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Does Lotronex (alosetron) cause side effects?
Lotronex (alosetron) is a selective serotonin 5-HT3 receptor antagonist used to treat severe diarrhea-predominant irritable bowel syndrome (IBS) among women who have chronic IBS symptoms lasting longer than 6 months and have not responded to conventional IBS treatment.
The discomfort and diarrhea of IBS is believed to be due to abnormal activity of the muscles of the intestines and/or the nerves that control the muscles. One of the chemical messengers which is important in coordinating the activity of intestinal nerves is serotonin. Serotonin and its receptors in the intestines may control pain sensation, contraction of intestinal muscle, and release of fluid into the intestines.
Common side effects of Lotronex include:
Serious side effects of Lotronex include:
- severe constipation and ischemic colitis (signs include rectal bleeding or a sudden worsening of abdominal pain).
- HIV medicines,
- protease inhibitors,
- nelfinavir, and
- quinolone antibiotics.
The available data with Lotronex use in pregnant women are insufficient to draw conclusions about any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.
What are the important side effects of Lotronex (alosetron)?
The most common side effect with alosetron is constipation. One-quarter to one-third of patients may develop this side effect. Severe constipation or intestinal inflammation caused by poor circulation of blood (ischemic colitis) are rare but life-threatening, may require surgery, and may cause death.
Therefore, alosetron must be discontinued immediately, and immediate medical attention should be sought if constipation or the signs of ischemic colitis (rectal bleeding or a sudden worsening of abdominal pain) occur.
Other important but less common side effects include:
Lotronex (alosetron) side effects list for healthcare professionals
The following adverse reactions are described in more detail in other sections of the label:
- Complications of constipation
- Ischemic colitis
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.
Patients With Irritable Bowel Syndrome
Table 1 summarizes adverse reactions from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of Lotronex twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received Lotronex and occurred more frequently on Lotronex than on placebo. A statistically significant difference was observed for constipation in patients treated with Lotronex compared to placebo (p<0.0001).
Table 1. Adverse Reactions Reported in ≥1% of Patients with Irritable Bowel Syndrome and More Frequently on Lotronex 1 mg Twice Daily Than Placebo
(n = 2,363)
|Lotronex 1 mg twice daily|
(n = 8,328)
|Abdominal discomfort and pain||4%||7%|
|Gastrointestinal discomfort and pain||3%||5%|
|Regurgitation and reflux||2%||2%|
- Constipation is a frequent and dose-related side effect of treatment with Lotronex. In clinical studies constipation was reported in approximately 29% of patients with IBS treated with Lotronex 1 mg twice daily (n = 9,316). This effect was statistically significant compared to placebo (p<0.0001).
- Eleven percent (11%) of patients treated with Lotronex 1 mg twice daily withdrew from the studies due to constipation.
- Although the number of patients with IBS treated with Lotronex 0.5 mg twice daily is relatively small (n = 243), only 11% of those patients reported constipation and 4% withdrew from clinical studies due to constipation.
- Among the patients treated with Lotronex 1 mg twice daily who reported constipation, 75% reported a single episode and most reports of constipation (70%) occurred during the first month of treatment, with the median time to first report of constipation onset of 8 days.
- Occurrences of constipation in clinical trials were generally mild to moderate in intensity, transient in nature, and resolved either spontaneously with continued treatment or with an interruption of treatment.
- However, serious complications of constipation have been reported in clinical studies and in postmarketing experience. In Studies 1 and 2, 9% of patients treated with Lotronex reported constipation and 4 consecutive days with no bowel movement.
- Following interruption of treatment, 78% of the affected patients resumed bowel movements within a 2-day period and were able to re-initiate treatment with Lotronex.
- A similar incidence in elevation of ALT (>2-fold) was seen in patients receiving Lotronex or placebo (1.0% vs. 1.2%).
- A single case of hepatitis (elevated ALT, AST, alkaline phosphatase, and bilirubin) without jaundice in a patient receiving Lotronex was reported in a 12-week study.
- A causal association with Lotronex has not been established.
- Patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking Lotronex for longer than 6 months.
Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome
- Table 2 summarizes the gastrointestinal adverse reactions from 1 repeat-dose study in female patients with severe diarrhea-predominant IBS who were treated for 12 weeks.
- The adverse reactions in Table 2 were reported in 3% or more of patients who received Lotronex and occurred more frequently with Lotronex than with placebo.
- Other events reported in 3% or more of patients who received Lotronex and occurring more frequently with Lotronex than with placebo included upper respiratory tract infection, viral gastroenteritis, muscle spasms, headaches, and fatigue.
Table 2. Gastrointestinal Adverse Reactions Reported in ≥3% of Women with Severe Diarrhea-Predominant Irritable Bowel Syndrome and More Frequently on Lotronex Than Placebo
(n = 176)
0.5 mg once daily
(n = 175)
1 mg once daily
(n = 172)
1 mg twice daily
(n = 176)
|Abdominal pain upper||1%||3%||1%||1%|
- Adverse reactions reported in another study of 701 women with severe diarrhea-predominant IBS were similar to those shown in Table 2.
- Gastrointestinal adverse reactions reported in 3% or more of patients who received Lotronex and occurring more frequently with Lotronex than with placebo included constipation (14% and 10% of patients taking Lotronex 1 mg twice daily or 0.5 mg as needed, respectively, compared with 2% taking placebo), abdominal pain, nausea, vomiting, and flatulence.
- Other events reported in 3% or more of patients who received Lotronex and occurring more frequently with Lotronex than with placebo included nasopharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, viral gastroenteritis, and cough.
- Constipation was the most frequent adverse reaction among women with severe diarrhea-predominant IBS represented in Table 2.
- There was a dose response in the groups treated with Lotronex in the number of patients withdrawn due to constipation (2% on placebo, 5% on 0.5 mg once daily, 8% on 1 mg once daily, and 11% on 1 mg twice daily).
- Among these patients with severe diarrhea-predominant IBS treated with Lotronex who reported constipation most (75%) reported one episode which occurred within the first 15 days of treatment and persisted for 4 to 5 days.
Other Events Observed During Clinical Evaluation Of Lotronex
- During its assessment in clinical trials, multiple and single doses of Lotronex were administered, resulting in 11,874 subject exposures in 86 completed clinical studies.
- The conditions, dosages, and duration of exposure to Lotronex varied between trials, and the studies included healthy male and female volunteers as well as male and female patients with IBS and other indications.
- In the listing that follows, reported adverse reactions were classified using a standardized coding dictionary.
- Only those events that an investigator believed were possibly related to Lotronex, occurred in at least 2 patients, and occurred at a greater frequency during treatment with Lotronex than during placebo administration are presented.
- Serious adverse reactions occurring in at least 1 patient for whom an investigator believed there was reasonable possibility that the event was related to treatment with Lotronex and occurring at a greater frequency in patients treated with Lotronex than placebo-treated patients are also presented.
- In the following listing, events are categorized by body system. Within each body system, events are presented in descending order of frequency.
- The following definitions are used: infrequent adverse reactions are those occurring on one or more occasion in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring on one or more occasion in fewer than 1/1,000 patients.
- Although the events reported occurred during treatment with Lotronex, they were not necessarily caused by it.
Blood and Lymphatic
Rare: Quantitative red cell or hemoglobin defects, and hemorrhage.
Rare: Arrhythmias, increased blood pressure, and extrasystoles.
Drug Interaction, Overdose, and Trauma
Rare: Contusions and hematomas.
Ear, Nose, and Throat
Rare: Ear, nose, and throat infections; viral ear, nose, and throat infections; and laryngitis.
Endocrine and Metabolic
Rare: Light sensitivity of eyes.
Infrequent: Hyposalivation, dyspeptic symptoms, gastrointestinal spasms, ischemic colitis, and gastrointestinal lesions.
Rare: Abnormal tenderness, colitis, gastrointestinal signs and symptoms, proctitis, diverticulitis, positive fecal occult blood, hyperacidity, decreased gastrointestinal motility and ileus, gastrointestinal obstructions, oral symptoms, gastrointestinal intussusception, gastritis, gastroduodenitis, gastroenteritis, and ulcerative colitis.
Hepatobiliary Tract and Pancreas
Rare: Abnormal bilirubin levels and cholecystitis.
Infrequent: Breathing disorders.
Infrequent: Hypnagogic effects.
Rare: Depressive moods.
Rare: Sexual function disorders, female reproductive tract bleeding and hemorrhage, reproductive infections, and fungal reproductive infections.
Infrequent: Urinary frequency.
Rare: Bladder inflammation; polyuria and diuresis; and urinary tract hemorrhage.
In addition to events reported in clinical trials, the following events have been identified during use of Lotronex in clinical practice. Because they were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Lotronex.
Impaction, perforation, ulceration, small bowel mesenteric ischemia.
What drugs interact with Lotronex (alosetron)?
In vivo data suggest that alosetron is primarily metabolized by cytochrome P450 (CYP) 1A2, with minor contributions from CYP3A4 and CYP2C9. Therefore, inducers or inhibitors of these enzymes may change the clearance of alosetron.
- Fluvoxamine is a known strong inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19.
- In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg/day for 16 days, with coadministration of alosetron 1 mg on the last day.
- Fluvoxamine increased mean alosetron plasma concentrations (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold.
- Concomitant administration of alosetron and fluvoxamine is contraindicated. Concomitant administration of alosetron and moderate CYP1A2 inhibitors, including quinolone antibiotics and cimetidine, has not been evaluated, but should be avoided unless clinically necessary because of similar potential drug interactions.
- Ketoconazole is a known strong inhibitor of CYP3A4.
- In a pharmacokinetic study, 38 healthy female subjects received ketoconazole 200 mg twice daily for 7 days, with coadministration of alosetron 1 mg on the last day.
- Ketoconazole increased mean alosetron plasma concentrations (AUC) by 29%.
- Caution should be used when alosetron and ketoconazole are administered concomitantly.
- Coadministration of alosetron and strong CYP3A4 inhibitors such as clarithromycin, telithromycin, protease inhibitors, voriconazole, and itraconazole has not been evaluated but should be undertaken with caution because of similar potential drug interactions.
- The effect of induction or inhibition of other pathways on exposure to alosetron and its metabolites is not known.
Other CYP Enzymes
- In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that alosetron did not inhibit CYP enzymes 3A4, 2C9, or 2C19.
- In vitro at total drug concentrations 27-fold higher than peak plasma concentrations observed with the 1 mg dose, alosetron inhibited CYP enzymes 1A2 (60%) and 2E1 (50%).
- In an in vivo metabolic probe study, alosetron did not inhibit CYP2E1 but did produce 30% inhibition of both CYP1A2 and N-acetyltransferase.
- Although not studied with alosetron, inhibition of N-acetyltransferase may have clinically relevant consequences for drugs such as isoniazid, procainamide, and hydralazine.
- The effect on CYP1A2 was explored further in a clinical interaction study with theophylline and no effect on metabolism was observed.
- Another study showed that alosetron had no clinically significant effect on plasma concentrations of the oral contraceptive agents ethinyl estradiol and levonorgestrel (CYP3A4 substrates).
- A clinical interaction study was also conducted with alosetron and the CYP3A4 substrate cisapride. No significant effects on cisapride metabolism or QT interval were noted.
- The effects of alosetron on monoamine oxidases and on intestinal first pass secondary to high intraluminal concentrations have not been examined.
- Based on the above data from in vitro and in vivo studies, it is unlikely that alosetron will inhibit the hepatic metabolic clearance of drugs metabolized by the CYP enzymes 2C9, 2C19, or 2E1.
- Alosetron does not appear to induce the major cytochrome P450 drug-metabolizing enzyme 3A. Alosetron also does not appear to induce CYP enzymes 2E1 or 2C19. It is not known whether alosetron might induce other enzymes.
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Related Disease Conditions
Low FODMAP Diet for IBS
FODMAPs are foods that contain sugar alcohols and short chain carbohydrates. The gut can't digest them very well. There are "low" FODMAP foods and "high" FODMAP foods. Foods high in FODMAPs lay in the gut and ferment, which causes symptoms of: Excessive gas Bloating Abdominal pain Diarrhea Some people with digestive diseases and disorders, for example, IBS, microscopic colitis, IBD (Crohn's disease and ulcerative colitis), and other functional bowel disorders often are placed on a low FODMAP diet to decrease the amount of high FODMAPs foods in the diet, which create uncomfortable symptoms.
Irritable Bowel Syndrome (IBS)
Irritable bowel syndrome (IBS) is a GI (gastrointestinal) disorder with signs and symptoms that include abdominal pain, bloating, increased gas (flatulence), abdominal cramping, diarrhea, constipation, and food intolerance.Two new tests are now available that may help diagnose irritable bowel syndrome with diarrhea and constipation (IBS-M) irritable bowel syndrome with diarrhea (IBS-D), and irritable bowel syndrome with constipation (IBS-C). Treatment for IBS includes diet changes, medications, and other lifestyle changes to manage symptoms.
IBS-D (Irritable Bowel Syndrome with Diarrhea)
IBS-D or irritable bowel syndrome with diarrhea refers to IBS with diarrhea. Symptoms of IBS-D include intestinal gas (flatulence), loose stools, frequent stools, abdominal pain, diarrhea, and nausea. New non-FDA approved IBS tests may help diagnose IBS and IBS-D. Treatment of IBS-D is geared to toward managing symptoms with diet, medication, and lifestyle changes.
IBS Triggers (Prevention)
Irritable bowel syndrome (IBS) is a functional disease that can affect the quality of those who suffer from this condition. People with IBS can make lifestyle changes that may modify or control the number and severity of episodes. Certain foods, medications, and hormone levels may trigger IBS episodes, for example fatty foods, dairy products, eating foods in large quantities, foods that contain high levels of sorbitol, foods that produce intestinal gas (broccoli, onions, cabbage, and beans), chocolate, caffeine, physiological stress, some antibiotics, some antidepressants, medicine with sorbitol, and menstrual pain. Exercise, diet, and other lifestyle changes can decrease IBS flares, and prevent the number and severity of IBS episodes of diarrhea and constipation.
IBS vs. IBD: Differences and Similarities
IBS (irritable bowel syndrome) and IBD (inflammatory bowel disease) are both problems with the digestive tract (gastrointestinal or GI tract), but they are not the same disease. IBS is a functional disorder (a problem with the way the GI tract functions), and IBD is a disease that causes chronic prolonged inflammation of the GI tract, that can lead to ulcers and other problems that may require surgery. The most common forms of IBD are Crohn's disease and ulcerative colitis, or UC. Researchers do not know the exact cause of either disease, but they believe that IBS may be caused and triggered by a variety of factors (foods, stress, and the nervous system of the GI tract), while IBD may be genetic or due a problem with the immune system.Common symptoms of both diseases are an urgent need to have a bowel movement, diarrhea, nausea, vomiting, and abdominal pain and cramping. There are differences between the signs and symptoms of irritable bowel syndrome and inflammatory bowel disease, for example, symptoms unique to IBD are: Fever Joint pain or soreness Skin changes Rectal bleeding Anemia Eye redness or pain Unintentional weight loss Feeling tired Symptoms unique to irritable bowel syndrome include: Sexual problems Fibromyalgia Abdominal bloating Whitish mucous in the stool Changes in bowel movements and in the way stools look An urgent need to urinate Urinating frequently Treatment for IBS is with diet recommendations from a doctor or nutritionist, medication, and lifestyle changes like stress management and avoiding foods that trigger the condition. Treatments for IBD depend upon the type of disease, its symptoms, and health of the patient. Surgery may be necessary for some individuals.REFERENCES: Brown, AC, et al. "Existing Dietary Guidelines for Crohn's Disease and Ulcerative Colitis." Medscape. Lehrer, J. "Irritable Bowel Syndrome." Medscape. Updated: Apr 04, 2017. Rowe, W. "Inflammatory Bowel Disease." Medscape. Updated: Jun 17, 2016. Romanowski, A, MS, RD. "Matching the Right Diet to the Right Patient." Medscape. Jan 27, 2017.
Irritable Bowel Syndrome in Children (IBS)
Irritable bowel syndrome (IBS) in children is a functional gastrointestinal disorder with signs and symptoms of: Abdominal pain Bloating Diarrhea Constipation The cause of IBS is unknown, however, certain foods, stress, anxiety, and depression may contribute to the symptoms of IBS. There is no cure for IBS in children; however, medications, dietary changes, and stress management may relieve symptoms.
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Medications & Supplements
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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.