Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2522
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
Zelnorm (Tablet)
|
| dailymed-instance:dosage |
IBS with Constipation: The recommended dosage of Zelnorm (tegaserod maleate) is 6 mg taken twice daily orally before meals for 4-6 weeks. For those women who respond to therapy at 4-6 weeks, an additional 4-6 week course can be considered. Chronic Idiopathic Constipation: The recommended dosage of Zelnorm is 6 mg taken twice daily orally before meals. Physicians and patients should periodically assess the need for continued therapy.
|
| dailymed-instance:descripti... |
Zelnorm (tegaserod maleate) tablets contain tegaserod as the hydrogen maleate salt. As the maleate salt, tegaserod is chemically designated as 3-(5-methoxy-1H-indol-3-ylmethylene)-N-pentylcarbazimidamide hydrogen maleate. Its empirical formula is CHNO���CHO. The molecular weight is 417.47 and the structural formula is Tegaserod as the maleate salt is a white to off-white crystalline powder and is slightly soluble in ethanol and very slightly soluble in water. Each 1.385 mg of tegaserod as the maleate is equivalent to 1 mg of tegaserod. Zelnorm is available for oral use in the following tablet formulations:
|
| dailymed-instance:clinicalP... |
Mechanism of Action: Irritable bowel syndrome with constipation and chronic idiopathic constipation are both lower gastrointestinal dysmotility disorders. Clinical investigations have shown that both motor and sensory functions of the gut appear to be altered in patients suffering from irritable bowel syndrome (IBS), while in patients with chronic idiopathic constipation, reduced intestinal motility is the predominant cause of the condition. Both the enteric nervous system, which acts to integrate and process information in the gut, and 5-hydroxytryptamine (5-HT, serotonin) are thought to represent key elements in the etiology of both IBS and idiopathic constipation. Approximately 95% of serotonin is found throughout the gastrointestinal tract, primarily stored in enterochromaffin cells but also in enteric nerves acting as a neurotransmitter. Serotonin has been shown to be involved in regulating motility, visceral sensitivity and intestinal secretion. Investigations suggest an important role of serotonin Type-4 (5-HT) receptors in the maintenance of gastrointestinal functions in humans. 5-HTreceptor mRNA has been found throughout the human gastrointestinal tract. Tegaserod is a 5-HTreceptor partial agonist that binds with high affinity at human 5-HTreceptors, whereas it has no appreciable affinity for 5-HTor dopamine receptors. It has moderate affinity for 5-HTreceptors. Tegaserod, by acting as an agonist at neuronal 5-HTreceptors, triggers the release of further neurotransmitters such as calcitonin gene-related peptide from sensory neurons. The activation of 5-HTreceptors in the gastrointestinal tract stimulates the peristaltic reflex and intestinal secretion, as well as inhibits visceral sensitivity. In vivo studies showed that tegaserod enhanced basal motor activity and normalized impaired motility throughout the gastrointestinal tract. In addition, studiesdemonstrated that tegaserod moderated visceral sensitivity during colorectal distension in animals.<br/>Pharmacokinetics:<br/>Absorption: Peak plasma concentrations are reached approximately 1 hour after oral dosing. The absolute bioavailability of tegaserod when administered to fasting subjects is approximately 10%. The pharmacokinetics are dose proportional over the 2 mg to 12 mg range given twice daily for 5 days. There was no clinically relevant accumulation of tegaserod in plasma when a 6 mg b.i.d. dose was given for 5 days. (See DOSAGE AND ADMINISTRATION.)<br/>Food Effects: When the drug is administered with food, the bioavailability of tegaserod is reduced by 40%-65% and Cby approximately 20%-40%. Similar reductions in plasma concentration occur when tegaserod is administered to subjects within 30 minutes prior to a meal, or 2.5 hours after a meal. Tof tegaserod is prolonged from approximately 1 hour to 2 hours when taken following a meal, but decreased to 0.7 hours when taken 30 minutes prior to a meal.<br/>Distribution: Tegaserod is approximately 98% bound to plasma proteins, predominantly alpha-1-acid glycoprotein. Tegaserod exhibits pronounced distribution into tissues following intravenous dosing with a volume of distribution at steady-state of 368��223 L.<br/>Metabolism: Tegaserod is metabolized mainly via two pathways. The first is a presystemic acid catalyzed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide. The main metabolite has negligible affinity for 5-HTreceptors in vitro. In humans, systemic exposure to tegaserod was not altered at neutral gastric pH values. The second metabolic pathway of tegaserod is direct glucuronidation which leads to generation of three isomeric N-glucuronides.<br/>Elimination: The plasma clearance of tegaserod is 77��15 L/h with an estimated terminal half-life (T) of 11��5 hours following intravenous dosing. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in the feces, with the remaining one-third excreted in the urine, primarily as the main metabolite.<br/>Sub Populations: Patients: The pharmacokinetics of tegaserod in IBS patients are comparable to those in healthy subjects. The pharmacokinetics of tegaserod in patients with chronic idiopathic constipation have not been studied. Reduced Renal Function: No change in the pharmacokinetics of tegaserod was observed in subjects with severe renal impairment requiring hemodialysis (creatinine clearance<15 mL/min/1.73 m). Cand AUC of the main pharmacologically inactive metabolite of tegaserod, 5-methoxy-indole-3-carboxylic acid glucuronide, increased 2- and 10-fold respectively, in subjects with severe renal impairment compared to healthy controls. No dosage adjustment is required in patients with mild-to-moderate renal impairment. Tegaserod is not recommended in patients with severe renal impairment. Reduced Hepatic Function: In subjects with mild hepatic impairment, mean AUC was 31% higher and C16% higher compared to subjects with normal hepatic function. No dosage adjustment is required in patients with mild impairment, however, caution is recommended when using tegaserod in this patient population. Tegaserod has not adequately been studied in patients with moderate and severe hepatic impairment, and is therefore not recommended in these patients. Gender: Gender has no effect on the pharmacokinetics of tegaserod. Race: Data were inadequate to assess the effect of race on the pharmacokinetics of tegaserod. Age: In a clinical pharmacology study conducted to assess the pharmacokinetics of tegaserod administered to healthy young (18-40 years) and healthy elderly (65-85 years) subjects, peak plasma concentration and exposure were 22% and 40% greater, respectively, in elderly females than young females but still within the variability seen in tegaserod pharmacokinetics in healthy subjects. Based on an analysis across several pharmacokinetic studies in healthy subjects, there is no age effect on the pharmacokinetics of tegaserod when allowing for body weight as a covariate. Therefore, dose adjustment in elderly patients who have IBS with constipation is not necessary.
|
| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
Zelnorm (tegaserod maleate) is contraindicated in those patients with:
|
| dailymed-instance:supply |
Zelnorm (tegaserod maleate) is available as whitish to slightly yellowish, marbled, circular flat tablets with a bevelled edge containing 2 mg or 6 mg tegaserod as follows: 2-mg Tablet - white round engraved with���NVR���and���DL��� Unit Dose (blister pack) Box of 60 (strips of 10)���������������������������������������������������.NDC 0078-0355-80 6-mg Tablet - white round engraved with���NVR���and���EH��� Unit Dose (blister pack) Box of 60 (strips of 10)���������������������������������������������������NDC 0078-0356-80 Bottle of 60������������������������������������������������������������������������...NDC 0078-0426-20 Store at 25��C (77��F); excursions permitted to 15-30��C (59-86��F). See USP Controlled Room Temperature. Protect from moisture. T2004-53
|
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... | |
| dailymed-instance:precautio... |
General: Zelnorm (tegaserod maleate) should be discontinued immediately in patients with new or sudden worsening of abdominal pain.<br/>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 should be discontinued immediately in patients who develop symptoms of ischemic colitis, such as rectal bleeding, bloody diarrheaor new or worsening abdominal pain. Patients experiencing these symptoms should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with Zelnorm should not be resumed in patients who develop findings consistent with ischemic colitis or other forms of intestinal ischemia.<br/>Information for Patients: Patients should take Zelnorm before a meal. Patients should stop Zelnorm treatment and consult their physician if they experience new or worsening abdominal pain with or without rectal bleeding. Patients should also be aware of the possible occurrence of diarrhea during therapy. Diarrhea can be a pharmacologic response to Zelnorm. The majority of the Zelnorm patients reporting diarrhea had a single episode. In most cases, diarrhea occurred within the first week of treatment. Typically, diarrhea resolved with continued therapy. Patients should consult their physician if they experience severe diarrhea, or if the diarrhea is accompanied by severe cramping, abdominal pain, or dizziness. Patients should not initiate therapy with Zelnorm if they are currently experiencing or frequently experience diarrhea. (See ADVERSEREACTIONS.)<br/>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.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: 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) 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). 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) or 60 mg/kg/day (approximately 3 to 4 times the human exposure at 6 mg b.i.d. based on plasma AUC). 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) in male rats and 150 mg/kg/day (approximately 42 times the human exposure at 6 mg b.i.d. based on plasma AUC) in female rats was found to have no effect on fertility and reproductive performance.<br/>Pregnancy, Teratogenic Effects: Pregnancy Category B: 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) 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) 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.<br/>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.<br/>Pediatric Use: Zelnorm has not been studied in pediatric patients.<br/>Geriatric Use:<br/>IBS with Constipation: Of 4,035 patients in Phase 3 clinical studies of Zelnorm, 290 were at least 65 years of age, while 52 were at least 75 years old. No overall differences in safety were observed between these patients and younger patients with regard to adverse events. No dose adjustment is necessary when administering Zelnorm to patients with IBS with constipation over 65 years old. (See CLINICAL PHARMACOLOGY.)<br/>Chronic Idiopathic Constipation: Of 2,612 patients in Phase 3 clinical studies of Zelnorm, 331 were at least 65 years of age. Efficacy in patients 65 years of age or greater showed no significant difference between drug and placebo responses. Patients 65 years of age or greater who received Zelnorm experienced a higher incidence of diarrhea and discontinuations due to diarrhea than patients younger than 65.
|
| dailymed-instance:overdosag... |
There have been no reports of human overdosage with Zelnorm (tegaserod maleate). Single oral doses of 120 mg of tegaserod were administered to 3 healthy volunteers in 1 study. All 3 subjects developed diarrhea and headache. Two of these subjects also reported intermittent abdominal pain, and 1 developed orthostatic hypotension. In 28 healthy subjects exposed to doses of tegaserod of 90 to 180 mg/d for several days, adverse events were diarrhea (100%), headache (57%), abdominal pain (18%), flatulence (18%), nausea (7%) and vomiting (7%). Based on the large distribution volume and high protein binding of tegaserod it is unlikely that tegaserod could be removed by dialysis. In cases of overdosage treat symptomatically and institute supportive measures as appropriate.
|
| dailymed-instance:genericMe... |
tegaserod maleate
|
| dailymed-instance:fullName |
Zelnorm (Tablet)
|
| dailymed-instance:adverseRe... |
IBS with Constipation: In 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 and occurred more frequently on Zelnorm than placebo:<br/>Chronic Idiopathic Constipation: In Phase 3 clinical trials 2,603 male and female patients received Zelnorm 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 and occurred more frequently than in patients who received placebo. Zelnorm was not associated with changes in ECG intervals.<br/>Zelnorm-Induced Diarrhea:<br/>IBS with Constipation: In the Phase 3 clinical studies, 8.8% of patients receiving Zelnorm reported diarrhea as an adverse experience compared to 3.8% of patients receiving placebo. The majority of the Zelnorm 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-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.<br/>Chronic Idiopathic Constipation: In the two Phase 3 studies, 6.6% of patients treated with Zelnorm 6 mg b.i.d. and 4.2% of patients treated with Zelnorm 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 6 mg b.i.d. discontinued the study due to diarrhea (compared to 0.3% in the Zelnorm 2 mg b.i.d. group and 0.2% in the placebo group).<br/>Abdominal Surgeries, Including Cholecystectomy: An increase in abdominal surgeries was observed on Zelnorm (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 (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 vs. placebo groups: 9/1,752; 0.5% on Zelnorm versus 8/861; 0.9% on placebo. A causal relationship between abdominal surgeries and Zelnorm has not been established.<br/>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 than placebo; or which were considered by the investigator to be possibly related to Zelnorm and reported more frequently (>0.1%) on Zelnorm than placebo; or which lead to discontinuation more frequently (���0.1% and in more than 1 patient) on Zelnorm 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 which were either considered by the investigator as possibly drug related, or occurred in at least 2 more patients on Zelnorm than on placebo. Although the events reportedoccurred during treatment with Zelnorm, 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<br/>Post-Marketing Experience: Voluntary reports of adverse events occurring with the use of Zelnorm include the following: ischemic colitis (see PRECAUTIONS), mesenteric ischemia, gangrenous bowel, rectal bleeding, syncope, hypotension, hypovolemia, electrolyte disorders, suspected sphincter of Oddi spasm, bile duct stone, cholecystitis with elevated transaminases, and hypersensitivity reaction including rash, urticaria, pruritus and serious allergic Type I reactions. Because these cases are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. No causal relationship between these events and Zelnorm use has been established. Post-marketing reports of diarrhea, which can be a pharmacologic response to Zelnorm, have also been received.
|
| dailymed-instance:warning |
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 should be discontinued immediately in patients who develop severe diarrhea, hypotension or syncope. Zelnorm should notbe initiated in patients who are currently experiencing or frequently experience diarrhea (see ADVERSE REACTIONS).
|
| dailymed-instance:indicatio... |
IBS with Constipation: Zelnorm (tegaserod maleate) is indicated for the short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation. The safety and effectiveness of Zelnorm in men with IBS with constipation have not been established.<br/>Chronic Idiopathic Constipation: Zelnorm (tegaserod maleate) is indicated for the treatment of patients less than 65 years of age with chronic idiopathic constipation. The effectiveness of Zelnorm in patients 65 years or older with chronic idiopathic constipation has not been established (see Geriatric Use). The efficacy of Zelnorm for the treatment of IBS with constipation or chronic idiopathic constipation has not been studied beyond 12 weeks.
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Zelnorm
|