Lotronex

Alosetron may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• upset stomach
• swelling in the stomach area
• hemorrhoids

Some side effects can be serious. If you experience any of the symptoms listed in the IMPORTANT WARNING section, call your doctor immediately.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

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:

• nausea,
• hemorrhoids, and
• abdominal distention.

It is not known if alosetron is excreted in breast milk. Therefore, it should be used cautiously by nursing mothers.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Lotronex and other medicines may affect each other. Always check with your doctor before starting or stopping any medicines. Especially tell your doctor if you take:

• antihistamines
• certain antidepressants ('mood elevators') called tricyclic antidepressants
• certain medications to treat asthma, diarrhea, lung disease, mental illness, motion sickness, overactive bladder, pain, Parkinson's disease, stomach or intestinal cramps, ulcers and upset stomach

Also, be sure to mention to your doctor if you take:

• amiodarone (Cordarone, Pacerone)
• certain antifungals such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), and voriconazole (Vfend)
• aprepitant (Emend)
• cimetidine (Tagamet)
• clarithromycin (Biaxin, in Prevpac)
• cyclosporine (Neoral, Sandimmune)
• diltiazem (Cardizem, Dilacor, Tiazac, others)
• erythromycin (E.E.S., E-Mycin, Erythrocin)
• fluoroquinolone antibiotics including ciprofloxacin (Cipro), gatifloxacin (Tequin), levofloxacin (Levaquin), norfloxacin (Noroxin), ofloxacin (Floxin), others
• fluoxetine (Prozac, Sarafem)
• hormonal contraceptives (birth control pills, implants, injections, rings, and patches)
• hydralazine (Apresoline)
• isoniazid (INH, Nydrazid)
• lovastatin (Advicor, Altocor, Mevacor)
• certain medications for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) such as atazanavir (Reyataz), delavirdine (Rescriptor); efavirenz (Sustiva);indinavir (Crixivan), lopinavir (in Kaletra), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Fortovase, Invirase)
• nefazodone
• procainamide (Procanbid, Pronestyl)
• sertraline (Zoloft)
• telithromycin (Ketek)
• ticlopidine (Ticlid)
• troleandomycin (TAO)
• verapamil (Calan, Covera, Isoptin, Verelan)
• zafirlukast (Accolate)

Take Lotronex exactly as precribed by your doctor. Follow the directions on your prescription label carefully. Your doctor will determine the best dose for you.

The recommended dosage is:

• Begin with 0.5 mg two times a day for 4 weeks to see how Lotronex affects you. You and your doctor may decide that you should keep taking this dose if you are doing well. 
• Check with your doctor 4 weeks after starting Lotronex:
  • If you try 0.5 mg two times a day for 4 weeks, it may not control your symptoms. If you do not get constipation or other side effects from Lotronex, your doctor may increase your dose up to 1 mg two times a day. 
  • If 1 mg two times a day does not work after 4 weeks, Lotronex  is not likely to help you. You should stop taking it and call your doctor. 

SERIOUS GASTROINTESTINAL ADVERSE REACTIONS

Infrequent but serious gastrointestinal adverse reactions have been reported with the use of this medication. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization and, rarely, blood transfusion, surgery, and death.

The Prescribing Program for Lotronex was implemented to help reduce risks or serious gastrointestinal adverse reactions. Only prescribers who have enrolled in the Prometheus Prescribing Program for Lotronex should prescribe this medication.

This medication is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have not responded adequately to conventional therapy. Before receiving the initial prescription for this medication, the patient must read and sign the Patient Acknowledgement Form for Lotronex.

Discontinue this medication immediately in patients who develop constipation or symptoms of ischemic colitis. Do not resume this medication in patients who develop ischemic colitis. Patients should immediately report constipation or symptoms of ischemic colitis to their prescriber. Patients who have constipation should immediately contact their prescriber if the constipation does not resolve after this medication is discontinued. Patients with resolved constipation should resume this medication only on the advice of their treating prescriber.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Serious or fatal side effects on the stomach and intestines have occurred in some people taking alosetron. In rare cases, alosetron has caused severe constipation, or ischemic colitis (caused by reduced blood flow to the intestines).

Stop taking alosetron and call your doctor right away if you develop:

• new or worsening constipation;

• stomach pain;

• bright or dark red blood in your stools; or

• bloody diarrhea.

You may need to permanently discontinue alosetron if you have these side effects.

Older adults and those who are ill or debilitated may be more likely to have serious complications from constipation.

Common side effects may include:

• constipation;

• nausea; or

• pain or discomfort in your stomach or intestines.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Severe Diarrhea-predominant Irritable Bowel Syndrome in Women

Only for management of severe diarrhea-predominant IBS in women with chronic symptoms (generally lasting ≥6 months) who have had anatomic or biochemical GI abnormalities excluded and have not responded to conventional therapy.1 11 17 20 Diarrhea-predominant IBS is considered severe if accompanied by at least one of the following symptoms: frequent and severe abdominal pain and/or discomfort; frequent bowel urgency or fecal incontinence; or disability or restriction of daily activities.1 11

Use restricted to patients for whom benefit-to-risk balance is considered to be most favorable.1 (See Boxed Warning.)

Efficacy in men not adequately demonstrated in clinical studies.1 11 18 19

Metabolized by CYP isoenzymes, principally by CYP1A2, and to a lesser extent by CYP3A4 and 2C9.1

Inhibits CYP1A2 and CYP2E1 in vitro at very high concentrations (27-fold higher than peak plasma concentrations observed with 1-mg dose); in vivo, inhibits CYP1A2, but no effect on CYP2E1.1 Inhibits N-acetyltransferase in vivo.1 Does not inhibit CYP2C9, C19, 2E1, or 3A4.1

Does not appear to induce CYP3A, 2E1, or 2C19.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered alosetron clearance) when used concomitantly with drugs that inhibit or induce CYP1A2, 3A4, or 2C9.1

CYP1A2 inhibitors: Avoid concomitant use.1

CYP3A4 inhibitors: Caution advised when used concomitantly.1

Potential to inhibit clearance of drugs metabolized by CYP1A2.1 Unlikely to inhibit clearance of drugs metabolized by CYP2C9, 2C19, 2E1, or 3A4.1

Drugs Metabolized by N-Acetyltransferase

Potential pharmacokinetic interaction (decreased metabolism of drugs metabolized via N-acetyltransferase).1

Specific Drugs

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of alosetron hydrochloride is restricted.1 7 8 10 (See Restricted Distribution Programs under Dosage and Administration.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Pregnancy

Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 40 mg/kg/day (about 160 times the recommended human dose based on body surface area) and rabbits at oral doses up to 30 mg/kg/day (about 240 times the recommended daily human dose based on body surface area). These studies have revealed no evidence of impaired fertility or harm to the fetus due to alosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Lotronex should be used during pregnancy only if clearly needed.

Nursing Mothers

Alosetron and/or metabolites of alosetron are excreted in the breast milk of lactating rats. It is not known whether alosetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lotronex is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Use of Lotronex is not recommended in the pediatric population, based upon the risk of serious complications of constipation and ischemic colitis in adults.

Geriatric Use

In some studies in healthy men or women, plasma concentrations were elevated by approximately 40% in individuals 65 years and older compared to young adults [see Warnings and Precautions ( 5.1)] . However, this effect was not consistently observed in men.

Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation therefore, appropriate caution and follow-up should be exercised if Lotronex is prescribed for these patients [see Warnings and Precautions ( 5.1)] .

Hepatic Impairment

Due to the extensive hepatic metabolism of alosetron, increased exposure to alosetron and/or its metabolites is likely to occur in patients with hepatic impairment. Alosetron should not be used in patients with severe hepatic impairment and should be used with caution in patients with mild or moderate hepatic impairment.

A single 1 mg oral dose of alosetron was administered to 1 female and 5 male patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) and to 1 female and 2 male patients with severe hepatic impairment (Child-Pugh score of >9). In comparison with historical data from healthy subjects, patients with severe hepatic impairment displayed higher systemic exposure to alosetron. The female with severe hepatic impairment displayed approximately 14-fold higher exposure, while the female with moderate hepatic impairment displayed approximately 1.6-fold higher exposure, than healthy females. Due to the small number of subjects and high intersubject variability in the pharmacokinetic findings, no definitive quantitative conclusions can be made. However, due to the greater exposure to alosetron in the female with severe hepatic impairment, alosetron should not be used in females with severe hepatic impairment [see Dosage and Administration ( 2.2), Contraindications ( 4)] .

Renal Impairment

Renal impairment (creatinine clearance 4 to 56 mL/min) has no effect on the renal elimination of alosetron due to the minor contribution of this pathway to elimination. The effect of renal impairment on metabolite pharmacokinetics and the effect of end-stage renal disease have not been assessed.

There is no specific antidote for overdose of Lotronex. Patients should be managed with appropriate supportive therapy. Individual oral doses as large as 16 mg have been administered in clinical studies without significant adverse reactions. This dose is 8 times higher than the recommended total daily dose. Inhibition of the metabolic elimination and reduced first pass of other drugs might occur with overdoses of Lotronex [see Drug Interactions ( 7)].

1. Thompson WG, Creed F, Drossman DA, et al. Functional bowel disease and functional abdominal pain. Gastroenterol Int. 1992;5:75-91.

Lotronex (alosetron) blocks the action of a chemical called serotonin in the intestines. This slows the movement of stools (bowel movements) through the intestines.

Lotronex is used to treat severe, chronic irritable bowel syndrome (IBS) in women who have had diarrhea as the main symptom for at least 6 months. Alosetron should be used only by women who have tried other IBS treatments without success. Alosetron not been shown to be effective in men with IBS.

Lotronex is not a cure for irritable bowel syndrome. After you stop taking this medicine, your symptoms may return within 1 week.

Take Lotronex exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Do not start taking Lotronex if you are constipated. Stop taking the medicine and call your doctor if you become constipated.

You may take this medicine with or without food.

Lotronex does not improve the symptoms of IBS for everyone. This medicine can help reduce stomach pain and discomfort, bowel urgency, and diarrhea. Some or all symptoms may improve within 1 to 2 weeks of treatment.

Stop taking Lotronex and call your doctor if your IBS symptoms do not improve after 4 weeks of treatment.

If you stop taking Lotronex for any reason, do not start taking it again without your doctor's advice.

Store at room temperature away from moisture, heat, and light.

Applies to alosetron: oral tablet

Along with its needed effects, alosetron (the active ingredient contained in Lotronex) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking alosetron:

• Constipation

• Bloody diarrhea
• new or worsening stomach pain or discomfort
• rectal bleeding

• Abdominal or stomach pain, cramping, or burning
• black, tarry stools
• diarrhea
• fever
• heartburn
• indigestion
• nausea
• vomiting with or without blood or material that looks like coffee grounds

Get emergency help immediately if any of the following symptoms of overdose occur while taking alosetron:

• Clumsiness, unsteadiness, trembling, or other problems with muscle control or coordination
• convulsions (seizures)
• difficulty breathing
• shakiness and unsteady walk
• withdrawn or socially detached behavior

Some side effects of alosetron may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding after bowel movement
• full or bloated feeling
• pressure in the stomach
• swelling of abdominal or stomach area
• uncomfortable swelling around rectal area

• Headache
• skin rash