Tegaserod

Tegaserod is a Serotonin 5-HT₄ Receptor Agonist belonging to Gastrointestinal agent.

Tegaserod is a serotonin-4 (5-HT4) receptor agonist indicated for the treatment of constipation predominant irritable bowel syndrome (IBS-C) specifically in women under the age of 65.

Tegaserod rapidly absorbed from the gastrointestinal tract. Time taken to reach peak plasma concentration is Approximately 1 hour. Widely distributed into tissues. Plasma protein-binding is Approximately 98%, mainly to α₁-acid glycoprotein. Metabolization take place in the stomach via hydrolysis, followed by oxidation, conjugation and glucuronidation in the liver to form M29 metabolite (inactive main metabolite). Undergoes significant first-pass effect. Tegaserod excreted mainly via faeces approximately 66% as unchanged drug and approximately 33% as metabolites in urine.

Tegaserod shows side effects like Headache, diarrhea, nausea, gas, heartburn, dizziness.

Tegaserod is available in the form of Oral Tablet.

Tegaserod is available in India, UK, South Africa, Switzerland, Philippines, and Canada.

Tegaserod belongs to the Gastrointestinal agent acts as a Serotonin 5-HT₄ Receptor Agonist.

Tegaserod is a partial neuronal 5-HT₄ receptor agonist. Its action at the receptor site leads to stimulation of the peristaltic reflex and intestinal secretion, and moderation of visceral sensitivity.

The Data of Onset and duration of action of Tegaserod is not clinically established.

The Tmax of Tegaserod is approximately 1 hour.

Tegaserod is available in the form of Oral Tablet.

Tegaserod tablet is taken orally, usually twice daily.

Tegaserod is used for the short-term treatment of women who have irritable bowel syndrome (IBS) associated with constipation. This medicine is not recommended for use in patients below 18 years of age.

Tegaserod is a Serotonin 5-HT₄ Receptor Agonist belonging to Gastrointestinal agent.

Tegaserod is approved for use in the following clinical indications

• Irritable bowel syndrome with constipation

Tegaserod is a serotonin-4 (5-HT4) receptor agonist indicated for the treatment of constipation predominant irritable bowel syndrome (IBS-C) specifically in women under the age of 65.

• Irritable bowel syndrome with constipation

Oral: 6 mg twice daily; discontinue use in patients with an inadequate response after 4 to 6 weeks of treatment.

Tegaserod is available in various strengths as 2 mg and 6 mg.

Tegaserod is available in the form of Oral Tablet.

• Dosage Adjustment in Kidney Patient

eGFR ≥30 mL/minute/1.73 m²: No dosage adjustment necessary.

eGFR ≥15 to <30 mL/minute/1.73 m²: There are no specific dosage adjustments provided.

eGFR <15 mL/minute/1.73 m²: Use is contraindicated.

End-stage renal disease on hemodialysis: Use is contraindicated.

• Dosage Adjustment in Hepatic impairment Patient

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B or C): Use is contraindicated.

Tegaserod is contraindicated in patients with

• A history of myocardial infarction (MI), stroke, transient ischemic attack (TIA), or angina.
• A history of ischemic colitis or other forms of intestinal ischemia.
• Severe renal impairment (eGFR< 15 mL/min/1.73 m2 ) or end-stage renal disease.
• Moderate and severe hepatic impairment (Child-Pugh B or C).
• A history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions.
• Hypersensitivity to Tegaserod.

• Cardiovascular Ischemic Events, Including Major Adverse Cardiovascular Events (MACE) Stroke, MI, and cardiovascular death (major adverse cardiovascular events [MACE]) have been reported in adults taking Tegaserodwho had an increased risk of developing an adverse cardiovascular event based on their medical history. Tegaserodis contraindicated in patients with a history of MI, stroke, TIA, or angina. Assess female patients less than 65 years of age for a history of cardiovascular disease and cardiovascular risk factors prior to treatment with Tegaserod. The potential risks of treatment must be balanced with expectations in improvements in symptoms of IBS-C. Discontinue Tegaserod in patients who experience an MI, stroke, TIA, or angina. Evaluate the risks and benefits of continued use of Tegaserod in patients who develop clinical or other evidence of cardiovascular ischemic heart disease (e.g., coronary artery disease) and/or experience changes in health status that could increase cardiovascular risk during treatment with Tegaserod.
• Ischemic Colitis

Ischemic colitis and other forms of intestinal ischemia have been reported post marketing in patients receiving Tegaserod. In some cases, hospitalization was required. Discontinue Tegaserod in patients who develop symptoms of ischemic colitis, such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. Evaluate patients experiencing these symptoms promptly and perform appropriate diagnostic testing. Do not reinitiate Tegaserod in patients who develop findings consistent with ischemic colitis or other forms of intestinal ischemia.

• Volume Depletion Associated with Diarrhea

Diarrhea is one of the most common adverse reactions in Tegaserod-treated patients from the pooled IBS-C double-blind placebo-controlled trials. Diarrhea resulted in discontinuation in 1.6% of Tegaserod -treated patients compared to 0% in placebo. In post-marketing experience, serious consequences of diarrhea including hypovolemia, hypotension, and syncope have been reported in patients treated with Tegaserod. In some cases, these complications have required hospitalization for rehydration. Avoid use of Tegaserod in patients who are currently experiencing or frequently experience diarrhea. Instruct patients to discontinue Tegaserod and contact their healthcare provider if severe diarrhea, hypotension, or syncope occur.

• Suicidal Ideation and Behavior Suicide

Suicidal attempt and ideation, and self-injurious behavior have been reported in clinical trials of IBS-C and other gastrointestinal motility disorders. The frequency of suicidal ideation or attempts with Tegaserod treatment (8 patients out of 10,003) was higher than placebo (1 patient out of 5,425). Suicidal ideation/behavior in clinical trials was proportionately more frequent among patients receiving antidepressant medication. Monitor all Tegaserod -treated patients for clinical worsening of depression and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment. Counsel family members and caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Instruct patients to immediately discontinue Tegaserod and contact their healthcare provider if their depression is persistently worse or they are experiencing emergent suicidal thoughts or behaviors.

There are no data regarding the presence of Tegaserod in human milk, the effects on the breastfed infant, or the effects on milk production. Tegaserod and its metabolites are present in rat milk; the milk to plasma concentration ratio for Tegaserod is very high. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious reactions in the breastfed infant, including tumorigenicity, advise a lactating woman that breastfeeding is not recommended during treatment with Tegaserod.

Available data from case reports with tegaserod use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, decreased survival of rat pups was observed with maternal dietary administration of Tegaserod at 71 times the recommended dose during organogenesis and through lactation. Decreased body weight and delays in developmental landmarks in rat pups were observed with maternal dietary administration of 45 times the recommended dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Common

• Headache, Abdominal pain, Dizziness, migraine, vertigo, Diarrhea, nausea, flatulence, dyspepsia, increased appetite, Anemia, rectal hemorrhage, Arthropathy, asthenia, increased creatine phosphokinase in blood specimen, tendinopathy, Suicidal ideation, suicidal tendencies.

Rare

• Acute myocardial infarction, alopecia, anaphylaxis, cerebrovascular accident, cholecystitis, choledocholithiasis, hepatitis, hypersensitivity reaction, increased serum alanine aminotransferase, increased serum aspartate transaminase, increased serum bilirubin, intestinal necrosis (gangrenous bowel), ischemic colitis, mesenteric ischemia, severe diarrhea.

• Anticholinergic Agents: May diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic).

• Fosfomycin: Gastrointestinal Agents (Prokinetic) may decrease the serum concentration of Fosfomycin.

• Opioid Agonists: May diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic).

• P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Tegaserod.

• Sirolimus (Conventional): Gastrointestinal Agents (Prokinetic) may increase the serum concentration of Sirolimus (Conventional).

The common side effectsof Tegaserod include the following

Common side effects

• Headache, diarrhea, nausea, gas, heartburn, dizziness.

Rare side effects

• Rash, hives, itching, swelling of the face, throat, tongue, lips, or eyes, difficulty breathing and swallowing, or hoarseness, chest pain that may spread to the arms, neck, jaw, back, or stomach area; sweating; shortness of breath; or feeling sick or vomiting, sudden numbness or weakness, especially on one side of the body; severe headache or confusion, or problems with vision, speech, or balance, bleeding from the rectum, new or worsening stomach pain, diarrhea that is bloody or that causes you to feel lightheaded or faint.

• Pregnancy

Pregnancy Category

Available data from case reports with Tegaserod use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, decreased survival of rat pups was observed with maternal dietary administration of Tegaserod at 71 times the recommended dose during organogenesis and through lactation. Decreased body weight and delays in developmental landmarks in rat pups were observed with maternal dietary administration of 45 times the recommended dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

• Nursing Mothers

There are no data regarding the presence of Tegaserod in human milk, the effects on the breastfed infant, or the effects on milk production. Tegaserod and its metabolites are present in rat milk; the milk to plasma concentration ratio for Tegaserod is very high. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious reactions in the breastfed infant, including tumorigenicity, advise a lactating woman that breastfeeding is not recommended during treatment with Tegaserod.

• Pediatric Use

As per FDA, the Safety and effectiveness of Tegaserod in pediatric patients have not been established.

• Geriatric Use

Tegaserod is not indicated in patients 65 years of age and older.

Symptoms: Headache, diarrhoea, abdominal pain, nausea, vomiting, flatulence, and orthostatic hypotension.

Management: Symptomatic and supportive treatment.

Pharmacodynamic

• Cardiac Electrophysiology

Centrally analyzed ECGs were recorded in 4,605 male and female patients receiving Tegaserod6 mg twice daily or placebo for IBS-C and other related motility disorders. No subject receiving Tegaserod had an absolute QTcF above 480 ms.An increase in QTcF of 30 to 60 ms was observed in 7% of patients receiving Tegaserodand 8% receiving placebo. An increase in QTcF of greater than 60 ms was observed in 0.3% and 0.2% of subjects, respectively. The effects of Tegaserod on the QTcF interval were not considered to be clinically meaningful.

• Platelet Aggregation

There is a potential for Tegaserod and its main metabolite (M29) to increase platelet aggregation in vitro. In one in vitro study, Tegaserod, at concentrations up to 10-times the maximum plasma concentration (Cmax) at the recommended dose, significantly increased platelet aggregation in a concentration-dependent manner up to 74% (range 11% to 74%) compared to vehicle control (with potentiation by various agonists). In another in vitro study, M29, at concentrations up to 0.6-times the Cmax of M29 also showed a 5% to 16% increase in platelet aggregation compared to vehicle control. The clinical implications of the in vitro platelet aggregation results are unclear.

Pharmacokinetics

• Absorption

Rapidly absorbed from the gastrointestinal tract.Time taken to reach peak plasma concentration is Approximately 1 hour.

• Distribution

Widely distributed into tissues. Plasma protein-binding is Approximately 98%, mainly to α₁-acid glycoprotein.

• Metabolism and Excretion

Metabolization take place in the stomach via hydrolysis, followed by oxidation, conjugation and glucuronidation in the liver to form M29 metabolite (inactive main metabolite). Undergoes significant first-pass effect. Excreted mainly via faeces approximately 66% as unchanged drug and approximately 33% as metabolites in urine.

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