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Tegaserod Maleate

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

Synonyms: HTF-919; SDZ-HTF-919; Tegaserod, maleato de
BAN: Tegaserod Maleate [BANM]
USAN: Tegaserod Maleate
INN: Tegaserod Maleate [rINNM (en)]
INN: Maleato de tegaserod [rINNM (es)]
INN: Tégasérod, Maléate de [rINNM (fr)]
INN: Tegaserodi Maleas [rINNM (la)]
INN: Тегасерода Малеат [rINNM (ru)]
Chemical name: 1-{[(5-Methoxyindol-3-yl)methylene]amino}-3-pentylguanidine maleate
Molecular formula: C16H23N5O,C4H4O4 =417.5
CAS: 145158-71-0 (tegaserod); 189188-57-6 (tegaserod maleate)
ATC code: A03AE02

Stability and compatibility. Crushed tablets of tegaserod were found to be stable in water, and apple juice the latter may mask the taste of the drug. Orangejuice, milk, or yogurt were not recommended as vehicles because of incomplete dissolution or uncertainty about stability.

Adverse Effects

The most common adverse effects of tegaserod are gastrointestinal disturbances including abdominal pain, diarrhoea, nausea, vomiting, and flatulence. Diarrhoea generally occurs within the first week of treatment and is usually transient but may be severe. Ischaemic colitis has been reported. Headache, dizziness, migraine, insomnia, fatigue, leg or back pain, and arthropathy have also been commonly reported. Cardiovascular adverse effects include hypotension and arrhythmias. Serious cardiovascular ischaemic events such as myocardial infarction, unstable angina pectoris, and stroke have occurred fatalities have been reported. Other adverse effects include effects on the nervous system such as depression, and other gastrointestinal effects including cholelithiasis and dyspepsia.

Effects on the gastrointestinal tract. Severe diarrhoea, leading to hypovolaemia, hypotension, and syncope has been seen occasionally in patients receiving tegaserod. Some patients required hospitalisation for rehydration, and patients should be advised to stop taking the drug and seek medical attention if severe diarrhoea or associated dizziness or lightheadedness develop. In addition, ischaemic colitis has been reported rarely, and the drug should be stopped immediately in patients who develop symptoms such as rectal bleeding, bloody diarrhoea, or new and worsening abdominal pain. The FDA noted that it had received 20 reports of ischaemic colitis in patients taking tegaserod between August 2002 and March 2004 in 3 cases, the effect only developed after several months (7 to 13) of therapy. However, in reply the manufacturer (Novartis) suggested that there was no evidence from postmarketing surveillance to support an increased rate of ischaemic colitis over that normally seen in patients with irritable bowel syndrome, who are at increased risk of this diagnosis, nor any obvious pharmacological mechanism for such an adverse effect.

Effects on the heart. In an analysis of pooled data from 29 studies, 13 out of 11 614 patients taking tegaserod had serious cardiovascular ischaemic events, compared with 1 out of 7031 patients taking placebo. Events included unstable angina pectoris, stroke, and myocardial infarction, one of which was fatal. Most of these patients had at least one cardiovascular risk factor, but for some, no cardiovascular disease or risk had been diagnosed at the onset of treatment with tegaserod. Patients taking tegaserod should seek medical attention if they have severe chest pain, dyspnoea, dizziness, sudden onset of weakness, difficulty walking or talking, or any other symptoms suggestive of myocardial infarction or stroke.

Tegaserod Maleate

Precautions

Tegaserod is contra-indicated in patients with a history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions. Tegaserod should also not be given to patients who have diarrhoea or who frequently experience diarrhoea. It should be stopped in patients with new or sudden worsening of abdominal symptoms, hypotension, or syncope. Tegaserod should not be used in patients with severe renal impairment or moderate to severe hepatic impairment. For the possible cardiovascular risks of tegaserod therapy, see above in the USA use is restricted, and it is contra-indicated in patients with a history of heart disease or symptoms suggestive of cardiac disorders.

Pharmacokinetics

Tegaserod is rapidly absorbed from the gastrointestinal tract with peak plasma levels occurring after about 1 hour. The absolute bioavailability of an oral dose is 10% this is reduced by the presence of food. Tegaserod is widely distributed into the tissues and is about 98% bound to plasma proteins. Presystemic acid-catalysed hydrolysis in the stomach, and then oxidation and glucuronidation, produces the main metabolite, which is inactive direct systemic glucuronidation also occurs. Two-thirds of an oral dose is excreted unchanged in the faeces and one-third excreted in the urine primarily as the main metabolite. The terminal half-life of tegaserod is about 11 hours.

Uses and Administration

Tegaserod is a partial agonist at 5-HT4 receptors and has prokinetic properties. It is used in women for the short-term treatment of irritable bowel syndrome, particularly the constipation-predominant form. It has also been used for the treatment of chronic idiopathic constipation in men and women less than 65 years of age.

Tegaserod is given orally as the maleate but doses are expressed in terms of the base 8.31 mg of tegaserod maleate is equivalent to about 6 mg of tegaserod. It is given in a dose of 6 mg twice daily before food. For irritable bowel syndrome, it is given for 4 to 6 weeks a further 4 to 6 weeks of treatment may be given if a beneficial response is seen.

In March 2007, marketing of tegaserod was suspended in some countries because of a high incidence of cardiovascular ischaemic events (see Effects on the Heart, above). In the USA, the use of tegaserod was subsequently restricted to women younger than 55 years of age who have either constipation-predominant irritable bowel syndrome or chronic idiopathic constipation, and who meet specific guidelines patients should have no known or preexisting cardiac problems.

Proprietary Preparations

 

Argentina: Altezerod Coloserod Procinet Tegarod Zelmac

Australia: Zelmac †

Brazil: Zelmac

Canada: Zelnorm

Chile: Colonaid Distimax Tegasir Ther Zelmac

Czech Republic: Zelmac

Hong Kong: Zelmac

India: Tegibs Tegod

Indonesia: Zelmac

Israel: Zelmac

Malaysia: Zelmac

Mexico: Zelmac

New Zealand: Zelmac

Philippines: Zelnorm

Russia: Zelmac

South Africa: Zelnorm

Singapore: Zelmac

Switzerland: Zelmac

Thailand: Zelmac

Turkey: Zelmac

USA: Zelnorm

Venezuela: Zelmac

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