Newsletter: Volume 5

Introduction

Inflammatory Bowel Disease (IBD) is an umbrella term for two gastrointestinal diseases: ulcerative colitis (UC) and Crohn's disease (CD). These are chronic conditions that require life-long treatment for most patients. As has been highlighted in Dr. Kornbluth's newsletter, Treatment of IBD, many treatment options are available and treatment is tailored to the needs of the individual patient. Medications are available as oral tablets or capsules, liquid or foam enemas, suppositories, and injections. Like any medication that is taken long-term, some patients experience side effects when taking IBD medications. This newsletter will review the classes of medication used in the treatment of IBD and discuss the more common side effects patients encounter. As we discuss the side effects of these medications, it is important to keep in mind that these are life saving drugs and that while some people have significant problems with side effects, many more have few problems.

5-Aminosalicyclic Acid

The class of drugs called 5-aminosalicyclic acid (5-ASA) includes several medications used to treat mild-to-moderate IBD. These are approved by the FDA and are safe and effective for the treatment of UC. The mesalamine derivatives are often used for the treatment of patients with CD as well.

The oldest of these is sulfasalazine (generic name), often marketed as Azulfidine^®. Sulfasalazine is an effective treatment for mild-to-moderate symptoms of UC. While most patients tolerate sulfasalazine, as many as 30-40 percent of patients may experience significant side effects and some develop an allergic reaction to the sulfa it contains. The most common side effects are nausea or upset stomach, muscle and joint aches and pains, and headaches. These side effects can be minimized by starting sulfasalazine at a smaller than normal dose and slowly increasing it, and by taking the pills with food. People who are allergic to sulfasalazine typically experience fever or rash. Very rarely, patients have an allergic reaction to the 5-ASA itself.

Also very rarely, patients have experienced hepatitis (inflammation of the liver due to the medication), acute inflammation of the pancreas, inflammation of the lungs, anemia (low red blood cell count), and suppression of blood cell formation in the bone marrow.¹ Patients usually have regular blood tests in the first few months of treatment and then periodically thereafter to make sure no complications have occurred.²

While sulfasalazine can be used safely during pregnancy and nursing, it can also cause sperm abnormalities, which disappear when the drug is discontinued. Additionally, folic acid supplementation is recommended for all patients taking sulfasalazine.^1,2

Newer drugs have been developed that are designed to release 5-ASA in the gastrointestinal tract with fewer side effects than sulfasalazine. These have FDA approval for the acute treatment and maintenance therapy of UC.

Balsalazide, marketed as COLAZAL^® Capsules, is another 5-ASA like sulfasalazine that releases 5-ASA directly to the colon. Fortunately, COLAZAL has fewer side effects than sulfasalazine. Colazal is indicated for the treatment of mildly to moderately active ulcerative colitis. Safety and effectiveness of COLAZAL beyond 12 weeks has not been established. The most commonly reported side effects in patients treated with COLAZAL were headache, abdominal pain, nausea, respiratory infection, body pain, diarrhea, vomiting, arthralgia and dizziness. Less than 17 percent of patients reported any of these symptoms and they were reported no more frequently with COLAZAL than with placebo or other 5-ASA products. In these trials, the side effects were rarely severe enough for patients to discontinue therapy. There have been no reports of sperm abnormalities or low sperm counts published to date.^3,4,5,6,7,8

Controlled-release and pH-dependent formulations of mesalamine release the active ingredient differently in the gastrointestinal tract than sulfasalazine or COLAZAL. These mesalamine formulations are as effective as sulfsalazine and have fewer side effects. It is available in several formulations, including delayed- and controlled-release tablets, enemas, and suppositories. These are marketed as Pentasa^®, a controlled-release capsule that gradually releases 5-ASA from the stomach to the colon; Asacol^®, a delayed-release tablet that has a coating that dissolves to release 5-ASA in the distal ileum and colon (at a pH>7); and Rowasa^®, a suspension enema or suppository for release in the colon. Mesalamine is well tolerated; it can cause headaches, abdominal pain, diarrhea, and nausea and vomiting. However, these side effects are generally mild.9 While it is suspected there may be an increased risk of inflammation of the kidneys and pancreas with mesalamine, these side effects have been rare and the number of cases reported is very few. Abnormalities or low sperm counts have not been reported with these or any other mesalamine products.⁸

Olsalazine^®, marketed as Dipentum^®, is FDA approved for preventing relapse in UC. It has not been found to be effective for the treatment of active episodes of UC or for prevention of relapse in CD. It is a capsule that releases 5-ASA in the colon similarly to sulfasalazine and COLAZAL. In addition to the side effects common to all -5-ASA products, Dipentum in higher doses causes excessive secretion of water and electrolytes (a condition called secretory diarrhea) in up to 10 percent of patients.⁹

Patients with an allergic reaction to salicylates (aspirin or similar agents) may be hypersensitive to any of the 5-ASA products.⁸ Allergic reactions are much less frequent with the newer drugs than with sulfasalazine.¹ At the same time, patients who do not do well on one 5-ASA compound may do well another, so your physician may find it worthwhile to try another form of 5-ASA if you do not respond well to the first one you try.^8,10,11

5-ASAs are regarded as generally appropriate for use during pregnancy. Folic acid supplementation and good nutrition is recommended for all pregnant women, but this is especially true for pregnant women with IBD because some 5-ASA compounds may reduce the availability of folic acid in the body. 5-ASAs can be used with caution during breast-feeding with regular monitoring of the infant for allergic reactions.^8,12

The 5-ASAs are generally well tolerated and effective for the treatment of mild-to-moderate IBD and for the prevention of recurrences. They can be used either orally or rectally or in combination. These drugs do not adversely affect female fertility or permanently affect male fertility, and can be used during pregnancy.^10,12 Like all medications, they do have side effects. These are generally mild and should be managed in consultation with your physician.

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Corticosteroids

Corticosteroids have been used to treat IBD since the late 1950s and have played a dramatic role in reducing deaths in patients with UC from 31 percent in the 1950s to 1 percent today. These are powerful, life-saving medications taken legally under the supervision of a physician and not to be confused with the "steroids" that one hears about in the news. They are used for the treatment of acute episodes of IBD.

A variety of systemic corticosteroid preparations are available that have similar anti-inflammatory effects with differences in potency and side effect profiles. Corticosteroids for IBD may be taken orally, rectally (in the form of an enema, a rectal foam, or a suppository), or parenterally (intravenously or by injection). When taken intravenously, hydrocortisone or methylprednisolone is usually given. When taken orally or rectally, budesonide, prednisone, and prednisolone are frequently prescribed.^13,14

Often patients who have had a serious flare up of their disease will be treated in the hospital with intravenous corticosteroids and transferred to pills (in the form of prednisone or methylprednisolone) after a few days if they have made a good response. Once they have achieved remission they will be tapered off the pills over about a 10-week period. Patients are sometimes tempted to stop their corticosteroid therapy early because these drugs can have unpleasant side effects. Corticosteroids should never be stopped abruptly because doing so could cause adrenal insufficiency, a very serious condition that can cause death if not recognized and treated immediately.¹³ Patients taking corticosteroids should be placed on the lowest possible doses of for the shortest possible time to establish remission.¹⁵

The list of side effects from corticosteroids is long and can be intimidating so it is important to remember that these are lifesaving drugs. If you take corticosteroids, you probably will not experience most of these side effects and of the ones you do have, most of the symptoms will be mild. However, some people do have strong reactions to corticosteroids and will struggle with the benefits and the costs of taking them.¹⁶

Table 1 shows side effects that have been experienced by patients taking corticosteroids.

Table 1. Side Effects of Corticosteroids14,16,17
Immediate Onset in the Majority of Patients
Sleep disturbances Mood changes Fatigue	Increased appetite Fluid retention Cushingoid facies (moon face) Acne Plethora (facial redness) Bruising	Upset stomach Heartburn
Aggravation of an Existing Condition or Symptoms for which Patient May Have a Predisposition
Hypertension - common with long-term treatment Hyperglycemia	Gastric ulcers Duodenal ulcers	Diabetes Psychoses - rare Cognitive disorders - unusual
Effects of Long Term Use
Osteopenia - common (mild bone loss) Osteoporosis - (severe bone loss) Stunting of growth	Myalgia (muscle aches) Myopathy (weak muscles) Skin striae (stretch marks) Thinning of skin	Central redistribution of fat Headaches Seizures Susceptibility to infection
Highly Individual, Dose Dependent Side Effects
Avascular necrosis - rare (blood supply to bone ends becomes compromised)	Cataracts - unusual Glaucoma - unusual	Adrenal Suppression

When taking corticosteroids, it is very important to use them exactly as prescribed by your doctor. Taking less than the prescribed dose in an attempt to minimize the side effects could have a serious negative impact on your treatment and place you at higher risk for side effects by prolonging the length of time you need to be on corticosteroids. There are some things you can do to minimize the side effects: eat a low salt and low fat diet to minimize bloating and weight gain; engage in low-impact aerobic exercise regularly to help stabilize mood, aid sleep, minimize weight gain, and strengthen bones and muscles; limit coffee, tea, and soft drink consumption to minimize calcium depletion; avoid sun exposure and be sure to wear sunscreen when outside to minimize sun damage to your skin; and take extra calcium to prevent bone loss and make sure your diet contains healthy sources of calcium.17 An upcoming newsletter by Ellen Scherl, MD will discuss in greater detail some lifestyle issues and things you can do to help manage your IBD and the effect of medications.

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Antibiotics

Antibiotics are drugs used to eradicate infections caused by bacteria. The two most commonly used antibiotics in the treatment of IBD are metronidazole (Flagyl^®) and ciprofloxacin (Cipro^®). These potent antibiotics are used when infections are present and are generally well tolerated by patients. These drugs can be life saving and they should be used exactly as prescribed by your physician. Antibiotics must be used judiciously. Heavy use or improper use of antibiotics can lead to resistance whereby the bacteria mutate and become able to withstand the powerful effects of antibiotics.

The most common side effects of metronidazole are paresthesia (numbness or tingling sensations usually in the feet), upset stomach, an often unpleasant metallic taste, and an inability to tolerate alcohol in a small number of patients. These symptoms are usually but not always reversible and disappear when the metronidazole is no longer needed.18

Ciprofloxacin can interact badly with antacids; calcium, iron, and zinc, which are common ingredients in vitamin supplements; caffeine, which is common in many beverages and some medications; and some asthma medications. So be sure to discuss with your physician any other medications you may be taking and how to use them with ciprofloxacin. Most people take ciprofloxacin with no problems. The most commonly occurring problem is upset stomach, which occurs in about 15 percent of patients. Although uncommon, some people breakout with a skin rash with ciprofloxacin and you should stop taking it immediately if this happens.¹⁹

While it does not happen often, some people have experienced ruptured tendons while taking ciprofloxacin so you may wish to avoid rigorous exercise that puts undue stress on the joints and tendons while taking the drug. Check with your doctor to see if the type of exercise you do is a concern. Patients have been known to develop peripheral neuropathy while taking ciprofloxacin. These are sensations including pain, burning, tingling, numbness, and or weakness. If this happens stop the medication and call the doctor. Rarely patients have experienced convulsions, usually when they already have a condition that makes them vulnerable to seizures.¹⁹

All of this can sound pretty frightening, so it is important to keep this information in perspective and remember that most people take these antibiotics when they get an infection and never notice any of these symptoms other than a little bit of an upset stomach.

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Immunomodulators

A class of durgs known as immunomodulators, although approved by the FDA for the treatment of other diseases, are widely used to treat both UC and CD patients to control inflammation when 5-ASA products are not enough and further use of corticosteroids is undesirable. About 15 percent of patients experience some unpleasant side effects from these medications and about 3 percent have serious reactions.²⁰ These drugs are called immunomodulators because they suppress the body's immune system, which acts naturally to protect the body from infection. Fortunately serious infections are rare and most ordinary infections can be handled with the addition of antibiotics without otherwise changing medications.²¹

Side effects common to all three drugs that usually improve with time include upset stomach, nausea or vomiting, diarrhea, loss of appetite, and change in patterns of hair growth (loss of hair or its growth in unwanted places).^{22,23,24,25,26}

Serious side effects of immunomodulator medications include allergic reactions, pancreatitis, bone marrow suppression, nausea not related to pancreatitis, and infections.²⁷

Pancreatitis, which is inflammation of the pancreas, usually occurs during the first month of therapy and reverses with discontinuation of the drug. Its occurrence appears to be related to how much of the drug is given.²⁷

Bone marrow is involved in the production of white and red blood cells, and platelets. Red blood cells carry oxygen to the cells and remove carbon dioxide. White blood cells help the body fight infection. Platelets help blood cells clump together and clot. Immunomodulators can inhibit the production of these cells. This is called bone marrow suppression. When the white blood cell count is reduced it is called leukopenia. When the red blood cell count is reduced it is called anemia. You and your doctors will want to be alert to signs of bone marrow suppression and infection.

Table 2 shows the symptoms of bone marrow suppression that you will want to be watchful for and report to your doctor. It is important to keep in mind that the symptoms of bone marrow suppression also resemble some of the symptoms of IBD, such as diarrhea, and sometimes the hazards of daily living (for example, getting chilled from staying out in the cold too long or being really tired from staying up too late too many nights in a row). The goal is to be mindful when your body is warning you that something is amiss yet not worry about every ache and pain.

Table 2. Symptoms of Bone Marrow Suppression28
Low Red Blood Cell Count	Low White Blood Cell Count	Low Platelet Count
Fatigue Pale skin, lips, nail beds Increased heart rate Easily tired with exertion Dizziness Shortness of breath Fatigue	Fever and chills Rash Diarrhea Signs of Infection (anywhere in the body) Swelling Redness Area warm to touch	Bruising easily Unusual bleeding Nose bleeds Gums Mouth Tiny red spots on the skin Blood in urine Dark or black stool

If serious infections do occur, antibiotics are started and the immunomodulator drugs are discontinued. Some leukopenia is common in most patients who are treated with immunomodulating drugs, but significant bone marrow suppression occurs in only about 2 percent of patients and reverses when the drugs are discontinued.²⁹

Immunomodulator medications can also interact negatively with other medications so it's important to discuss all of your medications with your health care provider and not to take any over-the-counter medications without consulting your doctor first.^21,22

Both men and women should use birth control while taking immunomodulator medications because these drugs may cause birth defects either at the time of conception or during pregnancy. The drugs may also pass into breast milk, so consult your doctor before breastfeeding.^21,22

Do not have immunizations while taking immunomodulator medications without permission from your doctor because your lowered resistance to infection may cause you to develop the condition the immunization is designed to prevent. Try to avoid people who are ill and contact your physician right away if you think you are getting an infection.^23,24

About 2 to 5 percent of IBD patients develop an allergy to immunomodulator medications. The symptoms are typically fever, rash, and joint pain. Hypersensitivity reactions cannot be prevented and require discontinuation of the drug.^20,29

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Biologics

Infliximab (Remicade^®) is a monoclonal antibody and is the newest drug approved for the treatment of intractable CD and UC. It works to prevent inflammation by preventing the expression of a strong inflammatory substance known as tumor necrosis factor. Remicade is injected intravenously over a two-hour period either at a hospital or an infusion center. Serious side effects are infrequent.^29,30

Pain at the injection site and nausea may occur. Because Remicade suppresses your immune system, report promptly to your physician any signs of infection such as persistent sore throat, fever, chills, severe headache, chest pain, cough, extreme fatigue, stomach pain, unusual vaginal discharge, or white patches in the mouth.²⁹

Uncommon side effects of Remicade therapy include back pain, bloody or cloudy urine, cracks in the skin in the corners of the mouth, diarrhea, difficult or painful urination, frequent urge to urinate, high blood pressure, low blood pressure, pain or tenderness around the eyes and cheekbones, skin rash, sore mouth and tongue, soreness or redness around the fingernails and toenails, and vaginal burning, itching, or discharge. These symptoms should be reported to your physician immediately.²⁹ Tuberculosis, invasive fungal infections, and other opportunistic infections, while uncommon, have occurred in patients treated with Remicade and can be fatal. It is recommended that patients have a tuberculin skin test to detect a latent tuberculosis infection before taking Remicade.³¹

While occurrence is rare, patients taking Remicade may be at an increased risk for cancer so you should notify your doctor immediately if you have unusual lumps or growths, swollen glands, night sweats, or unexplained weight loss. Very rarely, patients taking Remicade develop a serious and potentially fatal liver disease. Tell your doctor immediately if you experience unwarranted extreme fatigue, stomach or abdominal pain, and yellowing of the eyes or skin.²⁹

As with the other medications, be sure to tell your health care provider about all the medications you are taking, including those obtained from the drug store or health food store. While the information on pregnancy and birth defects is less well established for Remicade than with the other medications we've discussed, make sure your doctor knows if you are pregnant or planning to become pregnant before taking Remicade.²⁹ At present, Remicade is a class B medication approved for use by pregnant women with active CD who have a need for acute medical therapy.

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Conclusion

All medications have side effects. The medications used to treat IBD are no different. Most of these side effects, such as upset stomach, headaches, and aches and pains are generally well tolerated and transient, while others can be very serious. IBD patients should feel reassured that most of the serious side effects, such as liver and blood abnormalities, can be easily detected, prevented, or minimized. Nonetheless, it is important to take your medications exactly as prescribed, monitor unusual symptoms, report all medications you are taking at every visit, and keep all of your doctor's appointments for monitoring your wellness. There are lifestyle adjustments IBD patients can make that may help minimize the impact of some side effects. These will be discussed in Volume 6 of this newsletter by Dr. Ellen Scherl.

This information has been reviewed and approved by CCFA's National Scientific Advisory Committee.

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31. Centcor, Inc. Dear Health Care Professional Letter. October 5, 2001. Boxed Warning.

The next newsletter in this series by Ellen Scherl, MD, will discuss lifestyle issues and things you can do to help manage your IBD and the effect of medications. To sign up for future newsletters click here.

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