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Lotronex (Alosetron Hydrochloride) - Warnings and Precautions

 
 



PRESCRIBING PROGRAM FOR LOTRONEX™

PHYSICIAN ENROLLMENT FORM

The Prescribing Program for LOTRONEX was implemented to help reduce risks of serious gastrointestinal adverse events, some fatal, associated with this medicine. The program is intended to help physicians and their patients understand the benefits and risks of treatment with LOTRONEX in order to make fully informed decisions.

I wish to participate in the Prescribing Program for LOTRONEX (PPL) and acknowledge that I have read the complete Prescribing Information for LOTRONEX and understand and will follow the requirements of the PPL described below.

  • For safety reasons, LOTRONEX is approved only for women with severe, diarrhea-predominant irritable bowel syndrome (D-IBS) who have: Chronic IBS symptoms (generally lasting for 6 months or longer),
  • had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and
  • not responded adequately to conventional therapy.

Diarrhea-predominant IBS is severe if it includes diarrhea and one or more of the following:

  • Frequent and severe abdominal pain/discomfort
  • Frequent bowel urgency or fecal incontinence
  • Disability or restriction of daily activities due to IBS
  • Physicians who enroll in the PPL should be able to diagnose and manage IBS, ischemic colitis, constipation, and complications of constipation, or refer patients to a specialist as needed.
  • Patients considering treatment with LOTRONEX must be educated on the benefits and risks of the drug, given a copy of the Medication Guide, instructed to read it, and encouraged to ask questions. The patient may be educated by the enrolled physician or a healthcare provider under a physician’s direction.
  • After reviewing the Medication Guide prior to the initial prescription, the physician and the patient must both sign the Patient-Physician Agreement form. The original signed form must be placed in the patient’s medical record, and a copy given to the patient.
  • Program stickers must be affixed to all prescriptions for LOTRONEX (i.e., the original and all subsequent prescriptions). Stickers will be provided as part of the Prometheus Prescribing Program for LOTRONEX. Refills are permitted to be written on prescriptions.
  • All prescriptions for LOTRONEX must be written and not transmitted by telephone, facsimile, or computer.
  • Prescribers must report all serious adverse events with LOTRONEX to Prometheus at 1-888-423-5227 or to the Food and Drug Administration at 1-800-FDA-1088.

    ________________________________

    Name of Physician (print)

    ________________________________

    ________________________________

    Signature

     Date

    DEA Number

    ________________________________

    Office Address:

    ________________________________

    ________________________________

    ________________________________

    Office Phone Number:

    ________________________________

    Office Fax Number:

    ________________________________

  • Upon enrollment, you will receive a prescribing kit for LOTRONEX with the complete Prescribing Information, Prescribing Program for LOTRONEX stickers, multiple copies of the Medication Guide and Patient-Physician Agreement for LOTRONEX, and instructions for ordering additional supplies of Program materials.

    You only need to enroll once, and you are under no obligation to prescribe LOTRONEX.

    If you have any questions, please call the Prescribing Program for LOTRONEX at 1-888-423-5227 or visit www.lotronex.com.

    TO ENROLL, VISIT WWW.LOTRONEX.COM OR PHONE 1-888-423-5227 OR COMPLETE THIS FORM IN ITS ENTIRETY AND MAIL OR FAX TO THE FOLLOWING ADDRESS:

    Prescribing Program for Lotronex

    9410 Carroll Park Drive
    San Diego, CA 92121
    1-888-423-5227
    Fax Number: 1-858-824-0896

    Prometheus®
    Therapeutics & Diagnostics

    For the person in every patient

    ©2007 Prometheus Laboratories Inc. All rights reserved LX001A08
    January 2008

    WARNING

    Infrequent but serious gastrointestinal adverse events have been reported with the use of LOTRONEX. 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 of serious gastrointestinal adverse events. Only physicians who have enrolled in Prometheus' Prescribing Program for LOTRONEX, based on their understanding of the benefits and risks, should prescribe LOTRONEX (see PRECAUTIONS: Prescribing Program for LOTRONEX).
    • LOTRONEX is indicated only for women with severe diarrhea-predominant IBS who have not responded adequately to conventional therapy (see INDICATIONS AND USAGE). Before receiving the initial prescription for LOTRONEX, the patient must read and sign the Patient-Physician Agreement for LOTRONEX (see PRECAUTIONS: Information for Patients).
    • LOTRONEX should be discontinued immediately in patients who develop constipation or symptoms of ischemic colitis. Patients should immediately report constipation or symptoms of ischemic colitis to their physician. LOTRONEX should not be resumed in patients who develop ischemic colitis. Patients who have constipation should immediately contact their physician if the constipation does not resolve after LOTRONEX is discontinued. Patients with resolved constipation should resume LOTRONEX only on the advice of their treating physician.
     

    WARNINGS (See BOXED WARNING and DOSAGE AND ADMINISTRATION.)

    Some patients have experienced serious complications of constipation or ischemic colitis without warning.

    Constipation

    Serious complications of constipation including obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia have been reported with use of LOTRONEX during clinical trials. In addition, rare cases of perforation and death have been reported from postmarketing clinical practice. In some cases, complications of constipation required intestinal surgery, including colectomy. In IBS clinical trials, approximately 10% of patients on LOTRONEX withdrew prematurely because of constipation. The incidence of serious complications of constipation was approximately 0.1% (1 per 1,000 patients) in women receiving either LOTRONEX or placebo. Patients who are elderly, debilitated, or taking additional medications that decrease gastrointestinal motility may be at greater risk for complications of constipation.

    LOTRONEX should be discontinued immediately in patients who develop constipation (see BOXED WARNING).

    Ischemic Colitis

    Ischemic colitis has been reported in patients receiving LOTRONEX in clinical trials as well as during marketed use of the drug. In IBS clinical trials, the cumulative incidence of ischemic colitis in women receiving LOTRONEX was 0.2% (2 per 1,000 patients, 95% confidence interval 1 to 3) through 3 months and was 0.3% (3 per 1,000 patients, 95% confidence interval 1 to 4) through 6 months. Ischemic colitis was not reported in women receiving placebo. The patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking LOTRONEX for longer than 6 months .

    LOTRONEX should be discontinued immediately in patients with signs of ischemic colitis such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. Because ischemic colitis can be life-threatening, patients with signs or symptoms of ischemic colitis should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with LOTRONEX should not be resumed in patients who develop ischemic colitis.

    PRECAUTIONS

    Prescribing Program for LOTRONEX

    To prescribe LOTRONEX, the physician must be enrolled in the Prescribing Program for LOTRONEX. To enroll, physicians must understand the benefits and risks of treatment with LOTRONEX for severe diarrhea-predominant IBS, including the information in the Prescribing Information, Medication Guide, and Patient-Physician Agreement for LOTRONEX. Physicians need to be able to:

    • Diagnose and manage IBS, ischemic colitis, constipation and complications of constipation, or refer patients to specialists as needed.
    • Educate patients on the benefits and risks of treatment with LOTRONEX, provide them with the Medication Guide, instruct them to read it, and encourage them to ask questions when first considering LOTRONEX. Patients may be educated by the enrolled physician or a healthcare provider under a physician’s direction.
    • Prior to the initial prescription of LOTRONEX, obtain the patient’s signature on the Patient-Physician Agreement form, sign it, place the original signed form in the patient’s medical record, and give a copy to the patient.
    • Affix program stickers to all prescriptions for LOTRONEX (i.e., the original and all subsequent prescriptions). Stickers will be provided as part of the Prometheus Prescribing Program for LOTRONEX. No telephone, facsimile, or computerized prescriptions are permitted with this program. Refills are permitted to be written on prescriptions.
    • Report all serious adverse events with LOTRONEX to Prometheus at 1-888-423-5227 or to the Food and Drug Administration’s MedWatch Program at 1-800-FDA-1088.

    To enroll in the Prescribing Program for LOTRONEX call 1-888-423-5227 or visit www.lotronex.com to complete the Physician Enrollment Form.

    Information for Patients

    Patients should be fully counseled on and understand the risks and benefits of LOTRONEX before an initial prescription is written. The patient may be educated by the enrolled physician or a healthcare provider under a physician’s direction.

    PHYSICIANS MUST:

    • Counsel patients for whom LOTRONEX is appropriate about the benefits and risks of LOTRONEX and discuss the impact of IBS symptoms on the patient’s life.
    • Give the patient a copy of the Medication Guide, which outlines the benefits and risks of LOTRONEX, and instruct the patient to read it carefully. Answer all questions the patient may have about LOTRONEX. The complete text of the Medication Guide is printed at the end of this document.
    • Review the Patient-Physician Agreement for LOTRONEX with the patient, answer all questions, and give a copy of the signed agreement to the patient.
    • Provide each patient with appropriate instructions for taking LOTRONEX.

    Copies of the Patient-Physician Agreement for LOTRONEX and additional copies of the Medication Guide are available by contacting Prometheus at 1-888-423-5227 or visiting www.lotronex.com.

    PATIENTS WHO ARE PRESCRIBED LOTRONEX SHOULD BE INSTRUCTED TO:

    • Read the Medication Guide before starting LOTRONEX and each time they refill their prescription.
    • Not start taking LOTRONEX if they are constipated.
    • Immediately discontinue LOTRONEX and contact their physician if they become constipated, or have symptoms of ischemic colitis such as new or worsening abdominal pain, bloody diarrhea, or blood in the stool. Contact their physician again if their constipation does not resolve after discontinuation of LOTRONEX. Resume LOTRONEX only if their constipation has resolved and after discussion with and the agreement of their treating physician.
    • Stop taking LOTRONEX and contact their physician if LOTRONEX does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day.

    Drug Interactions

    Because alosetron is metabolized by a variety of hepatic CYP drug-metabolizing enzymes, 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 per 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 (see CONTRAINDICATIONS).

    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.

    In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that alosetron did not inhibit CYP enzymes 2D6, 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 major CYP enzyme 3A4, as well as the CYP enzymes 2D6, 2C9, 2C19, 2E1, or 1A2.

    Alosetron does not appear to induce the major cytochrome P450 (CYP) 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.

    Hepatic Insufficiency

    Due to the extensive hepatic metabolism of alosetron, increased exposure to alosetron and/or its metabolites is likely to occur in patients with hepatic insufficiency. 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 (see CLINICAL PHARMACOLOGY: Population Subgroups: Reduced Hepatic Function).

    Carcinogenesis, Mutagenesis, Impairment of Fertility

    In 2-year oral studies, alosetron was not carcinogenic in mice at doses up to 30 mg/kg/day or in rats at doses up to 40 mg/kg/day. These doses are, respectively, about 60 to 160 times the recommended human dose of alosetron of 2 mg/day (1 mg twice daily) based on body surface area. Alosetron was not genotoxic in the Ames tests, the mouse lymphoma cell (L5178Y/TK±) forward gene mutation test, the human lymphocyte chromosome aberration test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, or the in vivo rat micronucleus test for mutagenicity. Alosetron at oral doses up to 40 mg/kg/day (about 160 times the recommended daily human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male or female rats.

    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.

    Geriatric Use

    Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation (see WARNINGS).

    Page last updated: 2008-04-11

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