Side Effects of Zelnorm (tegaserod)

Zelnorm (tegaserod) is a serotonin agonist used to treat severe, chronic, irritable bowel syndrome (IBS) in women whose primary bowel symptom is constipation (and not diarrhea).

Zelnorm is also used to treat chronic idiopathic (unknown cause) constipation in patients younger than 65 years old. The brand name Zelnorm is no longer available in the U.S.

Common side effects of Zelnorm include

• headache,
• dizziness,
• migraine,
• back pain,
• joint pain,
• stomach or abdominal pain,
• nausea,
• vomiting,
• gas (flatulence),
• bloating,
• diarrhea,
• leg pain, and
• fatigue.

Serious side effects of Zelnorm include

• dehydration due to diarrhea, including low blood volume (hypovolemia), low blood pressure (hypotension), and lightheadedness/fainting.

There are no listed drug interactions of Zelnorm. Tell your doctor all medications and supplements you use.

Tell your doctor if you are pregnant or plan to become pregnant during treatment with Zelnorm; it is unknow how it would affect a fetus.

It is unknown if Zelnorm passes into breast milk or if it could harm a nursing baby. Based on the potential for Zelnorm to cause cancer in a mouse carcinogenicity study, a decision should be made whether to discontinue breastfeeding or to discontinue Zelnorm, taking into account the importance of the drug to the mother.

Headache and diarrhea were the most common side effects seen with Zelnorm (tegaserod maleate).

Diarrhea was an occasional side effect of treatment with Zelnorm (tegaserod maleate).

• Most people who got diarrhea had it during the first week after starting Zelnorm (tegaserod maleate).
• Typically, diarrhea went away with continued therapy.
• If you get bad diarrhea, or if you get diarrhea together with bad cramping, abdominal pain, fainting, or dizziness, tell your doctor. Your doctor may tell you to stop taking Zelnorm (tegaserod maleate) or suggest other ways to manage your diarrhea.

There have been rare cases of rectal bleeding and severe abdominal pain in patients treated with Zelnorm (tegaserod maleate). Some of these problems were related to insufficient blood flow to part of the bowel. It is not known if this was related to Zelnorm (tegaserod maleate) use.

In studies, a very small number of patients were reported to have abdominal surgery.

• In IBS with constipation studies there were a few more reports of abdominal surgery in patients taking Zelnorm (tegaserod maleate) than in patients taking a sugar pill.
• Most of these were related to the gallbladder. It is not known if Zelnorm (tegaserod maleate) may increase your chance of abdominal surgery. Gallbladder surgery has been reported to occur more often in IBS patients than in the general population.

This list is not complete. Your doctor or pharmacist can give you a more complete list of possible side effects. Talk to your doctor about any side effects you may have.

The following adverse reactions are discussed in more detail elsewhere in the labeling:

• 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 Zelnorm 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 Zelnorm treatment group and at an incidence that was greater than in the placebo group.

Table 1: Most Common Adverse Reactions^a in Three Placebo-Controlled Trials of Zelnorm in Female IBS-C Patients Less than 65 Years of Age

Diarrhea

The majority (84%) 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. Diarrhea resulted in discontinuation in 1.6% of Zelnorm-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 Zelnorm 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

Zelnorm 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 Zelnorm (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 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 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 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 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

Suicidal Ideation/Behavior

• Two Zelnorm-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 Zelnorm included one completed suicide, two suicide attempts, four cases of selfinjurious 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 a female, less than 65 years of age with IBS-C, taking Zelnorm 2 mg twice daily.

Abdominal Surgeries, Including Cholecystectomy

• An 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 a 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%).
• A causal relationship between abdominal surgeries and Zelnorm has not been established.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Zelnorm. 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

• 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.