- Enbrel Side Effects
- In Summary
- For the Consumer
- For Healthcare Professionals
- Further information
- More about Enbrel (etanercept)
- What Is Enbrel (Etanercept)?
- How does Enbrel (etanercept) work to treat plaque psoriasis?
- How is Enbrel (etanercept) administered?
- Who can take Enbrel (etanercept)?
- What are the side effects and risks of taking Enbrel (etanercept)?
- Can Enbrel (etanercept) be used with other treatments or drugs?
- ‘I just want it straight’
- Signals of harm
- FDA scrutiny
- Abundant conflicts in safety studies
What should I discuss with my healthcare provider before using etanercept?
You should not use etanercept if you are allergic to it, or if you have a severe infection such as sepsis (infection of the blood).
Tell your doctor if you have any signs of infection, such as:
- fever, chills, sweats, flu-like symptoms, feeling very tired;
- cough, shortness of breath, coughing up blood;
- diarrhea, weight loss;
- skin warmth or redness, open sores; or
- increased urination, burning when you urinate.
Tell your doctor if you have ever had:
- a weak immune system, HIV, tuberculosis;
- hepatitis B;
- congestive heart failure;
- a nerve disorder such as multiple sclerosis or Guillain-Barré syndrome;
- a latex allergy; or
- if you are scheduled to receive any vaccines.
Using etanercept may increase your risk of developing certain types of cancer, including lymphoma. This has occurred mainly in children and teenagers using TNF-blockers. However, anyone with an inflammatory autoimmune disorder may have a higher risk of lymphoma. Talk with your doctor about your own risk.
Tell your doctor if you have ever had tuberculosis or if anyone in your household has tuberculosis. Also tell your doctor if you have recently traveled. Tuberculosis and some fungal infections are more common in certain parts of the world, and you may have been exposed during travel.
Children should be current on all childhood immunizations before starting treatment with etanercept.
Tell your doctor if you are pregnant or plan to become pregnant. You will need to tell your baby’s doctor if you used etanercept during pregnancy, especially before the baby receives any childhood vaccines.
It may not be safe to breast-feed while using this medicine. Ask your doctor about any risk.
How should I use etanercept?
Before you start treatment with etanercept, your doctor may perform tests to make sure you do not have an infection.
Etanercept is injected under the skin. A healthcare provider may teach you how to properly use the medication by yourself. Read and carefully follow any Instructions for Use provided with your medicine. Ask your doctor or pharmacist if you don’t understand all instructions.
Do not shake this medicine. Prepare an injection only when you are ready to give it. Do not use if the medicine looks cloudy, has changed colors, or has particles in it. Call your pharmacist for new medicine.
You may need to mix etanercept with a liquid (diluent). When using injections by yourself, be sure you understand how to properly mix and store the medicine.
Each cartridge, injection pen, or prefilled syringe is for one use only. Throw it away after one use, even if there is still medicine left inside.
Etanercept doses are based on weight in children. Your child’s dose needs may change if the child gains or loses weight.
If you need surgery, tell the surgeon ahead of time that you are using etanercept.
Etanercept affects your immune system. You may get infections more easily, even serious or fatal infections. Your doctor will need to examine you on a regular basis.
If you’ve ever had hepatitis B, using etanercept can cause this virus to become active or get worse. You may need frequent liver function tests while using this medicine and for several months after you stop.
Carefully follow all storage instructions provided with your medicine. Cartridges, injection pens, prefilled syringes, vials, and diluent are stable at specific temperatures for only a certain number of days or weeks. Throw away any medicine not used within that time.
Keep unopened etanercept in its original carton in the refrigerator. Protect from light. Do not freeze. Do not use after the expiration date on the label has passed.
If you need to store etanercept at room temperature, protect the medicine from light and extreme hot or cold temperatures. Once the medicine has reached room temperature, you should not put it back into the refrigerator.
Use a needle and syringe only once and then place them in a puncture-proof “sharps” container. Follow state or local laws about how to dispose of this container. Keep it out of the reach of children and pets.
There may be a possible answer to this but not so sure there is a solution. There are many others out there who also have the same problem. Weight gain with no probable cause and no loss with diet and exercise means there is a imbalance in body chemistry. In this case it’s a domino effect of problems. Some of the things affected are various glands and some hormones they produce, the brain, insulin (a hormone) leptin, fat cells and TNF factor. Leptin is a major game player in weight and appetite but TNF is the start of the problem.
I believe Enbrel is a TNF blocker. It took a few hours of research to solve for X which was why Enbrel may cause weight gain. There were many x’s to solve here but this excerpt from a research article Is one part of the solution.
It has recently been reported that tumor necrosis
factor-a(TNFa) could be involved in the pathogenesis of insulin resistance.10 ±12 This cytokine is produced in
excess by adipocytes of obese individuals, and this
results in a decrease in insulin-receptor kinase activity
in muscle and fat, thus contributing to the onset of
obesity-related insulin resistance.
Furthermore, the activation of the TNF a system seems to be associated with increased energy expenditure and weight loss in
This is what’s happening with Enbrel.
The blocking of TNF by Enbrel will decrease energy output. You now run on fewer calories meaning more of what you eat will converted to adipose tissue (fat cells). This also has a direct effect on the leptin protein responsible for signaling to the brain and other glands controlling appetite. While you may not have an increase or decrease in appetite a false signal can trigger fat storing hormones. Just another piece to the puzzle.
One more possible problem is now insulin production is involved because of the excess weight and inability to burn off these calories so you have to keep off the carbs.
Here is a link to the research article : https://www.researchgate.net/publication/12957679_Relationship_b…
TNF Is an inflammatory cell commonly produced in a number of immune disorders like rheumatoid arthritis.
I would suggest possibly getting checked for leptin and leptin resistance, something now found as a problem in obesity. Some people have been treated with a drug called Amylin, a peptide hormone cosecreted with insulin.
I’m certain there is more out there on this problem but we now have a basic answer. While we need drugs for some problems they can create other problems never anticipated. Worse yet is unless your prepared to do some home work you’ll never get an answer or solution. These are problems most doctors are unable to answer. He/she learned about Enbrel from a drug rep.
Enbrel Side Effects
Generic Name: etanercept
Medically reviewed by Drugs.com. Last updated on Jan 14, 2019.
- Side Effects
Note: This document contains side effect information about etanercept. Some of the dosage forms listed on this page may not apply to the brand name Enbrel.
Common side effects of Enbrel include: infection and injection site reaction. See below for a comprehensive list of adverse effects.
For the Consumer
Applies to etanercept: subcutaneous powder for solution, subcutaneous solution
Subcutaneous route (Solution; Powder for Solution)
Patients treated with etanercept are at increased risk for infections, some progressing to serious infections leading to hospitalization or death. These infections have included bacterial sepsis, tuberculosis, invasive fungal and other opportunistic infections, including Legionella and Listeria. Evaluate for latent tuberculosis and treat if necessary prior to initiation of therapy. Discontinue etanercept if a serious infection or sepsis occurs during treatment. Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including etanercept.
Subcutaneous route (Solution)
Patients treated with etanercept products are at increased risk for infections, some progressing to serious infections leading to hospitalization or death. These infections have included bacterial sepsis, tuberculosis, invasive fungal and other opportunistic infections, including Legionella and Listeria. Evaluate for latent tuberculosis and treat if necessary prior to initiation of therapy. Discontinue etanercept-szzs if a serious infection or sepsis occurs during treatment. Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including etanercept products.
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:
- sore throat
- Congestion in the chest
- fast heartbeat
- frequent or painful urination
- itching, pain, redness, or swelling on the skin
- joint or muscle stiffness, tightness, or rigidity
- 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
- dark urine
- decreased urine output
- decreased vision
- difficult, irregular, troubled, or labored breathing (or difficulty with 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
- 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
- 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
- sores, ulcers, or white spots on the lips or in the mouth
- swelling of the face, fingers, feet, or lower legs
- 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
- 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:
- Loss of energy or weakness
- pain or burning in the throat
- redness or itching, pain, or swelling at the injection site (under the skin)
- runny or stuffy nose
- stomach pain
- Bumps below the skin
- dry eyes
- dry mouth
- hair loss or thinning
- 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
- weight gain
For Healthcare Professionals
Applies to etanercept: subcutaneous kit, subcutaneous solution
Very common (10% or more): Non-upper respiratory infection (38%), upper respiratory infection (29%), rhinitis (12%)
Common (1% to 10%): Pharyngitis, cough, respiratory disorder, sinusitis
Uncommon (0.1% to 1%): Interstitial lung disease (including pneumonitis and pulmonary fibrosis)
Very common (10% or more): Infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections)
Uncommon (0.1% to 1%): Serious infections (including pneumonia, cellulitis, septic arthritis, sepsis, parasitic infection)
Rare (less than 0.1%): Tuberculosis, opportunistic infections (including invasive fungal, protozoal, bacterial, atypical mycobacterial, viral infections, Legionella), subacute cutaneous lupus erythematosus, discoid lupus erythematosus, lupus-like syndrome
Frequency not reported: Listeria, hepatitis B reactivation
Postmarketing reports: Macrophage activation syndrome, systemic vasculitis, sarcoidosis
Very common (10% or more): Headache (17%)
Common (1% to 10%): Dizziness
Rare (less than 0.1%): Seizures, CNS demyelinating events suggestive of multiple sclerosis or localized demyelinating conditions, such as optic neuritis and transverse myelitis
Very rare (less than 0.01%): Peripheral demyelinating events (including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, multifocal motor neuropathy)
Postmarketing reports: Paresthesias
Uncommon (0.1% to 1%): Dry mouth
Rare (less than 0.1%): Anorexia
Frequency not reported: Intestinal perforation
Postmarketing reports: Inflammatory bowel disease (IBD)
Rare (less than 0.1%): Worsening of congestive heart failure
Postmarketing reports: Chest pain
Common (1% to 10%): Pruritus, rash
Rare (less than 0.1%): Cutaneous vasculitis (including leukocytoclastic vasculitis), Stevens-Johnson syndrome, erythema multiforme
Very rare (less than 0.01%): Toxic epidermal necrolysis
Postmarketing reports: Angioedema
Very common (10% or more): Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling)
Uncommon (0.1% to 1%): Thrombocytopenia
Rare (less than 0.1%): Anemia, leukopenia, neutropenia, pancytopenia
Very rare (less than 0.01%): Aplastic anemia
Postmarketing reports: Lymphadenopathy
Uncommon (0.1% to 1%): Uveitis, scleritis
Rare (less than 0.1%): Inflammation, dry eyes
Common (1% to 10%): Allergic reactions, autoantibody formation
Uncommon (0.1% to 1%): Systemic vasculitis (including anti-neutrophilic cytoplasmic antibody positive vasculitis)
Rare (less than 0.1%): Serious allergic/anaphylactic reactions (including angioedema, bronchospasm), sarcoidosis
Frequency not reported: Macrophage activation syndrome, worsening of symptoms of dermatomyositis
Uncommon (0.1% to 1%): Non-melanoma skin cancers
Rare (less than 0.1%): Lymphoma, melanoma
Frequency not reported: Leukemia, Merkel cell carcinoma, leukemia
Rare (less than 0.1%): Elevated liver enzymes, autoimmune hepatitis
Postmarketing reports: Hepatitis B reactivation
Frequency not reported: Urinary tract infection
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.
Common (1% to 10%): Fever, asthenia
The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infections, bronchitis, bladder infections and skin infections), allergic reactions, development of autoantibodies, itching, and fever.
2. “Product Information. Enbrel (etanercept).” Wyeth-Ayerst Laboratories, Philadelphia, PA.
3. Cerner Multum, Inc. “UK Summary of Product Characteristics.” O 0
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.
Some side effects may not be reported. You may report them to the FDA.
- What is the difference between Erelzi and Enbrel?
- How many biosimilars have been approved in the United States?
- What are the new drugs for the treatment of plaque psoriasis?
- What are the new drugs for the treatment of rheumatoid arthritis (RA)?
More about Enbrel (etanercept)
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- Plaque Psoriasis
What Is Enbrel (Etanercept)?
Enbrel (etanercept) is a systemic treatment option for plaque psoriasis in patients 4 years old and above. It is also approved for treating psoriatic arthritis and rheumatoid arthritis. The medicine has been on the market under the brand name Enbrel since 2004, although it may be available generically in coming years1.
The active ingredient in Enbrel is etanercept, which is a type of biologic therapy that is created in the laboratory using human proteins. Enbrel is generally prescribed for people who need a stronger systemic medicine or phototherapy to treat their psoriasis symptom than topical treatments, or for people who have tried other types of systemic or biologic treatments but they have not worked well enough2.
As a systemic biologic therapy, Enbrel affects the way the patient’s immune system works to treat psoriasis. It is administered through an injection (usually once or twice per week) as a maintenance treatment to be taken over a longer period of time.
How does Enbrel (etanercept) work to treat plaque psoriasis?
Plaque psoriasis is a chronic autoimmune condition, in which excess inflammation in the body causes new skin cells to be produced more quickly than older skin cells can be shed. This causes plaques to develop on the skin. People with psoriasis have an immune system that is overactive and produces too many proteins called cytokines. These cytokines play a key role in the immune system processes that cause excess inflammation.
The active ingredient in Enbrel, etanercept, is a type of biologic therapy called a tumor necrosis factor-alpha (TNF-alpha) blocker2. TNF-alpha is a type of cytokine that is over-produced in the bodies of people with psoriasis, contributing to the excess inflammation that causes symptoms. Etanercept works by targeting and blocking the function of TNF-alpha cytokines to disrupt the cycle of inflammation and reduce symptoms3.
Clinical studies have examined the effect of Enbrel in treating psoriasis. The results show that after three months of treatment with Enbrel, almost half of adults had a reduction in their symptoms of at least 75%, and three-quarters of patients had 50% reduction4. Many of the patients had symptom improvement that was maintained after 6 months of treatment. Some patients (around 18%) begin to see improvement after 2 weeks of treatment with Enbrel.
How is Enbrel (etanercept) administered?
Patients take Enbrel by injecting it using a pre-filled syringe or auto-injector pen, usually into the thigh, upper arm, or abdomen. Also comes as “Enbrel Mini single-dose prefilled cartridge for use with the AutoTouch reusable autoinjector.5 Most patients are able to inject themselves with the medicine after being trained by a healthcare provider about how to do it safely. Injecting into a different area for each dose can help to reduce side effects on the skin, such as soreness2.
Generally, the starting dose of Enbrel in adults is one injection twice per week for the first 12 weeks. After that, the usual dose is one injection per week. The medicine needs to be kept in the refrigerator when not in use; it can be kept at room temperature, but only for a maximum of 14 days3. Pediatric patients will receive weight-based dosing.
Who can take Enbrel (etanercept)?
Enbrel is approved for treating patients 4 years old and above with moderate-to-severe plaque psoriasis who need treatment with phototherapy or systemic treatments. It is not suitable for women who are pregnant or breastfeeding3.
Before prescribing Enbrel, healthcare providers need to know if the patient4:
- has or has had heart failure
- has a surgery planned
- has a vaccine planned
- has or has had a nervous system condition, like multiple sclerosis or Guillain-Barre syndrome
- has been in contact with someone with chicken pox
- is allergic to latex
What are the side effects and risks of taking Enbrel (etanercept)?
TNF-alpha blocker medicines such as Enbrel are extremely strong and can cause some serious side effects. The way the drug affects the immune system can make it harder to fight various types of infections2. If you currently have any type of infection, it is unlikely your healthcare provider will prescribe Enbrel until the infection is completely cleared. Patients are tested for infections (such as tuberculosis) before starting Enbrel and are monitored for symptoms of infection during and after treatment. People who have had a hepatitis B infection in the past may develop the infection again during treatment with Enbrel. Patients will be tested for hepatitis B before starting treatment4.
In a small number of patients, Enbrel can cause very serious problems such as4:
- nervous system problems (such as multiple sclerosis, seizures, or eye problems)
- blood problems that affect the body’s ability to fight infections and/or stop bleeding
- heart failure
- worsened psoriasis symptoms
- allergic reactions
- autoimmune reactions, such as lupus-like syndrome or autoimmune hepatitis
- Cases of lymphoma have been reported in children and adolescents/li>
To monitor for these conditions, patients treated with Enbrel will usually have regular blood tests and symptom screening by healthcare providers.
The most common side effects of treatment with Enbrel are not as serious, such as reactions on the skin where the medicine is injected (redness, pain, itching, or swelling). These reactions tend to be worse when starting treatment, and then get better. Other common side effects are headaches and upper respiratory infections.
Can Enbrel (etanercept) be used with other treatments or drugs?
Your healthcare provider will advise you about whether you can take Enbrel with other types of treatments with psoriasis. Many patients are able to take Enbrel in combination with topical treatments, the systemic drug methotrexate, and/or phototherapy.
This is the first of two stories on monitoring the safety of new drugs — read the second here.
When a new remedy for rheumatoid arthritis arrived, ads called it a “unique” breakthrough that would “transform expectations” for patients and doctors. “If I knew then what I know now about rheumatoid arthritis, I would have been more proactive,” said one young woman, pictured happily kayaking.
Treatments for the disabling disease afflicting about 1.5 million Americans can have terrifying side effects, so doctors and patients were excited when Actemra reached the U.S. market in 2010. Unlike competing drugs, it wasn’t associated with heart attacks, heart failure, or life-threatening lung complications.
Yet hundreds of patients taking Actemra have died from such problems, and many more have suffered harm. STAT analyzed more than 500,000 side-effect reports on rheumatoid arthritis drugs, and found clear evidence that the risks of heart attacks, strokes, heart failure, and other conditions were as high or higher for Actemra patients than for patients taking some competing drugs.
Most of those medications warn about these risks on their labels. Actemra does not.
Consumers are barraged every day with drug ads accompanied by numbing lists of side effects, but STAT’s investigation shows that the risks to patients might be greater than they are led to believe. The Food and Drug Administration has received reports on 1,128 people who died after taking Actemra, and has reviewed its safety several times since it was approved. But the agency doesn’t have sophisticated tools to determine whether the drug was a culprit or a bystander in those deaths.
Though the agency is charged with monitoring the safety of prescription drugs, it doesn’t verify the side-effect reports it receives. The documents often lack crucial information, and they don’t prove that Actemra was the cause. Still, they can be telling.
In one striking example, obtained through the Freedom of Information Act, a doctor said no factor other than the drug could have explained a 73-year-old man’s fatal brain bleed two days after receiving an intravenous Actemra treatment. Another said of a 62-year-old German woman’s heart attack in 2014: “The company assessed fatal myocardial infarction as related to (Actemra).” That company was Roche, Actemra’s manufacturer.
But neither Roche nor the FDA has moved to change Actemra’s label to alert patients and doctors that potential risks turned up in the reports, as well as in clinical studies completed after the drug went on the market.
Experts who examined the data at STAT’s request said the FDA should immediately consider warnings for heart failure and pancreatitis — an inflammation of the pancreas that in its acute form can kill up to 50 percent of patients. They said the evidence that Actemra might increase the risk of heart attacks, strokes, and interstitial lung disease, a sometimes-fatal scarring of lung tissue, is less convincing but warrants further review.
The failure to warn the public, experts say, highlights the FDA’s inability to adequately scrutinize the safety of drugs after they have been approved, and to act promptly when potential danger signs appear.
“We’ve done a very good job of making it easier to approve drugs, often based on very preliminary evidence. But we haven’t ramped up the standards of post-marketing surveillance to make sure that what’s been out there for several years is safe and effective,” said Dr. Vinay Prasad, an oncologist and medical ethicist at the Oregon Health and Science University. “The system is broken, and all the financial incentives are lined up to keep it broken.”
The FDA has been trying for years to strengthen its monitoring of drugs, so far without much success. In 2015, the Government Accountability Office reported that the “FDA lacks reliable, readily accessible data” needed for systematic oversight and to ensure that drug companies comply with agreements to track safety after a drug comes to market.
It has spent $207 million since 2009 to build a troubled big-data system called Sentinel that scours insurance company records for serious side effects of recently approved drugs. Among its major shortcomings, critics say: It’s missing most data on deaths related to prescription drugs. The agency would not say if a Sentinel assessment of Actemra, also known by the generic name tocilizumab, has ever been initiated.
Sentinel’s track record is all the more worrisome amid the rise of an approve-first, monitor-later philosophy in Washington. The recently passed 21st Century Cures Act is intended to speed federal sign-off on new medicines by streamlining pre-approval reviews of drug safety and efficacy. The Trump administration and prominent members of Congress are itching to push drugs through the regulatory pipeline faster than ever, then hope to catch any missed safety problems after they’re on the market.
Taken intravenously or by injection, Actemra has been used by more than 760,000 patients globally and generated sales of $1.7 billion last year, making it Roche’s fifth highest-grossing drug. While primarily used to treat rheumatoid arthritis — an autoimmune disease that causes pain, swelling, and stiffness in joints — doctors prescribe the drug “off-label” for about 60 other conditions for which it has not completed testing for efficacy and safety.
The FDA declined to comment about Actemra. In a written statement, a spokeswoman said the agency “continually monitors postmarketing safety of approved drug products and remains committed to informing the public in a timely manner when the FDA identifies safety issues.”
Dr. Jeffrey Siegel, senior medical director for rheumatology products at Roche and its subsidiary Genentech, said STAT’s examination of Actemra included “important questions that we think about all the time. … We try very hard not to be complacent, and to fully explore these issues.”
In an interview at Genentech’s headquarters in South San Francisco, he cited a recent study as “definitive” proof that the drug does not increase cardiovascular risk. But experts consulted by STAT disputed that claim.
In 2008, when FDA scientific advisers met at a Silver Spring, Md., hotel near the agency’s headquarters to debate whether to recommend approval of Actemra, they were haunted by a notorious error just a few years earlier.
Vioxx, another arthritis drug, had been pulled from the market after it was implicated in tens of thousands of heart attack deaths, a problem that hadn’t shown up in the short-term clinical trials used for approval. Those early studies suggested Vioxx would be safer for patients than existing medicines. The new drug, Actemra, similarly seemed relatively safe based on short-term studies.
“I can foresee the possibility that in five years there’s another hearing like the one on Vioxx, where the cardiologists … say to us, what were you guys thinking when you approved this drug?” Dr. David Felson, a Boston University rheumatologist, worried aloud, according to a transcript of the Actemra meeting. He described patient blood test data showing elevated levels of the blood lipids cholesterol and triglyceride, suggesting that Actemra might cause serious heart problems over time.
Felson and every other scientific adviser ultimately recommended approval, on one condition: Roche would sponsor multiyear studies to monitor for unseen problems and cardiovascular events. In the meantime, no mention of those possible hazards would appear on Actemra’s label — the key reference doctors and patients use to weigh a drug’s risks and benefits.
In a recent interview, Felson called STAT’s findings “noteworthy and concerning.” He said Siegel’s assertion that Actemra’s cardiovascular safety had been proved “sounds like a drug company trying to defend themselves.”
Alicia Airs, 40, of Youngstown, Ohio, said her doctor told her that Actemra had minimal side effects when prescribing it for her rheumatoid arthritis. Stephanie Strasburg for STAT
‘I just want it straight’
Actemra might not be more dangerous than other arthritis drugs — many of which can have lethal side effects — but patients and doctors are misled into believing it might be safer because frequently reported, serious problems aren’t noted on its warning label.
Alicia Airs of Boardman Township, Ohio, said her doctor told her that Actemra had minimal side effects when prescribing it for her rheumatoid arthritis. But Airs, 40, said she suffered heart palpitations for days immediately after her first Actemra infusion in April.
This symptom — often reported by other patients on social media and in complaints to the FDA — is not listed on the drug’s warning label. When she sought help, her rheumatologist told her he’d never heard of such a side effect and referred her to her general practitioner.
“When I went to the doctor, they offered me an antidepressant, but I said I’m not anxious,” said Airs, still angry. “If you give them a symptom they don’t know, they treat you like you’re a little crazy … I felt like I was dismissed.”
Rheumatoid arthritis is different from the more common osteoarthritis, which is primarily a disease of old age. It often starts in middle age, but it also affects children and young adults like Alejandra Calzadillas, a 25-year old student in Seattle. She said that after starting Actemra, she experienced memory lapses and mental sluggishness she called “brain fog.”
“I’ve had moments where I’ve gone to start my car … and not remembered how to turn it on,” or at other times forgotten how to put on makeup, she said. Such cognitive side effects are not listed on the drug’s label but are a common complaint among Actemra users.
“It’s terrifying with a drug when you come to the realization that you haven’t been warned by your doctors,” Calzadillas said. “It kind of ruins your life.”
In interviews and reports to the FDA, patients described other unlabeled adverse events, including the heart-rhythm disorder tachycardia, small strokes, and tremors.
“I don’t want any sugar coating — I just want it straight,” Michelle Lucci, a 53-year-old banking consultant near Tampa, Fla., said in an interview. She suffered something else doctors don’t warn about: hair loss — another common complaint.
“Why would you use something that would do that when there are 15 other drugs to try? That was really depressing,” Lucci said. “ has been a miracle for some people. But I think that on the whole, more people have serious side effects.”
Signals of harm
In a review of millions of reports to the FDA involving more than 100 drugs approved since 2010, Actemra stood out. It showed that Actemra patients had experienced an unusually large number of serious side effects that didn’t appear on the drug’s warning label.
The initial review was performed for STAT by Advera Health Analytics in Santa Rosa, Calif., a company that collects and curates drug-related complaints to the FDA Adverse Events Reporting System, known as FAERS. The company then provided comparison data for all major rheumatoid arthritis drugs.
STAT’s analysis of that data, including more than 13,500 FAERS reports on Actemra, showed higher than expected numbers of several serious problems when compared to competing drugs. These included the blockbusters Humira and Remicade, which have many more users.
For example, about the same number of cases of interstitial lung disease have been reported in Actemra users as have been experienced by Humira users, and many more cases than with Remicade. The other drugs’ labels warn about that possible side effect. Actemra’s does not.
The results were similar for heart attacks, strokes, and heart failure. None of these conditions appears on Actemra’s label, while both Humira’s and Remicade’s warn about heart attacks and heart failure, and Humira’s also lists stroke as a risk.
Pancreatitis was reported in 132 patients taking Actemra, including 26 who died.
“Pancreatitis is very, very rare” and potentially life-threatening, Felson said, so that many cases is a serious matter. The disorder is known to be triggered by high cholesterol levels, and Actemra is known to increase these lipids, he noted. “So if I see a signal for pancreatitis among users, I would be worried.”
The actual number of deaths among Actemra users is likely higher, because the FDA monitoring system captures a fraction of adverse events that patients experience. Patients and their doctors are not obligated to report to the FDA or to drug companies, and the agency and outside experts have estimated that these filings represent only about 10 percent of cases, although some say the rate might have increased in recent years.
Dr. Eric Brodsky, associate director of the agency’s drug labeling development team, said there are numerous other challenges in using FAERS data. Inaccuracies, concurrent illnesses, and effects of other drugs a patient may be taking mean FAERS reports can “show an association, but not a causal relationship,” he said — signals of harm, not proof.
Adding warnings based on uncertain evidence from FAERS, said Roche’s Siegel, “would be a disservice to clinicians, because it would raise the concern of something where there really isn’t a risk.”
One difficulty in assessing whether arthritis drugs cause cardiovascular problems is that the disease itself is a risk factor for heart disease. That’s where longer-term and larger post-marketing safety studies can help.
In one of these studies, required by the FDA, Actemra was compared head-to-head with another arthritis drug — Enbrel, whose label strongly cautions about use by patients with cardiovascular disease, particularly heart failure. That was the study Siegel called “definitive” evidence of Actemra’s safety.
It found rates of stroke and heart failure were about 1.5 times higher in Actemra patients. That difference wasn’t statistically significant, but experts told STAT it was still worrisome.
“Since Enbrel includes a high-profile warning and precaution in the label about heart failure, it is concerning that Actemra might be similar or worse,” said Dr. Steven Woloshin, a professor of medicine at The Dartmouth Institute and an expert on risk communication.
Felson concurred. While the actual risk remains statistically uncertain, he said, if Enbrel’s label warns for heart failure, the FDA should consider that warning for Actemra.
Dr. David Pisetsky, a professor at Duke University who served with Felson on the FDA advisory panel for Actemra, cited another recent study, based on thousands of insurance claims, which concluded there was no increased cardiovascular risk among patients on the drug. But the study found nearly identical rates of heart attacks and strokes among users of competing drugs — some of which are labeled for those problems.
“If the rates are similar, it should be on the (Actemra) warning label,” although the company and FDA might have additional data to consider, Pisetsky said.
There was a lone dissenter on the 2008 FDA advisory panel that recommended Actemra’s approval — the single nonexpert, consumer representative Diane Aronson. She called STAT’s findings “very troubling.”
“As a ‘no’ voter, I felt there wasn’t enough data, it was too short-term,” Aronson said in an interview, regarding the research supporting approval. “There were some red flags.” Others on the panel nonetheless supported the drug because they “really believe that the long-term studies will be acted upon” and the warning label adjusted if needed, she said. “That’s why they voted ‘yes.’”
That hasn’t happened.
Alejandra Calzadillas, 25, said that she experienced memory lapses and mental sluggishness after starting Actemra. Courtesy Alejandra Calzadillas
Courtesy Alejandra Calzadillas
Actemra has appeared on the FDA’s radar at least three times since it was approved in 2010, but most safety concerns have been set aside — once after Genentech pushed back against an agency recommendation to expand the warning label.
In 2011, “fatal anaphylaxis” was added to the label, at Roche’s request, after two deaths occurred.
A year later, Roche asked the FDA to allow wider use of Actemra, for patients who have failed to get relief from only one other type of rheumatoid arthritis drug, rather than two. In its review, the agency found 258 cases of pancreatitis and 185 of interstitial lung disease among Actemra users in clinical trials, FAERS, and epidemiological data, according to a 2012 report.
An FDA clinical expert said that despite uncertainty in the pancreatitis data, a warning should be included on the drug label “given the potential seriousness of the event.” The expert wrote that interstitial lung disease should be monitored closely.
“The system is broken, and all the financial incentives are lined up to keep it broken.”
Dr. Vinay Prasad, an oncologist at the Oregon Health and Science University
But Genentech convinced the agency not to label for pancreatitis, arguing that the illness, like interstitial lung disease, had occurred at expected rates for rheumatoid arthritis patients. Without providing specifics about the company’s arguments, the FDA report said there wasn’t “sufficient evidence to support causality and include information in the product label at this time.” The agency approved the broader use of Actemra.
In 2013, the FDA drew the same conclusion about pancreatitis in a full safety review of Actemra, required by law 18 months following approval or after 10,000 patients have taken a medicine. STAT obtained the report — heavily redacted to protect commercial secrets — under the Freedom of Information Act.
It addressed progress on ongoing studies and about 3,500 reports to FAERS that had arrived as of August 2012, including 118 deaths — 42 linked to cardiac arrest or myocardial infarction. The FDA concluded that no further label changes were warranted.
The report said the heart attack cases were confounded by such factors as age or a history of heart problems, and by rheumatoid arthritis itself. And it noted that rates of serious adverse events, including heart disorders, “have remained stable or decreased numerically over time.”
The agency said it would revisit the issue when a long-term cardiovascular safety study was completed. That was the study published last year that compared Actemra to Enbrel. The FDA and Genentech declined to say whether this latest data had been analyzed by the agency.
Federal law requires companies to ensure accurate labeling. The FDA can force changes when serious hazards come to light after approval. Companies that don’t comply can be fined up to $10 million. But an FDA spokesperson said the agency had never fined a company for labeling failures.
That might be because once a drug has been approved, “the leverage that the FDA has is infinitely smaller,” said Dr. Caleb Alexander, co-director of the Johns Hopkins Center for Drug Safety and Effectiveness.
“We are so reliant on a strong, impartial, and scientifically driven Food and Drug Administration,” he said, calling the agency’s unwillingness to talk about Actemra troublingly typical. “This is exactly the type of setting where greater transparency on the part of the FDA would be welcome” — ongoing evaluations of “extremely serious risks associated with specific products.”
Some critics point to a revolving door culture — with FDA scientists regularly moving to more lucrative jobs with the companies they once regulated — as another concern, saying it can foster a cozy relationship between the agency and the drug industry.
Siegel, for example, was an FDA manager who guided Actemra through its approval before leaving a few months later for Roche and Genentech to oversee further development of the drug. He said the timing was coincidental and unrelated to his review of Actemra for the FDA.
Federal rules prohibit him from representing his employer before the agency on specific projects he worked on as a government official, including Actemra’s use for rheumatoid arthritis, he said. But he does work with the FDA to gain approval for other uses of the drug, based partly on safety data he evaluated as a government official.
Abundant conflicts in safety studies
The FDA relies heavily on post-marketing studies to monitor drugs’ safety, research that is almost always funded and conducted by the companies making the medications. That was the case with Actemra.
“One of the recurring criticisms of our drug safety system is that we rely upon the very companies that are so financially invested in a product’s success to conduct the studies that explore safety concerns,” Alexander said.
All 11 authors of the Roche-funded study Siegel called “definitive” disclosed financial conflicts with either Roche or Genentech, including five who worked for these companies. Similarly, three of the seven authors of the insurance claims study, funded by Genentech, were company employees, and three others disclosed financial conflicts with Genentech.
The companies also pay consulting fees and offer perks to many other academic researchers, and fund leading rheumatoid arthritis registries that track patient outcomes over many years.
For example, they paid Dr. Joel Kremer, founder and chief medical officer of the Corrona registry — the largest such organization — about $130,000 for research, consulting, and travel from 2013 to 2015, according to the federal Open Payments database. Corrona, a Southborough, Mass., company owned primarily by a private equity firm, guards its data closely. Corrona CEO Raymond Hill would not identify the group’s scientific advisers, citing privacy concerns, and said its data are restricted primarily to paying customers, such as Genentech.
Dr. David Blumenthal, a Veterans Affairs rheumatologist and professor at Case Western Reserve University in Cleveland, said he doesn’t think the evidence of harm from Actemra is yet strong enough to warrant label changes. But Blumenthal, who also served on the FDA advisory committee before Actemra was approved, said he worries about manufacturers’ influence over research.
“The companies don’t want to kill the golden goose,” he said. “I always wonder whether industry is basically commissioning a paper, knowing what the results are going to be, to get a certain point of view out in the literature. In the world of politics, this is like the difference between real news and fake news.”
Prasad, of Oregon Health and Science University, argued that the FDA should design and manage large post-market trials, paid for but not influenced by the industry.
“So much of the data is in the hands of people who are conflicted,” he said. “We have to ask ourselves if the current system is in the interests of public health.”
For all the questions about Actemra, its market and Genentech’s profit potential keep growing.
In May, the FDA approved Actemra to treat giant cell arteritis, an inflammation of the blood vessels that, like rheumatoid arthritis, is an autoimmune disease. It based the decision on a one-year study by Genentech that involved just 149 patients who took the drug. In a press release, the FDA said the trial’s “overall safety profile … was generally consistent with the known safety profile of Actemra.”
Reporting contributed by Sheila Kaplan.
If Enbrel’s business model is a good fit for today’s economy, its operation is a good match for the nature of disease today. Rich countries have moved from an infectious era to a degenerative era to a lifestyle era, and now to a new autoimmune era that encompasses the three prior eras all at once.
We can get a sense of what this autoimmune era means by understanding Enbrel’s mechanism of action. The drug interferes with a naturally occurring protein called tumor necrosis factor (TNF). Interfering with TNF is not normally something that we would want to do. TNF is released by immune cells for a reason: it binds to receptors on the surface of cells and triggers a cell death pathway. That is, TNF gives the immune system a way to destroy potentially harmful cells by causing them to commit suicide. But, in autoimmune disease, the immune system is not attacking potentially dangerous cellular intruders-it is attacking the body’s own cells. In this immune response gone awry, rogue TNF plays a role in excessive inflammation and resulting impairments to mobility and comfort. Enbrel is supposed to interfere with TNF by acting as a decoy. But as with any decoy, Enbrel can trick agents it never intended to snare.
Consequently, Enbrel’s immunosuppressant aspect also bears its principal risk. In patients contracting autoimmune diseases, the immune system is so eager to fight absent infection that it attacks the patient’s own body. Treating autoimmune diseases requires suppressing the immune system, which in turn compromises the body and thus makes it vulnerable to old-fashioned infections. In 2008, Enbrel and its cousin TNF-inhibitors Remicade and Humira were required to display the FDA’s strongest “black box” warning, meaning that the package insert must alert patients that Enbrel can cause death. One reason this warning was added: rare reports of Enbrel patients with the most prominent infectious disease of the 18th and 19th centuries: tuberculosis. In 2009, another risk of death was added: cancer, thanks to new instances of lymphoma and other malignancies in children and adolescents taking Enbrel. “May cause cancer” is obviously a worrying statement, albeit so common that we are perhaps desensitized to it. When cancer risk is combined with risk of TB, Enbrel’s black box warning becomes particularly ominous.
Enbrel is a drug that embraces weird recombination. First its engineers assemble unexpected parts of biological systems, parts which in turn churn out the proteins that confuse an overactive immune system when introduced by a patient’s unfamiliar, deliberate injections into the skin of a thigh pulled taut. And in so doing, Enbrel also recombines its predecessors by introducing new susceptibilities. Enbrel is a lifestyle drug that promises to enhance life’s quality by reducing the impact of arthritis and related conditions. And yet, it can render the body vulnerable to forms of disease that were never really left behind: infections like consumption, degenerations like cancer. The apotheosis of contemporary biotechnical achievement creates a strange loop to the past. Even as we coax hamster ovary cells to emanate life-affirming resilience, we also summon old demons that might otherwise remain shrouded in the shadows.