Drug Profile

Adalimumab (HUMIRA)

Adalimumab is a genetically engineered drug that is injected every other week.[1]It is an antibody that blocks the interaction of tumor necrosis factor (TNF) with TNF receptors. TNF plays an important role in the inflammatory processes of rheumatoid arthritis and other diseases.

Adalimumab is approved by the Food and Drug Administration (FDA) to treat moderate-to-severe rheumatoid arthritis, Crohn's disease (a disease that causes inflammation of the intestines), ulcerative colitis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis (a form of arthritis affecting the spine and large joints) and plaque psoriasis, among other conditions.[2]

This drug is intended for those patients with rheumatoid arthritis who have failed to see results from at least one disease-modifying antirheumatic drug (DMARD) and for use with other DMARDs, such as methotrexate (RHEUMATREX DOSE PACK, TREXALL).[3]

WorstPills.org lists adalimumab, anakinra (KINERET), etanercept (ENBREL) and infliximab (REMICADE) as Limited Use drugs.

Adverse effects

The major serious adverse effects associated with the use of adalimumab are serious infections and failure of blood cell production (see Humira's FDA black-box warning at the top of this page), especially with the combined use of adalimumab and anakinra; nervous system diseases that have been seen with TNF blockers; certain types of cancer reportedly associated with TNF blocker use; and lupus-like symptoms such as chest pains, shortness of breath, joint pain, rash and sun sensitivity.[4] Sarcoid-like granulomatosis (inflammatory lesions that can affect a variety of organs) associated with TNF blocker therapy has been observed in patients treated with these drugs.[5]

Use of adalimumab may lead to an increased risk of the viral infection herpes zoster — commonly known as shingles. Shingles is an infection caused by a herpes virus called varicella-zoster, the same virus that causes chickenpox. Herpes zoster causes a painful, blistering rash.[6],[7]

Adverse skin reactions are frequently seen in patients with ulcerative colitis and Crohn's disease.[8],[9] A study was conducted to examine whether psoriasis was a result of Crohn's disease or an adverse effect of the drugs used to treat the disease. The results of the study indicate that psoriasis may be induced by drug therapy. Adalimumab, anakinra, etanercept and infliximab also are used to treat certain forms of psoriasis, and patients need to be aware and inform their health care professionals if new or worsened skin lesions of psoriasis occur.

In 2006, New Zealand's Medicines and Medical Devices Safety Authority (Medsafe) issued a "Dear Healthcare Professional" letter advising that hepatitis B virus (HBV) reactivation had been reported in patients receiving the TNF antagonists adalimumab, etanercept and infliximab. Medsafe advised that patients who are at risk of HBV infection be evaluated for prior HBV infection before TNF antagonist therapy is begun and that those who are carriers of HBV infection should be closely monitored for HBV reactivation during TNF antagonist therapy and for several months after therapy ends.[10]

In 2013, Clinical Gastroenterology and Hepatology published an analysis of 34 cases of drug-induced liver injury that occurred with many different TNF blocker drugs.[11]

In 2016, Health Canada (an agency in Canada similar to the FDA) reported that women who used etanercept during pregnancy had a slightly higher risk of having a child born with birth defects than women who did not use the drug.[12]

Regulatory actions surrounding adalimumab

2005: The FDA added two warnings to the product label for adalimumab. The first warned of rare reports of a possible association between use of adalimumab and new cases of demyelination (damage to the insulating sheath that covers nerves). This can interfere with the ability of nerves to transmit information effectively. The second warning dealt with a slightly increased incidence of certain types of cancer in patients using adalimumab compared with those using a placebo.[4]

2008: The FDA issued an early communication informing the public that it would be investigating a possible association between TNF blockers and the development of lymphoma and other cancers in children and young adults. The FDA stated it would communicate the conclusions and any resulting recommendations to the public.[13]

2009: The FDA issued an advisory that it had completed its 2008 analysis and had concluded that there is an increased risk of lymphoma and other cancers associated with the use of these drugs in children and adolescents. The black-box warning for these drugs and the Medication Guides were updated with this information. The FDA also identified new safety information related to the occurrence of leukemia and new-onset psoriasis in patients treated with these drugs.[14]

2011: The FDA again informed the public that it continued to receive reports of a rare cancer of white blood cells (known as hepatosplenic T-cell lymphoma), primarily in adolescents and young adults with Crohn's disease and ulcerative colitis who were being treated with these drugs as well as with azathioprine (IMURAN) and mercaptopurine (PURINETHOL).[15]

The FDA also announced that it was updating the black-box warning for TNF blockers to include information on the risk of serious infections from Legionella and Listeria bacteria. This update was added based on a review of cases of infection in patients treated with TNF blockers.[16]

Anakinra (KINERET)

Anakinra is an interleukin-1 (IL-1) receptor blocker. IL-1 may play a role in the inflammation and local bone degradation seen with rheumatoid arthritis.[17]

Anakinra is approved by the FDA for the treatment of moderate-to-severe rheumatoid arthritis in adults (patients 18 years and older) who have failed to respond adequately to at least one DMARD, such as methotrexate, among other conditions.[18]

Anakinra also is approved for treatment of Neonatal-Onset Multisystem Inflammatory Disease, a disorder that causes persistent inflammation and tissue damage that primarily affects the nervous system, skin and joints.[19],[20]

Adverse effects

Anakinra has been associated with an increased incidence of serious infections.[8],[9] Patients should discontinue use of this drug if they develop an infection and should not start using the drug if they have an active infection.

Other serious adverse reactions seen with anakinra are an effect on blood cells and the appearance of certain types of malignancies, including lymphoma, in patients with rheumatoid arthritis.[21]

Patients should not use etanercept and anakinra at the same time due to the risk of serious infections.[22]The combination of adalimumab and anakinra also has been associated with serious infections.[4]

Use of anakinra may lead to an increased risk of the viral infection herpes zoster — commonly known as shingles. Shingles is an infection caused by a herpes virus called varicella-zoster, the same virus that causes chickenpox. Herpes zoster causes a painful, blistering rash.[6],[7]

Etanercept (ENBREL)

Etanercept is another TNF blocker. It is approved by the FDA for rheumatoid arthritis, psoriatic arthritis, juvenile rheumatoid arthritis, plaque psoriasis in adult patients[23] and ankylosing spondylitis.[22] Unlike other drugs in its class, it is not approved for Crohn's disease.[24],[25]

Adverse effects

Serious adverse effects associated with the use of etanercept include serious infections, nervous system diseases that have been seen with TNF blockers, blood cell problems, heart problems, malignancies (lymphomas) and severe allergic reactions.[22]

There have been cases of optic neuritis (inflammation of the nerve that connects the eye with the brain) associated with the use of etanercept for juvenile arthritis.[26]

There also have been cases of bronchospasm reported in patients during treatment with TNF blockers. (Bronchospasm is a spasm of the smaller airways in the lungs — the kind of abnormality seen in asthma — making exhalation difficult and often noisy.)[27],[28]

The occurrence of sarcoid-like granulomatosis associated with TNF-blocker therapy was reported in 10 patients treated with these drugs.[5]

New Zealand's Medsafe reported that there have been postmarketing reports of spontaneous uveitis (swelling and irritation of the middle layer of the eye) and that there may be a risk of uveitis in patients using etanercept. Medsafe has updated the product information to include uveitis as an uncommon adverse reaction.[29]

In 2006, New Zealand's Medsafe issued a "Dear Healthcare Professional" letter advising that hepatitis B virus (HBV) reactivation has been reported in patients receiving the TNF antagonists etanercept, adalimumab and infliximab. Medsafe has advised that patients who are at risk of HBV infection should be evaluated for prior HBV infection before TNF antagonist therapy begins, and those who are carriers of HBV should be closely monitored for HBV reactivation during TNF antagonist therapy and for several months after therapy ends.[10]

A study published in Annals of the Rheumatic Diseases strongly suggests that rheumatoid arthritis patients treated with TNF blockers have an increased risk of developing the viral skin infection shingles. The study also showed that this risk appears to peak at approximately one year after starting the drug.[6]

Patients should not use etanercept and anakinra together because the combination is no more effective than etanercept alone and the risk of serious infections is higher.[22]

Patients with Wegener's granulomatosis (an autoimmune disease that affects blood vessels) who are taking drugs that suppress the immune system should not take etanercept.

Patients receiving cyclophosphamide (CYTOXAN, NEOSAR) therapy should not take etanercept.[22]

In 2013, Clinical Gastroenterology and Hepatology published an analysis of 34 cases of drug-induced liver injury that occurred with many different TNF-blocker drugs.[11]

If you become pregnant while taking Enbrel, you are encouraged to enroll in Amgen's Pregnancy Surveillance Program. You can enroll by calling 1-800-77-AMGEN (1-800-772-6436).

If you choose to breastfeed while taking Enbrel, you are encouraged to enroll in Amgen's Lactation Surveillance Program. You can enroll by calling 1-800-77-AMGEN (1-800-772-6436).[30]

Use of etanercept may lead to an increased risk of the viral infection herpes zoster — commonly known as shingles. Shingles is an infection caused by a herpes virus called varicella-zoster, the same virus that causes chickenpox. Herpes zoster causes a painful, blistering rash.[6],[7]

Regulatory actions surrounding etanercept

2008: The FDA issued an early communication informing the public that it was investigating a possible association between TNF blockers and the development of lymphoma and other cancers in children and young adults. The FDA stated that it would communicate the conclusions and any resulting recommendations to the public.[13]

2009: The FDA issued an advisory that it had completed its 2008 analysis and had concluded that there is an increased risk of lymphoma and other cancers associated with the use of etanercept, adalimumab and anakinra in children and adolescents. The black-box warning for these drugs and the Medication Guide were updated. The FDA also identified new safety information related to the occurrence of leukemia and new-onset psoriasis in patients treated with these drugs.[14]

2011: The FDA again informed the public that it continued to receive reports of a rare cancer of white blood cells (known as hepatosplenic T-cell lymphoma), primarily in adolescents and young adults being treated for Crohn's disease and ulcerative colitis, associated with use of these drugs as well as with azathioprine and mercaptopurine.[15]

In September, the FDA announced that it was updating the black-box warning for TNF blockers to include information on the risk of serious infections from Legionella and Listeria. This update was added based on a review of cases of infection in patients treated with TNF blockers.[16]

Infliximab (REMICADE)

Infliximab is another TNF blocker. It is approved by the FDA for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis[31] and chronic severe plaque psoriasis in adults.[32],[33]The use of infliximab for ulcerative colitis should be reserved for the most severe cases due to the long-term risks of infection and adverse effects.[34],[35]

The efficacy of infliximab in treating ankylosing spondylitis has been established only in the short term. Long-term treatment exposes patients to a risk of serious adverse effects such as cancer and certain infections, but the extent of that risk is not clear.[36]

Adverse effects

Serious adverse effects associated with the use of infliximab include serious infections that have sometimes been fatal, a lupus-like syndrome, heart problems and the appearance of certain types of malignancies.[32]

There have been multiple cases of severe liver damage, including acute liver failure and autoimmune hepatitis, reported in infliximab users worldwide.

There have been cases of bronchospasm reported in patients during treatment with anti-TNF drugs.[27],[28]

Adverse skin reactions are frequently seen in patients with ulcerative colitis and Crohn's disease.[8],[9] A study was conducted to examine wherein psoriasis was a result of the disease or an adverse effect of the drugs used to treat the disease. The results of the study indicate that psoriasis may be induced by drug therapy. Infliximab also is used to treat certain forms of psoriasis, and patients need to be aware and inform their health care providers if new or worsened cases of psoriasis occur.

Another study examined the medical records of 73 children receiving infliximab therapy for inflammatory bowel disease and found that six of the 73 children developed infliximab-induced psoriasis.[37]

The occurrence of sarcoid-like granulomatosis associated with TNF blocker therapy was reported in 10 patients treated with these drugs.[5]

In October 2004, the FDA released an update on the risk of lymphoma and cancer in patients treated with infliximab. According to the update, the incidence of lymphoma was 12 cases per 10,000 patient-years after a median follow-up of 1.1 years. This is six times the incidence in the general population.[38]

Some physicians advise women of childbearing age to use birth control when using etanercept or infliximab.[39]

In 2006, New Zealand's Medsafe issued a "Dear Healthcare Professional" letter advising that hepatitis B virus (HBV) reactivation has been reported in patients receiving the TNF antagonists etanercept, adalimumab and infliximab. Medsafe has advised that patients who are at risk of HBV infection should be evaluated for prior HBV infection before TNF antagonist therapy is begun, and those who are carriers of HBV should be closely monitored for HBV reactivation during TNF antagonist therapy and for several months after therapy ends.[10]

A study published in Annals of the Rheumatic Diseases strongly suggests that rheumatoid arthritis patients treated with TNF blockers have an increased risk of developing the viral skin infection shingles. The study also showed that this risk appears to peak at approximately one year after starting the drug.[6]

In 2013, Clinical Gastroenterology and Hepatology published an analysis of 34 cases of drug-induced liver injury that occurred with many different TNF blocker drugs.[11]

Studies show...

A Prescrire International article published in 2007 looked at infliximab and psoriasis. In the article, infliximab was compared with a placebo in two clinical trials. The article states that "[t]here are no published comparisons with other treatments, especially etanercept. ... In practice, when a TNF-alpha antagonist is chosen to treat a psoriatic patient with no other options, infliximab seems to have no advantages over etanercept."[40]

In other words, infliximab is no more effective than etanercept for treating psoriasis.

Infliximab is associated with various infections. A report reviewing the occurrence of pneumonia with infliximab use found that from January 1998 to December 2003, the FDA had received 84 cases of pneumonia following infliximab therapy.

Use of infliximab may lead to an increased risk of the viral infection herpes zoster — commonly known as shingles. Shingles is an infection caused by a herpes virus called varicella-zoster, the same virus that causes chickenpox. Herpes zoster causes a painful, blistering rash.[6],[7]

Regulatory actions surrounding infliximab

2004: The manufacturer of infliximab added a warning of severe liver toxicity, including liver transplants, to the drug's product label. Patients with signs or symptoms of liver dysfunction should be evaluated for evidence of liver injury.[32]

2008: The FDA issued an early communication informing the public that it was investigating a possible association between TNF blockers and the development of lymphoma and other cancers in children and young adults. The FDA stated it would communicate the conclusions and any resulting recommendations to the public.[13]

2009: The FDA issued an advisory that it had completed its 2008 analysis and concluded that there is an increased risk of lymphoma and other cancers associated with the use of TNF blockers in children and adolescents. The black-box warning for these drugs and the Medication Guide were updated. The FDA also identified new safety information related to the occurrence of leukemia and new-onset psoriasis in patients treated with these drugs.[14]

2011: The FDA again informed the public that it continued to receive reports of a rare cancer of the white blood cells (known as hepatosplenic T-cell lymphoma), primarily in adolescents and young adults being treated for Crohn's disease and ulcerative colitis, associated with use of these drugs as well as with azathioprine and mercaptopurine.[15]

In September, the FDA announced that it was updating the black-box warning for TNF blockers to include information on the risk of serious infections from Legionella and Listeria bacteria. This update was added based on a review of cases of infection in patients treated with TNF blockers.[16]

2017: The FDA updated the drug product label of infliximab to warn that women using infliximab had an increased risk of cervical cancer. The update also stated that in some patients a heart attack or stroke may occur within 24 hours of taking the drug.[41]