.

A 65-year-old male with polyarticular rheumatoid arthritis experienced septic arthritis due to Listeria monocytogenes after being treated with etanercept and low-dose prednisolone. He presented with an inflamed knee joint, and aspiration yielded yellow-green turbid synovial fluid showing granulocytic effusion with 50,000 cells/mL, but Gram stain did not show any organisms. After 48 hours of culture, gram positive bacteria were observed, and Listeria monocytogenes was isolated after 72 hours. Antibiotic therapy started at presentation was continued, and later joint irrigation was done, which eliminated the infection, but joint destruction resulted eventually.

Local

Local side effects have included reports of mild to moderate injection site reactions (erythema, itching, pain, and/or swelling) in 24.67% to 37% of patients. Redness was experienced in 7% of patients at a previous injection site after subsequent injections were given. Injection site ecchymosis has also been reported. At least one case of eosinophilic cellulitis-like reaction has also been reported.

Injection site reactions occurred in the first month of administration with etanercept and decreased in frequency. The average duration of these reactions was 3 to 5 days.

A 57-year-old female with an 8-month history of rheumatoid arthritis (RA) experienced eosinophilic cellulitis-like reaction coincident with etanercept therapy. The patient was given etanercept 25 mg subcutaneously twice weekly for RA. Within 24 hours of her first dose, she developed an evanescent, pruritic, slightly indurated, erythematous plaque surrounding the injection site. Within 12 to 24 hours after her second injection, a much larger injection site reaction (ISR) was observed. On presentation, 3 days after second injection, the patient reported that the reaction had continued to increase in size. A skin biopsy was conducted, and the patient was treated with oral antihistamines and prednisone, with complete resolution of the ISR over the next 2 days.

Hematologic

Hematologic side effects have included anemia, leukopenia, and thrombocytopenia. Rare reports of pancytopenia, including aplastic anemia, some with a fatal outcome have been reported. At least one case of leukocytoclastic vasculitis has also been reported, in addition to a case of macrophage activation syndrome.

Postmarketing hematologic side effects have included pancytopenia, anemia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, and aplastic anemia.

Cases of pancytopenia have occurred as early as 2 weeks after initiation of therapy.

A 42-year-old female with a history of rheumatoid arthritis (RA) experienced macrophage activation syndrome (MAS) coincident with etanercept therapy. She presented to the hospital with a two month history of fever, chills, night sweats, rigors, and a dry cough. Two months prior to presentation, she had discontinued etanercept therapy due to her presenting complaint of a fever of unknown origin. She was diagnosed with MAS and was given cyclosporine, intravenous immunoglobulin, and dexamethasone. She then developed a gram-negative bacilli septicemia and acute renal failure. She was transferred to the intensive care unit, where all immunosuppressant treatment was discontinued. She developed anasarca and 2 weeks later died of acute respiratory distress syndrome and multiorgan failure considered secondary to sepsis and uncontrolled MAS 6 weeks after being admitted.

Ocular

Ocular side effects have rarely included ocular inflammation and dry eyes. Uveitis and scleritis have also been reported during postmarketing experience.

Hypersensitivity

Hypersensitivity side effects including allergic reactions (less than 2%) and leukocytoclastic vasculitis have been reported. Postmarketing hypersensitivity side effects have included angioedema.

Oncologic

Oncologic side effects have included malignant lymphomas, solid malignancies, and rare cancers including lymphomas and Hepatosplenic T-Cell Lymphoma occurring mostly in adolescents and young adults.
Lymphoproliferative disorders have been reported during postmarketing experience. The majority of cases (81%) were non-Hodgkin's lymphomas. At least six cases of solid cancers including two cases of mucinous adenocarcinoma of the colon, one metastatic cholangiocarcinoma, one renal-cell carcinoma, one breast carcinoma, and one liposarcoma have been reported. Prostate carcinoma has been reported. Additionally, reports of multiple cutaneous squamous cell carcinomas, keratoacanthoma, melanoma, and Merkel cell carcinoma have been received.

Postmarketing adverse events including lymphoproliferative disorders developed, on average, 8 weeks after initiation of therapy with etanercept.

A 64-year-old male with a history of psoriasis experienced multiple cutaneous squamous cell carcinomas (SCC) and keratoacanthomas (KAs) coincident with etanercept therapy. The patient was given a 3-month course of therapy with etanercept 50 mg weekly in divided doses. Approximately 10 weeks later, he noticed lumps appearing on his legs. There were at least 50 nodules on his legs but the rest of his body did not have any lesions that looked like skin cancer. Two large lesions were excised and histological examination showed them to be SCC. Seven of the smaller lesions were removed and showed KAs on histological examination. The KAs regressed after therapy with etanercept was discontinued.

Hepatic

Hepatic side effects have included autoimmune hepatitis. At least 2 cases of hepatotoxicity have also been reported. Postmarketing hepatic side effects have included autoimmune hepatitis and elevated transaminases.

Genitourinary

Genitourinary side effects including urinary tract infection have been reported. Herpes simplex and vaginal mycosis/candidiasis have been reported.

Renal

A 32-year-old female with typical rheumatoid arthritis experienced necrotizing crescentic glomerulonephritis, associated with a positive antineutrophil cytoplasmic antibody, causing acute renal failure coincident with etanercept (the active ingredient contained in Enbrel) therapy. A renal biopsy demonstrated segmental necrosis within one glomerulus and partial fibrosis of the glomerular tuft with fibrocellular crescents within a number of other glomeruli. Extensive irreversible tubular damage was also evident. The patient was treated with steroids and cyclophosphamide following withdrawal of etanercept, with a good clinical outcome.

A 22-year-old female with juvenile rheumatoid arthritis (JRA) experienced proliferative lupus nephritis coincident with etanercept therapy. The patient presented with purpuric rash and lower extremity edema. Four years prior to the current admission, she was started on etanercept for JRA and responded immediately. A renal biopsy showed lupus nephritis. Rapid resolution of the clinical features and accompanying improvements were observed following discontinuation of etanercept.

Renal side effects including pyelonephritis have been reported. At least one case of necrotizing crescentic glomerulonephritis has been reported, in addition to a case of proliferative lupus nephritis.

Other

The development of a new positive antinuclear antibody occurred in 11% of patients. New positive anti-double-stranded DNA antibodies occurred in 15% of patients. The number of patients who developed anticardiolipin antibodies was similarly increased compared to patients treated with placebo. No patients have developed a lupus-like syndrome or other autoimmune diseases. The impact of long-term treatment with etanercept (the active ingredient contained in Enbrel) however, in the development of autoimmune diseases is unknown.

Other side effects have included asthenia (5% to 8%), autoantibodies development (11% to 15%), adenopathy, fever, flu syndrome, weight gain, accidental injury, abscess, otitis media, and sepsis/urosepsis. Fatigue and generalized pain have been reported infrequently. Opportunistic infections, including atypical mycobacterial infection, herpes zoster, Listeria monocytogenes infection, aspergillosis and Pneumocystis jiroveci pneumonia, and protozoal infections have been reported during postmarketing use.

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