ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in more detail elsewhere in the labeling:Cardiovascular Ischemic Events, including MACE [see Warnings and Precautions 5.1 )] Ischemic Colitis [see Warnings and Precautions 5.2 )] Volume Depletion Associated with Diarrhea [see Warnings and Precautions 5.3 )] Suicidal Ideation and Behavior [see Warnings and Precautions 5.4 )] Cardiovascular Ischemic Events, including MACE [see Warnings and Precautions 5.1 )] Ischemic Colitis [see Warnings and Precautions 5.2 )] Volume Depletion Associated with Diarrhea [see Warnings and Precautions 5.3 )] Suicidal Ideation and Behavior [see Warnings and Precautions 5.4 )] Most common adverse reactions (>2%) are headache, abdominal pain, nausea, diarrhea, flatulence, dyspepsia, and dizziness. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Alfasigma USA at 1-855-697-9232 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Common Adverse ReactionsIn three clinical trials 2,343 female patients less than 65 years of age with IBS-C received ZELNORM mg twice daily or placebo. The majority of patients were Caucasian. Table provides the incidence of common adverse reactions reported in >2% of IBS-C patients in the ZELNORM treatment group and at an incidence that was greater than in the placebo group.Table 1. Most Common Adverse Reactionsa in Three Placebo-Controlled Trials of ZELNORM in Female IBS-C Patients Less than 65 Years of AgeAdverse ReactionsZELNORM6 mg twice daily[N 1,184]%Placebo [N 1,159]%Headache1410Abdominal Painb 1110Nausea87Diarrhea83Flatulence65Dyspepsia43Dizziness43a Reported in >2% of ZELNORM-treated patients and at an incidence greater than placebo Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort, abdominal tenderness, epigastric pain or discomfortDiarrheaThe majority (84%) of the ZELNORM patients reporting diarrhea had single episode. In most cases, diarrhea occurred within the first week of treatment. Typically, diarrhea resolved with continued therapy. Diarrhea resulted in discontinuation in 1.6% of ZELNORM-treated patients compared to 0% in placebo [see Warnings and Precautions 5.3 )].Less Common Adverse ReactionsThe following is list of less common adverse reactions reported in <= 2% of patients in clinical trials of IBS-C on ZELNORM but more frequently than placebo:Blood and Lymphatic System Disorders: AnemiaEar and Labyrinth Disorders: VertigoGastrointestinal Disorders: Rectal hemorrhage General Disorders and Administration Site Conditions: AstheniaInvestigations: Increased blood creatine phosphokinase Metabolism and Nutrition Disorders: Increased appetiteMusculoskeletal and Connective Tissue Disorders: Arthropathy, tendonitis Nervous System Disorders: MigraineAdverse Reactions of Special InterestZELNORM is recommended for use in female patients with IBS-C, and is not recommended for other motility disorders [see Indications and Dosage 1 )].Major Adverse Cardiovascular Events (MACE)A retrospective analysis of the pooled clinical trial database data (involving 18,645 patients, both male and female) of 29 placebo-controlled trials of IBS-C and other gastrointestinal motility disorders of at least four weeks duration was conducted. An external adjudication of the reported cardiovascular ischemic (CVI) events identified an imbalance in patients taking ZELNORM (13 events, 0.1%) compared to placebo (1 event, 0.01%). second external adjudication was conducted with additional patient-level information, and used comprehensive pre-specified methodology regarding both case selection and assessment. This adjudication confirmed seven CVI events (0.06%) on ZELNORM compared to one event (0.01%) on placebo. An imbalance in MACE events (defined as cardiovascular death, non-fatal MI, non-fatal stroke) was observed in patients taking ZELNORM compared to placebo, as reported in both external adjudications. All events occurred in male and female patients with history of cardiovascular ischemic disease and/or more than one cardiovascular risk factor.A summary of the event rates from both adjudications is provided in Table 2. The rate of MACE events for ZELNORM-treated patients ranged from 0.03% to 0.06% in the overall population and 0.01% to 0.03% in the female population less than 65 years of age without history of cardiovascular ischemic disease compared to zero in the placebo-treated group.Table 2. Number of MACE Events Confirmed in Two External Adjudications of the Clinical Trial DatabaseAll Patients(Male and Female) Females 65 Years of Age Without History of Cardiovascular Ischemic Diseasea Without History of Cardiovascular Ischemic Diseasea andOne or Fewer Cardiovascular Risk Factorsb ZELNORM (N=11,614) Placebo (N=7,031) ZELNORM (N=9,547) Placebo (N=5,748) ZELNORM (N=7,785) Placebo (N=4,686) (%)n (%)n (%)n (%)n (%) (%) First ExternalAdjudication7c 3e 0 0.06%0.03%SecondExternalAdjudication4d 01f 0 0.03%0.01%a Defined as prior MI, stroke, transient ischemic attack, angina, etc. Defined as active smoking, current hypertension/history of antihypertensive treatment, current hyperlipidemia/history of lipid lowering medication, history of diabetes mellitus, age >=55 years, or obesity (BMI >30 kg/m2) Five females less than 65 years, one male less than 65 years and one male greater than 65 years of age Three females less than 65 years of age and one male greater than 65 years of age Cardiovascular death, MI and stroke; all three patients had one cardiovascular risk factor at baseline Cardiovascular death (one of the three cases confirmed in the 1st external adjudication)Suicidal Ideation/BehaviorTwo ZELNORM-treated patients committed suicide, one in controlled study of IBS-C and one during open label treatment for another motility disorder. In 27 placebo-controlled trials, assessing tegaserod at total daily dose of mg to 50 mg (up to four times the recommended daily dose), or placebo for the treatment of IBS-C or other gastrointestinal motility disorders, the frequency of suicidal ideation/behavior with tegaserod treatment (8 events/10,003, or 0.08%) was higher than placebo (1 event/5,425, or 0.02%). Events on ZELNORM included one completed suicide, two suicide attempts, four cases of self-injurious behavior, and one case of suicidal ideation. There was one suicide attempt on placebo. Of the eight ZELNORM-treated patients who experienced an event, all were less than 65 years of age, seven were female and three had IBS-C. The patient who committed suicide was female, less than 65 years of age with IBS-C, taking ZELNORM mg twice daily. Abdominal Surgeries, Including CholecystectomyAn increase in abdominal surgeries was observed on ZELNORM (9 patients out of 2,965 or 0.3%) versus placebo (3 patients out of 1,740 or 0.2%) in clinical trials of men and women treated with ZELNORM for IBS-C. The increase was primarily due to numerical imbalance in cholecystectomies reported in patients treated with ZELNORM (5 patients out of 2,965 or 0.17%) versus placebo (1 patient out of 1,740 or 0.06%). causal relationship between abdominal surgeries and ZELNORM has not been established.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of ZELNORM. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Ischemic colitis, mesenteric ischemia, gangrenous bowel and rectal bleeding [see Warnings and Precautions 5.2 )] Severe diarrhea resulting in syncope, hypotension, hypovolemia, electrolyte disorders [see Warnings and Precautions 5.3 )] Sphincter of Oddi spasm, bile duct stone, cholecystitis with elevated transaminases, elevation in ALT, AST and bilirubin, hepatitis [see Contraindications 4 )] Alopecia Hypersensitivity reactions, including anaphylaxis [see Contraindications 4 )] Ischemic colitis, mesenteric ischemia, gangrenous bowel and rectal bleeding [see Warnings and Precautions 5.2 )] Severe diarrhea resulting in syncope, hypotension, hypovolemia, electrolyte disorders [see Warnings and Precautions 5.3 )] Sphincter of Oddi spasm, bile duct stone, cholecystitis with elevated transaminases, elevation in ALT, AST and bilirubin, hepatitis [see Contraindications 4 )] Alopecia Hypersensitivity reactions, including anaphylaxis [see Contraindications 4 )].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Inhibition of the hERG (human Ether-a-go-go-Related Gene) channel was evident only in the micromolar concentration range with an IC50 of 13 micromolar (approximately 1300 times the Cmax in humans at the recommended dose). In in vitro studies, tegaserod had no effects on impulse conduction in isolated guinea pig papillary muscle at up to 100 times the Cmax in humans, Langendorff-perfused isolated rabbit heart (QT interval) at up to 1000 times the Cmax in humans, or human atrial myocytes at multiples up to 10 times the Cmax in humans. The major metabolite, M29, had no effect on QT in the Langendorff-perfused isolated rabbit heart at multiples up to 323 times the Cmax in humans.In anesthetized and conscious dogs, tegaserod at doses up to 92 to 134 times the recommended dose based on Cmax did not alter heart rate, QRS interval duration, QTc or other ECG parameters. In chronic toxicology studies in rats and dogs, there were no treatment-related changes in cardiac morphology after tegaserod administration at doses up to 660 times the recommended dose based on AUC.Although tegaserod is expected to bind to HT2B receptors in humans at the recommended dose, there does not appear to be any potential for heart valve injury based on functional evidence of HT2B receptor antagonism.Studies with isolated coronary and mesenteric blood vessels from non-human primates and humans showed no vasoconstrictor effect at concentrations approximately 100 times the human Cmax. Tegaserod exhibited antagonism of HT-mediated vasoconstriction via HT1B receptors. In rat thoracic aortic rings that were pre-constricted with phenylephrine or norepinephrine, tegaserod produced vasorelaxation, with IC50 values and 64 times the Cmax plasma concentrations in humans, respectively. No effects were observed in the basal tone of aortic rings at concentrations up to 1000 times the human Cmax.In studies with an anesthetized rat model for measuring macro- and micro-circulation of the colon, intraduodenal dosing with tegaserod (approximately times the recommended dose based on Cmax) produced no clinically relevant effect on blood pressure, heart rate, or vascular conductance.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tegaserod is an agonist of serotonin type-4 (5-HT4) receptors that stimulates the peristaltic reflex and intestinal secretion, inhibits visceral sensitivity, enhances basal motor activity, and normalizes impaired motility throughout the gastrointestinal tract. Based on in vitro binding affinity and functional assessment, at clinically relevant plasma concentrations, tegaserod is an antagonist at 5-HT2B receptors in humans. It is expected to have minimal binding to 5-HT1 receptors. Tegaserod has no affinity for 5-HT3 or dopamine receptors. The main metabolite, M29, has negligible affinity for 5-HT4 receptors in vitro.In vivo studies showed that tegaserod enhanced basal motor activity and normalized impaired motility throughout the gastrointestinal tract. In addition, studies demonstrated that tegaserod moderated visceral sensitivity during colorectal distension in animals.. 12.2 Pharmacodynamics Cardiac ElectrophysiologyCentrally analyzed ECGs were recorded in 4,605 male and female patients receiving ZELNORM 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 ZELNORM and 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 AggregationThere is 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 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 5% to 16% increase in platelet aggregation compared to vehicle control. The clinical implications of the in vitro platelet aggregation results are unclear.. 12.3 Pharmacokinetics The pharmacokinetics of tegaserod in IBS-C patients are comparable to those in healthy subjects. The mean (+-SD) peak tegaserod concentration (Cmax) was 2.9 (+-1.1) ng/mL, and mean (+-SD) AUC was 10.5 (+-4.6) hong/mL following single ZELNORM dose at mg. Tegaserod systemic exposure at steady state increase proportionally over dose range of mg to 12 mg twice daily (0.3 to times the approved recommended dosage). There was no significant accumulation (~10%) of tegaserod following the approved recommended dosage.AbsorptionThe absolute bioavailability of tegaserod is approximately 10% when administered to fasting subjects. The median time to peak tegaserod plasma concentration (Tmax) is approximately one hour (range 0.7 to hours).Effect of FoodCompared to under fasted conditions, the tegaserod AUC was reduced by 40% to 65%, Cmax was reduced by approximately 20% to 40% and median Tmax was 0.7 hours when ZELNORM was administered 30 minutes before high-fat, high-calorie meal (approximately 150 calories from protein, 250 calories from carbohydrates, and 500 calories from fat). Plasma concentrations were similar when ZELNORM was administered within 30 minutes prior to meal or 2.5 hours after meal [see Dosage and Administration (2)].DistributionProtein binding of tegaserod is approximately 98%. The mean volume of distribution of tegaserod (+- SD) at steady-state is 368 +- 223 following intravenous administration (ZELNORM is not approved for intravenous administration).EliminationThe mean tegaserod terminal elimination half-life ranged from 4.6 to 8.1 hours following oral administration and the mean (+- SD) plasma clearance was 77 +- 15 L/h following intravenous administration.MetabolismTegaserod is metabolized via hydrolysis and direct glucuronidation. Tegaserod undergoes hydrolysis in the stomach followed by oxidation and conjugation which produces the M29 metabolite.ExcretionApproximately two-thirds of ZELNORM dose is excreted unchanged in the feces, with the remaining one-third excreted in the urine as metabolites.Specific PopulationsPatients with Renal ImpairmentNo change in the pharmacokinetics of tegaserod was observed in subjects with end stage renal disease (creatinine clearance normalized by body surface area (CrCL) 15 mL/min/1.73 m2) requiring hemodialysis. Although renal impairment does not affect the pharmacokinetics of tegaserod, the pharmacokinetics of its main metabolite (M29) are altered, the Cmax of M29 doubling and the AUC increasing 10-fold in patients with severe renal impairment (CrCL 15 mL/min/1.73 m2) compared to healthy subjects with normal renal function (CrCL 80 mL/min/1.73 m2) [see Contraindications 4 ), Use in Specific Populations 8.6 )].Patients with Hepatic ImpairmentIn subjects with mild hepatic impairment (Child-Pugh A), the mean tegaserod AUC was 31% higher and the Cmax was 16% higher compared to healthy subjects with normal hepatic function. The increase in exposure in subjects with mild impairment is not considered to be clinically relevant.In single subject with moderate hepatic impairment, the Cmax and AUC were 140% and 200% of that observed in healthy controls. ZELNORM has not been studied in patients with moderate or severe hepatic impairment (Child-Pugh or C) [see Contraindications 4 ), Use in Specific Populations 8.7 )].Drug Interaction StudiesEffect of Other Drugs on TegaserodQuinidine: Coadministration of single dose of 600 mg quinidine (P-gp inhibitor) with single dose of ZELNORM mg increased the mean tegaserod AUC(0-12h) and the mean Cmax by 50% and 44%, respectively, compared to ZELNORM administered alone. Coadministration of multiple doses of quinidine (600 mg once daily for three days) with ZELNORM mg twice daily for six days increased the mean tegaserod AUC(0-12h) and Cmax by 71% and 63%, respectively, compared to ZELNORM administered alone.Inhibitors of P-gp (e.g., ritonavir, clarithromycin, itraconazole) may modestly increase the oral bioavailability of tegaserod. The clinical relevance of increased systemic exposure as result of P-gp inhibition is unclear.Omeprazole: Administration of omeprazole 20 mg once daily for four days followed by ZELNORM mg twice daily on day four increased the mean tegaserod AUC and Cmax by 15% and 17%, respectively, compared to ZELNORM administered alone. This increase in exposure is not considered clinically relevant.Effect of Tegaserod on Other DrugsNo clinically significant effects of tegaserod on the pharmacokinetics of the following drugs were observed when used concomitantly with single dose of ZELNORM mg: theophylline (CYP1A2 substrate), dextromethorphan (CYP2D6 substrate), digoxin (P-gp substrate), warfarin (CYP2C9 substrate), or oral contraceptives (ethynyl estradiol and levonorgestrel).Digoxin: Administration of single dose of digoxin following ZELNORM mg twice daily for days reduced the mean Cmax and AUC of digoxin by approximately 15%. This reduction in digoxin exposure is not considered clinically relevant. Warfarin: Coadministration of ZELNORM mg twice daily with warfarin for seven days did not significantly alter the pharmacokinetics of either R- or S-warfarin or change the prothrombin time in healthy subjects. Oral Contraceptives: Coadministration of ZELNORM mg twice daily with 0.3 mg of ethinyl estradiol and 0.125 mg of levonorgestrel once daily did not affect the steady-state (Day 21) pharmacokinetics of ethinyl estradiol but reduced both the Cmax and AUC of levonorgestrel by 8%. This change in exposure is not considered clinically relevant.In Vitro Studies Where the Drug Interaction Potential Was Not Further Evaluated ClinicallyCYP enzymesTegaserod does not inhibit CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A4, and it does not induce CYP3A4 and CYP2B6.Limited induction of CYP1A2 was observed at tegaserod concentrations in excess of 100 times the clinically relevant range.M29 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, and it does not induce CYP1A2, CYP2B6, or CYP3A4.TransportersTegaserod is substrate for BCRP and P-gp, but not substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K or BSEP. Drug transporter data indicated potential inhibition of MATE1, MATE2-K, and BCRP by tegaserod at high concentrations. However, at the clinical dose of ZELNORM, significant in vivo drug interaction via inhibition of these transporters is unlikely.M29 is substrate of BCRP, P-gp, OAT3 and BSEP transporters, but not substrate of OAT1, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, and MATE2-K. M29 does not inhibit the following transporters: OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, and BSEP.

CLINICAL STUDIES SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Common Adverse ReactionsIn three clinical trials 2,343 female patients less than 65 years of age with IBS-C received ZELNORM mg twice daily or placebo. The majority of patients were Caucasian. Table provides the incidence of common adverse reactions reported in >2% of IBS-C patients in the ZELNORM treatment group and at an incidence that was greater than in the placebo group.Table 1. Most Common Adverse Reactionsa in Three Placebo-Controlled Trials of ZELNORM in Female IBS-C Patients Less than 65 Years of AgeAdverse ReactionsZELNORM6 mg twice daily[N 1,184]%Placebo [N 1,159]%Headache1410Abdominal Painb 1110Nausea87Diarrhea83Flatulence65Dyspepsia43Dizziness43a Reported in >2% of ZELNORM-treated patients and at an incidence greater than placebo Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort, abdominal tenderness, epigastric pain or discomfortDiarrheaThe majority (84%) of the ZELNORM patients reporting diarrhea had single episode. In most cases, diarrhea occurred within the first week of treatment. Typically, diarrhea resolved with continued therapy. Diarrhea resulted in discontinuation in 1.6% of ZELNORM-treated patients compared to 0% in placebo [see Warnings and Precautions 5.3 )].Less Common Adverse ReactionsThe following is list of less common adverse reactions reported in <= 2% of patients in clinical trials of IBS-C on ZELNORM but more frequently than placebo:Blood and Lymphatic System Disorders: AnemiaEar and Labyrinth Disorders: VertigoGastrointestinal Disorders: Rectal hemorrhage General Disorders and Administration Site Conditions: AstheniaInvestigations: Increased blood creatine phosphokinase Metabolism and Nutrition Disorders: Increased appetiteMusculoskeletal and Connective Tissue Disorders: Arthropathy, tendonitis Nervous System Disorders: MigraineAdverse Reactions of Special InterestZELNORM is recommended for use in female patients with IBS-C, and is not recommended for other motility disorders [see Indications and Dosage 1 )].Major Adverse Cardiovascular Events (MACE)A retrospective analysis of the pooled clinical trial database data (involving 18,645 patients, both male and female) of 29 placebo-controlled trials of IBS-C and other gastrointestinal motility disorders of at least four weeks duration was conducted. An external adjudication of the reported cardiovascular ischemic (CVI) events identified an imbalance in patients taking ZELNORM (13 events, 0.1%) compared to placebo (1 event, 0.01%). second external adjudication was conducted with additional patient-level information, and used comprehensive pre-specified methodology regarding both case selection and assessment. This adjudication confirmed seven CVI events (0.06%) on ZELNORM compared to one event (0.01%) on placebo. An imbalance in MACE events (defined as cardiovascular death, non-fatal MI, non-fatal stroke) was observed in patients taking ZELNORM compared to placebo, as reported in both external adjudications. All events occurred in male and female patients with history of cardiovascular ischemic disease and/or more than one cardiovascular risk factor.A summary of the event rates from both adjudications is provided in Table 2. The rate of MACE events for ZELNORM-treated patients ranged from 0.03% to 0.06% in the overall population and 0.01% to 0.03% in the female population less than 65 years of age without history of cardiovascular ischemic disease compared to zero in the placebo-treated group.Table 2. Number of MACE Events Confirmed in Two External Adjudications of the Clinical Trial DatabaseAll Patients(Male and Female) Females 65 Years of Age Without History of Cardiovascular Ischemic Diseasea Without History of Cardiovascular Ischemic Diseasea andOne or Fewer Cardiovascular Risk Factorsb ZELNORM (N=11,614) Placebo (N=7,031) ZELNORM (N=9,547) Placebo (N=5,748) ZELNORM (N=7,785) Placebo (N=4,686) (%)n (%)n (%)n (%)n (%) (%) First ExternalAdjudication7c 3e 0 0.06%0.03%SecondExternalAdjudication4d 01f 0 0.03%0.01%a Defined as prior MI, stroke, transient ischemic attack, angina, etc. Defined as active smoking, current hypertension/history of antihypertensive treatment, current hyperlipidemia/history of lipid lowering medication, history of diabetes mellitus, age >=55 years, or obesity (BMI >30 kg/m2) Five females less than 65 years, one male less than 65 years and one male greater than 65 years of age Three females less than 65 years of age and one male greater than 65 years of age Cardiovascular death, MI and stroke; all three patients had one cardiovascular risk factor at baseline Cardiovascular death (one of the three cases confirmed in the 1st external adjudication)Suicidal Ideation/BehaviorTwo ZELNORM-treated patients committed suicide, one in controlled study of IBS-C and one during open label treatment for another motility disorder. In 27 placebo-controlled trials, assessing tegaserod at total daily dose of mg to 50 mg (up to four times the recommended daily dose), or placebo for the treatment of IBS-C or other gastrointestinal motility disorders, the frequency of suicidal ideation/behavior with tegaserod treatment (8 events/10,003, or 0.08%) was higher than placebo (1 event/5,425, or 0.02%). Events on ZELNORM included one completed suicide, two suicide attempts, four cases of self-injurious behavior, and one case of suicidal ideation. There was one suicide attempt on placebo. Of the eight ZELNORM-treated patients who experienced an event, all were less than 65 years of age, seven were female and three had IBS-C. The patient who committed suicide was female, less than 65 years of age with IBS-C, taking ZELNORM mg twice daily. Abdominal Surgeries, Including CholecystectomyAn increase in abdominal surgeries was observed on ZELNORM (9 patients out of 2,965 or 0.3%) versus placebo (3 patients out of 1,740 or 0.2%) in clinical trials of men and women treated with ZELNORM for IBS-C. The increase was primarily due to numerical imbalance in cholecystectomies reported in patients treated with ZELNORM (5 patients out of 2,965 or 0.17%) versus placebo (1 patient out of 1,740 or 0.06%). causal relationship between abdominal surgeries and ZELNORM has not been established.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. ZELNORM is contraindicated in patients with:A history of myocardial infarction (MI), stroke, transient ischemic attack (TIA), or angina [see Warnings and Precautions 5.1 )] history of ischemic colitis or other forms of intestinal ischemia [see Warnings and Precautions 5.2 )] Severe renal impairment (eGFR< 15 mL/min/1.73 m2) or end-stage renal disease [see Use in Specific Populations 8.6 )] Moderate and severe hepatic impairment (Child-Pugh or C) [see Use in Specific Populations 8.7 )] history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions [see Adverse Reactions 6.2 )] Hypersensitivity to tegaserod [see Adverse Reactions 6.2 )] A history of myocardial infarction (MI), stroke, transient ischemic attack (TIA), or angina [see Warnings and Precautions 5.1 )] A history of ischemic colitis or other forms of intestinal ischemia [see Warnings and Precautions 5.2 )] Severe renal impairment (eGFR< 15 mL/min/1.73 m2) or end-stage renal disease [see Use in Specific Populations 8.6 )] Moderate and severe hepatic impairment (Child-Pugh or C) [see Use in Specific Populations 8.7 )] A history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions [see Adverse Reactions 6.2 )] Hypersensitivity to tegaserod [see Adverse Reactions 6.2 )] ZELNORM is contraindicated in patients with:A history of myocardial infarction, stroke, transient ischemic attack, or angina. (4, 5.1) history of ischemic colitis or other forms of intestinal ischemia. (4, 5.2) Severe renal impairment (eGFR< 15 mL/min/1.73 m2) or end-stage renal disease. (4, 8.6) Moderate or severe hepatic impairment (Child-Pugh or C). (4, 8.7) history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions. (4) Hypersensitivity to tegaserod. (4). history of myocardial infarction, stroke, transient ischemic attack, or angina. (4, 5.1) A history of ischemic colitis or other forms of intestinal ischemia. (4, 5.2) Severe renal impairment (eGFR< 15 mL/min/1.73 m2) or end-stage renal disease. (4, 8.6) Moderate or severe hepatic impairment (Child-Pugh or C). (4, 8.7) A history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions. (4) Hypersensitivity to tegaserod. (4).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).Cardiovascular Ischemic Events, Including MACEInform patients that stroke, myocardial infarction, and cardiovascular death have been reported in adults taking ZELNORM who had an increased risk of developing an adverse cardiovascular event based on their medical history. Advise patients to promptly seek medical attention if they develop symptoms of an MI, stroke, TIA, or angina. Also, advise patients to immediately inform their healthcare provider if they develop clinical or other evidence of cardiovascular ischemic heart disease (e.g., coronary artery disease) or other changes in their health status that could increase cardiovascular risk (e.g., smoking, hypertension, hyperlipidemia, diabetes mellitus, obesity) while taking ZELNORM [see Warnings and Precautions 5.1 )].Ischemic ColitisAdvise patients to stop taking ZELNORM and seek medical attention if they develop symptoms of ischemic colitis, such as rectal bleeding, bloody diarrhea or new or worsening abdominal pain [see Warnings and Precautions 5.2 )].Volume Depletion Associated with DiarrheaInstruct patients to discontinue ZELNORM and contact their healthcare provider if they develop severe diarrhea, especially if they also experience symptoms of volume depletion (hypotension and/or syncope) [see Warnings and Precautions 5.3 )].Suicidal Ideation and BehaviorCounsel patients, their caregivers, and their families that ZELNORM may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Instruct patients, caregivers, and families that if any of these symptoms occur, they should immediately discontinue ZELNORM and report behaviors of concern to their healthcare provider [see Warnings and Precautions 5.4 )].LactationAdvise woman that breastfeeding is not recommended during treatment with ZELNORM [see Use in Specific Populations 8.2 )].Administration InformationAdvise patients to take ZELNORM at least 30 minutes before meal [see Dosage and Administration 2 )].Made in Germany Distributed by:Alfasigma USA, Inc.Covington, LA 70433 USA(C)2019. ZELNORM is trademark of Alfasigma, USA Inc. All rights reserved.PM-000413.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 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 recommended dose based on AUC) for 110 to 124 weeks.In mice, dietary administration of tegaserod for 104 weeks produced mucosal hyperplasia and adenocarcinoma of the small intestine at 600 mg/kg/day (approximately 83 to 110 times the recommended dose based on AUC). There was no evidence of carcinogenicity at lower doses (3 to 35 times the recommended dose based on AUC).Tegaserod was not genotoxic in the in vitro Chinese hamster lung fibroblast (CHL/V79) cell chromosomal aberration and forward mutation test, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) test or the in vivo mouse micronucleus test. The results of the Ames test for mutagenicity were equivocal.Tegaserod at oral (dietary) doses up to 240 mg/kg/day (approximately 57 times the recommended dose based on AUC) in male rats and 150 mg/kg/day (approximately 42 times the recommended dose based on AUC) in female rats was found to have no effect on fertility and reproductive performance.. 13.2 Animal Toxicology and/or Pharmacology. Inhibition of the hERG (human Ether-a-go-go-Related Gene) channel was evident only in the micromolar concentration range with an IC50 of 13 micromolar (approximately 1300 times the Cmax in humans at the recommended dose). In in vitro studies, tegaserod had no effects on impulse conduction in isolated guinea pig papillary muscle at up to 100 times the Cmax in humans, Langendorff-perfused isolated rabbit heart (QT interval) at up to 1000 times the Cmax in humans, or human atrial myocytes at multiples up to 10 times the Cmax in humans. The major metabolite, M29, had no effect on QT in the Langendorff-perfused isolated rabbit heart at multiples up to 323 times the Cmax in humans.In anesthetized and conscious dogs, tegaserod at doses up to 92 to 134 times the recommended dose based on Cmax did not alter heart rate, QRS interval duration, QTc or other ECG parameters. In chronic toxicology studies in rats and dogs, there were no treatment-related changes in cardiac morphology after tegaserod administration at doses up to 660 times the recommended dose based on AUC.Although tegaserod is expected to bind to HT2B receptors in humans at the recommended dose, there does not appear to be any potential for heart valve injury based on functional evidence of HT2B receptor antagonism.Studies with isolated coronary and mesenteric blood vessels from non-human primates and humans showed no vasoconstrictor effect at concentrations approximately 100 times the human Cmax. Tegaserod exhibited antagonism of HT-mediated vasoconstriction via HT1B receptors. In rat thoracic aortic rings that were pre-constricted with phenylephrine or norepinephrine, tegaserod produced vasorelaxation, with IC50 values and 64 times the Cmax plasma concentrations in humans, respectively. No effects were observed in the basal tone of aortic rings at concentrations up to 1000 times the human Cmax.In studies with an anesthetized rat model for measuring macro- and micro-circulation of the colon, intraduodenal dosing with tegaserod (approximately times the recommended dose based on Cmax) produced no clinically relevant effect on blood pressure, heart rate, or vascular conductance.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The pharmacokinetics of tegaserod in IBS-C patients are comparable to those in healthy subjects. The mean (+-SD) peak tegaserod concentration (Cmax) was 2.9 (+-1.1) ng/mL, and mean (+-SD) AUC was 10.5 (+-4.6) hong/mL following single ZELNORM dose at mg. Tegaserod systemic exposure at steady state increase proportionally over dose range of mg to 12 mg twice daily (0.3 to times the approved recommended dosage). There was no significant accumulation (~10%) of tegaserod following the approved recommended dosage.AbsorptionThe absolute bioavailability of tegaserod is approximately 10% when administered to fasting subjects. The median time to peak tegaserod plasma concentration (Tmax) is approximately one hour (range 0.7 to hours).Effect of FoodCompared to under fasted conditions, the tegaserod AUC was reduced by 40% to 65%, Cmax was reduced by approximately 20% to 40% and median Tmax was 0.7 hours when ZELNORM was administered 30 minutes before high-fat, high-calorie meal (approximately 150 calories from protein, 250 calories from carbohydrates, and 500 calories from fat). Plasma concentrations were similar when ZELNORM was administered within 30 minutes prior to meal or 2.5 hours after meal [see Dosage and Administration (2)].DistributionProtein binding of tegaserod is approximately 98%. The mean volume of distribution of tegaserod (+- SD) at steady-state is 368 +- 223 following intravenous administration (ZELNORM is not approved for intravenous administration).EliminationThe mean tegaserod terminal elimination half-life ranged from 4.6 to 8.1 hours following oral administration and the mean (+- SD) plasma clearance was 77 +- 15 L/h following intravenous administration.MetabolismTegaserod is metabolized via hydrolysis and direct glucuronidation. Tegaserod undergoes hydrolysis in the stomach followed by oxidation and conjugation which produces the M29 metabolite.ExcretionApproximately two-thirds of ZELNORM dose is excreted unchanged in the feces, with the remaining one-third excreted in the urine as metabolites.Specific PopulationsPatients with Renal ImpairmentNo change in the pharmacokinetics of tegaserod was observed in subjects with end stage renal disease (creatinine clearance normalized by body surface area (CrCL) 15 mL/min/1.73 m2) requiring hemodialysis. Although renal impairment does not affect the pharmacokinetics of tegaserod, the pharmacokinetics of its main metabolite (M29) are altered, the Cmax of M29 doubling and the AUC increasing 10-fold in patients with severe renal impairment (CrCL 15 mL/min/1.73 m2) compared to healthy subjects with normal renal function (CrCL 80 mL/min/1.73 m2) [see Contraindications 4 ), Use in Specific Populations 8.6 )].Patients with Hepatic ImpairmentIn subjects with mild hepatic impairment (Child-Pugh A), the mean tegaserod AUC was 31% higher and the Cmax was 16% higher compared to healthy subjects with normal hepatic function. The increase in exposure in subjects with mild impairment is not considered to be clinically relevant.In single subject with moderate hepatic impairment, the Cmax and AUC were 140% and 200% of that observed in healthy controls. ZELNORM has not been studied in patients with moderate or severe hepatic impairment (Child-Pugh or C) [see Contraindications 4 ), Use in Specific Populations 8.7 )].Drug Interaction StudiesEffect of Other Drugs on TegaserodQuinidine: Coadministration of single dose of 600 mg quinidine (P-gp inhibitor) with single dose of ZELNORM mg increased the mean tegaserod AUC(0-12h) and the mean Cmax by 50% and 44%, respectively, compared to ZELNORM administered alone. Coadministration of multiple doses of quinidine (600 mg once daily for three days) with ZELNORM mg twice daily for six days increased the mean tegaserod AUC(0-12h) and Cmax by 71% and 63%, respectively, compared to ZELNORM administered alone.Inhibitors of P-gp (e.g., ritonavir, clarithromycin, itraconazole) may modestly increase the oral bioavailability of tegaserod. The clinical relevance of increased systemic exposure as result of P-gp inhibition is unclear.Omeprazole: Administration of omeprazole 20 mg once daily for four days followed by ZELNORM mg twice daily on day four increased the mean tegaserod AUC and Cmax by 15% and 17%, respectively, compared to ZELNORM administered alone. This increase in exposure is not considered clinically relevant.Effect of Tegaserod on Other DrugsNo clinically significant effects of tegaserod on the pharmacokinetics of the following drugs were observed when used concomitantly with single dose of ZELNORM mg: theophylline (CYP1A2 substrate), dextromethorphan (CYP2D6 substrate), digoxin (P-gp substrate), warfarin (CYP2C9 substrate), or oral contraceptives (ethynyl estradiol and levonorgestrel).Digoxin: Administration of single dose of digoxin following ZELNORM mg twice daily for days reduced the mean Cmax and AUC of digoxin by approximately 15%. This reduction in digoxin exposure is not considered clinically relevant. Warfarin: Coadministration of ZELNORM mg twice daily with warfarin for seven days did not significantly alter the pharmacokinetics of either R- or S-warfarin or change the prothrombin time in healthy subjects. Oral Contraceptives: Coadministration of ZELNORM mg twice daily with 0.3 mg of ethinyl estradiol and 0.125 mg of levonorgestrel once daily did not affect the steady-state (Day 21) pharmacokinetics of ethinyl estradiol but reduced both the Cmax and AUC of levonorgestrel by 8%. This change in exposure is not considered clinically relevant.In Vitro Studies Where the Drug Interaction Potential Was Not Further Evaluated ClinicallyCYP enzymesTegaserod does not inhibit CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A4, and it does not induce CYP3A4 and CYP2B6.Limited induction of CYP1A2 was observed at tegaserod concentrations in excess of 100 times the clinically relevant range.M29 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, and it does not induce CYP1A2, CYP2B6, or CYP3A4.TransportersTegaserod is substrate for BCRP and P-gp, but not substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K or BSEP. Drug transporter data indicated potential inhibition of MATE1, MATE2-K, and BCRP by tegaserod at high concentrations. However, at the clinical dose of ZELNORM, significant in vivo drug interaction via inhibition of these transporters is unlikely.M29 is substrate of BCRP, P-gp, OAT3 and BSEP transporters, but not substrate of OAT1, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, and MATE2-K. M29 does not inhibit the following transporters: OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, and BSEP.

SPL MEDGUIDE SECTION.

Medication GuideZELNORMa (ZEL-norm)(tegaserod) tablets, for oral useWhat is the most important information should know about ZELNORMZELNORM can cause serious side effects, including:Major heart (cardiovascular) events. Major cardiovascular events such as stroke, heart attack, and death from stroke or heart attack have happened in adults taking ZELNORM who had an increased risk of having cardiovascular event.Risk factors that increase your risk of major cardiovascular event include:currently smoke high blood pressure or your blood pressure is controlled with medicine that lowers your blood pressurehigh blood cholesterol levels or your blood cholesterol levels are controlled with medicine that lowers your blood cholesterol levels have or have had diabetes mellitus age 55 years or older obesityTalk to your healthcare provider about risk factors you may have for major cardiovascular event before you start taking ZELNORM.Get emergency medical help right away if you have signs or symptoms of heart attack, stroke, mini stroke (transient ischemic attack or TIA) or angina (chest pain that happens because your heart is not getting enough oxygen), including:o chest pain that may spread to the arms, neck, jaw, back, or stomach area (abdomen)o feeling sweatyo shortness of breatho feeling sick or vomitingo sudden numbness or weakness, especially on one side of the bodyo severe headache or confusiono problems with vision, speech, or balanceTell your healthcare provider right away if you are told that you have narrowing in the blood vessels that carry blood to your heart (coronary artery disease).Inflammation and injury of the intestines caused by reduced blood flow to the intestines (ischemic colitis). Ischemic colitis and other problems of the intestines caused by reduced blood flow to the intestines, that sometimes required hospitalization, have happened in some people taking ZELNORM. Stop taking ZELNORM and call your healthcare provider or get medical help if you have symptoms of ischemic colitis such as bleeding from your rectum, bloody diarrhea, or new or worsening stomach-area (abdominal) pain. Loss of body fluids caused by diarrhea. Diarrhea is common side effect of ZELNORM, and it can sometimes be severe. Severe diarrhea can result in the loss of too much fluid from your body, low blood pressure, and fainting (loss of consciousness). Some people who had severe diarrhea during treatment with ZELNORM were hospitalized due to loss of too much body fluid. Stop taking ZELNORM and call your healthcare provider right away if you have severe diarrhea, especially if you also feel lightheaded, dizzy, or you faint. Suicidal thoughts and behavior. ZELNORM may increase the risk of suicidal thoughts and behavior. You, your caregiver, and your family should monitor you for changes in behavior. If you have any new or worsening symptoms of depression, unusual changes in mood or behavior, begin to have suicidal thoughts or behavior, or thoughts of self-harm, stop taking ZELNORM right away and tell your healthcare provider. What is ZELNORMZELNORM is prescription medicine used for the treatment of adult women less than 65 years of age who have irritable bowel syndrome with constipation (IBS-C).It is not known if ZELNORM is safe and effective in men with IBS-C.It is not known if ZELNORM is safe and effective in children.Do not take ZELNORM if you:have had heart attack, stroke, transient ischemic attack or TIA, or angina. have had inflammation and injury of the intestines caused by reduced blood flow to the intestines (ischemic colitis). have severe kidney problems or end-stage kidney disease. have moderate or severe liver problems. have had an intestinal blockage (bowel obstruction), gallbladder problems that caused symptoms, or scar tissue that formed between the tissues of the abdomen and other organs in the abdomen. have or may have had problem with the muscular valve that controls the flow of digestive juices (bile and pancreatic juice) to the first part of your intestine (sphincter of Oddi). are allergic to tegaserod.Before taking ZELNORM, tell your healthcare provider about all of your medical conditions, including if you:currently smoke. have or have had high blood pressure or are taking medicine to lower your blood pressure. have or have had high blood cholesterol levels or are taking medicine to lower your blood cholesterol levels. have or have had diabetes. are having diarrhea or have diarrhea often. are pregnant or plan to become pregnant. It is not known if ZELNORM will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if ZELNORM passes into your breast milk. You should not breastfeed if you take ZELNORM. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should take ZELNORMTake ZELNORM exactly as your healthcare provider tells you to take it. The usual dose of ZELNORM is tablet times each day, taken by mouth. Take ZELNORM at least 30 minutes before meal. If you take too much ZELNORM, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of ZELNORMZELNORM can cause serious side effects, including:See What is the most important information should know about ZELNORM The most common side effects of ZELNORM are:o headacheo stomach-area (abdominal) paino nauseao gaso indigestiono dizzinessThese are not all the possible side effects of ZELNORM. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store ZELNORMStore ZELNORM at room temperature between 68F to 77F (20C to 25C). Protect ZELNORM from moisture.Keep ZELNORM and all medicines out of the reach of children.General information about the safe and effective use of ZELNORM.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use ZELNORM for condition for which it was not prescribed. Do not give ZELNORM to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about ZELNORM that is written for health professionals.What are the ingredients in ZELNORMActive ingredient: tegaserod Inactive Ingredients: colloidal silicon dioxide, crospovidone, glyceryl behenate, hypromellose, and lactose monohydrate Distributed by: Alfasigma USA, Inc., Covington, LA 70433 USA(C)2019. ZELNORM is trademark of Alfasigma, USA Inc. All rights reserved.For more information, call 1-855-697-9232.This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: July 2019PM-000413. Major heart (cardiovascular) events. Major cardiovascular events such as stroke, heart attack, and death from stroke or heart attack have happened in adults taking ZELNORM who had an increased risk of having cardiovascular event.. currently smoke high blood pressure or your blood pressure is controlled with medicine that lowers your blood pressurehigh blood cholesterol levels or your blood cholesterol levels are controlled with medicine that lowers your blood cholesterol levels have or have had diabetes mellitus age 55 years or older obesity. Inflammation and injury of the intestines caused by reduced blood flow to the intestines (ischemic colitis). Ischemic colitis and other problems of the intestines caused by reduced blood flow to the intestines, that sometimes required hospitalization, have happened in some people taking ZELNORM. Stop taking ZELNORM and call your healthcare provider or get medical help if you have symptoms of ischemic colitis such as bleeding from your rectum, bloody diarrhea, or new or worsening stomach-area (abdominal) pain. Loss of body fluids caused by diarrhea. Diarrhea is common side effect of ZELNORM, and it can sometimes be severe. Severe diarrhea can result in the loss of too much fluid from your body, low blood pressure, and fainting (loss of consciousness). Some people who had severe diarrhea during treatment with ZELNORM were hospitalized due to loss of too much body fluid. Stop taking ZELNORM and call your healthcare provider right away if you have severe diarrhea, especially if you also feel lightheaded, dizzy, or you faint. Suicidal thoughts and behavior. ZELNORM may increase the risk of suicidal thoughts and behavior. You, your caregiver, and your family should monitor you for changes in behavior. If you have any new or worsening symptoms of depression, unusual changes in mood or behavior, begin to have suicidal thoughts or behavior, or thoughts of self-harm, stop taking ZELNORM right away and tell your healthcare provider. have had heart attack, stroke, transient ischemic attack or TIA, or angina. have had inflammation and injury of the intestines caused by reduced blood flow to the intestines (ischemic colitis). have severe kidney problems or end-stage kidney disease. have moderate or severe liver problems. have had an intestinal blockage (bowel obstruction), gallbladder problems that caused symptoms, or scar tissue that formed between the tissues of the abdomen and other organs in the abdomen. have or may have had problem with the muscular valve that controls the flow of digestive juices (bile and pancreatic juice) to the first part of your intestine (sphincter of Oddi). are allergic to tegaserod.. currently smoke. have or have had high blood pressure or are taking medicine to lower your blood pressure. have or have had high blood cholesterol levels or are taking medicine to lower your blood cholesterol levels. have or have had diabetes. are having diarrhea or have diarrhea often. are pregnant or plan to become pregnant. It is not known if ZELNORM will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if ZELNORM passes into your breast milk. You should not breastfeed if you take ZELNORM. Take ZELNORM exactly as your healthcare provider tells you to take it. The usual dose of ZELNORM is tablet times each day, taken by mouth. Take ZELNORM at least 30 minutes before meal. If you take too much ZELNORM, call your healthcare provider or go to the nearest hospital emergency room right away.. See What is the most important information should know about ZELNORM Store ZELNORM at room temperature between 68F to 77F (20C to 25C). Protect ZELNORM from moisture.. Alfasigma.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding not recommended. (8.2). 8.1 Pregnancy Risk SummaryAvailable data from case reports with ZELNORM use in pregnant women have not identified 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 (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.Data Animal DataNo adverse developmental effects were observed with oral administration of tegaserod to pregnant rats at doses up to 100 mg/kg/day (approximately 15 times the recommended dose based on area under the plasma concentration-time curve [AUC]) or to pregnant rabbits at doses up to 120 mg/kg/day (approximately 51 times the recommended dose based on AUC) during organogenesis.A pre- and postnatal developmental toxicity study was performed in rats using dietary administration of up to 300 mg/kg/day (71 times the recommended dose based on AUC) during organogenesis and through lactation. The survival rate through postnatal days and 21 was 59% at 300 mg/kg/day as compared to 95% to 99% in the control group. At doses of 150 mg/kg/day and higher (45 times the recommended dose based on AUC), decreased body weight and delays in developmental landmarks were observed. No adverse effects were observed at 75 mg/kg/day (14 times the recommended dose based on AUC). 8.2 Lactation Risk SummaryThere 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 (see Data). When 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 [see Nonclinical Toxicology 13.1 )], advise lactating woman that breastfeeding is not recommended during treatment with ZELNORM.DataFollowing oral administration, tegaserod and its metabolites are excreted in the milk of lactating rats with milk to plasma concentration ratio of 33:1 at eight hours.. 8.4 Pediatric Use Safety and effectiveness of ZELNORM in pediatric patients have not been established.. 8.5 Geriatric Use ZELNORM is not indicated in patients 65 years of age and older.. 8.6 Renal Impairment. ZELNORM is contraindicated in patients with severe renal impairment (eGFR 15 mL/min/1.73 m2) or end stage renal disease [see Contraindications 4 )]. The Cmax and AUC of the tegaserod metabolite, 5-methoxyindole-3-carboxylic acid glucuronide (M29), are substantially increased in severe renal impairment [see Clinical Pharmacology 12.3 )].No dosage adjustment is recommended in patients with mild to moderate renal impairment (eGFR >= 30 mL/min/1.73 m2).. 8.7 Hepatic Impairment. ZELNORM is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh or C) [see Contraindications 4 )].No dosage adjustment is necessary in patients with mild hepatic impairment [see Clinical Pharmacology 12.3 )].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Cardiovascular Ischemic Events, Including Major Adverse Cardiovascular Events (MACE): The potential risks of treatment must be balanced with expectations in improvements in symptoms of IBS-C. Discontinue ZELNORM treatment in patients who experience myocardial infarction, stroke, transient ischemic attack or angina. (4) Evaluate the risks and benefits of continued treatment in patients who develop clinical or other evidence of cardiovascular ischemic heart disease and/or experience changes in health status that could increase cardiovascular risk during treatment. (4, 5.1) Ischemic Colitis: Monitor for rectal bleeding, bloody diarrhea, and new or worsening abdominal pain and discontinue ZELNORM if symptoms develop. (5.2) Volume Depletion Associated with Diarrhea: Avoid use in patients with severe diarrhea. Instruct patients to discontinue ZELNORM and contact their healthcare provider if severe diarrhea, hypotension or syncope occur. (5.3) Suicidal Ideation and Behavior: Monitor patients for clinical worsening of depression and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment. Instruct patients to immediately discontinue ZELNORM and contact their healthcare provider if their depression is persistently worse or they are experiencing emergent suicidal thoughts or behaviors. (5.4). Cardiovascular Ischemic Events, Including Major Adverse Cardiovascular Events (MACE): The potential risks of treatment must be balanced with expectations in improvements in symptoms of IBS-C. Discontinue ZELNORM treatment in patients who experience myocardial infarction, stroke, transient ischemic attack or angina. (4) Evaluate the risks and benefits of continued treatment in patients who develop clinical or other evidence of cardiovascular ischemic heart disease and/or experience changes in health status that could increase cardiovascular risk during treatment. (4, 5.1) Ischemic Colitis: Monitor for rectal bleeding, bloody diarrhea, and new or worsening abdominal pain and discontinue ZELNORM if symptoms develop. (5.2) Volume Depletion Associated with Diarrhea: Avoid use in patients with severe diarrhea. Instruct patients to discontinue ZELNORM and contact their healthcare provider if severe diarrhea, hypotension or syncope occur. (5.3) Suicidal Ideation and Behavior: Monitor patients for clinical worsening of depression and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment. Instruct patients to immediately discontinue ZELNORM and contact their healthcare provider if their depression is persistently worse or they are experiencing emergent suicidal thoughts or behaviors. (5.4). 5.1 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 ZELNORM who had an increased risk of developing an adverse cardiovascular event based on their medical history [see Adverse Reactions 6.1 )].ZELNORM is contraindicated in patients with history of MI, stroke, TIA, or angina [see Contraindications 4 )]. Assess female patients less than 65 years of age for history of cardiovascular disease and cardiovascular risk factors prior to treatment with ZELNORM [see Adverse Reactions 6.1 )]. The potential risks of treatment must be balanced with expectations in improvements in symptoms of IBS-C.Discontinue ZELNORM in patients who experience an MI, stroke, TIA, or angina [see Contraindications 4 )]. Evaluate the risks and benefits of continued use of ZELNORM 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 ZELNORM.. 5.2 Ischemic Colitis. Ischemic colitis and other forms of intestinal ischemia have been reported postmarketing in patients receiving ZELNORM [see Adverse Reactions 6.2 )]. In some cases, hospitalization was required. Discontinue ZELNORM 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 ZELNORM in patients who develop findings consistent with ischemic colitis or other forms of intestinal ischemia [see Contraindications 4 )].. 5.3 Volume Depletion Associated with Diarrhea. Diarrhea is one of the most common adverse reactions in ZELNORM-treated patients from the pooled IBS-C double-blind, placebo-controlled trials. Diarrhea resulted in discontinuation in 1.6% of ZELNORM-treated patients compared to 0% in placebo [see Adverse Reactions 6 )].In postmarketing experience, serious consequences of diarrhea including hypovolemia, hypotension, and syncope have been reported in patients treated with ZELNORM. In some cases, these complications have required hospitalization for rehydration. Avoid use of ZELNORM in patients who are currently experiencing or frequently experience diarrhea. Instruct patients to discontinue ZELNORM and contact their healthcare provider if severe diarrhea, hypotension, or syncope occur. 5.4 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) [see Adverse Reactions 6.1 )]. Suicidal ideation/behavior in clinical trials was proportionately more frequent among patients receiving antidepressant medication.Monitor all ZELNORM-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 ZELNORM and contact their healthcare provider if their depression is persistently worse or they are experiencing emergent suicidal thoughts or behaviors.