Irritable Bowel Syndrome (IBS):     Therapy    

Overview
Management of patients with Irritable Bowel Syndrome is based on a positive diagnosis of the syndrome, exclusion of organic disorders, and specific therapies. Treatment for IBS should address the three main pathophysiologically important factors—psychosocial disturbances, visceral hypersensitivity, and dysmotility. Treatment should be patient oriented and geared towards symptom –specific relief. The majority of conventional IBS treatments currently used is empiric and has not been formally reviewed and approved by the FDA. Therapies may include fiber consumption for constipation, anti-diarrheals, smooth muscle relaxants for pain, and psychotropic agents for pain, diarrhea and depression. Female patients with diarrhea predominant-IBS may benefit from alosetron, a new 5-HT3 agonist, while female patients with constipation predominant-IBS may benefit from Tegaserod Maleate, a partial 5HT4 agonist.

Patients with mild or infrequent symptoms may benefit from the establishment of a physician-patient relationship, patient education and reassurance, dietary modification, and simple measures such as fiber consumption. Patients with constipation-predominant IBS can generally be treated with osmotic mild laxatives such as Milk of Magnesia. Stronger laxatives should be reserved for patients who do not respond to fiber consumption and gentle osmotic laxatives. 
 

Table 4. Management recommendations for Irritable Bowel Syndrome

Physician-Patient Relationship
Patients suffering from IBS often present for medical care only after frustrating self-diagnostic attempts to determine symptom causation and resolution. It is very important, therefore, that the responsible physician foster a positive relationship with the patient in order to aid in successful clinical management. A positive, confident diagnosis, accompanied by a clear explanation of possible mechanisms and an honest account of probable disease course, can be critical in achieving desired management goals. In order to facilitate a positive relationship, it is important that the physician practice the following principles:

•  Reassure the patient that they are not unusual  
•  Identify why the patient is currently presenting 
• Obtain a history of referral experiences 
• Examine patient fears or agendas 
• Ascertain patient expectations of physician 
• Determine patient willingness to aid in treatment 
• Uncover the symptom most impacting quality of life and the specific treatment designed to improve management of that symptom 

In addition to addressing patient fears and concerns, physicians must evaluate whether or not the introduction of physician aids, such as dietitians, counselors, and support groups, may be of long-term assistance to the patient.

A. Incidence of IBS symptoms in the general population and its relevance to the patient
B. Gastrointestinal physiology including gastrocolonic response, production of gas, gut sensitivity to certain stimuli, and possible
C. The potential impact of stress in triggering or exacerbating symptoms, with reassurance that symptoms are not psychosomatic
D. Any anxieties, including concerns about underlying disease and major symptoms
E. The need for the patient to accept responsibility for condition management
F. The recognition that no panacea exits, but that therapies can greatly improve quality of life and significantly reduce symptom severity

Well informed patients are more apt to make choices and changes in lifestyle and diet that can reduce the severity and the frequency of their symptoms. It is recommended that physicians discuss new information during patient visits, and build on previous information by disseminating any new educational materials that may have become available since the patient’s last visit.

Physicians should encourage patients with both constipation-predominant and diarrhea-predominant IBS symptoms to gradually incorporate fiber into their diets. Fiber gently stretches the bowel wall, decreasing tension. Fiber supplements such as bran, psyllium derivatives, or polycarbophil (20–30 grams/day) may aid in relief of constipation and may also improve symptoms of diarrhea. However, the efficacy of bulking agents has not yet been clearly established—despite the fact that they are widely prescribed.

Dietary modifications are the therapy of choice for patients with abdominal pain, diarrhea, flatulence and abdominal distension, with reported response rates of 50-70%. In these patients, certain foods can initiate or aggravate symptoms of IBS as evidenced by symptom occurrence after meals. Lactose (milk sugar), caffeine, fatty foods, gassy vegetables (i.e., broccoli or beans), foods containing sorbitol, wheat cereals, or alcohol may trigger symptoms. These foods should be avoided. To determine dietary triggers, patients should try an exclusion diet—restricting their diet to basic bland foods, gradually adding new foods and recording symptoms. Any food causing symptoms should be avoided. Elimination diets are intended for short-term use only as they are nutritionally deficient, and should be supervised by a dietitian or medical professional with experience in this field.

A daily food diary is another important tool in identifying trends in food or stress triggers. For each day of the week, patients should be encouraged to record the types of foods and beverages they have consumed, the number of bowel movements they have experienced, any pain they have experienced (on a scale form 1-10), their mood while eating, the time of day for each variable and any other relevant symptoms (Figure 14). Food diaries should be as specific as possible (i.e. noting food preparation and condiments), honest in reporting every food and beverage consumed, and updated throughout the day. The diary should be brought to physician visits for review in order to provide valuable information about potential relationships between dietary triggers and symptoms.  

Figure 14. Daily food diary (To view the complete printable PDF version, click on the image above).

Dairy products are the most common dietary triggers of gas, bloating, and occasional abdominal pain. A lactose breath hydrogen test, measuring the spike of breath hydrogen when malabsorbed lactose enters the colon, is the definitive test for lactose intolerance. While lactose intolerant patients should avoid consumption of milk and milk products (cheese, ice cream, and butter), it remains unclear whether or not a lactose-free diet demonstrates symptom resolution. One explanation for this may be that subjective lactose intolerance is increased in patients with IBS even though there is no increase in the prevalence of lactose maldigestion. Other research speculates that patients who are lactose intolerant may experience improvement not solely by abstaining from dairy, but by adhering to a fully exclusionary diet. Therefore, there appears to be little benefit in separating lactose malabsorbers from others with IBS. Instead, physicians should encourage all patients with IBS to try an exclusion diet. In cases where milk products are reduced, care must be taken that enough calcium is added to the diet through either foods high in calcium, or a calcium supplement.

The sweeteners, fructose and sorbitol may produce symptoms similar to those of lactose intolerance. The sugar sorbitol is only passively absorbed in the small intestine, and in clinical studies 10 g doses produced symptoms identical to lactose malabsorption in about half the patients tested. Fructose alone, or in combination with sorbitol, may produce significant symptoms in IBS patients. One study found that fructose-sorbitol malabsorption is frequently seen in IBS patients, but this result did not differ from the observation of fructose-sorbitol malabsorption in healthy volunteers. The authors concluded that this type of malabsorption does not seem to play an important role in the etiology of IBS. However, several other researchers argued this conclusion by suggesting that some patients do react adversely to sorbitol-fructose intake (especially those with diarrhea). Generation of symptoms could therefore be related to both the nature of colonic fermentation and individual sensitivity. High levels of sorbitol are found in apples, pears, cherries, plums, prunes, peaches and their juices. Dietetic foods and pharmaceuticals may also contain added sorbitol. Honey, all fruits and many processed foods contain high levels of fructose. Reducing or eliminating foods containing these products may be considered as part of an elimination diet.

Some patients with IBS may experience an aggravation of symptoms with the consumption of wheat and gluten-related products. Many patients with diarrhea-predominant IBS respond well to a short-term gluten- or wheat-free diet. This means eliminating all products that might contain wheat and wheat flour, as well as other offending grains such as rye, oats and barley. Elimination of these products need not be lifelong, but adjusted according to symptom occurrence.

Probiotics (e.g. yogurts, acidophilus supplements) have been found to be helpful to some patients. A lactobacillus supplement may help return the balance of microflora in the bowel to normal, thereby significantly reducing IBS symptoms. Researchers suggest that lactobacillus supplement works by preventing disease-causing bacteria from attaching to the bowel wall.

In general, patients should be encouraged to adhere to a healthy, well-balanced diet avoiding foods that aggravate symptoms. IBS patients should also be encouraged to eat slowly, avoid gum and artificial sweeteners, as well as caffeinated and carbonated beverages. Patients should be referred to a dietitian for additional assistance in menu planning if necessary.

Psychotherapy
A history of stressful life events or a current distress often precedes development of IBS. In several clinical studies it has been demonstrated that the onset of psychiatric disorders occurs prior to, or concurrent with, IBS symptom onset. When determining treatment for a patient with IBS, physicians should inventory: psychological distress, including the existence of anxiety or depressive disorder; personality characteristics, including a strong propensity to worry, possibly regarding health concerns; current social stresses and inadequate coping mechanisms; and abnormal illness behavior.

Of all psychiatric symptomology, IBS patients most frequently present with depression and anxiety. While these disorders typically respond well to treatment, left unchecked they can compromise clinical IBS management as well as exacerbate bowel symptoms. Psychiatric referral is recommended whenever the physician believes further assessment is in the patient’s best interest, for example when the patient is depressed and expresses suicidal ideation or when the patient has questions regarding psychotropics. Additionally, psychiatric referral is warranted when there is serious social impairment not related to IBS, when there is repeated somatization with referral to various departments, or if a history of abuse or any major trauma is uncovered.

Several psychological interventions have been suggested for the treatment of IBS, including psychotherapy. Cognitive Behavioral Therapy (CBT) has shown promise for patients with moderate to severe IBS and those with IBS and concomitant anxiety or mood disorders. CBT can help patients learn coping strategies to control the symptoms brought on by anxiety or preoccupation. In Cognitive Behavioral Therapy, IBS patients work with a therapist to address specific concerns and perceptions about their functional gastrointestinal symptoms. These perceptions are modified in ways that lead to changes in cognitive appraisal of stress, which in turn impacts the patient's bowel symptoms. Additionally, CBT teaches patients how to recognize situations that may trigger their IBS symptoms. As a result, patients can learn how to find healthier ways of responding to those situations, thereby reducing stress. Combination therapy—medical management plus psychotherapy—has, in recent research, demonstrated great success, and may represent the future of IBS treatment.

Stress Management
Given the connection between the nervous system and colonic function, it is clear that stress plays a role in the frequency and severity of symptoms in patients with IBS. Patients should be encouraged to recognize and accept stressors in their lives. Breathing techniques and physical activity have proven useful in alleviating or helping patients deal with stress in their lives. Biofeedback and relaxation techniques, such as imagery or self-hypnosis, encourage control of physical and emotional responses—especially when coping with stress.

A diary may help patients recognize stressors that activate symptoms. The diary should include the date and time, the symptom experienced and its severity (for example, pain or diarrhea on a scale of 1-10), associated factors (such as diet, activity or stress), emotional response (angry, sad, anxious), and thoughts associated with the incident (out of control, hopeless). A written record of stressors and associated responses may help patients more easily identify triggers and more rapidly implement appropriate stress management techniques.

Drug Therapy

Smooth muscle relaxants
Recent clinical trials of anticholinergic and antispasmodic agents have shown these drugs to be significantly more efficacious than placebo in relieving IBS symptoms. However, it should be noted that these trials have been criticized for methodological failings, and the efficacy of anticholinergics and antispasmodics has not yet been proven definitively. As a result, these drugs are only recommended on an “as needed” basis, with dosing up to twice a day for bloating, distention and acute attacks of pain. Mebeverine and Dicyclomine appear to lose their effectiveness with chronic use. Currently available antispasmodics are separated into the general therapeutic classifications of anticholinergics, calcium-channel blockers, and opiod receptor modulators.

The most commonly prescribed anticholinergics in the U.S. are dicyclomine, hyoscyamine, and clidinium (in combination with chlordiazepoxide hydrochloride (Librium) = Librax). Gut-selective calcium-channel blockers, used to regulate movement of calcium ions into smooth muscle cells and neurons, have been developed to treat IBS and to avoid the undesired cardiovascular and systemic effects of traditional calcium-channel blockers. Peppermint oil, a carminative long utilized to treat IBS pain, has seen inconsistent outcomes. Opiates such as trimebutine have often been used not only as antidiarrheals but also as antispasmodics. Newer classes of antispasmodics (neurokinin [NK]2 receptor antagonist and ß3-adrenoceptor agonists) are in phase II clinical trials.

Antidiarrheal agents
Antidiarrheal agents are used to treat diarrhea adjunctly with rehydration therapy to correct fluid and electrolyte depletion. In patients with diarrhea as the predominant symptom, small bowel and proximal colonic transit times are accelerated. Loperamide (2–4 mg up to 4 times/day) decreases transit time, enhances bile acid absorption, increases anal sphincter tone, and reduces abdominal pain. This synthetic opioid is also effective in reducing postprandial urgency and improving control at times of anticipated stress. Loperamide is preferable to other narcotics for treating irritable bowel patients with diarrhea and/or incontinence. Cholestyramine may also be useful as a second or third line treatment for bile acid malabsorption.

Psychotropic agents
In the subset of patients with pain and diarrhea as the predominant symptoms of IBS, tricyclic agents have been found to be particularly beneficial (Table 5). This therapy is typically recommended in patients with severe symptoms, or symptoms resistant to first-line approaches, due to side effects. Lower dosages are used compared with dosages used for the treatment of depression

Tricyclic agents function as analgesics by modulating pain via their anticholinergic properties. It is hypothesized that tricyclic antidepressants directly influence brain-gut axis abnormalities inherent to the function process. Initially, a low dose is administered, and subsequently the dose is titrated to control pain. In addition, low doses have been found to slow orocecal transit, potentially replacing antidiarrheals in diarrhea-predominant patients. Because of the delayed onset of action, 3 to 4 weeks of therapy should be attempted before considering a dose insufficient. Amitriptyline, at a starting dose of 10 to 25 mg daily, or imipramine, at 25 to 50 mg daily, is useful for this purpose. Certain tricyclic agents, such as amitriptyline, may be particularly helpful for patients who complain of insomnia or who have well-defined depression or panic attacks.

Tricyclic antidepressants can cause or aggravate constipation, and should thus be avoided in patients with constipation-predominant IBS. These agents are also unsafe to use in patients who are pregnant. As in the case of any drug therapy, patients should be warned about anticholinergic side effects (see chart below).

Selective Serotonin Reuptake Inhibitors
While there have been few randomized trials conducted to gauge the effectiveness of serotonin reuptake inhibitors (SSRIs: paroxetine, fluoxetine and sertraline), these drugs do appear to be beneficial at typical psychiatric dosages (Table 5). The newer SSRIs, in particular Zoloft and Effexor, may be preferable in older patients or in those with constipation, because they are associated with fewer anticholinergic side effects. Citalopram was given to patients in a well-conducted small study in Belgium. The results of this study demonstrated that the drug induced a small degree of colonic relaxation, increased colonic tone and reduced the degree of discomfort associated with colonic distention.

It is believed that SSRIs impact IBS symptoms through a different mechanism than tricyclic antidepressants. In a small, retrospective review of patients receiving SSRIs for psychiatric treatment, the addition of tricyclic antidepressants improved gastrointestinal functioning. As a result, it is thought that SSRIs may impact IBS by modifying the cognitive environment and the patient’s sense of well-being. Early results from a recent study report that paroxetine also improved global measures in patients with severe IBS. In this study, in contrast to research using low-dose tricyclic antidepressants, a correlation was found between paroxetine use and reduction of psychological ratings. It has been suggested, therefore, that reduced anxiety and depression may result in positive outcomes in global well-being, which may generalize to secondary positive effects on IBS.

There is growing interest in this class of drugs and their potential in the treatment of IBS. Due to the lack of large trials using these agents, however, additional research is needed to determine their effectiveness in the treatment of IBS.

Drug summary table 
     

Table 5. Drugs used for the treatment of Irritable Bowel Syndrome

Alternative Therapy
Alternative therapies have been found to be useful for some patients. Herbs, including chamomile, ginger and mint have been found to be helpful in alleviating gastrointestinal pain in a subgroup of patients. One particular Chinese herb, which is made up of 20 herbs, has demonstrated efficacy in a formal clinical trial. Patients should understand that some herbs can interact negatively with prescribed or over-the counter medications and information about the use of any complimentary medicine should be shared with the responsible physician.

Some patients report symptom improvement from meditation and biofeedback therapies. Still others have achieved a degree of success and relief from symptoms with relaxation therapy. Several small studies suggest acupuncture provides significant relief from chronic pain. In IBS patients, there are reports that acupuncture can relax muscle spasms and improve bowel function.

Hypnotism is another alternative therapy gaining attention for the treatment of IBS. Hypnotism may help IBS patients manage stress and anxiety and enhance coping skills. By focusing the patient on the physiology of the gut through visualization techniques, colonic motility and visceral sensitivity may be modified. Several randomized controlled trials have demonstrated improvement in bowel function, pain, abdominal distention and global well-being associated with hypnosis. While this type of therapy is more expensive than traditional medications, symptom cessation may be longer-lasting than with other agents.

Other alternative therapies used to treat IBS include pro-flora supplements such as acidophilus and lactobacillus species, taken two to three times per day, to rebalance normal bowel bacteria and reduce gas and bloating. Regular exercise, such as walking, can reduce stress and encourage bowel movements. Therapeutic massage may help in reducing the effects of stress. No well-designed studies have evaluated the effect of chiropractic treatments on individuals with IBS, but it has been reported that spinal manipulation may improve symptoms of the condition in some individuals. It is hypothesized that in these cases, spinal manipulation may have a balancing effect on the nerves that supply impulses to the intestinal tract.

The current integrated understanding of IBS as a biopsychosocial entity has led to the use of psychological treatments, which have shown benefits in several well-designed studies. Cognitive Behavioral Therapy, dynamic/interpersonal psychotherapy, hypnotherapy and stress management training (relaxation and biofeedback) have all been studied. These strategies should be offered to patients with disabling symptoms, associated psychiatric disorders, and abuse history, although patients with less severe symptoms may also benefit.

An integrated approach that views IBS as a biopsychosocial illness is effective in most patients. The biopsychosocial model offers a framework that helps both the physician and the patient understand the interaction of physical and psychosocial factors and their contribution to illness. This model serves as a basis for the current state-of-the-art approach to the diagnosis and management of IBS and also provides a rationale for the development of future treatment modalities. 
   
 

Newer Therapy Options

Overview
Several novel treatment approaches are currently being studied. 5HT3 antagonists (such as alosetron) have been found to diminish visceral sensitivity and slow colonic transit. Alosetron has been shown to improve pain and bowel habits in women with diarrhea-predominant IBS. 5HT4 agonists (tegaserod and prucalopride), M3 muscarinic receptor antagonists (zamifenacin and darifenacin), and cholecystokinin (CCK) receptor antagonists (loxiglumide) appear promising for relief of constipation-predominant IBS and are currently in clinical trials. Tegaserod has been shown to improve pain and bowel habits in women with constipation-predominant IBS. New therapeutic approaches also target abnormal visceral sensitivity. These agents include 5HT3 antagonists, 5HT1 agonists (Buspirone), kappa-opioid agonists (fedotozine) and alpha-2 adrenergic agonists (Clonidine). These agents seem to reduce gut sensation in addition to altering motility (Figure 15). 

Figure 15. Specific locations in the enteric nervous system of the colon wall targeted by newer therapies.

    
Lotronex™ (Alosetron Hydrochloride) tablets
Pregnancy Category: B

WARNING: Serious bowel side effects, including some deaths, have been reported with the use of Lotronex™. These events include ischemia, colitis, and serious complications of constipation, which may lead to hospitalization. Only physicians who have been qualified by GlaxoSmithKline’s Prescribing Program are permitted to treat patients with Lotronex™, and patients must sign a Patient-Physician Agreement with their doctor.

Actions/Kinetics: Lotronex™ is a potent and selective 5HT 3 receptor antagonist, which inhibits activation of enteric neurons in the human gastrointestinal tract that cause pain and constipation in IBS. The 5HT3 antagonists diminish visceral sensitivity and slow colonic transit. Taken orally, Lotronex™ is quickly absorbed with a mean bioavailability of approximately 50% to 60%. Following oral administration of a 1.0 mg Lotronex™ dose to young women, the mean peak plasma concentration is approximately 9ng/mL after 1 hour. Renal elimination of unchanged Lotronex™ accounts for only 6% of the dose. Renal clearance is approximately 9ng/mL/min. Alosetron is extensively metabolized in humans, with only 7% of a radiolabeled dose recovered as unchanged drug.

Uses: Lotronex™ is indicated only for women with severe diarrhea-predominant IBS of at least 6 months duration, who have not responded to conventional therapy and have symptoms that include frequent and severe abdominal pain and frequent bowel urgency/incontinence that causes disruption of daily activities.

Contraindications: Lotronex™ is contraindicated in patients with:

•  Crohn’s disease, ulcerative colitis, or diverticulitis 
• A history of ischemic colitis, compromised intestinal circulation, thrombophlebitis and other clotting disorders 
• A histtory of severe or chronic constipation with subsequent problems/complications 
• A history of intestinal obstruction, toxic megacolon, stricture, and gastrointestinal adhesions or perforation.

Side Effects: GI: Acute ischemic colitis, constipation, nausea, GI discomfort and pain, abdominal discomfort and pain, GI gaseous symptoms, viral gastrointestinal infections, dyspeptic symptoms, abdominal distension, hemorrhoids. Otolaryngology: Throat and tonsil discomfort and pain, allergic rhinitis, bacterial ear, nose, and throat infections. Cardiovascular: Hypertension. CNS: Sleep disorders. Psychiatry: Depressive disorders.

Risk of Side Effects
Ischemic colitis has been reported in patients receiving Lotronex™ in clinical trials as well as during marketed use of the drug. In IBS clinical trials, the cumulative incidence of ischemic colitis in women receiving Lotronex™ was 2 per 1,000 patients (95% confidence interval 1 to 3) over 3 months and was 3 per 1,000 patients (95% confidence interval 1 to 4) over 6 months. Patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking Lotronex™ for longer than 6 months.

Infrequent adverse events, those occurring on one or more occasion in 1/100 to 1/1000 patients include; rare adverse events are those occurring on one or more occasion in fewer than 1/1000 patients. These events include:

Blood and Lymphatic: Rare: Quantitative red cell or hemoglobin defects, hemorrhage, and lymphatic signs and symptoms.

Cardiovascular: Infrequent: Tachyarrhythmias. Rare: Arrhythmias, increased blood pressure, and extrasystoles.

Drug Interaction, Overdose, and Trauma: Rare: Contusions and hematomas.

Ear, Nose, and Throat: Rare: Ear, nose, and throat infections; viral ear, nose, and throat infections; and laryngitis.

Endocrine and Metabolic: Rare: Disorders of calcium and phosphate metabolism, hyperglycemia, hypothalamus/pituitary hypofunction, hypoglycemia, and fluid disturbances.

Eye: Rare: Light sensitivity of eyes.

Gastrointestinal: Infrequent: Hyposalivation, dyspeptic symptoms, gastrointestinal spasms, ischemic colitis and gastrointestinal lesions. Rare: Abnormal tenderness, colitis, gastrointestinal signs and symptoms, proctitis, diverticulitis, positive fecal occult blood, hyperacidity, decreased gastrointestinal motility and ileus, gastrointestinal obstructions, oral symptoms, gastrointestinal intussusception, gastritis, gastroduodenitis, gastroenteritis, and ulcerative colitis.

Hepatobiliary Tract and Pancreas: Rare: Abnormal bilirubin levels and cholecystitis.

Lower Respiratory: Infrequent: Breathing disorders. Rare: Viral respiratory infections.

Musculoskeletal: Rare: Muscle pain; muscle stiffness, tightness and rigidity; and bone and skeletal pain.

Neurological: Infrequent: Hypnagogic effects. Rare: Memory effects, tremors, dreams, cognitive function disorders, disturbances of sense of taste, disorders of equilibrium, confusion, sedation, and hypoesthesia.

Non-site Specific: Infrequent: Malaise and fatigue, cramps, pain, temperature regulation disturbances. Rare: General signs and symptoms, non-specific conditions, burning sensations, hot and cold sensations, cold sensations, and fungal infections.

Psychiatry: Infrequent: Anxiety. Rare: Depressive moods.

Reproduction: Rare: Sexual function disorders, female reproductive tract bleeding and hemorrhage, reproductive infections, and fungal reproductive infections.

Skin: Infrequent: Sweating and urticaria. Rare: Hair loss and alopecia; acne and folliculitis; disorders of sweat and sebum; allergic skin reaction; eczema; skin infections; dermatitis and dermatosis; and nail disorders.

Urology: Infrequent:
Urinary frequency. Rare: Bladder inflammation; polyuria and diuresis; and urinary tract hemorrhage.

Postmarketing Experience: The following events have been identified during use of Lotronex™ in clinical practice. Because they were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Lotronex™.

Gastrointestinal: Constipation, ileus, impaction, obstruction, perforation, ulceration, ischemic colitis, small bowel mesenteric ischemia

Neurological: Headache.

Skin: Rash.

DRUG ABUSE AND DEPENDENCE: Lotronex™ has no known potential for abuse or dependence.

Special Concerns:
Hepatic Insufficiency: Lotronex™ is metabolized primarily in the liver; therefore increased exposure to Lotronex™ and its metabolites is likely to occur in patients with hepatic insufficiency.

Geriatric Use: Elderly patients may be at greater risk for complications of constipation.

Drug Interactions: Based on data from in vitro and in vivo studies, it is unlikely that alosetron will inhibit the hepatic metabolic clearance of drugs metabolized by the major CYP enzyme 3A4, as well as the CYP enzymes2D6, 2C9, 2C19, 2E1, or 1A2.

Overdose Management: There is no specific antidote for overdose of Lotronex™. However, individual oral doses of 16 mg have been administered in clinical studies without significant adverse events (usual dose is 2mg).

Dosage and Administration: In order to prescribe Lotronex™, physicians must be enrolled in the GlaxoSmithKline Prescribing Program. Lotronex™ should be started at a dosage of 1 mg orally once a day for 4 weeks. If it is well tolerated but does not adequately control IBS symptoms, then the dosage may be increased to 1 mg twice a day. Lotronex™ should be discontinued if IBS symptoms are not adequately controlled after 4 weeks of therapy of 1 mg twice daily. Lotronex™ should be discontinued in patients who develop constipation or symptoms of ischemic colitis.

Prescribing Program for Lotronex™
Physicians must enroll in the Prescribing Program for Lotronex™, which is a component of the Risk Management Program. Physicians must complete a revised indication that reflects the intent to reserve Lotronex™ for patients in whom the medical benefits outweigh the risks, namely, women with severe diarrhea-predominant IBS. These changes are reflective of the serious gastrointestinal adverse events, some fatal, that have been reported with its use. Only physicians enrolled in the GlaxoSmithKline Prescribing Program may prescribe Lotronex™. For more information visit: http://www.fda.gov/cder/drug/infopage/lotronex/lotronex.htm, the Lotronex Web Site or call 1-888-825-5249.

In order for the patient to fill the prescription and any refills, the Prescribing Program Sticker must be on the prescription. No telephone, fax or computer-generated prescriptions for Lotronex™ will be filled. If no sticker is present, the patient will be referred back to the physician. Once the prescription is filled, the patient will be given a Retail Pack containing the Medication guide, Package Insert, Medicine, and the Follow-up Survey. At this time, the pharmacist will once again encourage the patient to enroll in the follow-up survey.

Zelnorm™ (Tegaserod Maleate)
Tegaserod is a partial 5HT4 agonist, one of a class of new drugs with promise in treating IBS. Patients marked by chronic constipation may experience relief with the drug’s pro-motile properties and modulating effect on visceral sensitivity. Tegaserod has been approved by the FDA for the short-term treatment of women who have IBS, with constipation as their main symptom.

Clinical Results: Three multicenter, double blind, placebo-controlled studies evaluated Tegaserod in 2,470 women with IBS symptoms, namely abdominal pain, bloating and constipation. Two studies were fixed dose studies and the third was a dose-titration study. In all three studies, Tegaserod was administered for 12 weeks and efficacy was evaluated based on patients' ratings of their relief of symptoms and the intensity of symptoms. Tegaserod-treated patients reported greater relief from symptoms and a greater increase in number of stools than placebo-treated patients, with the largest difference during the first four weeks.

Pregnancy Category: B

Actions/Kinetics: Tegaserod is a partial agonist that binds with high affinity at human 5-HT4 receptors, and has no appreciable affinity for 5-HT3 or dopamine receptors. There is moderate affinity for 5-HT1 receptors. By acting as an agonist at neuronal 5-HT4 receptors, the release of further neurotransmitters such as calcitonin gene-related peptide from sensory neurons is triggered. The activation of 5-HT4 receptors in the gastrointestinal tract stimulates peristaltic reflex and intestinal secretion, as well as inhibiting visceral sensitivity. Fasting oral bioavailability is approximately 10% and administration with food reduces bioavailability by >40%. Peak plasma concentration is obtained in 1 hour. The medication is 98% protein bound and highly lipophilic, with extensive tissue distribution. Tegaserod is metabolized via GI hydrolysis and hepatic glucuronidation. With no active metabolites, it has a half-life of 11 hours.

Uses: Tegaserod has been approved by the FDA for the short-term treatment of women who have IBS with constipation as their main symptom.

Insufficient data exists to support Tegaserod use in other populations, including men with IBS. Efficacy has not been studied beyond 12 weeks.

Dose: 6 mg PO BID before meals for 4-6 weeks. If a positive response is achieved, an additional 4-6 weeks can be considered.

Monitoring: Relief of constipation should be demonstrated, with diarrhea the most common side effect. During episodes of diarrhea lasting >2 days, periodically monitor electrolyte levels (sodium, potassium, chloride, bicarbonate).

Contraindications: Tegaserod is contraindicated in patients hypersensitive to the drug and in those with a history of bowel obstruction, gallbladder disease, and severe renal impairment, moderate to severe hepatic impairment, abdominal adhesion, and suspected sphincter of Oddi dysfunction. Caution should be exercised in patients with diarrhea and in pregnant and breast-feeding patients.

Interactions: None reported.

Special Concerns: Diarrhea may occur; do not give to patients with diarrhea; discontinue if new or sudden worsening of abdominal pain or diarrhea occurs

Side Effects: Adverse events associated with the use of Tegaserod may include (but are not limited to) the following:
CNS: Headache, dizziness, migraine.
GI: Abdominal pain, nausea, diarrhea, flatulence.
Musculoskeletal: Back pain, arthropathy, and accidental injury.
Other: Leg pain. 
    

Table 6. Treatment Algorithm

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