[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: [Web] and [Web].
[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: [Web] and [Web].
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.
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.
Dosage and Administration
Administration
Oral Administration
Administer orally before a meal.
Dosage
Available as tegaserod maleate; dosage expressed in terms of tegaserod.
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.
Consider additional 4- to 6-week course of therapy in patients who respond.
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.
Periodically assess need for continued therapy.
Prescribing Limits
Adults
Constipation-predominant IBS in Women
Oral
Efficacy beyond 12 weeks of therapy not studied.
Chronic Idiopathic Constipation
Oral
Efficacy beyond 12 weeks of therapy not studied.
Special Populations
Hepatic Impairment
Mild hepatic impairment: Dosage adjustment not necessary. (See Contraindications and also Hepatic Impairment under Cautions.)
Renal Impairment
Mild to moderate renal impairment: Dosage adjustment not necessary. (See Contraindications under Cautions.)
Geriatric Patients
Dosage adjustment not necessary in patients ≥65 years of age with constipation-predominant IBS.
Known hypersensitivity to tegaserod or any ingredient in the formulation.
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.
Immediately discontinue if hypotension or syncope occurs.
Do not initiate tegaserod in patients with diarrhea or in those who frequently experience diarrhea.
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. (See Ischemic Colitis under Cautions.)
Ischemic Colitis
Ischemic colitis and other intestinal ischemia reported during postmarketing use; causal relationship not established.
Immediately discontinue if symptoms of ischemic colitis (e.g., rectal bleeding, bloody diarrhea, new or worsening abdominal pain) occur. Promptly evaluate patients with these symptoms, perform appropriate diagnostic tests; do not resume treatment if findings are consistent with ischemic colitis.
Specific Populations
Pregnancy
Category B.
Lactation
Not known whether tegaserod is distributed into human milk. Discontinue nursing or the drug.
Pediatric Use
Safety and efficacy not established in pediatric patients.
Geriatric Use
In geriatric patients with constipation-predominant IBS, no substantial differences in safety or pharmacokinetics relative to younger adults.
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. Higher incidence of tegaserod-related diarrhea and diarrhea-related discontinuance of the drug in these patients than in younger adults.
Hepatic Impairment
Not recommended in patients with moderate or severe hepatic impairment; not adequately studied. Caution in patients with mild impairment.
Renal Impairment
Not recommended in patients with severe renal impairment.
Gender
Safety and efficacy not established in men with constipation-predominant IBS.
Common Adverse Effects
IBS patients: headache, migraine, dizziness, abdominal pain, diarrhea, nausea, flatulence, back pain, leg pain, accidental trauma, arthropathy.
Peak plasma concentrations attained within 1 hour.
Bioavailability is about 10% in fasting individuals.
Food
Food reduces bioavailability by 40–65% and delays time to peak plasma concentrations.
Administration of tegaserod ≤30 minutes before, with, or 2.5 hours after a meal reduces peak plasma concentrations by 20–40%.
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.
Moderate to severe hepatic impairment: Not adequately studied.
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.
Distribution
Extent
Widely distributed.
Not known whether tegaserod crosses the placenta. Distributed into milk in rats; not known whether distributed into human milk.
Plasma Protein Binding
98%.
Elimination
Metabolism
Presystemic gastric acid hydrolysis, then undergoes oxidation and glucuronidation to main inactive metabolite; also undergoes direct glucuronidation.
Elimination Route
Excreted mainly (about 67%) in feces as unchanged drug and in urine (about 33%) principally as main metabolite.
Half-life
About 11 hours (range: 6–16 hours).
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15–30°C). Protect from moisture.
Actions
Binds with high affinity to 5-HT4 receptors on neurons in the GI tract. Activates these receptors, stimulating the peristaltic reflex and intestinal secretion, and inhibits visceral sensitivity.
Also may enhance basal motor activity and normalize impaired motility throughout the GI tract.
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.
Importance of not starting tegaserod if currently experiencing diarrhea or if diarrhea occurs frequently.
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.
Importance of taking before a meal.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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