Tegaserod

Tegaserod is a 5-HT₄ agonist manufactured by Novartis and sold under the names Zelnorm and Zelmac for the management of irritable bowel syndrome and constipation.^[1] Approved by the FDA in 2002, it was subsequently removed from the market in 2007 due to FDA concerns about possible adverse cardiovascular effects. Before then, it was the only drug approved by the United States Food and Drug Administration to help relieve the abdominal discomfort, bloating, and constipation associated with irritable bowel syndrome. Its use was also approved to treat chronic idiopathic constipation.^[2]

Tegaserod

Clinical data
Trade names	Zelnorm, Zelmac
AHFS/Drugs.com	Monograph
Pregnancy category	AU: B3
Routes of administration	Oral
ATC code	A06AX06 (WHO)
Legal status
Legal status	US: Usage requires authorization from the FDA
Pharmacokinetic data
Bioavailability	10%
Protein binding	98%
Metabolism	Gastric and hepatic
Elimination half-life	11 ± 5 hours
Excretion	Fecal and renal
Identifiers
IUPAC name (2E)-2-[(5-Methoxy-1H-indol-3-yl)methylene]-N-pentylhydrazinecarboximidamide
CAS Number	145158-71-0 N
PubChem CID	5362436
IUPHAR/BPS	226
DrugBank	DB01079 Y
ChemSpider	10609889 Y
UNII	458VC51857
KEGG	D02730 Y
ChEMBL	ChEMBL76370 Y
CompTox Dashboard (EPA)	DTXSID6045955
ECHA InfoCard	100.158.793
Chemical and physical data
Formula	C16H23N5O
Molar mass	301.394 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCCCCNC(=N)NN=Cc1c[nH]c2ccc(OC)cc12
InChI InChI=1S/C16H23N5O/c1-3-4-5-8-18-16(17)21-20-11-12-10-19-15-7-6-13(22-2)9-14(12)15/h6-7,9-11,19H,3-5,8H2,1-2H3,(H3,17,18,21)/b20-11+ Y Key:IKBKZGMPCYNSLU-RGVLZGJSSA-N Y
NY (what is this?)  (verify)

Mechanism of action

The drug functions as a motility stimulant, achieving its desired therapeutic effects through activation of the 5-HT₄ receptors of the enteric nervous system in the gastrointestinal tract. It also stimulates gastrointestinal motility and the peristaltic reflex, and allegedly reduces abdominal pain.^[3] Additionally, tegaserod is a 5-HT_2B receptor antagonist.^[4]

Withdrawal from market

On 30 March 2007, the United States Food and Drug Administration requested that Novartis withdraw tegaserod from shelves.^[5] The FDA alleged a relationship between prescriptions of the drug and increased risks of heart attack or stroke. An analysis of data collected on over 18,000 patients demonstrated adverse cardiovascular events in 13 of 11,614 patients treated with tegaserod (a rate of 0.11%) as compared with 1 of 7,031 patients treated with placebo (a rate of 0.01%). Novartis alleged all of the affected patients had preexisting cardiovascular disease or risk factors for such, and further alleged that no causal relationship between tegaserod use and cardiovascular events has been demonstrated.^[6] On the same day as the FDA announcement, Novartis Pharmaceuticals Canada announced that it was suspending marketing and sales of the drug in Canada in response to a request from Health Canada.^[7] In a large cohort study based on a US health insurance database, no increase in the risk of cardiovascular events were found under tegaserod treatment.^[8] In 2019, tegaserod was reintroduced as for use in irritable bowel syndrome with constipation (IBS-C) in women under 65.^[9]

References

1. "New Data for Zelnorm". Archived from the original on December 9, 2007. Retrieved March 30, 2007.
2. "FDA approves first treatment for women with irritable-bowel syndrome". Food and Drug Administration. Archived from the original on February 5, 2007. Retrieved March 30, 2007.
3. Rossi, S. (2004). Australian Medicines Handbook. Adelaide: Health Communication Network. ISBN 0-9578521-4-2.
4. Beattie DT, Smith JA, Marquess D, et al. (November 2004). "The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo". Br. J. Pharmacol. 143 (5): 549–60. doi:10.1038/sj.bjp.0705929. PMC 1575425. PMID 15466450.
5. "FDA Announces Discontinued Marketing of GI Drug, Zelnorm, for Safety Reasons". FDA Press Release. 30 March 2007.
6. "Zelnorm" (PDF). Novartis. Archived from the original (PDF) on 2007-04-10. Retrieved 2007-03-30.
7. "Novartis suspends Canadian marketing and sales of Zelnorm in response to request from Health Canada". Retrieved 2007-03-30.
8. Loughlin J, Quinn S, Rivero E, Wong J, Huang J, Kralstein J, Earnest DL, Seeger JD (2010). "Tegaserod and the Risk of Cardiovascular Ischemic Events: An Observational Cohort Study". J Cardiovasc Pharmacol Ther. 15 (2): 151–7. doi:10.1177/1074248409360357. PMID 20200325. S2CID 37964792.
9. WorldMeds, U. S. "FDA approves the reintroduction of Zelnorm™ (tegaserod) for Irritable Bowel Syndrome with Constipation (IBS-C) in women under 65". www.prnewswire.com (Press release). Retrieved 2019-09-17.