Tegaserod (Zelnorm) Adverse Reactions
- abdominal pain
- arthropathy
- back pain
- bowel ischemia
- bowel necrosis
- cholecystitis
- colitis
- diarrhea
- dizziness
- dyspepsia
- elevated hepatic enzymes
- flatulence
- GI bleeding
- headache
- hypokalemia
- migraine
- myocardial infarction
- nausea/vomiting
- orthostatic hypotension
- syncope
Tegaserod (Zelnorm) Adverse Reactions
Gastrointestinal adverse events are the most common side effects of tegaserod. Tegaserod (Zelnorm) appears to be well tolerated; the primary adverse effects being abdominal pain (12%), dyspepsia, flatulence (6%) and nausea/vomiting (8%). Diarrhea is a dose-related and expected pharmacological effect of tegaserod. In Phase III clinical trials, roughly 9% of tegaserod-treated patients developed diarrhea. The diarrhea was transient, usually occurred once in the first week of therapy, and lasted a median of 2 days. Roughly 2 - 6% of patients discontinued medication due to diarrhea. In one study, the onset of loose stool occurred 2.5 hours after dose administration and lasted approximately 2 minutes. If any patient experiences severe diarrhea during therapy with tegaserod, they should be directed to their prescriber. Some medications, such as lactulose, magnesium salts, misoprostol, stool softeners, some antibiotics, polyethylene glycol, cholinergic agents and stimulant laxatives may aggravate the diarrhea induced by tegaserod. Bulk-producing laxatives, such as psyllium and fiber have been used safely in combination with tegaserod. In chronic constipation studies, diarrhea occurred at an incidence of > 12% in females > 65 years of age vs. 6% in females <= 65 years. Sphincter of Oddi spasm, bile duct stones, (cholelithiasis), and cholecystitis with elevated hepatic enzymes have also been reported spontaneously. An increase in cholecystectomies was observed in Phase III trials with tegaserod (5/2965; 0.17%) vs. placebo (1/1740; 0.06%), which lead to a higher number of abdominal surgeries in general for tegaserod (9/2965; 0.3%) vs. placebo (3/1740; 0.2%). A causal relationship between increased numbers of abdominal surgeries and tegaserod has not been established. In post-marketing reports, ischemic colitis, mesenteric or bowel ischemia, bowel necrosis, gangrenous bowel, GI bleeding (rectal bleeding), and syncope have been noted although the numbers are too small to assign causality. Because these cases are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Hypokalemia secondary to diarrhea has also been reported.
In clinical trials, 15% of patients receiving tegaserod reported headache vs. 12% of the placebo group. Mild to moderate headache has been reported to occur from 0.5 to 11 hours after administration of tegaserod. In some subjects the headaches persisted for up to 40 hours. The incidence of headache was dose-dependent, but the intensity did not increase with the dose. It has not been reported if headache is a transient or recurrent side effect of tegaserod. Dizziness (4% vs. 3%) and migraine (2% vs. 1%) were other reported CNS-related adverse events.
Orthostatic hypotension has been reported to occur infrequently in patients receiving higher doses of tegaserod. One subject, receiving 24 mg of tegaserod, discontinued the study due to orthostatic hypotension. The causal relationship of orthostatic hypotension with tegaserod is uncertain. No other clinically relevant cardiovascular effects, including QT-interval prolongation, other ECG changes, alterations in blood pressure or heart rate have been noted.
Musculoskeletal disorders such as back pain (5% tegaserod vs. 4% placebo) and arthropathy (2% vs. 1%) occurred infrequently. Leg pain was also reported in 1% of tegaserod-treated patients, but occurred at a similar rate to placebo.
The following events were also reported in at least 2 patients during tegaserod Phase III trials, and occurred more often with tegaserod than with placebo: albuminuria, angina pectoris, appendicitis, arrhythmia, asthma, attempted suicide, bilirubinemia, breast carcinoma, bundle branch block, cholecystitis, cramps, depression, emotional liability, eructation, facial edema, fecal incontinence, flushing, frequent micturition, hypotension, impaired concentration, increased appetite, increased creatine phosphokinase, increased SGOT, increased SGPT, increased sweating, irritable colon, menorrhagia, miscarraige, ovarian cyst, pain, polyuria, pruritus, renal pain, sleep disorder, subileus, supraventricular tachycardia, syncope, tenesmus, vertigo. The causality of tegaserod in relation to these adverse events is not known. Ovarian cysts have been reported in clinical trials with tegaserod, but a causal relationship has not been demonstrated. The manufacturer noted that 9 ovarian cysts have been reported in clinical trials (one patient on placebo). In 5 patients, the ovarian cyst was confirmed (including the one placebo patient), and 4 cysts were not confirmed. It appears these reports came from a population of approximately 4000 patients receiving tegaserod.
A single case report documents the occurrence of myocardial infarction in a patient who had received two 6-mg doses of tegaserod, which is primarily a 5HT4-agonist. The authors hypothesize the cardiac event may have been due to the partial 5HT1-receptor agonist activity exhibited by tegaserod. Cardiac adverse events have also been reported for the anti-migraine agents (i.e., the triptans, such as sumatriptan), which are potent 5HT-1 agonists. Clinicians may consider screening patients for cardiovascular risk factors prior to prescribing tegaserod, but further data are required to determine causality.
[ Last revised: 7/15/2004 10:44:00 AM ]
References
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. Appel S, Kumle A, Meier R. Clinical pharmacodynamics of SDZ HTF 919, a new 5-HT-4 receptor agonist, in a model of slow-colonic transit. Clin Pharmacol Ther 1997;62:546 - 55.
. Prather CM, Camilleri M, Zinsmeister AR, et al. Tegaserod (Zelnorm) accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2000;118:463 - 68.
. Rueeg PC, Dunger Baldauf C, Dingemanse SA, et al. Tegaserod (Zelnorm), a 5HT - 4 receptor partial agonist, devoid of significant electrocardiographic effects. Gastroenterology 2001:abstract no. 3257.
. Drici M, Ebert S, 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.)
. Busti AJ, Murillo JR Jr, Cryer B. Tegaserod-induced myocardial infarction: case report and hypothesis. Pharmacotherapy. 2004;24:526 - 31.
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