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Tegaserod

Class: Prokinetic Agents
VA Class: GA900
Chemical Name: 2-[(5-methoxy-1H-indol-3-yl)methylene]-N-pentylhydrazinecarboximidamide
Molecular Formula: C16H23N5O
CAS Number: 145158-71-0
Brands: Zelnorm

Medically reviewed by Drugs.com. Last updated on May 11, 2020.

Introduction

Partial type 4 serotonergic (5-HT4) receptor agonist; modulator of serotonin-sensitive GI processes and stimulant of GI motility (prokinetic agent).1 2 3 4 5 6 7 8 9

Uses for Tegaserod

Constipation-predominant Irritable Bowel Syndrome

Management of irritable bowel syndrome (IBS) in women <65 years of age whose predominant intestinal symptom is constipation.1 2 3 4 5 9

Initially approved by FDA in 2002 for the short-term treatment of constipation-predominant IBS in women; received a second FDA-labeled indication in 2004 for treatment of chronic idiopathic constipation in adults <65 years of age.23 Data available in early 2007 indicated a potential increased risk of ischemic cardiovascular events.17 19 20 (See Cardiovascular Effects under Cautions.) Based on these data, FDA concluded that tegaserod's benefits no longer outweighed its risks, and the manufacturer voluntarily withdrew the drug from the US market in March 2007;17 19 20 tegaserod subsequently was available only to selected patients (through an investigational, limited-access program or in emergency situations).21 22 24 Based on reevaluation of the data to identify potential subpopulations in which benefits would be expected to outweigh risks, FDA allowed reintroduction of tegaserod in 2019 with a narrower indication and with contraindications related to cardiovascular risk.23 (See Contraindications under Cautions.)

Safety and efficacy not established in men with constipation-predominant IBS.1 9 (See Gender under Cautions.)

Tegaserod Dosage and Administration

Administration

Oral Administration

Administer orally twice daily ≥30 minutes before meals.1 2 4

Dosage

Available as tegaserod maleate; dosage expressed in terms of tegaserod.1

Adults

Constipation-predominant IBS in Women
Oral

Women <65 years of age: 6 mg twice daily.1 Discontinue if adequate symptomatic response not achieved within 4–6 weeks.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.1 (See Contraindications and also Hepatic Impairment under Cautions.)

Renal Impairment

Mild to moderate renal impairment (eGFR ≥30 mL/minute per 1.73 m2): Dosage adjustment not necessary.1 (See Contraindications and also Renal Impairment under Cautions.)

Geriatric Patients

Not indicated for use in patients ≥65 years of age.1

Cautions for Tegaserod

Contraindications

  • History of MI, stroke, TIA, or angina.1

  • History of ischemic colitis or other forms of intestinal ischemia.1

  • Severe renal impairment (eGFR <15 mL/minute per 1.73 m2) or end-stage renal disease (ESRD).1 9

  • Moderate or severe hepatic impairment (Child-Pugh class B or C).1 9

  • History of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions.1 9

  • Known hypersensitivity to tegaserod.1

Warnings/Precautions

Cardiovascular Effects

Major adverse cardiovascular events (MACE [i.e., stroke, MI, cardiovascular death]) reported in adults receiving tegaserod who were at increased cardiovascular risk.1

Increased risk of ischemic cardiovascular events (e.g., angina, unstable angina, myocardial infarction or ischemia, stroke, TIA), including MACE, reported in 2 pooled analyses of 29 short-term (1–3 months) placebo-controlled trials involving approximately 18,600 patients (88% women, average age of 43 years) with various GI motility disorders.1 17 19 20 23 Ischemic cardiovascular events reported in 0.06–0.1% of patients receiving tegaserod versus 0.01% of placebo recipients.1 17 19 20 23 MACE reported in 0.03–0.06% of patients receiving tegaserod (including 0.01–0.03% of women <65 years of age with no history of ischemic cardiovascular disease) versus 0% of placebo recipients.1 23 All patients who experienced MACE had a history of ischemic cardiovascular disease and/or >1 cardiovascular risk factor.1 No discernible pattern with regard to timing of the event.19 23 Events did not appear to be dose related.19

Available clinical trial data revealed no clinically meaningful effects on corrected QT (QTc) interval.1 23

Contraindicated in patients with a history of MI, stroke, TIA, or angina.1

Assess cardiovascular risk (i.e., presence of risk factors, history of cardiovascular disease) before initiating tegaserod in women <65 years of age (see Constipation-predominant Irritable Bowel Syndrome under Uses).1 Weigh potential risks of tegaserod against anticipated improvements in IBS symptoms.1

Discontinue tegaserod in patients who experience an MI, stroke, TIA, or angina.1

Evaluate risks and benefits of continued therapy in those who develop clinical or other evidence of ischemic cardiovascular disease (e.g., CAD) and/or experience changes in health status that could increase cardiovascular risk.1

Ischemic Colitis

Ischemic colitis and other intestinal ischemia reported during postmarketing use; causal relationship not established.1 13 14 16

Immediately discontinue if ischemic colitis symptoms (e.g., rectal bleeding, bloody diarrhea, new or worsening abdominal pain) occur.1 13 14 16 Evaluate patients promptly and perform appropriate diagnostic tests; do not resume tegaserod if results are consistent with ischemic colitis.1 13 16

Volume Depletion Associated with Diarrhea

Treatment discontinued because of diarrhea in 1.6 or 0% of patients with constipation-predominant IBS receiving tegaserod or placebo, respectively, during clinical trials.1

Diarrhea resulting in serious consequences (e.g., hypovolemia, hypotension, syncope) reported; hospitalization for rehydration required in some cases.1 13 14 16

Immediately discontinue if diarrhea with hypotension or syncope occurs.1 13 14 16 (See Advice to Patients.)

Avoid use in patients with diarrhea or in those who frequently experience diarrhea.1 13 14 16

Suicidality

Suicide, suicidal attempt and ideation, and self-injurious behavior reported in patients receiving tegaserod.1 Suicidal ideation/behavior reported in 0.08 or 0.02% of patients with GI motility disorders receiving tegaserod or placebo, respectively, during clinical trials; was proportionately more common in those receiving concomitant antidepressant drugs.1

Monitor all patients receiving tegaserod for clinical worsening of depression and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment.1 (See Advice to Patients.)

Specific Populations

Pregnancy

Available data from case reports of tegaserod use in pregnant women have not identified a drug-associated risk of major birth defects, spontaneous abortion, or adverse maternal or fetal outcomes.1

In studies in rats, decreased pup survival, decreased pup body weight, and developmental delays observed.1

Lactation

Distributed into milk in rats (see Distribution under Pharmacokinetics); not known whether tegaserod distributes into human milk or affects nursing infants or milk production.1

Because of potential for serious adverse effects, including tumorigenicity, in nursing infants, breast-feeding not recommended during tegaserod therapy.1 In animal studies, mucosal hyperplasia and adenocarcinoma of the small intestine observed in mice.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

Not indicated for use in patients ≥65 years of age.1 (See Constipation-predominant Irritable Bowel Syndrome under Uses.)

Hepatic Impairment

Contraindicated in patients with moderate or severe hepatic impairment; not adequately studied.1

No dosage adjustment required in patients with mild impairment.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Contraindicated in patients with severe renal impairment or ESRD.1 Exposure to main metabolite of tegaserod is increased.1 (See Special Populations under Pharmacokinetics.)

No dosage adjustment required in patients with mild to moderate renal impairment.1

Gender

Safety and efficacy not established in men with constipation-predominant IBS.1 9 In 2 clinical trials in patients with constipation-predominant IBS, subgroup analysis indicated that in men the response rate to the drug did not differ substantially from the response rate to placebo.1

Common Adverse Effects

Women <65 years of age with constipation-predominant IBS: Headache, abdominal pain, diarrhea, nausea, flatulence, dizziness, dyspepsia.1

Interactions for Tegaserod

Tegaserod and its main metabolite (M29) do not inhibit CYP 2B6, 2C8, 2C9, 2C19, 2E1, or 3A4 or induce CYP 2B6 or 3A4 in vitro.1 M29 does not inhibit CYP 1A2 or 2D6 and does not induce CYP1A2 in vitro; tegaserod causes only limited induction of CYP1A2 at concentrations greatly exceeding clinically relevant concentrations.1

Tegaserod and M29 are substrates for breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) in vitro, but are not substrates for organic anion transporter (OAT) 1, organic cation transporter (OCT) 1 or OCT2, organic anion transport protein (OATP) 1B1 or OATP1B3, or multidrug and toxin extrusion (MATE) transporter 1 or MATE2-K.1 M29 is a substrate for OAT3 and bile salt export pump (BSEP) in vitro; tegaserod is not a substrate for OAT3 or BSEP.1

Tegaserod inhibits MATE1, MATE2-K, and BCRP in vitro at high concentrations.1

M29 does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, or BSEP in vitro.1

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP 1A2, 2C9, or 2D6 substrates: No clinically important effect on pharmacokinetics of CYP 1A2, 2C9, or 2D6 prototype substrates observed.1

Drugs Affecting or Affected by Transport Systems

P-gp inhibitors: Possible modest increase in oral bioavailability of tegaserod; clinical importance unclear.1

P-gp substrates: No clinically important effect on pharmacokinetics of a P-gp prototype substrate observed.1

MATE1, MATE2-K, or BCRP substrates: Interactions unlikely at clinically relevant concentrations.1

Specific Drugs

Drug

Interaction

Comments

Clarithromycin

Possible modest increase in oral bioavailability of tegaserod1

Clinical importance unclear1

Dextromethorphan

No clinically important effect on dextromethorphan pharmacokinetics1

Digoxin

Decreased digoxin peak plasma concentration and AUC1

Not considered clinically important1

Hormonal contraceptives

Ethinyl estradiol/levonorgestrel: Decreased peak plasma concentration and AUC of levonorgestrel; no clinically important effect on pharmacokinetics of ethinyl estradiol1

Not considered clinically important1

Itraconazole

Possible modest increase in oral bioavailability of tegaserod1

Clinical importance unclear1

Omeprazole

Increased peak plasma concentration and AUC of tegaserod1

Not considered clinically important1

Quinidine

Increased peak plasma concentration and AUC of tegaserod1

Ritonavir

Possible modest increase in oral bioavailability of tegaserod1

Clinical importance unclear1

Theophylline

No clinically important effect on theophylline pharmacokinetics1

Warfarin

No clinically important effect on PT or pharmacokinetics of R- or S-warfarin1

Tegaserod Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained at median of 1 hour after oral administration.1

Bioavailability is about 10% in fasting individuals.1

Food

Administration 30 minutes before a high-fat, high-calorie meal reduces AUC by 40–65% and peak plasma concentration by 20–40% compared with administration in fasting state; median time to peak plasma concentration is 0.7 hours.1 Administration ≤30 minutes before or 2.5 hours after a meal results in similar concentrations.1

Special Populations

ESRD requiring hemodialysis (Clcr ≤15 mL/minute): No change in pharmacokinetics of tegaserod, but severe renal impairment increases peak plasma concentration and AUC of main metabolite by twofold and tenfold, respectively.1

Mild hepatic impairment: Peak plasma concentration increased 16%, AUC increased 31%; increases not considered clinically important.1

Moderate to severe hepatic impairment: Not adequately studied.1

Distribution

Extent

Distributed into milk in rats in high milk-to-plasma ratio (33:1 at 8 hours after administration); not known whether distributed into human milk.1

Plasma Protein Binding

98%.1

Elimination

Metabolism

Presystemic gastric hydrolysis, then undergoes oxidation and glucuronidation to main metabolite (5-methoxyindole-3-carboxylic acid glucuronide [M29]); also undergoes direct glucuronidation.1 M29 has negligible affinity for 5-HT4 receptors.1

Elimination Route

Excreted mainly (about 66%) in feces as unchanged drug and in urine (about 33%) as metabolites.1

Half-life

Terminal elimination half-life: 4.6–8.1 hours.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Protect from moisture.1

Actions

  • Binds with high affinity to 5-HT4 receptors on neurons in the GI tract.1 2 3 4 5 6 8 9 Also exhibits antagonistic activity at type 2B serotonergic (5-HT2B) receptors, but has no affinity for type 3 serotonergic (5-HT3) or dopaminergic receptors and is expected to bind only minimally to type 1 serotonergic (5-HT1) receptors.1

  • Activates 5-HT4 receptors, stimulating the peristaltic reflex and intestinal secretion, and inhibits visceral sensitivity.1 2 3 4 5 6 8 9 Also may enhance basal motor activity and normalize impaired motility throughout the GI tract.1 2 4 5 6 7 8

  • Certain nonselective 5-HT4 receptor agonists (i.e., tegaserod, cisapride) have been associated with adverse cardiovascular events; cardiac arrhythmias associated with cisapride use attributed to the drug's lack of selectivity for the 5-HT4 receptor (i.e., affinity for human ether-a-go-go-related gene [hERG]-encoded potassium channel), but precise mechanism by which tegaserod may be associated with ischemic cardiovascular events not fully established.23 25 26 (See Cardiovascular Effects under Cautions.)

  • Tegaserod and its main metabolite increase platelet aggregation in vitro; clinical importance not established.1

Advice to Patients

  • Importance of reading manufacturer's medication guide for tegaserod.1 Importance of understanding the potential risks and benefits of tegaserod therapy prior to initiating therapy with the drug.21 22

  • Inform patients that stroke, MI, and cardiovascular death have been reported in adults receiving tegaserod who were at increased risk for such adverse cardiovascular events.1 Importance of seeking immediate emergency medical care if symptoms suggestive of MI, stroke, TIA, or angina (e.g., severe chest pain, shortness of breath, dizziness, sudden onset of weakness or difficulty in walking or talking) occur.1 17 20 Importance of immediately informing clinician if clinical or other evidence of ischemic cardiovascular disease (e.g., CAD) has been detected or if there are any other changes in health status that could increase cardiovascular risk (e.g., smoking, hypertension, hyperlipidemia, diabetes mellitus, obesity).1

  • Importance of discontinuing tegaserod and seeking medical care if symptoms of ischemic colitis (e.g., rectal bleeding, bloody diarrhea, new or worsening abdominal pain) occur.1

  • Importance of not starting tegaserod if currently experiencing diarrhea or if diarrhea occurs frequently.1

  • Diarrhea may occur during therapy, but usually will resolve with continued use; importance of immediately discontinuing tegaserod and informing clinician if diarrhea is severe, especially if accompanied by symptoms of volume depletion (e.g., dizziness, feeling lightheaded or faint).1 13 14 15 16

  • Advise patients and their caregivers and families that suicidal thoughts and behavior have been reported in patients receiving tegaserod.1 Importance of being alert to new or worsening symptoms of depression, unusual changes in mood or behavior, and emergence of suicidal thoughts/behavior or thoughts of self-harm.1 Importance of immediately discontinuing tegaserod and seeking medical care if such symptoms occur.1

  • Importance of taking tegaserod ≥30 minutes before a meal.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise women that breast-feeding is not recommended during tegaserod therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tegaserod Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

6 mg (of tegaserod)

Zelnorm

Alfasigma

AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 11, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Alfasigma USA. Zelnorm (tegaserod maleate) tablets prescribing information. Louisville, KY; 2019 Jul.

2. Camilleri M. Management of irritable bowel syndrome. Gastroenterol. 2001; 120:652-68.

3. Talley NJ. Serotoninergic neuroenteric modulators. Lancet. 2001; 358:2061-8. http://www.ncbi.nlm.nih.gov/pubmed/11755632?dopt=AbstractPlus

4. Camilleri M. Novel medications for the irritable bowel syndrome: motility and sensation. J Pediatr Gastroenterol Nutr. 2001; 32:S35-7. http://www.ncbi.nlm.nih.gov/pubmed/11321419?dopt=AbstractPlus

5. Beglinger C. Tegaserod: a novel, selective 5-HT4 receptor partial agonist for irritable bowel syndrome. Int J Clin Pract. 2002; 56:47-51. http://www.ncbi.nlm.nih.gov/pubmed/11831835?dopt=AbstractPlus

6. 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; 39:911-19. http://www.ncbi.nlm.nih.gov/pubmed/10471981?dopt=AbstractPlus

7. Prather CM, Camilleri M, Zinsmeister AR et al. Tegaserod accelerates orocecal transit in patents with constipation-predominant irritable bowel syndrome. Gastrenterol. 2000; 118:463-8.

8. Scott LJ, Perry CM. Tegaserod. Drugs. 1999; 58:491-6. http://www.ncbi.nlm.nih.gov/pubmed/10493276?dopt=AbstractPlus

9. Anon. Tegaserod maleate for IBS with constipation. Med Lett Drugs Ther. 2002; 44:79-80. http://www.ncbi.nlm.nih.gov/pubmed/12237618?dopt=AbstractPlus

10. GlaxoWellcome Inc. Lotronex (alosetron hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2000 Feb.

11. Anon. FDA approves irritable bowel syndrome treatment for women. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2000 Feb. 9.

12. Novartis, East Hanover, NJ: Personal communication.

13. Bess AL, Cunningham SR. Dear health care professional letter regarding diarrhea and ischemic colitis. East Hanover, NJ: Novartis; 2004 Apr 26.

14. Food and Drug Administration. Questions and answers in Zelnorm (tegaserod maleate). Rockville, MD; 2004 Aug 10. From FDA website (http://www.fda.gov/cder/drug/infopage/zelnorm/zelnorm_QA.htm).

15. Novartis. Zelnorm (tegaserod maleate) tablets information for the patient. East Hanover, NJ; 2004 Aug.

16. FDA updates Zelnorm labeling with new risk information. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2004 Apr 28. From FDA website (http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01285.html).

17. FDA public health advisory: tegaserod maleate (marketed as Zelnorm). Rockville, MD; 2007 Mar 30. From FDA website (http://www.fda.gov/cder/drug/advisory/tegaserod.htm).

18. Novartis. Reimbursement policy for Zelnorm patients and frequently asked questions about reimbursement. From Zelnorm website (http://www.zelnorm.com). Accessed 2007 May 23.

19. Bess AL, Cunningham SR. Dear health care professional letter: Urgent: marketing and sales suspension notice for Zelnorm tablets, 2-mg and 6-mg, all lots within expiry. East Hanover, NJ: Novartis Pharmaceuticals Corporation: 2007 Mar 30.

20. Questions and answers on Zelnorm (tegaserod maleate). Rockville, MD: Food and Drug Administration; 2007 Mar 30. From FDA website (http://www.fda.gov/cder/drug/infopage/zelnorm/zelnorm_QA_2007.htm).

21. Novartis. The Zelnorm reimbursement program ends September 30, 2007. 2007 Oct. From Zelnorm website (http://www.zelnorm.com). Accessed 2007 Oct 29.

22. US Food and Drug Administration. FDA permits restricted use of Zelnorm for qualifying patients. Rockville, MD; 2007 Jul 27. From FDA website (http://www.fda.gov/bbs/topics/NEWS/2007/NEW01673.html).

23. US Food and Drug Administration. Application number 021200s015: NDA/BLA multi-disciplinary review and evaluation. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/021200Orig1s015MultidisciplineR.pdf

24. US Food and Drug Administration. Questions and answers about the voluntary discontinuation of Zelnorm's (tegaserod maleate) treatment investigational new drug (IND). Silver Spring, MD; 2008 Apr 2.

25. Tack J, Camilleri M, Chang L et al. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther. 2012; 35:745-67. http://www.ncbi.nlm.nih.gov/pubmed/22356640?dopt=AbstractPlus

26. Conlon K, De Maeyer JH, Bruce C et al. Nonclinical Cardiovascular Studies of Prucalopride, a Highly Selective 5-Hydroxytryptamine 4 Receptor Agonist. J Pharmacol Exp Ther. 2018; 364:156-169. http://www.ncbi.nlm.nih.gov/pubmed/29180358?dopt=AbstractPlus

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