Tegaserod

Risk Summary

Available data from case reports with tegaserod use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, decreased survival of rat pups was observed with maternal dietary administration of tegaserod at 71 times the recommended dose during organogenesis and through lactation. Decreased body weight and delays in developmental landmarks in rat pups were observed with maternal dietary administration of 45 times the recommended dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

No 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 4 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).

Risk Summary

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

Data

Following oral administration, tegaserod and its metabolites are excreted in the milk of lactating rats with a milk to plasma concentration ratio of 33:1 at eight hours.

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.

• Cardiovascular Ischemic Events, including MACE
• Ischemic Colitis
• Volume Depletion Associated with Diarrhea
• Suicidal Ideation and Behavior

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 Reactions

In three clinical trials 2,343 female patients less than 65 years of age with IBS-C received tegaserod 6 mg twice daily or placebo. The majority of patients were Caucasian. Table 1 provides the incidence of common adverse reactions reported in >2% of IBS-C patients in the tegaserod 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 Tegaserod in Female IBS-C Patients Less than 65 Years of Age:

^a Reported in >2% of tegaserod-treated patients and at an incidence greater than placebo
^b Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort, abdominal tenderness, epigastric pain or discomfort

Diarrhea

The majority (84%) of the tegaserod patients reporting diarrhea had a 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 tegaserod-treated patients compared to 0% in placebo.

Less Common Adverse Reactions

The following is a list of less common adverse reactions reported in ≤2% of patients in clinical trials of IBS-C on tegaserod but more frequently than placebo:

Blood and Lymphatic System Disorders: Anemia

Ear and Labyrinth Disorders: Vertigo

Gastrointestinal Disorders: Rectal hemorrhage

General Disorders and Administration Site Conditions: Asthenia

Investigations: Increased blood creatine phosphokinase

Metabolism and Nutrition Disorders: Increased appetite

Musculoskeletal and Connective Tissue Disorders: Arthropathy, tendonitis

Nervous System Disorders: Migraine

Adverse Reactions of Special Interest

Tegaserod is recommended for use in female patients with IBS-C, and is not recommended for other motility disorders.

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 tegaserod (13 events, 0.1%) compared to placebo (1 event, 0.01%). A second external adjudication was conducted with additional patient-level information, and used a comprehensive pre-specified methodology regarding both case selection and assessment. This adjudication confirmed seven CVI events (0.06%) on tegaserod 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 tegaserod compared to placebo, as reported in both external adjudications. All events occurred in male and female patients with a 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 tegaserod-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 a 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 Database:

^a Defined as prior MI, stroke, transient ischemic attack, angina, etc.
^b 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)
^c Five females less than 65 years, one male less than 65 years and one male greater than 65 years of age
^d Three females less than 65 years of age and one male greater than 65 years of age
^e Cardiovascular death, MI and stroke; all three patients had > one cardiovascular risk factor at baseline
^f Cardiovascular death (one of the three cases confirmed in the 1^st external adjudication)

Suicidal Ideation/Behavior

Two tegaserod-treated patients committed suicide, one in a controlled study of IBS-C and one during open label treatment for another motility disorder. In 27 placebo-controlled trials, assessing tegaserod at a total daily dose of 4 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 tegaserod 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 tegaserod-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 a female, less than 65 years of age with IBS-C, taking tegaserod 2 mg twice daily.

Abdominal Surgeries, Including Cholecystectomy

An increase in abdominal surgeries was observed on tegaserod (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 tegaserod for IBS-C. The increase was primarily due to a numerical imbalance in cholecystectomies reported in patients treated with tegaserod (5 patients out of 2,965 or 0.17%) versus placebo (1 patient out of 1,740 or 0.06%). A causal relationship between abdominal surgeries and tegaserod has not been established.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of tegaserod. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Ischemic colitis, mesenteric ischemia, gangrenous bowel and rectal bleeding
• Severe diarrhea resulting in syncope, hypotension, hypovolemia, electrolyte disorders
• Sphincter of Oddi spasm, bile duct stone, cholecystitis with elevated transaminases, elevation in ALT, AST and bilirubin, hepatitis
• Alopecia
• Hypersensitivity reactions, including anaphylaxis