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TEGASEROD

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tegaserod is an aminoguanidine indole that acts selectively as a partial agonist at the serotonin type-4 (5-HT4) receptor. Affinity for 5-HT1D and 5-HT1B receptor subtypes is weak. It has no appreciable affinity for muscarinic, adrenergic, dopaminergic, or opiate receptors.

Specific Substances

    1) HTF-919
    2) SDZ-HTF-919
    3) Zelnorm(TM)
    4) Molecular Formula: C16-H23-N5-O,C4-H4-O4
    5) CAS 145158-71-0 (tegaserod)
    6) CAS 189188-57-6 (tegaserod maleate)

Available Forms Sources

    A) FORMS
    1) Tegaserod was available as 2 mg and 6 mg tablets (Prod Info Zelnorm(TM), tegaserod, 2002).
    B) USES
    1) MARKET WITHDRAWAL: Tegaserod was withdrawn from the market in March 2007 following results of a safety analysis that found a higher risk of heart attack, stroke, and worsening chest pain in patients treated with tegaserod compared to placebo-treated patients. The supplier (Novartis Pharmaceuticals Corporation) will suspend sales of tegaserod (US Food and Drug Administration, 2007).
    a) In late February and early March 2007, Novartis Pharmaceuticals gave FDA the results of 29 clinical studies of tegaserod for the treatment of a variety of gastrointestinal tract conditions; the data from all the studies were combined to assess the risk of life threatening adverse effects. These 29 studies included 11,614 patients treated with tegaserod and 7,031 treated with placebo. The average age of patients in these studies was 43 years and most patients were women (88%). The number of patients who suffered a heart attack, stroke, or severe chest pain was small. However, patients treated with tegaserod had a higher chance of having these serious and life-threatening side effects compared to the placebo group. Thirteen patients treated with tegaserod (0.1%) had serious and life-threatening cardiovascular side effects; among these, four patients with myocardial infarction (one died), six experienced severe chest pain, and three had a stroke. Among the patients taking placebo, only one (or 0.01%) had symptoms suggesting the beginning of a stroke that resolved without complication (US Food and Drug Administration, 2007).
    2) Tegaserod was indicated for the short-term treatment of irritable bowel syndrome in women whose main symptom includes constipation (Prod Info Zelnorm(TM), tegaserod, 2002). Therapy appeared to be well tolerated in men being treated for chronic constipation (Fried et al, 2007).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Tegaserod was withdrawn from the market in March 2007 following results of a safety analysis that found a higher risk of heart attack, stroke, and worsening chest pain in patients treated with tegaserod compared to placebo-treated patients.
    B) WITH THERAPEUTIC USE
    1) Diarrhea, abdominal pain, flatulence, and headache are the most common adverse effects with tegaserod therapy.
    2) Other adverse effects that may occur less frequently, following therapeutic administration of tegaserod, include dizziness, fatigue, and nausea and vomiting.
    3) Rare cases of ischemic colitis have been associated with therapeutic use of tegaserod.
    C) WITH POISONING/EXPOSURE
    1) Ingestion of up to 20 times the normal therapeutic dose has caused headache, orthostatic hypotension, abdominal pain, diarrhea, nausea, vomiting and flatulence.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Non-ST elevation myocardial infarction has been reported in association with tegaserod use.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Headaches may commonly occur with tegaserod therapy. Dizziness and fatigue are less frequent events.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Transient diarrhea, flatulence, and abdominal pain may frequently occur with tegaserod use. Nausea and vomiting have been infrequently reported adverse events.
    2) Rare cases of ischemic colitis have been associated with therapeutic use of tegaserod.
    0.2.20) REPRODUCTIVE
    A) Tegaserod is classified as FDA pregnancy category B. There was no evidence of teratogenicity following maternal ingestion of tegaserod in rats or rabbits. It is unknown whether tegaserod is excreted in human milk; tegaserod is excreted in the milk of lactating rats.

Laboratory Monitoring

    A) Serum tegaserod levels are not clinically useful.
    B) Monitor fluid and electrolyte levels in patients with severe diarrhea or vomiting.
    C) Monitor blood pressure in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Serious toxicity is unlikely after acute overdose. Gastrointestinal decontamination should only be considered after very large ingestions, or if significant coingestants are involved. Care is symptomatic and supportive
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.

Range Of Toxicity

    A) In clinical trials, single doses up to 120 milligrams were well tolerated; one patient developed orthostatic hypotension. Doses of up to 90 to 180 mg/day over several days resulted in diarrhea (100%), headache (57%), abdominal pain (18%) and nausea and vomiting (7% each).

Clinical Effects

Summary Of Exposure

    A) Tegaserod was withdrawn from the market in March 2007 following results of a safety analysis that found a higher risk of heart attack, stroke, and worsening chest pain in patients treated with tegaserod compared to placebo-treated patients.
    B) WITH THERAPEUTIC USE
    1) Diarrhea, abdominal pain, flatulence, and headache are the most common adverse effects with tegaserod therapy.
    2) Other adverse effects that may occur less frequently, following therapeutic administration of tegaserod, include dizziness, fatigue, and nausea and vomiting.
    3) Rare cases of ischemic colitis have been associated with therapeutic use of tegaserod.
    C) WITH POISONING/EXPOSURE
    1) Ingestion of up to 20 times the normal therapeutic dose has caused headache, orthostatic hypotension, abdominal pain, diarrhea, nausea, vomiting and flatulence.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Non-ST elevation myocardial infarction has been reported in association with tegaserod use.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Orthostatic hypotension was reported in two patients following therapeutic administration of tegaserod, once under fasting conditions and once under fed conditions, during a randomized, cross-over, open label clinical study. Because a placebo control was not administered, the relationship between tegaserod administration and the occurrence of hypotension was not clearly established (Appel-Dingemanse et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) Orthostatic hypotension was reported in one patient following ingestion of a single 120 mg dose of tegaserod (Prod Info ZELNORM(R) oral tablets, 2004).
    B) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) Non-ST elevation myocardial infarction has been reported in association with tegaserod use.
    b) CASE REPORT - A 64-year-old male developed chest pain, nausea and significant elevations in troponin-T levels after receiving two, 6 mg doses of tegaserod. No EKG changes were observed. The patient did well with medical management and no coronary angiography was performed. Medical history was significant for congestive heart failure, diabetes mellitus, coronary artery disease, chronic renal failure and a previous myocardial infarction (Busti et al, 2004).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Headaches may commonly occur with tegaserod therapy. Dizziness and fatigue are less frequent events.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches have been reported frequently following tegaserod therapy and appeared to be dose-related (Fidelholtz et al, 2002; Norman, 1999; Appel-Dingemanse et al, 1999; Anon, 1999; pp 1-3; Appel et al, 1997a). More recent trials have noted similar occurrence of headache between doses of 2 mg or 6 mg twice daily (Muller-Lissner et al, 2006).
    b) INCIDENCE - During phase III clinical trials, headaches occurred in 15% of patients taking tegaserod (n=1327), as compared with 12% of patients taking placebo (n=1305) (Prod Info Zelnorm(TM), tegaserod, 2002). Post marketing trials of tegaserod have noted headache incidence rates of 3.2% to 11.3%, with no significant difference from patients taking placebo (Fried et al, 2007; Tack et al, 2005; Muller-Lissner et al, 2006).
    c) ONSET AND DURATION - During a randomized, placebo-controlled trial, mild to moderate headaches were reported 30 minutes to 11 hours following administration of tegaserod, 1 to 100 mg twice daily, and persisting up to 40 hours later (Appel et al, 1997). Although the incidence of headache increased with increasing dose, the intensity and duration of the headaches remained the same with all dosages.
    2) WITH POISONING/EXPOSURE
    a) Headaches occurred in 3 patients who ingested single doses of 120 mg tegaserod and in 57% of patients (n=28) following ingestions of 90 to 180 mg/day for several days (Prod Info ZELNORM(R) oral tablets, 2004).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness and fatigue may occur infrequently with tegaserod therapy (Prod Info ZELNORM(R) oral tablets, 2004; Fidelholtz et al, 2002) and do not appear to be related to changes in blood pressure (Zhou et al, 1999).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Transient diarrhea, flatulence, and abdominal pain may frequently occur with tegaserod use. Nausea and vomiting have been infrequently reported adverse events.
    2) Rare cases of ischemic colitis have been associated with therapeutic use of tegaserod.
    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Transient diarrhea has been frequently reported, as a dose-related adverse effect, following therapeutic administration of tegaserod (Fidelholtz et al, 2002; Appel-Dingemanse et al, 2001; Muller-Lissner et al, 2001; Anon, 1999; pp 1-3) and is related to the promotile action of tegaserod (Appel-Dingemanse et al, 1999). In rare cases (1 in 250 cases), diarrhea may be severe enough to result in hypovolemia and hypotension (Heading et al, 2006; Wooltorton, 2004).
    b) INCIDENCE - During phase III clinical trials, diarrhea occurred in 8.8% of patients taking tegaserod (n=1327) as compared with 3.8% of patients in the placebo group (n=1305) (Prod Info Zelnorm(TM), tegaserod, 2002).
    c) ONSET AND DURATION - Diarrhea usually occurs during the first week of tegaserod therapy and lasts an average of 2 to 4 days (Prod Info Zelnorm(TM), tegaserod, 2002; Camilleri, 2001; Muller-Lissner et al, 2001). During one randomized, placebo-controlled trial, diarrhea was the most commonly reported gastrointestinal adverse effect, with the onset of each episode occurring approximately 2.5 hours after dose administration (Appel et al, 1997).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea occurred in three patients who ingested single 120 mg doses of tegaserod, and in 100% of patients (n=28) following ingestion of 90 to 180 mg/day for several days (Prod Info ZELNORM(R) oral tablets, 2004).
    B) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) Flatulence may frequently occur with tegaserod therapy (Fidelholtz et al, 2002; Appel-Dingemanse et al, 2001a; Anon, 1999; pp 1-3; Appel-Dingemanse et al, 1999; Appel et al, 1997; Appel et al, 1997a)
    b) INCIDENCE - During phase III clinical trials, flatulence occurred in 6% of patients in the tegaserod group (n=1327) as compared with 5% of patients in the placebo group (n=1305) (Prod Info Zelnorm(TM), tegaserod, 2002).
    c) Flatulence occurred in 18% of patients (n=28) who ingested 90 to 180 mg/day of tegaserod for several days (Prod Info Zelnorm(TM), tegaserod, 2002).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain may commonly occur following therapeutic administration of tegaserod (Fidelholtz et al, 2002; Appel et al, 1997) and may be dose-related (Appel-Dingemanse et al, 2001a; pp 1-3). A study of tegaserod use in men with chronic constipation noted identical incidence of abdominal pain at doses of 2 mg or 6 mg twice daily (Muller-Lissner et al, 2006).
    b) INCIDENCE - During phase III clinical trials, abdominal pain occurred in 12% of patients in the tegaserod group (n=1327) as compared with 11% of patients in the placebo group (n=1305) (Prod Info Zelnorm(TM), tegaserod, 2002).
    2) WITH POISONING/EXPOSURE
    a) Intermittent abdominal pain occurred in 2 patients following ingestion of single 120 mg doses of tegaserod, and in 18% of patients (n=28) who ingested 90 to 180 mg/day for several days (Prod Info ZELNORM(R) oral tablets, 2004).
    D) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are infrequent occurrences following tegaserod therapy (Prod Info ZELNORM(R) oral tablets, 2004; pp 1-3; Appel et al, 1997a) and may be dose-related (Appel-Dingemanse et al, 2001a; Appel et al, 1997).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting developed in 7% of 28 subjects taking 90 to 180 milligrams/day for seven days (Prod Info ZELNORM(R) oral tablets, 2004).
    E) ISCHEMIC COLITIS
    1) WITH THERAPEUTIC USE
    a) The FDA MedWatch system received 20 post-marketing reports of ischemic colitis associated with tegaserod therapy within 20 months (Brinker et al, 2004). The exact incidence is unknown, but probably occurs in less than 1 in 11,000 patients (Wooltorton, 2004). The etiology of ischemic colitis is unclear, since tegaserod does not appear to have vasoconstrictive effects (Shetzline et al, 2005). Another confounding factor is the higher incidence of ischemic colitis in patients with irritable bowel syndrome compared to the general population (DiBaise, 2005; Heading et al, 2006). Seventeen of the 20 patients reported to MedWatch were being treated for irritable bowel syndrome (Brinker et al, 2004).
    b) No cases of ischemic colitis have been reported in multiple, large clinical trials (over 11,000 patients) involving tegaserod (Fried et al, 2007; Tack et al, 2005; Heading et al, 2006; Muller-Lissner et al, 2006).
    c) CASE REPORT – A 44-year-old woman was started on tegaserod treatment at 6 mg twice daily for a 20 year history of chronic abdominal pain, nausea and diarrhea. Her other medications included polyethylene glycol laxative, lansoprazole, citalopram, clonazepam, promethazine and ondansetron. Over a year after starting treatment she experienced worsening lower abdominal pain with hematochezia. Sigmoidoscopy and colonic mucosal biopsy findings were consistent with ischemic colitis. Tegaserod therapy was discontinued and the patients symptoms resolved within one week (DiBaise, 2005).
    F) NONSPECIFIC ABDOMINAL SYMPTOM
    1) WITH THERAPEUTIC USE
    a) ABDOMINAL SURGERY - Although a slight increase in abdominal surgeries have occurred following tegaserod administration (0.3%, n=2965), as compared with placebo administration (0.2%, n=1740) during phase III clinical trials, a causal relationship has not been established (Prod Info ZELNORM(R) oral tablets, 2004).

Reproductive

    3.20.1) SUMMARY
    A) Tegaserod is classified as FDA pregnancy category B. There was no evidence of teratogenicity following maternal ingestion of tegaserod in rats or rabbits. It is unknown whether tegaserod is excreted in human milk; tegaserod is excreted in the milk of lactating rats.
    3.20.2) TERATOGENICITY
    A) ANIMAL DATA
    1) RATS - There was no evidence of teratogenicity following maternal ingestion of tegaserod doses up to 100 mg/kg/day (approximately 15 times the human exposure at 6 mg twice daily) (Prod Info Zelnorm(TM), tegaserod, 2002).
    2) RABBITS - There was no evidence of teratogenicity following maternal ingestion of tegaserod doses up to 120 mg/kg/day (approximately 51 times the human exposure at 6 mg twice daily) (Prod Info Zelnorm(TM), tegaserod, 2002).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Tegaserod is classified as FDA pregnancy category B (Prod Info Zelnorm(TM), tegaserod, 2002).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) RATS - Tegaserod is excreted in the milk of lactating rats, with a high milk to plasma ratio (Prod Info Zelnorm(TM), tegaserod, 2002).
    2) HUMANS - It is unknown whether tegaserod is excreted in human milk (Prod Info Zelnorm(TM), tegaserod, 2002).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) ANIMAL DATA
    1) RATS - There was no evidence of carcinogenicity following ingestion of tegaserod doses up to 180 mg/kg/day (approximately 93 to 111 times the human exposure at 6 mg twice daily) for 110 to 124 weeks (Prod Info Zelnorm(TM), tegaserod, 2002).
    2) MICE - There was no evidence of carcinogenicity following ingestion of tegaserod doses up to 60 mg/kg/day (approximately 3 to 4 times the human exposure at 6 mg twice daily) and at 200 mg/kg/day (approximately 24 to 35 times the human exposure at 6 mg twice daily). However, mucosal hyperplasia and adenocarcinoma of the small intestine developed following tegaserod ingestion of 600 mg/kg/day (approximately 83 to 110 times the human exposure at 6 mg twice daily) for 104 weeks (Prod Info Zelnorm(TM), tegaserod, 2002).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum tegaserod levels are not clinically useful.
    B) Monitor fluid and electrolyte levels in patients with severe diarrhea or vomiting.
    C) Monitor blood pressure in symptomatic patients.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Serum tegaserod levels are not clinically useful.
    B) Monitor fluid and electrolyte levels in patients with severe diarrhea or vomiting.
    C) Monitor blood pressure in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Serious toxicity is unlikely after acute overdose. Gastrointestinal decontamination should only be considered after very large ingestions, or if significant coingestants are involved.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Serious toxicity is unlikely after acute overdose. Gastrointestinal decontamination should only be considered after very large ingestions, or if significant coingestants are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In case of tegaserod intoxication, treatment is SYMPTOMATIC and SUPPORTIVE.
    B) MONITORING OF PATIENT
    1) Fluid and electrolyte levels should be monitored in patients who develop severe diarrhea or vomiting.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Because of high protein binding and a large volume of distribution, it is unlikely that removal of tegaserod by hemodialysis or hemoperfusion will be effective (Prod Info ZELNORM(R) oral tablets, 2004).

Range Of Toxicity

Summary

    A) In clinical trials, single doses up to 120 milligrams were well tolerated; one patient developed orthostatic hypotension. Doses of up to 90 to 180 mg/day over several days resulted in diarrhea (100%), headache (57%), abdominal pain (18%) and nausea and vomiting (7% each).

Therapeutic Dose

    7.2.1) ADULT
    A) MARKET WITHDRAWAL
    1) Tegaserod was withdrawn from the market in March 2007 following results of a safety analysis that found a higher risk of heart attack, stroke, and worsening chest pain in patients treated with tegaserod compared to placebo-treated patients.
    B) GENERAL
    1) IRRITABLE BOWEL SYNDROME with CONSTIPATION: The recommended dosage of tegaserod is 6 milligrams twice daily orally before meals for 4 to 6 weeks. If a response occurs, treatment can be continued for an additional 4 to 6 weeks (Prod Info ZELNORM(R) oral tablets, 2004).
    2) CHRONIC IDIOPATHIC CONSTIPATION: Recommended dose is 6 mg taken twice daily before meals with periodic assessment for the continued need for therapy (Prod Info ZELNORM(R) oral tablets, 2004).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) Safety and efficacy of tegaserod therapy in the pediatric population has not been established (Prod Info ZELNORM(R) oral tablets, 2004).

Maximum Tolerated Exposure

    A) ACUTE
    1) In clinical trials, diarrhea, headache, abdominal pain, and orthostatic hypotension (one patient) were reported following single-dose ingestions of 120 mg of tegaserod (Prod Info ZELNORM(R) oral tablets, 2004).
    B) CHRONIC
    1) Tegaserod ingestions of 90 to 180 mg/day for several days, in several patients, resulted in the development of diarrhea (100%), headache (57%), abdominal pain (18%), and nausea and vomiting (7% each) (Prod Info ZELNORM(R) oral tablets, 2004).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Tegaserod is a selective partial agonist at the serotonin-4 (5-HT4) receptor, and possesses gastrointestinal prokinetic activity (Appel et al, 1997; Scarpignato & Pelosini, 1999). It triggers the release of neurotransmitters, such as calcitonin gene-related peptide from sensory neurons. The activation of 5-HT4 receptors in the gastrointestinal tract stimulates peristalsis and intestinal secretion, and inhibits visceral sensitivity (Prod Info Zelnorm(TM), tegaserod, 2002; Lacy & Yu, 2002). The affinity of tegaserod for the 5-HT4 receptor is approximately 21% of the naturally occurring serotonin (Lacy & Yu, 2002).
    B) Tegaserod exhibits greater selectivity and affinity for the 5-HT4 receptor than cisapride, and may lack the cardiotoxicity of the latter (Norman, 1999; Anon, 1999). The drug has minimal-to-no binding affinity for 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2C, or 5-HT3 receptor subtypes; no significant affinity for muscarinic, histamine-1 (H1), dopaminergic, opioid, or alpha-1 or alpha-2 adrenergic receptors has been demonstrated (Appel et al, 1997).

Physicochemical

Physical Characteristics

    A) Tegaserod maleate is a white to off-white crystalline powder. It is slightly soluble in ethanol and very slightly soluble in water (Prod Info Zelnorm(TM), tegaserod, 2002).

Molecular Weight

    A) 417.5 (S Sweetman , 2002)

References

General Bibliography

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