SIDE EFFECTS
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 Reactionsa in Three Placebo-Controlled Trials of ZELNORM in Female IBS-C Patients Less than 65 Years of Age
| Adverse Reactions | ZELNORM 6 mg twice daily [N = 1,184] % |
Placebo [N = 1,159] % |
| Headache | 14 | 10 |
| Abdominal Painb | 11 | 10 |
| Nausea | 8 | 7 |
| Diarrhea | 8 | 3 |
| Flatulence | 6 | 5 |
| Dyspepsia | 4 | 3 |
| Dizziness | 4 | 3 |
| a Reported in >2% of ZELNORM-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 |
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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
| All Patients (Male and Female) | Females < 65 Years of Age | |||||
| Without a History of Cardiovascular Ischemic Diseasea | Without a History of Cardiovascular Ischemic Diseasea and One or Fewer Cardiovascular Risk Factorsb | |||||
| ZELNORM (N=11,614) n (%) |
Placebo (N=7,031) n (%) |
ZELNORM (N=9,547) n (%) |
Placebo (N=5,748) n (%) |
ZELNORM (N=7,785) n (%) |
Placebo (N=4,686) n (%) |
|
| First External Adjudication | 7c (0.06%) | 0 | 3e (0.03%) | 0 | 0 | 0 |
| Second External Adjudication | 4d (0.03%) | 0 | 1f (0.01%) | 0 | 0 | 0 |
| aDefined as prior MI, stroke, transient ischemic attack, angina, etc. bDefined 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). cFive females less than 65 years, one male less than 65 years and one male greater than 65 years of age dThree females less than 65 years of age and one male greater than 65 years of age eCardiovascular death, MI and stroke; all three patients had > one cardiovascular risk factor at baseline fCardiovascular death (one of the three cases confirmed in the 1st external adjudication) |
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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
SRC: NLM .