Arthritis Medications

Remember Dolly? She is the world's first cloned sheep and she was diagnosed with arthritis. There is fear amongst researchers that the cloning process may have given her a genetic defect. Sheep get arthritis but Dolly developed it at an unusually young age. This raises the question, has the incidence of arthritis changed; or is it still a disease mainly associated with aging?  

There are more than 100 types of arthritis, but the most common arthritic diagnoses are osteoarthritis, also known as degenerative joint disease, and rheumatoid arthritis (RA).  Health experts reported that osteoarthritis of the knees afflicts approximately 10 million people, making it the most common type of arthritis in the United States affecting older people, mostly over 45 years or age.  Arthritis affects more than 42 million American adults and children.  By the year 2020, the Centers for Disease Control (CDC) estimates that 60 million people will be affected, and more than 12 million will be disabled⁵.

Treatment of osteoarthritis and rheumatoid arthritis requires a long-term approach to managing pain, maintaining joint function and slowing or stopping joint damage. Short-term is aimed at reducing joint inflammation. Pain andswelling subside once joint inflammation is reduced. When there is joint inflammation the joint is exposed to further damage.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications used to treat arthritis of which acetylsalicylic acid (aspirin) is the most common. The Bayer Company in Germany developed aspirin in the late 1800s but it wasn't until the late 1970s and early 1980s that inflammation and the way aspirin works to control it was understood. ² Later, other forms of NSAIDs were developed, ranging from over-the-counter Advil, Motrin IB, and Aleve to other medications requiring a prescription.

Since September 1998, new drug treatment strategies have become available to combat the joint inflammation and pain that occurs in osteoarthritis and rheumatoid arthritis (RA). In 1982, Sir John Vane was one of three recipients of the Noble Prize for Medicine for the discovery of how prostaglandins work.  ² Prostaglandins are natural hormones that affect practically every system in the body. Vane discovered that aspirin slows the body's production of some prostaglandins and proposed that aspirin works as a painkiller.² That idea is not only widely accepted but it also laid the foundation for newer drug discoveries for treating arthritis such as Celebrex and Vioxx.

There are nine new drugs for the treatment of arthritis. They are listed below by category. The brand names are in parenthesis. Each will be presented in detail in this course, including the United States Pharmacopeia (USP) authoritative information about the appropriate use and the FDA alerts & warnings as of 01/04/2003.

1. Biological response modifiers for RA
   1. Etanercept (Enbrel)
   2. Adalimumab (Humira)
   3. Anakinra (Kineret)
   4. Infliximab (Remicade)
2. Nonsteroidal Anti-Inflammatory Drug (NSAID), specifically Cyclo-Oxygenase-2 (COX-2) Inhibitor, for RA and Osteoarthritis
   1. Valdecoxib (Bextra)
   2. Celecoxib (Celebrex)
   3. Meloxicam (Mobic)
   4. Rofecoxib (Vioxx)
3. Disease-Modifying Anti-rheumatic Drugs (DMARDs) for RA
   1. Leflunomide (Arava)

Prostaglandins belong to a lipid class of biochemicals known as the eicosanoids. Prostaglandins act similarly to hormones by stimulating target cells into action. They perform a variety of physiological processes. It was originally named “prostaglandins” because the first prostaglandin was found in semen and thought to originate from the prostate gland. However, most of the prostaglandins have nothing to do with the prostate.

Prostaglandins differ from hormones in that they function locally, near their site of synthesis, and they are metabolized very rapidly.  Also unusual, is that some prostaglandins act differently in different tissues. Specific prostaglandins appear to have contrary functions; some prostaglandins aggravate inflammatory conditions and some alleviate them. The cyclical prostaglandin compounds are potent, short-lived mediators of the inflammation response. They are not stored in cells but are synthesized as needed in response to injury or irritation.  In summary, prostaglandins perform the following functions:

• prevents blood platelet aggregation;
• removes excess sodium fluid from the kidneys;
• relaxes blood vessels and lowers the blood pressure;
• decreases inflammation due to arthritis;
• improves insulin function;
• regulates calcium metabolism;
• improves function of T-cells;
• prevents release of arachidonic acid (prostaglandins that have the opposite effect): and
• serves as cytoprotectants in the GI tract.

Aspirin and NSAIDs work by inhibiting the enzyme called cyclo-oxygenase (Cox). Blocking Cox reduces the amount of inflammation supporters, prostaglandins, which helps reduce inflammation. Unfortunately, prostaglandins also perform functions that your body requires. Reducing prostaglandins can lead to stomach bleeding and ulcers. Researchers have learned that there is more than one kind of Cox. By blocking only one type of Cox, Cox-2, it may be possible to lower the amount of prostaglandins that promote inflammation, while leaving other types of prostaglandins alone. The newer COX-2 inhibitors, such as Celebrex, Vioxx and Bextra, are thought to be safer anti-inflammatory agents for patients at high risk of ulcer disease or who have had ulcers in the past; however, current research is casting doubt. Individuals who avoid aspirin or other NSAIDs because of allergic reactions or asthma should not take cox-2 inhibitors. In addition, Cox-2 inhibitors can harm the kidneys in people with decreased kidney function.

RA is characterized by chronic synovial inflammation and infiltration of immune and inflammatory cells into the joint. Enlarged synovial tissue, called pannus, can cause the destruction of the adjacent articular structures of the joint, including the resorption of cartilage and bone tissues, and damage to ligaments and tendons. Destructive enzymes associated with cartilage and bone erosion are present at the onset of RA, creating a potential for joint damage very early in the disease. In fact, 70% of RA patients have shown erosion on x-rays within 2 years of the onset of symptoms.

1. It is indicated for the treatment of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis.

• It is supplied in 10 mg and 20 mg, film-coated, capsule shaped pill.
• It is prescribed as 10 mg. once daily for arthritis.
• “BEXTRA is contraindicated in patients who have had allergic-type reactions to sulfonamides; in patents with known hypersensitivity to valdecoxib; and in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or NSAIDs because severe, rarely fatal, anaphylactic-like reactions to NSAIDs are possible in such patients.”⁶
• “Serious GI toxicity can occur with or without warning symptoms with NSAIDs.“ ⁶
• “Serious skin reactions have been reported in patients treated with Bextra. As some of these reactions can be life threatening, BEXTRA should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.“ ⁶

• “Bextra should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Bextra should be avoided during late pregnancy.” ⁶
• “Most common side effects in clinical trials were headache, abdominal pain, dyspepsia, upper respiratory tract infection, nausea, and diarrhea, and were generally mild to moderate.” ⁶
• Post Marketing: cases of hypersensitivity have been reported in patients receiving Bextra, these cases have occurred in patients with and without a history of allergic-type reactions to sulfonamides Bextra should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. ^{6, 12}

2. Mobic ¹⁸ (meloxicam) was FDA-approved on April 14, 2000.  It is a COX-2 inhibitor marketed by Boehringer Ingelheim Pharmaceuticals⁵. 

• It is indicated for the treatment of osteoarthritis and RA.   
• It is supplied in 7.5 and 15 mg yellow tablets.
• It is prescribed as a once-daily medication and can be taken without regard to timing of meals.
• It should not be given to patients who are sensitive to meloxicam; who have asthma; or who have had an adverse reaction to aspirin or other NSAIDs.

3. Vioxx ^{10, 15, 18}: Vioxx (rofecoxib) was FDA-approved on May 21, 1999.  It is a COX-2 inhibitor manufactured by Merck in competition to Pharmacia's Celebrex.

• It is indicated for the treatment of osteoarthritis and rheumatoid arthritis. 

• VIOXX, 12.5 mg are cream colored, round, shallow cup tablets engraved MRK 74 on one side and VIOXX on the other side. VIOXX, 25 mg, are yellow, round tablets engraved MRK 110 on one side and VIOXX on the other. ^{10, 18} VIOXX, 50 mg, are orange, round tablets engraved MRK 114 on one side and VIOXX on the other. ^10,18

• Merck changed Vioxx’s label text and precautions based on the results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) demonstrating higher incidence of stroke, heart attack and other serious cardiovascular events than originally thought. The FDA had also sent Merck a warning to change it’s marketing which minimized cardiovascular side effects.  ¹⁵

• The new labeling information approved by FDA advises physicians to use caution in prescribing Vioxx for patients with ischemic heart disease. ¹⁵
• In addition, the new label provides information from the VIGOR study of patients with rheumatoid arthritis at the chronic dose of 25 mg, showing that Vioxx was associated with a higher incidence of hypertension compared to naproxen 1000 mg. ¹⁵
• Vioxx 50 mg is not recommended for chronic use.
• FDA Alerts/Warnings over name confusion, Vioxx vs. Zyvox, causing medical errors.

4. Celebrex ^7,8,18: (celecoxib) was FDA-approved on December 31, 1998.  It was first drug approved in the new class known as COX-2 inhibitors marketed by Pharmacia.

• It is indicated for the relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis.
• It is available in 100 mg or 200 mg capsules. Celebrex recommends 200-mg dose once a day or 100-mg dose twice a day for osteoarthritis and for rheumatoid arthritis 100mg or 200mg twice a day.
• It should not be taken by someone with an allergy to sulfa-containing medications.
• On December 26, 2002, the Associated Press released information suggestive that Celebrex doesn't protect the stomach from ulcers as well as once thought.
• According to the study, arthritis patients at high risk of recurrent ulcers are at a higher risk of developing another bleeding ulcer. Lead researcher, Dr. Francis K.L. Chan stated that previous studies reported a very low incidence of renal side effects because they excluded patients with major medical illnesses. 
  • Dr. John H. Klippel, medical director of the Arthritis Foundation was quoted as saying “I think patients and doctors need to be aware ... there is a risk of gastrointestinal bleeding and there is a risk of renal toxicity," so high-risk patients should be monitored closely by their doctor.  High-risk patients (those who have a history of ulcers) need to be monitored for symptoms of an ulcer as well as signs that the kidneys can't excrete enough fluid, such as lower extremity swelling and elevated blood pressure.
  •  The American College of Rheumatology's guidelines for treating arthritis supports the use of Celebrex and COX-2 inhibitors. 

The USP Practitioners' Reporting Network^SM has received, and continues to receive, numerous reports of confusion resulting from the similar names Cerebyx^®, Celebrex^®, and Celexa^®. In addition, USP received one report expressing concern that the nonprescription dietary supplement, Cerebra^TM could potentially be confused with the prescription products. Table One helps to distinguish among the prescription agents Cerebyx, Celebrex, and Celexa.¹⁹

Note:  The USP PRNTM requests practitioners continue to report concerns about these look-alike sound-alike names; continued reporting provides data to be compiled that may encourage regulators or manufacturers to take proactive steps that may prevent errors.

Tumor Necrosis Factor (TNF) is an immune system protein that is overproduced in people with rheumatoid arthritis and other inflammatory diseases. It is found in synovial cells and macrophages in the tissues and shares many properties with another cytokine, interleukin-1. Anti-TNF drugs work by blocking this protein. Humira, Enbrel and Remicade are TNF blocking drugs and have similar side effects, including serious and sometimes fatal infections linked to the suppression of the immune protein.

1. It is indicated for RA.

• It is administered as a single subcutaneous injection every other week. The package insert carries a bolded warning stating that patients with rheumatoid arthritis should discuss therapy options with their healthcare providers.
• FDA Alerts/Warnings state that contraindications include serious, sometimes fatal, infections (including cases of tuberculosis and sepsis) have been reported with the use of TNF-blocking agents including Humira. The most serious adverse events associated with Humira are, as with other TNF blockers, serious infections, neurologic effects, and certain malignancies of the lymphoid system. A higher rate of lymphomas was observed than the expected rate in the general population, but RA patients, particularly those with active disease, may be at a higher risk for development of lymphoma.
• FDA Alerts/Warnings state that the labeling is being updated with new warnings following post marketing reports of serious adverse effects including life-threatening risks related to skin reactions, including Stevens Johnson Syndrome, and anaphylactoid reactions. In addition, the labeling will state that the drug is contraindicated in patients allergic to sulfa containing products.

2. Kineret¹³ (generic name: anakinra) was FDA-approved on November 14, 2001 and is marketed by Amgen.

• It is indicated for RA patients who have failed one or more disease-modifying anti-rheumatic drugs. Kineret is the first selective blocker of interleukin-1, a protein that is found in excess in rheumatoid arthritis patients.  
• Subcutaneous injections are given once a day. Each Kineret™ dose comes in a 1 ml pre-filled glass syringe. There are 7 syringes in a box, one for each day of the week. 
• Side effects, as with other new drugs for RA, including serious infections, are a concern since Kineret can suppress the immune system's ability to fight off infection. The most common adverse reaction is injection site reactions. Most people have a reaction at the injection site. These reactions include redness, swelling, bruising, itching and/or stinging. Most of the time the reactions are mild and last about 2-4 weeks. 
  • The Kineret needle cover contains latex so individuals with an allergy to latex need to discuss this with his/her physician. Since patients may not communicate this information, clinicians need to ask patients specifically about latex allergies.
  • Kineret has a special site for the nursing profession which contains a wealth of information about Kineret as well as material for patient education including how to teach patients how to self-inject. The web address is http://www.anakinra.com/professional/for_nurses.jsp. This site is a clinician’s dream!

3. Remicade^{17, 18}:  (generic name: infliximab) an anti-TNF was FDA-approved on November 10, 1999, marketed by Centocor. 

• It is indicated for the treatment of signs and symptoms of rheumatoid arthritis in patients who have had an inadequate response to methotrexate alone. Remicade inhibits joint space narrowing and joint erosion.  In addition, it helps control pain and stiffness caused by rheumatoid arthritis by reducing inflammation and by slowing the tumor necrosis factor/TNF. 
• Remicade is administered as an intravenous infusion under medical supervision. The infusion rate must not be less than two hours. The intravenous treatments are given three times during the first six weeks of therapy, then every eight weeks. Remicade should be used in combination with methotrexate
• Remicade is contraindicated in patients with moderate or severe congestive heart failure. Tuberculosis, invasive fungal infections and other opportunistic infections have been observed in patients receiving Remicade; some infections have been fatal. Patients should be evaluated, with a tuberculin skin test, for latent tuberculosis infection. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their disease, could predispose them to infections. Remicade should not be given to patients diagnosed with a clinically significant, active infection. Patients should be monitored for infection while on or after treatment with Remicade.

• Remicade also has a wonderful site for accessing clinician and patient information and tools such as ACR Guidelines from The 2002 American College of Rheumatology Practice Guidelines, A list of Remicade materials useful for your practice and a site for requesting medical data from the Centocor, Inc., Department of Medical Information. The web address is http://www.remicade-ra.com/d_for_healthcarepros/for_nurses.jsp. 

4.  Enbrel ^9,18: (generic name: etanercept) was FDA-approved on November 2, 1998 as the first drug in a new class of tumor necrosis factor (TNF) drugs for the treatment of rheumatoid arthritis. Enbrel is manufactured by the Immunex Corporation and marketed by Amgen and Wyeth Pharmaceuticals

• It is indicated for reducing signs and symptoms and inhibiting the progression of structural damage in patients with moderately to severely active rheumatoid arthritis. In addition to RA, Enbrel is approved for reduction in signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis (JRA) in patients 4 years of age and older who have had an inadequate response to one or more antirheumatic drugs. Enbrel is also indicated for reducing signs and symptoms of active arthritis in patients with psoriatic arthritis.
• It is supplied in single-use 25-mg vials for reconstitution. The recommended dose for adults with rheumatoid arthritis or psoriatic arthritis is 25 mg twice weekly as a subcutaneous injection 72 to 96 hours apart. The recommended dose for pediatric patients ages 4 to 17 years with active polyarticular-course juvenile rheumatoid arthritis is 0.4 mg/kg (up to a maximum of 25 mg per dose) given twice weekly as a subcutaneous injection 72 to 96 hours apart. The safety of Enbrel has not been studied in children younger than 4 years.
• Enbrel is injected under the skin twice a week and can be self-injected. A kit is available from the manufacturer that makes drawing up the medicine and injecting it easier for patients who self-administer.
• Studies on Enbrel indicate it may cause irritation at the injection site.
• Important Treatment Considerations include the following.
  • Enbrel can suppress the immune system and make it more difficult to fight infection. It should be discontinued if signs and symptoms of infection occur. Use caution in patients predisposed to infection, such as those with advanced or poorly controlled diabetes.
  • Patients exposed to the varicella virus should temporarily discontinue Enbrel.
  • Patients with JRA should be current with all immunizations prior to initiating therapy with Enbrel.
  • Live vaccines should not be given concurrently with Enbrel.
  • In post marketing use, serious infections and sepsis, including fatalities, have been reported. Many of these infections occurred in patients predisposed to infections because of concomitant immunosuppressive therapy and/or underlying disease.
  • Cases of CNS demyelinating disorders, transverse myelitis, optic neuritis, multiple sclerosis, and new onset or exacerbation of seizure disorder have been observed, although the causal relationship to Enbrel remains unclear. Exercise caution when considering Enbrel for patients with these disorders.
  • The most common adverse events in clinical trials were injection site reactions, infections and headache. 

In December 2002 Amgen and Wyeth Pharmaceuticals announced that the FDA approved Amgen's Rhode Island a manufacturing facility for Enbrel. With this approval, significant supply of Enbrel is available for patients; in the past Enbrel was often in short supply.

Enbrel users have access to free support tools that make learning the self-injection process easy for patients. Example of available tools are a dosing system kit which includes a step-by-step guide for preparing and injecting Enbrel, a video demonstration of the preparation and injection processes and a “mixing station” which is a specially designed, arthritis-friendly device that makes preparing the Enbrel solution easier.  In addition, users have access to a nurse able to answer patient questions about self-injecting.  The telephone number is toll-free at 1-888-4ENBREL (1-888-436-2735), Monday through Friday, 9 a.m. to 9 p.m., Eastern Time.

1. Arava was the first oral treatment for active rheumatoid arthritis approved for relieving painful, swollen joints and slowing joint damage.  

• Arava is taken in pill form in a dose of 10 mg. or 20 mg. once a day. Because it builds up in the body slowly, it is necessary to take a loading dose of 100 mg. daily for two or three days. This loading dose is followed by a maintenance dose of 10 mg. or 20-mg. daily. Arava can be taken on an empty stomach or with meals.
• The current studies on Arava suggest possible side effects of rash, reversible hair loss, irritation of the liver, nausea, diarrhea and abdominal pain. When taking Arava, it is necessary to have periodic blood tests to detect liver irritation. Arava is not recommended for people who have liver disease, pregnant or nursing women, or people with immune systems weakened by a deficiency or a disorder.
• Arava might cause birth defects. Both men and women should use a reliable method of birth control while being treated with Arava. If a woman taking Arava wants to become pregnant, she needs to stop the Arava and take cholestyramine for 11 days to get cleanse her body of Arava, andthen have a blood test to verify that the Arava is notdetectable.  Less is known about the effects of Arava on men planning to father children and the physician may recommend the same for men.
• The Public Citizen, (a watchdog research group) has stated that Arava is linked to 22 deaths in its first three years of approval and, twelve of the deaths appear directly due to liver damage from the drug.  Arava is working with the FDA on adding a “black box” label rather than pulling the drug from the market.  A black box label is a warning that the FDA uses for particularly dangerous drugs.

Even with the newer medications on the market, pharmacological treatment and management of arthritis is best achieved when other modalities are used simultaneously.  New medications can be more expensive than previously available therapies. Patients need to be familiar with the risks, benefits, costs and alternatives; hopefully before making a decision with his or her physician. The FDA requires that studies be conducted to establish the safety and effectiveness of any new drug or treatment before it is approved for prescription use. Unfortunately, even thorough studies conducted over several years may not reveal side effects that occur only rarely, or those that occur only with long-term use.  In many drug approval processes, healthy individuals are used in studies, which later present as adverse reactions in patients with co-morbidities. Furthermore, most drugs have not been approved for women who are pregnant. Although the risk is usually small, a new treatment might cause a side effect that could not be anticipated by the prescribing physician.

Two good resources for accessing current drug warnings or alerts are the FDA and USP Practitioners’ Reporting Network.  Clinicians need to keep current on available drug therapies and FDA alerts in order to better educate the patient, reduce medication errors, and promote the intent of treatment, a better quality of life.   

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