Tegaserod Maleate

Class: GI Drugs, Miscellaneous
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

Warning(s)

Special Alerts:

[UPDATE 07/27/2007] FDA announced that it is permitting the restricted use of tegaserod (Zelnorm) under a treatment investigational new drug (IND) protocol to treat irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in women younger than 55 who meet specific guidelines.

In some instances, patients with a serious or life-threatening disease or condition who are not enrolled in a clinical trial may be treated with a drug not approved by the FDA. Generally, such use is allowed within guidelines called a treatment IND, when no comparable or satisfactory alternative drug or therapy is available. These patients must meet strict criteria and have no known or pre-existing heart problems and be in critical need of this drug. Tegaserod will remain off the market for general use. Physicians with IBS-C or CIC patients, who meet the IND criteria should contact Novartis at 888-669-6682 or 800-QUI-NTILE. Those who do not qualify for the tegaserod treatment protocol may contact FDA's Division for Drug Information about other options at 888-463-6332. For more information visit the FDA website at: and .

[Posted 03/30/2007] FDA notified healthcare professionals and patients that Novartis has agreed to discontinue marketing tegaserod (Zelnorm), a drug used for the short-term treatment of women with irritable bowel syndrome with constipation and for patients younger than 65 years of age with chronic constipation. FDA analysis of safety data pooled from 29 clinical trials involving over 18,000 patients showed an excess number of serious cardiovascular adverse events, including angina, heart attacks, and stroke, in patients taking tegaserod compared to patients given placebo. Patients taking tegaserod should contact their healthcare professional to discuss treatment alternatives and seek emergency medical care if they experience severe chest pain, shortness of breath, sudden onset of weakness or difficulty walking or talking, or other symptoms of a heart attack or stroke. Healthcare professionals should assess their patients and transition them to other therapies as appropriate. For more information visit the FDA website at: and .

Introduction

Partial type 4 serotonergic (5-HT4) receptor agonist; modulates serotonin-sensitive GI processes.1 2 3 4 5 6 7 8 9

Uses for Tegaserod Maleate

Constipation-predominant Irritable Bowel Syndrome in Women

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

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Chronic Idiopathic Constipation

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Management of chronic idiopathic constipation in adults <65 years of age.1

Tegaserod Maleate Dosage and Administration

Administration

Oral Administration

Administer orally before a meal.1 12

Dosage

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

Adults

Constipation-predominant IBS in Women

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Oral

6 mg twice daily for 4–6 weeks.1 2 4

Consider additional 4- to 6-week course of therapy in patients who respond.1

Chronic Idiopathic Constipation

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Oral

Adults <65 years of age: 6 mg twice daily.1

Periodically assess need for continued therapy.1

Prescribing Limits

Adults

Constipation-predominant IBS in Women
Oral

Efficacy beyond 12 weeks of therapy not studied.1

Chronic Idiopathic Constipation
Oral

Efficacy beyond 12 weeks of therapy not studied.1

Special Populations

Hepatic Impairment

Mild hepatic impairment: Dosage adjustment not necessary.1 5 (See Contraindications and also Hepatic Impairment under Cautions.)

Renal Impairment

Mild to moderate renal impairment: Dosage adjustment not necessary.1 (See Contraindications under Cautions.)

Geriatric Patients

Dosage adjustment not necessary in patients ≥65 years of age with constipation-predominant IBS.1

Cautions for Tegaserod Maleate

Contraindications

  • Severe renal impairment.1 9

  • Moderate or severe hepatic impairment.1 9

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

  • Known hypersensitivity to tegaserod or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Diarrhea

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 hypotension or syncope occurs.1 13 14 16

Do not initiate tegaserod in patients with diarrhea or in those who frequently experience diarrhea.1 13 14 16

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Abdominal Pain

Immediately discontinue if new (or suddenly worsening) abdominal pain occurs.1 13 (See Ischemic Colitis under Cautions.)

Ischemic Colitis

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

Immediately discontinue if symptoms of ischemic colitis (e.g., rectal bleeding, bloody diarrhea, new or worsening abdominal pain) occur.1 13 14 16 Promptly evaluate patients with these symptoms, perform appropriate diagnostic tests; do not resume treatment if findings are consistent with ischemic colitis.1 13 16

Specific Populations

Pregnancy

Category B.1

Lactation

Not known whether tegaserod is distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

In geriatric patients with constipation-predominant IBS, no substantial differences in safety or pharmacokinetics relative to younger adults.1

Efficacy not established in geriatric patients with chronic idiopathic constipation; tegaserod was no more effective than placebo in patients ≥65 years of age with this condition.1 Higher incidence of tegaserod-related diarrhea and diarrhea-related discontinuance of the drug in these patients than in younger adults.1

Hepatic Impairment

Not recommended in patients with moderate or severe hepatic impairment; not adequately studied.1 Caution in patients with mild impairment.1

Renal Impairment

Not recommended in patients with severe renal impairment.1

Gender

Safety and efficacy not established in men with constipation-predominant IBS.1 9

Common Adverse Effects

IBS patients: headache, migraine, dizziness, abdominal pain, diarrhea, nausea, flatulence, back pain, leg pain, accidental trauma, arthropathy.1 5 6 8 9

Patients with chronic idiopathic constipation: diarrhea, abdominal pain, nausea, abdominal distension, upper abdominal pain, vomiting, dizziness, insomnia, aggravated headache, fatigue, upper respiratory tract infection, sinusitis, fungal infection, back pain, myalgia, dysmenorrhea, pharyngitis, sinus congestion, urinary tract infection, rash, pruritus.1

Interactions for Tegaserod Maleate

Does not inhibit CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4 in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 and CYP1A2 substrates: Pharmacokinetic interaction unlikely.1

Specific Drugs

Drug

Interaction

Comments

Captopril

Pharmacokinetic interaction unlikely1

Dextromethorphan

Pharmacokinetic interaction unlikely1

Digoxin

Decreased digoxin peak plasma concentrations and exposure1

Not considered clinically important1

Fluoxetine

Pharmacokinetic interaction unlikely1

Hormonal contraceptives

Levonorgestrel: Decreased peak plasma concentrations and exposure (8%) 1

Ethinyl estradiol: Pharmacokinetic interaction unlikely1

Unlikely to be clinically important (risk of ovulation not expected to be altered) or require oral contraceptive dosage adjustment1

Omeprazole

Pharmacokinetic interaction unlikely1

Theophylline

Pharmacokinetic interaction unlikely1

Warfarin

Interaction unlikely1

Warfarin dosage adjustment not necessary1

Tegaserod Maleate Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained within 1 hour.1

Bioavailability is about 10% in fasting individuals.1

Food

Food reduces bioavailability by 40–65% and delays time to peak plasma concentrations.1

Administration of tegaserod ≤30 minutes before, with, or 2.5 hours after a meal reduces peak plasma concentrations by 20–40%.1

Special Populations

Severe renal impairment requiring dialysis (Clcr ≤15 mL/minute): No change in pharmacokinetics of tegaserod; peak plasma concentration and AUC of main (inactive) metabolite increased.1

Mild hepatic impairment: Peak plasma concentration increased 16%, AUC increased 31%.1

Moderate to severe hepatic impairment: Not adequately studied.1

Geriatric women (65–85 years of age): Peak plasma concentration and exposure increased relative to younger women; values in geriatric women were within variability reported in healthy individuals.1

Distribution

Extent

Widely distributed.1

Not known whether tegaserod crosses the placenta.1 Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

98%.1

Elimination

Metabolism

Presystemic gastric acid hydrolysis, then undergoes oxidation and glucuronidation to main inactive metabolite; also undergoes direct glucuronidation.1

Elimination Route

Excreted mainly (about 67%) in feces as unchanged drug and in urine (about 33%) principally as main metabolite.1

Half-life

About 11 hours (range: 6–16 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 Activates these 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

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of immediately discontinuing tegaserod and informing clinician if new or worsening abdominal pain, rectal bleeding, or bloody diarrhea occurs.1 13 14 15 16

  • 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 informing clinician if diarrhea is severe or is accompanied by severe cramping, abdominal pain, dizziness, feeling lightheaded or faint.1 13 14 15 16

  • Importance of taking before a meal.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.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.

Tegaserod Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2 mg (of tegaserod)

Zelnorm

Novartis

6 mg (of tegaserod)

Zelnorm

Novartis

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis. Zelnorm (tegaserod maleate) tablets prescribing information. East Hanover, NJ; 2004 Aug.

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

3. Talley NJ. Serotoninergic neuroenteric modulators. Lancet. 2001; 358:2061-8. [IDIS 473777] [PubMed 11755632]

4. Camilleri M. Novel medications for the irritable bowel syndrome: motility and sensation. J Pediatr Gastroenterol Nutr. 2001; 32:S35-7. [IDIS 463880] [PubMed 11321419]

5. Beglinger C. Tegaserod: a novel, selective 5-HT4 receptor partial agonist for irritable bowel syndrome. Int J Clin Pract. 2002; 56:47-51. [IDIS 478384] [PubMed 11831835]

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. [IDIS 432020] [PubMed 10471981]

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. [PubMed 10493276]

9. Anon. Tegaserod maleate for IBS with constipation. Med Lett Drugs Ther. 2002; 44:79-80. [PubMed 12237618]

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 on Zelnorm (tegaserod maleate). Rockville, MD; 2004 Aug 10. From FDA website.

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.

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