DESCRIPCION

El tegaserod es un agonista parcial del receptor 5-HT4 de la serotonina indicado en el tratamiento de los pacientes con el síndrome del colon irritable, cuyos síntomas más importantes con el dolor abdominal y la constipación

Mecanismo de acción: tanto el síndrome del colon irritable como la constipación idiopática crónica son desórdenes de la motilidad del tracto digestivo inferior. En la etiología de ambas enfermedades, la serotonina (o 5-hidroxitriptamina) juega un papel primordial en la transmisión de señales en el sistema nervioso entérico. La serotonina modula la motilidad, la sensibilidad visceral y las secreciones intestinales. En el tracto digestivo humano se han identificado cuatro receptores de serotonina (denominados 5-HT1, 5-HT2, 5-HT3 y 5-HT4) de los cuales el 5-HT3 y 5-HT4 participan en diversos procesos reguladores. Se han identificado y clonado varias isoformas del receptor 5-HT4 humano Diversos experimentos utilizando este receptor han puesto de manifiesto que juega un papel importante desencadenando el reflejo peristáltico, modulando el tono de la musculatura lisa intestinal y regulando la secreción intestinal.

El tegaserod es un agonista parcial del receptor 5-HT4 que muestra una elevada afinidad hacia los mismos mientras que practicamente no es ligando de los receptores 5-HT3 o dopaminérgicos. Muestra una afinidad moderada hacia los receptores 5-HT1. Al fijarse a los receptores 5-HT4 del tracto digestivo, el tegaserod desencadena una cascada de reacciones cuyo resultado final es la estimulación del reflejo peristáltico y de las secreciones intestinales. Estudios realizados en animales de experimentación han puesto de manifiesto que el tegaserod aumenta la actividad motora basal del intestino y normaliza la motilidad de todo el tracto digestivo.

Farmacocinética: después de una dosis oral, las máximas concentraciones plasmáticas de tegaserod se alcanzan al cabo de una hora. Cuando se administra en ayunas, la biodisponibilidad absoluta del fármaco es del 10%. El tegaserod muestra una farmacocinética lineal dentro de rango de dosis de 2 a 12 mg dos veces al día. No se observa acumulación del fármaco en plasma cuando se administran dosis de 6 mg dos veces al día durante 5 días. Cuando el tegaserod se administra con las comidas la biodisponibilidad se reduce en un 40-65% con una reducción de las Cmax de un 20%-40%. La misma situación tiene lugar si el fármaco se administra 30 minutos antes de la comida o hasta 2.5 horas despues. El tegaserod se une a los proteínas del plasma en un 98%, en particular a la glicoproteína ácida a1 y se distribuye ampliamente por todos tejidos con un volumen de distribución de 368 ± 223 L cuando se alcanza el equilibrio.

La semi-vida de eliminación oscila entre 5.8 ± 1.2 h para la dosis de 2 mg hasta o 9.8 ± 3.2 horas para la dosis de 12 mg. El sexo del paciente o su edad no afectan la farmacocinética del tegaserod, aunque en los pacientes de la tercera edad se observa un aumento de las áreas bajo la curva, aumento que no tiene ninguna repercusión clínica. Por lo tanto, no es necesario ningún reajueste de la dosis en estos pacientes. Tampoco se observan diferencias en la farmacocinética de pacientes con el síndrome del colon irritable en comparación con la de los voluntarios sanos.

El tegaserod es metabolizado de varias maneras. En una de ellas, experimenta una hidrólisis pH dependiente en el estómago, seguida de una oxidación y glucuronización, dando el metabolito M29 que no conserva ninguna de las propiedades del fármaco nativo. En una segunda, se forman varios glucurónidos isómeros del tegaserod tanto en el hígado como en el intestino. Finalmente, en los microsomas hepáticos el tegaserod se metaboliza a O-desmetiltegaserod, siendo esta transformación inhibida por la quinidina. Aproximadamente los dos tercios de la dosis administrada por vía oral se elimina en las heces sin alterar, mientras que el resto se elimina en forma de metabolitos por vía renal.

No son necesarios reajustes en las dosis en los pacientes con insuficiencia renal ligera o moderada, pero no se recomienda su administración a pacientes con insuficiencia renal grave. Tampoco son necesarios reajustes en las dosis en pacientes con insuficiencia hepática moderada, si bien se recomienda una estrecha vigilancia. En los casos de hepatitis grave, no se recomienda el uso de este fármaco.

Tegaserod was not carcinogenic in rats given oral dietary doses up to 180 mg/kg/day (approximately 93 to 111 times the human exposure at 6 mg b.i.d. based on plasma AUC 0-24 hr ) for 110 to 124 weeks.

In mice, dietary administration of tegaserod for 104 weeks produced mucosal hyperplasia and adenocarcinoma of small intestine at 600 mg/kg/day (approximately 83 to 110 times the human exposure at 6 mg b.i.d. based on plasma AUC 0-24 hr ). There was no evidence of carcinogenicity at a lower dose of 200 mg/kg/day (approximately 24 to 35 times the human exposure at 6 mg b.i.d. based on plasma AUC 0-24 hr ) or 60 mg/kg/day (approximately 3 to 4 times the human exposure at 6 mg b.i.d. based on plasma AUC 0-24 hr ).

Tegaserod was not genotoxic in the in vitro Chinese hamster lung fibroblast (CHL/V79) cell chromosomal aberration test, the in vitro Chinese hamster lung fibroblast (CHL/V79) cell forward mutation test, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) test or the in vivo mouse micronucleus test. The results of Ames test for mutagenicity were equivocal.

Tegaserod at oral doses up to 240 mg/kg/day (approximately 57 times the human exposure at 6 mg b.i.d. based on plasma AUC 0-24 hr ) in male rats and 150 mg/kg/day (approximately 42 times the human exposure at 6 mg b.i.d. based on plasma AUC 0-24 hr ) in female rats was found to have no effect on fertility and reproductive performance.

INDICACIONES Y POSOLOGIA

Tratamiento del síndrome del colon irritable con constipación:

Administración oral:

• Adultos: las dosis recomendadas son de 6 mg de tegaserod por vía, administrados antes de las comidas durante 4 a 6 semanas. En los pacientes que responden al tratamiento al cabo de las 4-6 semanas, puede considerarse un segundo curso idéntico al primero

CONTRAINDICACIONES Y PRECAUCIONES

Serious consequences of diarrhea , including hypovolemia , hypotension , and syncope have been reported in the clinical studies and during marketed use of Zelnorm (tegaserod maleate) . In some cases, these complications have required hospitalization for rehydration . Zelnorm (tegaserod maleate) should be discontinued immediately in patients who develop severe diarrhea, hypotension or syncope. Zelnorm (tegaserod maleate) should not be initiated in patients who are currently experiencing or frequently experience diarrhea

Zelnorm ® (tegaserod maleate) should be discontinued immediately in patients with new or sudden worsening of abdominal pain .

Ischemic colitis

Ischemic colitis and other forms of intestinal ischemia have been reported in patients receiving Zelnorm during marketed use of the drug (see ADVERSE REACTIONS : Post-Marketing Experience). In some cases, hospitalization was required. Zelnorm (tegaserod maleate) should be discontinued immediately in patients who develop symptoms of ischemic colitis, such as rectal bleeding, bloody diarrhea or new or worsening abdominal pain . Patients experiencing these symptoms should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with Zelnorm (tegaserod maleate) should not be resumed in patients who develop findings consistent with ischemic colitis or other forms of intestinal ischemia.

Reproduction studies have been performed in rats at oral doses up to 100 mg/kg/day (approximately 15 times the human exposure at 6 mg b.i.d. based on plasma AUC 0-24 hr ) and rabbits at oral doses up to 120 mg/kg/day (approximately 51 times the human exposure at 6 mg b.i.d. based on plasma AUC 0-24 hr ) and have revealed no evidence of impaired fertility or harm to the fetus due to tegaserod. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Tegaserod and its metabolites are excreted in the milk of lactating rats with a high milk to plasma ratio. It is not known whether tegaserod is excreted in human milk. Many drugs, which are excreted in human milk, have potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for tegaserod in the mouse carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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Zelnorm

1. Irritable Bowel Syndrome Slideshow: Understanding IBS
2. Digestive Disease Myths Slideshow Pictures
3. Irritable Bowel Syndrome (IBS) Quiz

• Patient Information Overview

DRUG INTERACTIONS

In vitro drug-drug interaction data with tegaserod indicated no inhibition of the cytochrome P450 isoenzymes CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4, whereas inhibition of CYP1A2 and CYP2D6 could not be excluded. However, in vivo , no clinically relevant drug-drug interactions have been observed with dextromethorphan (CYP2D6 prototype substrate), and theophylline (CYP1A2 prototype substrate). There was no effect on the pharmacokinetics of digoxin, oral contraceptives, and warfarin . The main human metabolite of tegaserod hydrogen maleate, 5-methoxyindole-3-carboxylic acid glucuronide, did not inhibit the activity of any of the above cytochrome P450 isoenzymes in in vitro tests.

Dextromethorphan

A pharmacokinetic interaction study demonstrated that co-administration of tegaserod and dextromethorphan did not change the pharmacokinetics of either compound to a clinically relevant extent. Dose adjustment of either drug is not necessary when tegaserod is combined with dextromethorphan. Therefore, tegaserod is not expected to alter the pharmacokinetics of drugs metabolized by CYP2D6 (e.g., fluoxetine, omeprazole, captopril).

Theophylline

A pharmacokinetic interaction study demonstrated that co-administration of tegaserod and theophylline did not affect the pharmacokinetics of theophylline. Dose adjustment of theophylline is not necessary when tegaserod is co-administered. Therefore, tegaserod is not expected to alter the pharmacokinetics of drugs metabolized by CYP1A2 (e.g., estradiol, omeprazole).

Digoxin

A pharmacokinetic interaction study with digoxin demonstrated that concomitant administration of tegaserod reduced peak plasma concentration and exposure of digoxin by approximately 15%. This reduction of bioavailability is not considered clinically relevant. When tegaserod is co-administered with digoxin dose adjustment is unlikely to be required.

Warfarin

A pharmacokinetic and pharmacodynamic interaction study with warfarin demonstrated no effect of concomitant administration of tegaserod on warfarin pharmacokinetics and pharmacodynamics. Dose adjustment of warfarin is not necessary when tegaserod is co-administered.

Oral Contraceptives

Co-administration of tegaserod did not affect the steady-state pharmacokinetics of ethinylestradiol and reduced peak concentrations and exposure of levonorgestrel by 8%. Tegaserod is not expected to alter the risk of ovulation in subjects taking oral contraceptives. No alteration in oral contraceptive medication is necessary when tegaserod is co-administered.

REACCIONES ADVERSAS

n Phase 3 clinical trials 2,632 female and male patients received Zelnorm ® (tegaserod maleate) 6 mg b.i.d. or placebo . The frequency and type of adverse events for females and males were similar. The following adverse experiences were reported in 1% or more of patients who received Zelnorm (tegaserod maleate) and occurred more frequently on Zelnorm (tegaserod maleate) than placebo:

Chronic Idiopathic Constipation

In phase 3 clinical trials 2,603 male and female patients received Zelnorm (tegaserod maleate) 6 mg b.i.d., 2 mg b.i.d. or placebo. The following adverse experiences were reported in 1% or more of patients who received Zelnorm (tegaserod maleate) and occurred more frequently than in patients who received placebo.

Zelnorm (tegaserod maleate) was not associated with changes in ECG intervals.

Zelnorm (tegaserod maleate) -Induced Diarrhea

IBS with Constipation

In the Phase 3 clinical studies, 8.8% of patients receiving Zelnorm (tegaserod maleate) reported diarrhea as an adverse experience compared to 3.8% of patients receiving placebo. The majority of the Zelnorm (tegaserod maleate) patients reporting diarrhea had a single episode. In most cases, diarrhea occurred within the first week of treatment. Typically, diarrhea resolved with continued therapy . Overall, the discontinuation rate from the studies due to diarrhea was 1.6% among the Zelnorm (tegaserod maleate) -treated patients. In clinical studies, a small number of patients (0.04%) experienced clinically significant diarrhea including hospitalization, hypovolemia , hypotension and need for intravenous fluids. Diarrhea can be the pharmacologic response to Zelnorm (tegaserod maleate) .

Chronic Idiopathic Constipation

In the two Phase 3 studies, 6.6% of patients treated with Zelnorm (tegaserod maleate) 6 mg b.i.d. and 4.2% of patients treated with Zelnorm (tegaserod maleate) 2 mg b.i.d. reported diarrhea as an adverse event , versus 3.0% of patients receiving placebo.

The diarrhea episodes experienced by patients treated with tegaserod occurred early after initiation of treatment ( median of 5.5 days), were of short duration (median of 2.5 days), and occurred only once in the majority of patients.

Typically, diarrhea resolved with continued therapy; only 0.9% of patients treated with Zelnorm (tegaserod maleate) 6 mg b.i.d. discontinued the study due to diarrhea (compared to 0.3% in the Zelnorm (tegaserod maleate) 2 mg b.i.d. group and 0.2% in the placebo group).

Abdominal Surgeries, Including Cholecystectomy

An increase in abdominal surgeries was observed on Zelnorm (tegaserod maleate) (9/2,965; 0.3%) vs. placebo (3/1,740; 0.2%) in the Phase 3 IBS clinical studies. The increase was primarily due to a numerical imbalance in cholecystectomies reported in patients treated with Zelnorm (tegaserod maleate) (5/2,965; 0.17%) vs. placebo (1/1,740; 0.06%). In chronic idiopathic constipation clinical trials there was no increase in the frequency of abdominal and pelvic surgeries in active versus placebo groups: 9/1752; 0.5% on Zelnorm (tegaserod maleate) versus 8/861; 0.9% on placebo. A causal relationship between abdominal surgeries and Zelnorm (tegaserod maleate) has not been established.

Other adverse events

The following list of adverse events includes those from phase 3 clinical studies (6 mg b.i.d. or 2 mg b.i.d.) which were reported more frequently (>0.2%) in patients on Zelnorm (tegaserod maleate) than placebo; or which were considered by the investigator to be possibly related to Zelnorm (tegaserod maleate) and reported more frequently (>0.1%) on Zelnorm (tegaserod maleate) than placebo; or which lead to discontinuation more frequently ( 0.1% and in more than 1 patient) on Zelnorm (tegaserod maleate) than placebo. The list also contains those serious adverse events from all clinical trials in patients treated with either 6 mg b.i.d. or 2 mg b.i.d. Zelnorm (tegaserod maleate) which were either considered by the investigator as possibly drug related, or occurred in at least 2 more patients on Zelnorm (tegaserod maleate) than on placebo. Although the events reported occurred during treatment with Zelnorm (tegaserod maleate) , they were not necessarily caused by it.

Cardiac disorders : Angina pectoris , supraventricular tachycardia , syncope

Ear and labyrinth disorders : Vertigo

Eye disorders : Visual disturbance

Gastrointestinal disorders : Hemorrhoids , proctalgia, stomach discomfort, fecal incontinence , irritable bowel syndrome , dyspepsia , gastroesophageal reflux , gastritis

General disorders and administration site conditions : Chest pain , peripheral edema

Hepatobiliary disorders : Cholelithiasis

Immune system disorders : Hypersensitivity reactions

Investigations : Creatinine phosphokinase increased, increased eosinophil count, low neutrophil count

Metabolism and nutrition disorders : increased appetite

Neoplasms benign , malignant and unspecified (including cysts and polyps ) : Breast carcinoma

Psychiatric disorders : Depression , sleep disorder, restlessness

Respiratory, thoracic and mediastinal disorders : Dyspnea , pharyngolaryngeal pain

Reproductive system and breast disorders : Miscarriage , menorrhagia

Surgical and medical procedures : Cholecystectomy

Vascular disorders : Flushing, hypotension

REFERENCIAS

• Wolfe, Michael: Therapy of Digestive Disorders. 2006. Saunders. 1051 páginas

• P Layer, J Keller, S Mueller-Lissner, P Rüegg, H Loeffl: Tegaserod: Long-Term Treatment for Irritable Bowel Syndrome Patients with Constipation in Primary Care. Digestion 2005;71:238–244
• Hasler W, Schoenfeld P. Safety Profile of Tegaserod, a 5-HT4 Receptor Agonist, for the Treatment of Irritable Bowel Syndrome. Drug Safety, 2004, Vol. 27 Issue 9, p619-631

Monografía creada el .Equipo de redacci�n de IQB (Centro colaborador de La Administraci�n Nacional de Medicamentos, alimentos y Tecnolog�a M�dica -ANMAT - Argentina).