Safety and Tolerability of Tegaserod in Irritable Bowel Syndrome Management

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Safety and Tolerability of Tegaserod in Irritable Bowel Syndrome Management Rosemary R. Berardi

Received October 9, 2003, and in revised form November 7, 2003. Accepted for publication November 21, 2003.

ABSTRACT

Objectives: To discuss the need for safe and effective therapy for patients with irritable bowel syndrome (IBS) and to provide up-to-date information on the safety and tolerability profile of tegaserod, a novel treatment for women with IBS whose primary bowel symptom is constipation. Data Sources: PubMed and abstracts from gastroenterology conferences were searched through October 2003 using the following search terms: irritable bowel syndrome, IBS, tegaserod, cisapride, alosetron, systematic review, safety, tolerability, serotonin, 5-HT, 5-HT3 receptor antagonist, and 5-HT4 receptor agonist; all information on the safety and tolerability of tegaserod published up to October 2003 is included.

Rosemary R. Berardi, PharmD, FCCP, FASHP, is Professor of Pharmacy, College of Pharmacy, and Clinical Pharmacist, Gastrointestinal and Liver Diseases, Department of Pharmacy, University of Michigan Health-System, University of Michigan, Ann Arbor, Mich. Correspondence: Rosemary R. Berardi, PharmD, FCCP, FASHP, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1965. Fax: 734763-4480. E-mail: [email protected]. Disclosure: The author has served as a speaker and consultant for Novartis Pharmaceuticals Corporation, receiving honoraria in both roles. She declares no other relevant conflicts of interest or financial interests.

Data Synthesis: A comprehensive review of the medical literature (through 2001) finds no adequate therapies that address the multiple symptoms of IBS. Traditional agents, although occasionally effective, often cause adverse effects. Tegaserod, a selective serotonin type 4 receptor (5-HT4) partial agonist, overcomes a number of obstacles associated with traditional therapies. Important information for pharmacists about the safety and tolerability of tegaserod is presented. Conclusion: Tegaserod is effective in treating multiple IBS symptoms in women with IBS whose primary bowel symptom is constipation, and it is safe and well tolerated. Keywords: Irritable bowel syndrome, tegaserod, cisapride, alosetron, serotonin. J Am Pharm Assoc. 2004;44:41–51.

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Tegaserod in Irritable Bowel Syndrome

T

egaserod (Zelnorm, Novartis) was approved in July 2002 for the treatment of IBS in women whose primary bowel symptom is constipation (IBS-C). The first agent in a novel drug class (aminoguanidine indoles), tegaserod targets the multiple symptoms of IBS-C (abdominal pain or discomfort, bloating, and constipation) and has an excellent safety profile. Tegaserod improves the symptoms of IBS-C by promoting motility along the entire gastrointestinal (GI) tract, increasing intestinal secretions, and decreasing visceral sensitivity. The previous withdrawal from the marketplace of two other agents with promotility properties—cisapride and alosetron—prompted safety concerns in the minds of health care professionals and the public.

Objectives The purpose of this paper is to clarify the safety concerns and to update pharmacists on the safety and tolerability profile of tegaserod.

mate because symptoms can wax and wane, and primary bowel symptoms alternate over time. IBS affects up to 20% of the United States population,4 and population-based studies show an approximate 2:1 ratio of women to men.4 IBS typically presents between the ages of 30 and 50 years5; it is one of the most common disorders managed by gastroenterologists.6 IBS symptoms are chronic, episodic, and often bothersome, substantially affecting the daily lives of patients.7,8 Studies have shown that the quality of life of IBS patients can be severely diminished compared with population norms and persons with other chronic conditions, such as gastroesophageal reflux disease (GERD), asthma, or migraine.9-12 IBS symptoms can also negatively affect the social lives of patients (e.g., sports/recreational activities, travel, diet, relationships with family/friends) and limit work-related opportunities.2,7,13,14 The overall economic burden of IBS (direct and indirect costs) is substantial: an estimated $30 billion per year (1999- and 2000-adjusted dollars, respectively).15,16

Treatment Epidemiology and Impact IBS is characterized by abdominal discomfort or pain associated with defecation or a change in bowel habit.1 It is generally categorized into three subtypes—IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and IBS with alternating diarrhea and constipation (IBS-A).2 Although these subtypes occur with approximately equal frequency,3 their exact prevalence is difficult to esti-

AT A GLANCE Synopsis: The availability of tegaserod addresses the dearth of medications that are effective in managing irritable bowel syndrome (IBS) with constipation as the predominant symptom (IBS-C). Tegaserod represents a new class of drugs and is structurally and pharmacologically distinct from other agents with promotility properties, such as cisapride and alosetron. Throughout the clinical trials with tegaserod, most patients saw significant improvement in their IBS symptoms, and the medication was well tolerated. Tegaserod has received marketing approval in more than 55 countries around the world. In the United States, more than 1 million prescriptions have been filled since its approval in July 2002, attesting to the experience that physicians are gaining in using tegaserod to treat patients with IBS-C. Analysis: Tegaserod is an important addition to the therapeutic arsenal for treating patients with IBS-C. Other agents, primarily aimed at single symptom relief, have been largely ineffective at relieving the multiple symptoms of IBS.

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The goal of IBS treatment is to achieve global symptom improvement, including overall well-being, and improvement in single symptoms, such as abdominal pain, altered bowel habits, and bloating, as per the evidence-based position statement on the management of IBS in North America, recently published by the American College of Gastroenterology (ACG) Functional Gastrointestinal Disorders (FGID) Task Force.17 Treating only single symptoms is deemed suboptimal.17 In addition to providing global symptom relief, treatment options should be safe and well tolerated and should be free of associated serious adverse effects and drug–drug interactions. Traditional treatment options for patients with IBS, such as laxatives, bulking agents/fiber supplements, antidiarrheals, and antidepressants, typically target only one of the multiple symptoms of IBS.18 Evidence-based and systematic reviews indicate that most of these agents are no more effective than placebo at providing global relief of IBS symptoms and that they often produce undesirable adverse effects (AEs), leaving patients dissatisfied.4,7,17,19 The effectiveness of laxatives has not been evaluated in controlled clinical trials with IBS patients. Although select antispasmodic agents available outside the United States (e.g., the smooth muscle relaxants cimetropium, pinaverium, otilonium, and trimebutine) have demonstrated global improvement, evidencebased recommendations regarding agents approved for use in this country (e.g., the anticholinergics dicyclomine and hyoscyamine) cannot be made because of poor-quality clinical trials and insufficient data for establishing effectiveness.4,17,19 The AEs associated with traditional IBS treatment options (e.g., constipation from antispasmodics and tricyclic antidepressants, bloating from high doses of fiber supplements) often mimic or exacerbate IBS symptoms.7,18,20 When traditional therapies fail,

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patients frequently turn to alternative care options, but these are generally ineffective.18,21

Serotonergic Mechanisms The three key pathophysiologic abnormalities in IBS are altered GI motility, altered intestinal secretion, and enhanced visceral perception (hypersensitivity and pain).22,23 These processes are regulated by the brain–gut axis through bidirectional pathways between the central nervous system (CNS) and the enteric nervous system (the “mini-brain” that organizes, coordinates, and processes the activity patterns of the intestines essentially independently of the CNS). One common link among these three processes is serotonin (5hydroxytryptamine [5-HT]), a neurotransmitter that is produced and stored mainly in the gut (95%; the other 5% is found in the CNS).23 Serotonin stimulates both intrinsic primary afferent neurons that initiate secretory and peristaltic reflexes and extrinsic sensory neurons that affect sensation.24 Physiologic abnormalities in IBS may be related to alterations in serotonin levels25-28 or to dysfunction in the communication tract along the brain–gut axis.22,23 Because serotonin and its receptors (primarily 5-HT type 3 [5-HT3] and type 4 [5-HT4]) play a major role in gut function,23 5-HT is a promising target for pharmacologic intervention in IBS.

5-HT Modulators Alosetron (Lotronex, GlaxoSmithKline), a selective 5-HT3 receptor antagonist, was launched in February 2000 for women with diarrhea-predominant IBS.29 In November 2000, alosetron was withdrawn from the market because of reports to the Food and Drug Administration (FDA) of serious complications of constipation (13 cases, including two deaths) and acute ischemic colitis (84 cases, including two deaths).30,31 Alosetron was subsequently reapproved in June 2002 under restrictive prescribing guidelines,30 and it is now indicated exclusively for the treatment of women with severe diarrhea-predominant IBS in whom traditional therapies have failed.4,32 Alosetron has been shown in Phase III clinical trials to significantly improve the abdominal pain/discomfort and diarrhea associated with IBS-D and to provide global symptom improvement.4,32 In two 12-week prospective trials, patients receiving alosetron had 13% to 16% increases over placebo in median percentage of days with urgency control. Two retrospective analyses in a subset of women who experienced urgency 5 days per week at baseline revealed that alosetron was 13% to 21% more effective than placebo in reducing urgency to no more than 1 day per week during the last week of the trial. Further, alosetron provided greater relief than placebo of IBS-related pain and discomfort.33 Tegaserod is a selective 5-HT4 receptor partial agonist that is indicated for use in women with IBS-C. An aminoguanidine indole, this unique compound mimics the action of endogenous serotonin at 5-HT4 receptors.34 Tegaserod is considered a partial

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agonist because its intrinsic activity in guinea pig ileum is 21%, considerably less than the 100% intrinsic activity of endogenous 5HT.34 Partial agonists are associated with a lower likelihood of receptor desensitization (leading to tachyphylaxis) than are full agonists because they produce a limited, yet positive, physiologic effect. Tegaserod is, therefore, more likely than a full agonist to modulate 5-HT4 receptor activity in a balanced fashion.34 In three large, double-blind, randomized clinical studies, tegaserod provided global relief of IBS symptoms and relief of single symptoms (constipation, abdominal pain, bloating) in women with IBS-C,35-37 with a 13% to 14% therapeutic gain at 4 weeks and a 5% to 11% therapeutic gain at 12 weeks, compared with placebo.35 At study end point (final 4 weeks of the trial), tegaserod response rates ranged from 39% to 44%, compared with 28% to 39% in patients receiving placebo.35 Up to 67% of patients responded to tegaserod at 12 weeks.37 Efficacy began in the first week and was sustained throughout the trials.36,37 When tegaserod use was discontinued, IBS symptoms returned.

Tegaserod Safety and Tolerability Profile Information presented in this article was obtained by searching PubMed and abstracts from gastroenterology conferences using the following search terms: irritable bowel syndrome, IBS, tegaserod, cisapride, alosetron, systematic review, safety, tolerability, serotonin, 5-HT, 5-HT3 receptor antagonist, and 5-HT4 receptor agonist; all information on the safety and tolerability of tegaserod published through October 2003 is included. Short-Term Trials

The safety and tolerability of tegaserod have been evaluated in several trials, including three multicenter, double-blind, placebocontrolled studies in which 2,632 patients with IBS-C received tegaserod (6 mg twice daily) or placebo for 12 weeks, preceded by a 4-week baseline.35-38 Concomitant use of any medication that could affect GI motility or perception was disallowed. However, patients were permitted to continue use of long-term stable doses of bulking agents36-38 or fiber37 or use of concomitant medications common to this patient population, including tricyclic antidepressants (TCAs)36 and serotonin reuptake inhibitors (SSRIs).36,38 In some studies, predefined laxatives were allowed as rescue medication in patients with severe constipation,36,38 and loperamide was allowed in patients with bothersome diarrhea.36 AEs reported by 1% or more of patients are shown in Table 1.35 The most frequently reported GI symptoms were abdominal pain, diarrhea, nausea, flatulence, and constipation. Headache, back pain, and flulike symptoms were also reported. Diarrhea and headache were the only AEs reported with greater frequency in patients taking tegaserod than in patients receiving placebo (9% versus 4% and 15% versus 12%, respectively).35 Most diarrheal episodes were mild and occurred during the first week of treatment; they typically resolved within a few days without treatment interruption. Diarrhea did not cause dehydration or depletion of

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Table 1. Adverse Events in 1% or More of IBS Patients Receiving Oral Tegaserod or Placebo During Phase III, 12-Week Trials35

Adverse Event

Tegaserod 6 mg Twice Daily % Patients (n = 1,327)

Tegaserod % Patients (n = 567)

Adverse Event Placebo % Patients (n = 1,305)

Gastrointestinal reactions Abdominal pain

Table 2. Most Frequently Occurring Adverse Events During an Open-Label, 12-Month Study39

Headache

29.5

Abdominal pain

17.1

Upper respiratory tract infection

16.2

Diarrhea

14.6

12

11

Diarrhea

9

4

Back pain

Nausea

8

7

Sinusitis

8.3

Flatulence

6

5

Nausea

8.1

Central or peripheral nervous system reactions Headache Dizziness Migraine

8.6

Flatulence

7.6

Dyspepsia

7.2 6.9

15

12

4

3

Rhinitis

1

Influenza-like symptoms

6.0

Pharyngitis

5.3

Insomnia

5.1

2

Body as a whole—general disorder reactions Accidental trauma

3

2

Leg pain

1

<1

Back pain

5

4

Arthropathy

2

1

Musculoskeletal system reactions

electrolytes, nor did it necessitate hospitalization.35-37 Diarrhea caused 1.6% of patients receiving tegaserod to discontinue treatment during these trials.35 Longer-Term Trials

Tegaserod is indicated for the short-term treatment of women with IBS-C, but many patients experience symptom recurrence on withdrawal (though returning symptoms are less severe than those reported at baseline).37 Studies evaluating the use of tegaserod for extended periods have been conducted39; others are under way. A 12-month, multicenter, open-label study was conducted to determine the long-term safety and tolerability of tegaserod in patients with IBS-C (n = 579).39 Overall, 52.5% of the patients who received treatment with tegaserod completed the planned 12month treatment period. The most commonly reported AEs in this trial (Table 2)39 were similar to those of the 12-week Phase III clinical trials. A total of 65 patients (11.2%) terminated study participation because of AEs, with the highest rate of discontinuation (3.5%) attributed to diarrhea. Diarrhea, however, was not accompanied by dehydration or electrolyte imbalance and did not result in any hospitalizations.39 Two open-label studies of patients with IBS-C, presented at the 2003 Digestive Diseases Week meeting, evaluated the safety of tegaserod use during continuous treatment or retreatment. In one trial, patients received tegaserod 6 mg twice daily for 4 weeks (initial treatment phase) and were then randomly assigned to continue

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treatment for 2 months (maintenance arm) or to discontinue treatment (withdrawal arm).40 In the second study, after receiving tegaserod 6 mg twice daily for 12 weeks (initial treatment phase), all patients were withdrawn from treatment. Those considered treatment responders were observed for up to 8 weeks to detect symptom recurrence. Patients in whom symptoms recurred were retreated with tegaserod for 4 weeks (retreatment phase).41 Safety assessments from both studies demonstrated that tegaserod use (for 12 weeks versus 4 weeks, or as retreatment after withdrawal) is not associated with an increase in AEs.40,41 Trials in Patients with IBS-D

Although tegaserod is FDA-approved only for IBS-C, it has been studied in patients with IBS whose predominant symptom is diarrhea. In an 8-week, prospective, multicenter study of the safety and tolerability of tegaserod in 69 patients with IBS-D, no significant safety problems were observed with either the 4 mg/day (n = 35) or the 12 mg/day (n = 34) dose of tegaserod compared with placebo (n = 17).42 Diarrhea was the most common AE reported with tegaserod (33%); incidence was similar to that reported by the placebo group (35%).42 As in studies with IBS-C patients, most episodes of diarrhea occurred within 1 to 7 days of treatment initiation and were infrequent, transient, and single episodes that resolved with continued therapy.42 Again, diarrhea was not associated with dehydration or electrolyte abnormalities. Eleven patients in the tegaserod group (13% of patients, compared with no one in the group taking placebo) discontinued treatment as a result of AEs; five discontinuations (6%) were attributed to diarrhea, abdominal pain, or both.42

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Asian-Pacific Patients

Other clinical trials examining the safety and tolerability of tegaserod also reveal a low incidence of AEs. In a randomized, double-blind, multicenter, 12-week study, an Asian-Pacific population of IBS patients whose primary bowel symptom was not diarrhea was evaluated. Patients were treated with tegaserod (6 mg twice daily; n = 259) or placebo (n = 261).43 Headache was the most frequently reported AE (12% in the tegaserod group and 11% in the placebo group), which led 1.2% and 0.4% of patients to discontinue treatment, respectively. Diarrhea was the only AE considered to be drug related. It occurred significantly more often in the tegaserod treatment group (6.6%) than in the placebo group (3.1%); this incidence was similar to that observed in previous studies. Episodes of diarrhea were mild and transient and led to discontinuation in 2.3% of tegaserod-treated patients, compared with none in the placebo group. Reports of serious AEs were infrequent; these occurred in 3.4% of patients in the tegaserod-treated patients and 1.5% of patients taking placebo. No patients in the tegaserod group discontinued treatment as a result of serious adverse effects, while 1.5% of patients taking placebo did so.43 Swiss Patients

The safety and tolerability of tegaserod were also investigated in an open-label trial of 843 Swiss patients with IBS whose primary bowel symptom was not diarrhea.44 Patients were treated with 6 mg tegaserod twice daily for 8 weeks. Again, the most commonly reported AEs were headache (12%) and GI effects (abdominal pain, 6%; nausea, 4%; constipation, 2%; and dyspepsia, 1%). A similar pattern of AEs was observed during 4 optional 12-week extension periods. During the 8-week study, 112 of 843 patients (13.2%) discontinued treatment because of AEs; 17 patients (2%) discontinued treatment because of diarrhea.44 Nordic Patients

An additional 12-week, double-blind, randomized, placebocontrolled study assessed the safety and efficacy of tegaserod in a Nordic population of IBS patients whose primary bowel symptom was not diarrhea.45 Patients received tegaserod 6 mg twice daily (n = 327) or placebo (n = 320). The overall frequency of AEs was comparable between treatment and placebo groups. The most common AE was diarrhea, reported in 9.2% of tegaserod-treated patients and 1.3% of those receiving placebo. The overall discontinuation rate was 15.3% for the tegaserod group versus 10.3% for the placebo group. Discontinuation rates because of AEs were 7.0% for the tegaserod group and 2.5% for the placebo group. Discontinuation rates because of diarrhea were 2.8% for those receiving tegaserod and none for the placebo group.45

REVIEWS

Unfortunately, cisapride use is associated with prolongation of the QT interval and with serious arrhythmias, including torsades de pointes.46-48 Sudden deaths have been reported in adults and children taking recommended doses of cisapride.46 Several patients reporting serious events while on cisapride were also taking agents known to interfere with cisapride metabolism, including imidazole antifungal agents (e.g., itraconazole) and macrolide antibiotics (e.g., clarithromycin); both drug classes decrease CYP3A4 activity. This decreased activity leads to 10-fold to 20-fold increases in cisapride plasma concentrations, resulting in concentrationdependent arrhythmias.46 Because of its AE profile and potential for serious CYP450 drug–drug interactions, the manufacturer voluntarily withdrew cisapride from the marketplace in March 2000.49 The arrhythmogenic potential of cisapride naturally raises concern among health care professionals and the public regarding whether its cardiac effects are common to all agents that stimulate GI motility. Tegaserod is an aminoguanidine indole structurally distinct from substituted benzamides such as cisapride.50 The potential for tegaserod and its primary human metabolite, 5methyoxy-indole-3 carboxylic acid glucuronide, to induce QTinterval abnormalities was tested in a rabbit heart model.51 QT intervals remained unchanged at therapeutically equivalent doses of tegaserod. In contrast, both cisapride and erythromycin slowed cardiac repolarization at their respective therapeutically equivalent doses in this model. The potential for tegaserod to cause cardiac abnormalities in humans was investigated in 2,516 patients with IBS-C who were receiving placebo (n = 837) or tegaserod 2–6 mg twice daily (n = 1,679) in three randomized, double-blind, placebo-controlled, Phase III trials. Evaluation of more than 11,000 electrocardiograms revealed no differences between tegaserod- and placebotreated patients.50 In a separate study, 36 healthy male volunteers received placebo and then escalating, single, intravenous (IV) doses of tegaserod 0.8, 3.2, 5, 8, 14, and 20 mg (each dose, n = 6).50 Tegaserod was not associated with clinically important electrocardiographic effects, even at IV doses producing plasma concentrations up to 100 times those measured after therapeutic doses were administered.50 In summary, safety data from well-designed 12-week clinical trials, long-term trials, and trials in specific IBS patient populations are remarkably consistent in demonstrating that tegaserod is generally well tolerated. The most commonly reported AEs— headache and mild, transient diarrhea—occurred in a relatively low proportion of IBS patients receiving treatment.

Cardiac Effects

Patients Undergoing Abdominal Surgery and Cholecystectomy

Cisapride, a substituted piperidinyl benzamide, is a promotility agent that inhibits the cytochrome (CYP) P450 system, specifically CYP3A4. Previously, it was widely used for the treatment of patients with GERD and other GI disorders, including IBS.

Numerous studies have documented that abdominal surgery rates are greater among IBS patients than in the general population.52-58 During Phase III trials of tegaserod, a numeric imbalance exist-

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ed between the rates of abdominal surgery (primarily cholecystectomies) in patients receiving tegaserod versus patients receiving placebo. Although these differences were not statistically significant, an in-depth, independent evaluation of abdominal surgeries in patients with IBS, including those receiving tegaserod, was performed by an expert panel of 10 independent consultants. The results of this evaluation were submitted to the FDA as part of its reconsideration of the market approval of tegaserod. The results are scheduled to be published in detail later this year.59 According to one analysis, cholecystectomies were performed in 5 of 2,965 patients (0.17%) receiving tegaserod and in 1 of 1,740 patients (0.06%; P = .22) receiving placebo.35,59 Blinded evaluation of each of the cholecystectomy cases was conducted to investigate this relationship. Cholecystectomies performed on three of the five tegaserod-treated patients were deemed not treatment related: One patient had right upper quadrant pain at baseline (cholelithiasis was discovered only 2 days after treatment initiation), and two patients scheduled elective cholecystectomies during the trial (both had symptoms before study entry). No evidence suggested that tegaserod precipitated biliary symptoms in patients with preexisting cholelithiasis, or that tegaserod increased the risk for cholecystectomy or gallstone formation. The expert panel concluded that the incidence of cholecystectomy in the Phase III clinical trials of tegaserod was consistent with expected rates in the total population of women with IBS.59 A critical review of all abdominal surgery cases, including cholecystectomies (9 of 2,965 patients receiving tegaserod [0.3%] versus 3 of 1,740 patients receiving placebo [0.17%]; P = .37), was also performed.59 In this review, 6 incidents were excluded from analysis (5 in the tegaserod group and 1 in the placebo group) because of preexisting conditions and unrelated procedures required after conclusion of double-blind therapy (those relating to cholecystectomies were described above). After these exclusions, the numeric imbalance between tegaserod (0.13%) and placebo (0.11%) was eliminated. No statistically significant differences were found between the tegaserod and placebo groups. In light of this critical review and the reanalysis of data from the entire Phase III clinical program for tegaserod in patients with IBS-C, the consultants concluded that no evidence linked tegaserod to an increased risk for abdominal or pelvic surgery.59 In addition, the effect of tegaserod on meal-induced gallbladder motility and biliary tract diameter was investigated in a 6-week, placebo-controlled, crossover study in healthy volunteers and IBSC patients.60 Tegaserod 6 mg twice daily had no significant effect on the dynamics of gallbladder emptying in healthy volunteers or in IBS-C patients compared with placebo. Tegaserod did not appear to induce an increase in sphincter of Oddi resistance to bile flow, as evidenced by bile duct diameter during gallbladder emptying. Similar results were observed with a dose regimen of tegaserod 12 mg given twice daily.60

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Special Patient Populations

Precautions related to the use of drugs in special patient populations, such as older patients or those with organ dysfunction, are critical issues about which pharmacists should be aware. Table 3 summarizes the results from tegaserod clinical trials and pharmacokinetic studies for specific patient populations and lists potential needs and precautions to be observed for these groups.35,61-67

Pharmacokinetics The pharmacokinetics of tegaserod has been extensively studied in animal models and humans.34,67,68 Important pharmacokinetic parameters are listed in Table 4. Under fasted conditions, the oral bioavailability of tegaserod is approximately 10%.61,68–70 Food intake (30 minutes, 15 minutes, or 1 minute before or 2.5 hours after tegaserod administration) reduced bioavailability (area under the serum concentration–time curve) by 40% to 65% and maximal concentration (Cmax) by 20% to 40% compared with the fasted state. In addition, when tegaserod was taken after a meal, the time to peak concentration (Tmax) was prolonged from 1 hour to 2 hours, but it decreased by 0.7 hour when tegaserod was taken 30 minutes before a meal.61,71 In Phase III clinical trials in which tegaserod demonstrated significant global improvement and relief of single IBS symptoms, the drug was administered within 30 minutes before morning and evening meals.34 Thus, the recommended dosage schedule for tegaserod is 6 mg twice daily orally before meals.35

Drug–Drug Interactions Tegaserod has no known clinically important drug interactions.35 Unlike with cisapride, the CYP450 metabolic pathway plays an insignificant role in tegaserod metabolism, and tegaserod therefore does not interact with agents metabolized by this route, including azole antifungal agents and SSRIs. The safety of tegaserod in patients who concomitantly took antidepressants (including SSRIs) during Phase III trials was recently evaluated. Results showed that the frequency of AEs in patients taking tegaserod alone was similar to that in patients taking tegaserod and an antidepressant. Diarrhea was reported in 5.2% of patients taking tegaserod and an SSRI compared with 2.9% of patients taking an SSRI and placebo, and in 9.1% of patients taking tegaserod alone compared with 4.0% of patients taking placebo.72 In vitro and in vivo studies of tegaserod show no clinically important drug interactions with digoxin, warfarin, oral contraceptives, dextromethorphan, or theophylline.61,73–77 Patients in Phase III trials who were taking fiber or bulking agents for at least 1 month before enrollment were allowed to continue taking them as long as they maintained their pre-enrollment fiber administration schedule. Laxatives were also occasionally used as rescue medication. Concomitant use of these agents did not appear to affect the safety or efficacy of tegaserod.56 Concomitant use of GI motility agents was not permitted in the Phase III clinical trials.

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Table 3. Considerations About Tegaserod Therapy in Special Patient Populations Population

Relevant Trial Results

Potential Special Need

Advanced age (older than 65 years)

No overall differences in pharmacokinetics of tegaserod were observed between healthy volunteers older than 65 years and those younger than 65 years, although AUC∞ and Cmax were found to be 40% (significant difference) and 22% (nonsignificant difference) higher in older women than in younger women, respectively.61,62 Variabilities in Cmax and AUC observed in this study were similar to those normally observed in healthy subjects and are therefore unlikely to be of clinical relevance.35

Dosage adjustment not required in patients older than 65 years.35

Of 4,035 patients in Phase III clinical studies, 290 (7.2%) were at least 65 years of age. No overall differences in safety were observed between these patients and younger patients with regard to AEs.35 Men

In clinical trials with healthy volunteers, gender had no effect on the pharmacokinetics of tegaserod.35,61,62

Tegaserod is not indicated for use in men.35

Three pivotal Phase III clinical trials (n = 2,470) included 163 men; this number was insufficient for useful conclusions to be drawn about the efficacy of tegaserod in men.35 In a small, open-label study of patients with IBS-C (n = 117; 69% men), tegaserod was well tolerated by patients of both sexes and was equally effective in men and women in relieving abdominal pain and straining.66 Renal impairment

Similar single-dose pharmacokinetics of tegaserod (AUC, Cmax) was observed in patients with severe renal disease requiring hemodialysis.65 However, compared with healthy control patients, Cmax and AUC∞ of the pharmacologically inactive metabolite 5-methoxy-indole-3-carboxylic acid glucuronide increased by 2-fold and 10-fold, respectively, in patients with severe renal impairment.35,61 Tegaserod had similar tolerability in renally impaired patients and healthy volunteers, with AEs related to the gastrointestinal actions of the drug.65

Hepatic impairment

No single-dose pharmacokinetic parameter was statistically significantly different between patients with biopsy-proven, mild to moderate hepatic impairment (cirrhosis, Child–Pugh clinical assessment score ≥5 and ≤11) and patients with normal liver function, although mean AUC∞ and Cmax increased by 43% and 18%, respectively, in patients with liver cirrhosis compared with healthy controls.61

Dosage adjustment not required for mild to moderate renal impairment. Tegaserod is not recommended in patients with severe renal impairment because of the 10-fold increase in AUC∞ of the inactive metabolite.35,61

No dosage adjustment required in patients with mild impairment. Not recommended for patients with moderate to severe hepatic impairment.35

Tegaserod has not been adequately studied in patients with moderate and severe hepatic impairment.35,61 Pregnant women

Animal studies show no evidence of impaired fertility or harm to the fetus.35

Pregnancy category B. Because animal reproduction studies are not always predictive of human response, tegaserod should be used during pregnancy only if clearly indicated.35

Nursing mothers

Tegaserod and its metabolites are excreted in the milk of animal models. Human excretion is unknown. A potential for tumorigenicity was seen in a mouse model at 600 mg/kg/day (doses 83–110 times the normal human exposure of 6 mg twice a day).35

Depending on the importance of the drug to the mother, a decision must be made to discontinue medication or discontinue nursing.35

Young age (younger than 18 years)

The safety and efficacy of tegaserod in pediatric patients have not been established.35

Tegaserod is not indicated for use in pediatric patients (younger than 18 years).35

Abbreviations used: AUC∞ = area under the serum concentration–time curve from 0 to infinity; Cmax = maximum serum concentration; AEs = adverse events; IBS-C = irritable bowel syndrome with constipation.

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Table 4. Tegaserod Pharmacokinetic Parameters and Features34,35,61

Table 5. Tegaserod Indications, Dosage, Contraindications, Precautions, and Drug Interactions35

Absorption ■ Rapidly absorbed ■ Peak concentration: 1 hour after administration ■ Bioavailability (in fasting state): 10%

Indications ■ Short-term treatment of women with irritable bowel syndrome whose primary bowel symptom is constipation Contraindications ■ Severe renal impairment

Distribution ■ Fraction bound to plasma proteins: 98% ■ Distribution at steady state: 368 ± 223 L

Metabolism ■ Presystemic metabolism by acid hydrolysis in stomach ■ Subsequent oxidation and conjugation ■ Main metabolite is a glucuronide with negligible affinity for 5-HT4 receptors

Elimination ■ Excreted as N-glucuronides in the bile ■ Terminal half-life: 11 ± 5 hours ■ Blood clearance following intravenous administration: 48 L/hour ■ Two thirds of orally administered dose is excreted unchanged in feces and one third in urine as metabolite

■ Moderate or severe hepatic impairment ■ History of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions ■ Known hypersensitivity to tegaserod or any of its excipients (crospovidone, glyceryl monostearate, hydroxypropyl methylcellulose, lactose monohydrate, poloxamer 188, polyethylene glycol 4000) Precautions ■ Tegaserod should not be initiated in patients who have or frequently experience diarrhea ■ Tegaserod should be discontinued immediately in patients with new or sudden worsening of abdominal pain Dosing ■ Recommended dose: 6 mg twice daily before meals for 4 to 6 weeks. An additional 4 to 6 weeks may be considered in those who respond to treatment ■ No dose adjustment necessary in patients older than 65, with mild to moderate renal impairment, or with mild hepatic impairment Drug interactions ■ No known drug–drug interactions and specifically no clinically important drug–drug interactions found with the following:

Patient Counseling Pharmacists can play an important role in educating patients who present with new prescriptions for tegaserod or who may be candidates for its use. The pharmacist should review with the patient the ways in which tegaserod will relieve IBS symptoms. In addition, the pharmacist should counsel patients on the recommended dosage schedule, duration of therapy, potential adverse effects, and instances that warrant direct reporting to their physicians (Table 5). Pharmacists should advise patients that they may experience headache or diarrhea, the two adverse effects reported more commonly with tegaserod than with placebo in clinical studies. Diarrhea, which occurred in less than 10% of patients in clinical trials, usually occurs within the first week of therapy. It is mild and generally resolves on its own with continued tegaserod therapy. Mild diarrhea is, therefore, a transient adverse effect that does not warrant discontinuation of therapy. If, however, diarrhea is severe or is accompanied by bothersome cramping, abdominal pain, or dizziness, patients should be advised to stop taking the medication and to contact their physicians immediately.35 In clinical trials, headache was also mild to moderate and resolved with continued

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– Theophylline – Dextromethorphan – Digoxin – Warfarin – Oral contraceptives Availability ■ Supplied in 2-mg tablets and 6-mg tablets

therapy. The incidence of migraine headache was similarly small in the tegaserod and placebo groups.35 Pharmacists should ensure that patients are aware of populations for whom tegaserod is not intended or in whom it must be used with caution. These include pregnant and nursing women, children, patients with severe kidney disease, and patients with moderate to severe liver disease (Tables 3 and 5). Despite the efforts of numerous patient education campaigns to raise public awareness of the prevalence and impact of IBS, many patients with this disorder feel inadequately informed about its causes and consequences. As important members of integrated

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health care teams, pharmacists can fill these educational gaps by addressing questions and referring patients to easily accessible, patient friendly resources for more information (see Table 6). Pharmacists can also play a critical role in identifying the medications patients are taking that may be exacerbating their IBS symptoms, particularly over-the-counter medications (those that cause diarrhea, constipation, bloating, or abdominal cramping) and in helping patients to find alternatives.

Conclusion

REVIEWS

positive. Throughout the clinical trials, most patients saw improvement in their IBS symptoms, and tegaserod was well tolerated. Tegaserod has received marketing approval in more than 55 countries around the world. In the United States, more than 1 million prescriptions have been filled since its approval in July 2002, attesting to the experience that physicians are gaining in using tegaserod to treat patients with IBS-C.56 Pharmacists can help to ensure successful treatment outcomes by providing effective patient counseling and by monitoring the safety, tolerability, and efficacy of medications, including tegaserod, that are used in the treatment of patients with IBS.

Clinical experience with tegaserod has been overwhelmingly

References Table 6. Selected IBS Resources Frequently asked questions http://www.fascrs.org/brochures/irritable-bowel.html http://www.angelfire.com/il/ibshelp/

General information Medline Plus (comprehensive information about IBS for patients) http://www.nlm.nih.gov/medlineplus/irritablebowelsyndrome. html MedScape IBS Resource Center http://www.medscape.com/pages/editorial/resourcecenters /public/ibs/rc-ibs.ov WebMD http://my.webmd.com/search/search_results?query= IBS&filter=mywebmd_all_filter&go.x=19&go.y=15

Association Web sites International Foundation for Gastrointestinal Disorders http://www.iffgd.org/ Irritable Bowel Syndrome Association http://www.ibsassociation.org/ American Gastroenterological Association http://www.gastro.org/public/brochures/ibs.html American College of Gastroenterology http://www.acg.gi.org/ National Digestive Diseases Information Clearinghouse http://www.niddk.nih.gov/health/digest/pubs/irrbowel/ irrbowel.htm

Self-help and support groups http://www.IBSgroup.org http://www.aboutibs.org/ http://www.talkibs.org

Commercial sites http://www.ibsvillage.com/

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1. Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut. 1999;45:1143–47. 2. Schuster MM. Defining and diagnosing irritable bowel syndrome. Am J Manag Care. 2001;7:S246–S251. 3. Mayer EA. Emerging disease model for functional gastrointestinal disorders. Am J Med. 1999;107:12S–19S. 4. Brandt LJ, Bjorkman D, Fennerty MB, et al. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol. 2002;97:S7–S26. 5. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108–31. 6. Mitchell CM, Drossman DA. Survey of the AGA membership relating to patients with functional gastrointestinal disorders. Gastroenterology. 1987;92:1282–84. 7. International Foundation for Functional Gastrointestinal Disorders. IBS in the real world survey. Milwaukee, Wis.: International Foundation for Functional Gastrointestinal Disorders; 2002:1–19. 8. Hungin APS, Tack J, Mearin F, et al. Irritable bowel syndrome (IBS): prevalence and impact in the USA—the Truth in IBS (T-IBS) Survey [abstract]. Am J Gastroenterol. 2002;97:S280–S281. 9. Frank L, Kleinman L, Rentz A, et al. Health-related quality of life associated with irritable bowel syndrome: comparison with other chronic diseases. Clin Ther. 2002;24:675–89. 10. Koloski NA, Talley NJ, Boyce PM. The impact of functional gastrointestinal disorders on quality of life. Am J Gastroenterol. 2000;95:67–71. 11. Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer EA. The impact of irritable bowel syndrome on health-related quality of life. Gastroenterology. 2000;119:654–60. 12. Hungin AP, Tack J, Whorwell PJ, Mearin F. The Truth in IBS (T-IBS) Survey—an international study to assess the prevalence, epidemiology, and impact of irritable bowel syndrome (IBS) [abstract]. Am J Gastroenterol. 2001;96:S318. 13. Silk DB. Impact of irritable bowel syndrome on personal relationships and working practices. Eur J Gastroenterol Hepatol. 2001;13:1327–32. 14. Dancey CP, Backhouse S. Towards a better understanding of patients with irritable bowel syndrome. J Adv Nurs. 1993;18:1443–50. 15. Martin R, Barron JJ, Zacker C. Irritable bowel syndrome: toward a costeffective management approach. Am J Manag Care. 2001;7:S268–S275. 16. American Gastroenterological Association. The burden of gastrointestinal diseases. Bethesda, Md.: American Gastroenterological Association; 2001:1–86. Available at: http://www.gastro.org/pdf/burden-report.pdf. 17. American College of Gastroenterology Functional Gastrointestinal Disorders Task Force. Evidence-based position statement on the management of irritable bowel syndrome in North America. Am J Gastroenterol. 2002;97:S1–S5. 18. Rosemore JG, Lacy BE. Irritable bowel syndrome: basis of clinical management strategies. J Clin Gastroenterol. 2002;35:S37–S44. 19. Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials. Ann Intern Med. 2000;133:136–47.

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20. Lembo T, Rink R. Current pharmacologic treatments of irritable bowel syndrome. Participate. 2002;11:1–4. 21. Spanier JA, Howden CW, Jones MP. A systematic review of alternative therapies in the irritable bowel syndrome. Arch Intern Med. 2003;163:265–74. 22. Ringel Y, Drossman DA. Irritable bowel syndrome: classification and conceptualization. J Clin Gastroenterol. 2002;35:S7–S10. 23. Crowell MD. The role of serotonin in the pathophysiology of irritable bowel syndrome. Am J Manag Care. 2001;7:S252–S260. 24. Talley NJ. Serotoninergic neuroenteric modulators. Lancet. 2001;358:2061–68. 25. Bearcroft CP, Perrett D, Farthing MJ. Postprandial plasma 5-hydroxytryptamine in diarrhea predominant irritable bowel syndrome: a pilot study. Gut. 1998;42:42–6. 26. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47:804–11. 27. El Salhy M, Norrgard O, Spinnell S. Abnormal colonic endocrine cells in patients with chronic idiopathic slow-transit constipation. Scand J Gastroenterol. 1999;34:1007–11. 28. Miwa J, Echizen H, Matsueda K, et al. Patients with constipationpredominant irritable bowel syndrome (IBS) may have elevated serotonin concentrations in colonic mucosa as compared with diarrheapredominant patients and subjects with normal bowel habits. Digestion. 2001;63:188–94. 29. Moynihan R. Alosetron: a case study in regulatory capture, or a victory for patients' rights? BMJ. 2002;325:592–95. 30. US FDA/FDA approves restricted marketing of Lotronex. 2002. Accessed June 10, 2002. Available at: http://www/fda.gov/bbs/topics/ NEWS/2002/NEW00814.html 31. Lievre M. Alosetron for irritable bowel syndrome. BMJ. 2002;325:555–56. 32. Cremonini F, Delgado-Aros S, Camilleri M. Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials. Neurogastroenterol Motil. 2003;15:79–86. 33. Lotronex (alosetron hydrochloride) prescribing information. Research Park Triangle, N.C.: GlaxoSmithKline; 2002. 34. Camilleri M. Review article: tegaserod. Aliment Pharmacol Ther. 2001;15:277–89. 35. Zelnorm (tegaserod maleate) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals; 2002. 36. Muller-Lissner SA, Fumagalli I, Bardhan KD, et al. Tegaserod, a 5-HT4 receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating, and constipation. Aliment Pharmacol Ther. 2001;15:1655–66. 37. Novick J, Miner P, Krause R, et al. A randomized, double-blind, placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2002;16:1877–88. 38. Data on file. Study B351. Novartis Pharmaceuticals; 2002. 39. Tougas G, Snape WJ, Otten MH, et al. Long-term safety of tegaserod in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2002;16:1701–08. 40. The Latin America Investigation Group of Tegaserod, Cohen Munoz V. Relapse of symptoms following withdrawal of tegaserod treatment in irritable bowel syndrome with constipation (IBS-C) [abstract]. Gastroenterology. 2003;124:571. 41. Mueller-Lissner S, Holtmann G, Loeffler H, Rueegg P. Tegaserod is effective in the retreatment of irritable bowel syndrome with constipation (IBS-C). Gastroenterology. 2003;124:574. 42. Fidelholtz J, Smith W, Rawls J, et al. Safety and tolerability of tegaserod in patients with irritable bowel syndrome and diarrhea symptoms. Am J Gastroenterol. 2002;97:1176–81. 43. Kellow J, Lee OY, Chang FY, et al. An Asia-Pacific, double-blind, placebo-controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Gut. 2003;52:671–76. 44. Fried M, Beglinger C, Gilgen Bobalj N, et al. Safety of tegaserod in patients with irritable bowel syndrome: the Swiss experience. Paper presented at: 10th United European Gastroenterology Week; October 19–23, 2002; Geneva, Switzerland. 45. Nyhlin H, Bang C, Elsborg L, et al. Tegaserod is an effective and safe therapy for irritable bowel syndrome in a Nordic population. Gastroenterology. 2003;124:Y-389.

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46. Drolet B, Khalifa M, Daleau P, et al. Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval. Circulation. 1998;97:204–10. 47. Kamm MA. The complexity of drug development for irritable bowel syndrome. Aliment Pharmacol Ther. 2002;16:343–51. 48. Bran S, Murray WA, Hirsch IB, Palmer JP. Long QT syndrome during high-dose cisapride. Arch Intern Med. 1995;155:765–68. 49. US Food and Drug Administration. Janssen Pharmaceutica stops marketing cisapride in the US. Rockville, Md.: US Food and Drug Administration; 2000:T00–T14. 50. Morganroth J, Ruegg PC, Dunger-Baldauf C, et al. Tegaserod, a 5hydroxytryptamine type 4 receptor partial agonist, is devoid of electrocardiographic effects. Am J Gastroenterol. 2002;97:2321–27. 51. Drici MD, Ebert SN, Wang W, et al. Comparison of tegaserod (HTF 919) and its main human metabolite with cisapride and erythromycin on cardiac repolarization in the isolated rabbit heart. J Cardiovasc Pharmacol. 1999;34:82–8. 52. Burns DG. The risk of abdominal surgery in irritable bowel syndrome. S Afr Med J. 1986;70:91. 53. Longstreth GF, Wolde-Tsadik G. Irritable bowel-type symptoms in HMO examinees: prevalence, demographics, and clinical correlates. Dig Dis Sci. 1993;38:1581–89. 54. Hungin APS, Tack J, Mearin F, et al. The truth in IBS (T-IBS) survey— healthcare utilization and medication use among IBS patients in the USA [abstract]. Am J Gastroenterol. 2002;97:S281. 55. Barghout V, Yokoyama K, Gause D, Frech F. IBS-related hospitalizations and procedures [abstract]. Gastroenterology. 2002;122:A-570. 56. Olden KW, Chey WD, Boyle J, et al. Health related quality of life in irritable bowel syndrome: a community based study [abstract]. Gastroenterology. 2001;120:A634. 57. Kennedy TM, Jones RH. Epidemiology of cholecystectomy and irritable bowel syndrome in a UK population. Br J Surg. 2000;87:1658–63. 58. Hasler WL, Schoenfeld P. Systematic review: abdominal and pelvic surgery in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2003;17:997–1005. 59. Schoenfeld P. Incidence of abdominal pelvic surgeries among patients taking tegaserod in randomized controlled trials. Aliment Pharmacol Ther. In press. 60. Fisher R, Thistle J, Lembo A, et al. What is the impact of tegaserod on gallbladder emptying [abstract]? Am J Gastroenterol. 2003;98:S270–S271. 61. Appel-Dingemanse S. Clinical pharmacokinetics of tegaserod, a serotonin 5-HT(4) receptor partial agonist with promotile activity. Clin Pharmacokinet. 2002;41:1021–42. 62. Appel-Dingemanse S, Horowitz A, Campestrini J, Osborne S, McLeod J. The pharmacokinetics of the novel promotile drug, tegaserod, are similar in healthy subjects—male and female, elderly, and young. Aliment Pharmacol Ther. 2001;15:937–44. 63. Zhou H, McLeod J, Alladina L, et al. Pharmacokinetics (PK) of SDZ HTF 919 (HTF) not altered in subjects with severe renal insufficiency requiring hemodialysis [abstract]. Clin Pharmacol Ther. 1999;65:203. 64. Appel-Dingemanse S, Hubert M, Alladina L, McLeod J. Pharmacokinetics and safety of SCZ HTF 919, a new promotile drug, in healthy subjects and patients with hepatic cirrhosis [abstract]. Digestion. 1998;59:736. 65. Swan SK, Zhou H, Horowitz A, et al. Tegaserod pharmacokinetics are similar in patients with severe renal insufficiency and in healthy subjects. J Clin Pharmacol. 2003;43:359–64. 66. Shah SHA, Jafri SW, Gul M, et al. An open-label study to determine the efficacy and tolerability of tegaserod in the treatment of constipationdominant irritable bowel syndrome (IBS-C) [abstract]. Gastroenterology. 2003;124:A533. 67. Vickers AEM, Zollinger M, Dannecker R, et al. In vitro metabolism of tegaserod in human liver and intestine: assessment of drug interactions. Drug Metab Dispos. 2001;29:1269–76. 68. Lacy BE, Yu S. Tegaserod: a new 5-HT4 agonist. J Clin Gastroenterol. 2002;34:27–33. 69. Beglinger C. Tegaserod: a novel, selective 5-HT4 receptor partial agonist for irritable bowel syndrome. Int J Clin Pract. 2002;56:47–51. 70. Zimmerman AE. Tegaserod: a 5-HT4 agonist for women with constipation-predominant irritable bowel syndrome. Formulary. 2002;37:449–61.

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Tegaserod in Irritable Bowel Syndrome 71. Zhou H, Khalilieh S, Lau H, et al. Effect of meal timing not critical for the pharmacokinetics of tegaserod (HTF 919). J Clin Pharmacol. 1999;39:911–9. 72. Ruegg P, Lefkowitz M, Drossman D, Shi V. Tegaserod alone or in combination with antidepressant drugs is well tolerated in patients with IBS-C [abstract]. Am J Gastroenterol. 2002;97:S279–S280. 73. Zhou H, Khalilieh S, Svendsen K, et al. Tegaserod coadministration does not alter the pharmacokinetics of theophylline in healthy subjects. J Clin Pharmacol. 2001;41:987–93. 74. Kalbag J, Migoya E, Osborne S, et al. Tegaserod does not significantly affect the pharmacokinetics of dextromethorphan in healthy subjects [abstract]. Gastroenterology. 2000;118:A1179.

REVIEWS

75. Zhou H, Horowitz A, Ledford PC, et al. The effects of tegaserod (HTF 919) on the pharmacokinetics and pharmacodynamics of digoxin in healthy subjects. J Clin Pharmacol. 2001;41:1131–9. 76. Ledford P, On N, Ligueros-Saylan M, Campestrini J, Osborne S. Tegaserod does not significantly affect the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects [abstract]. Gastroenterology. 2000;118:A1184. 77. Zhou H, Walter Y, Hubert M, et al. Tegaserod (HTF919) does not decrease the effectiveness of an oral contraceptive when coadministered to healthy female subjects [abstract]. Gastroenterology. 2000;118:A1207.

PHARMACY THROUGH THE AGES

Medicinal Leeches One of the pharmacist’s oldest products is quietly coming back into service—the medicinal leech. Once an antiquarian’s topic, the leech has entered the 21st century as an important adjunct in microsurgery. Daniel B. Smith, a founder of the Philadelphia College of Pharmacy and the first president of the American Pharmaceutical Association (APhA), wrote in 1833 what was probably the first paper in American pharmacy literature on the leech. Smith noted the importance of care and handling of the leech in the shop while acknowledging the possible difference in effectiveness between the European and American varieties. At the fourth annual APhA meeting in 1855, Frederick Stearns (later the 14th APhA president) discussed the production of leeches in Michigan and noted their superiority and economy to those imported. The debate continued with at least one leech dealer asserting that the American variety was worthless, requiring more than 10 to do the duty of 1 Swedish leech. The glass leech tube provided a means for dispensing a leech with the added advantage of helping the patient place the leech. As late as 1923 a paper in the Journal of the American Pharmaceutical Association suggested dispensing leeches in test tubes, again to facilitate placement by the average man or woman. The author charged patients $1.00 for each leech dispensed. Dennis B. Worthen, PhD, is Lloyd Scholar, Lloyd Library and Museum, Cincinnati, Ohio, and JAPhA Contributing Editor, Heroes of Pharmacy. Illustration courtesy of the Lloyd Library and Museum.

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