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alosetron hcl 1 mg tablet generic lotronex

In stock Manufacturer ACTAVIS/TEVA 45963048003
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Uses

Severe Diarrhea-predominant Irritable Bowel Syndrome in Women

Alosetron is used only for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women with chronic symptoms (generally lasting 6 months or longer) who have had anatomic or biochemical GI abnormalities excluded and who have failed to respond to conventional therapy. Diarrhea-predominant IBS is considered severe if diarrhea is accompanied by one or more of the following manifestations: frequent and severe abdominal pain and/or discomfort, frequent bowel urgency or fecal incontinence, or disability or restriction of daily activities because of IBS. Because of the potential for serious adverse GI effects, use of alosetron is restricted to patients for whom the benefit-to-risk balance is considered to be most favorable.(See Warnings under Cautions: Warnings/Precautions.) Efficacy of alosetron in men has not been adequately demonstrated in clinical studies.

Efficacy of alosetron in the management of diarrhea-predominant IBS in women was established in 2 placebo-controlled studies in nonconstipated women with IBS for at least 6 months and in 3 separate placebo-controlled studies in women with severe diarrhea-predominant IBS. Approximately two-thirds of the women in the first 2 studies had diarrhea-predominant IBS. Adequate relief of IBS abdominal pain and discomfort was experienced by 10-19% more of these women receiving alosetron 1 mg twice daily than those receiving placebo. Retrospective analysis of the subset of women with severe diarrhea-predominant IBS in these 2 studies indicated that alosetron was more effective than placebo in providing adequate relief of pain and discomfort. In additional retrospective analyses of the 57% of women who had bowel urgency 5 or more days each week at the beginning of these studies, 32% of those receiving alosetron had bowel urgency no more than 1 day in the last week of the studies compared with 19% of those receiving placebo. Patients with severe diarrhea-predominant IBS who received alosetron in these studies also reported improvements in several outcomes related to IBS; such improvements included less difficulty sleeping, less fatigue, fewer eating problems, and less interference with social and work activities.

Among the 3 studies in women with severe diarrhea-predominant IBS, 2 of the studies included patients who had bowel urgency on at least 50% of days prior to study entry; such patients were randomized to receive alosetron 1 mg twice daily or placebo for 12 weeks. In these studies, women receiving alosetron experienced a substantial (13-16%) increase in the median percentage of days with control of bowel urgency compared with those receiving placebo. Retrospective analysis of the subset of patients who had bowel urgency 5 or more days each week at the beginning of the studies (66% of the study population) indicated that 50% of those receiving alosetron had bowel urgency no more than 1 day during the last week of the studies compared with 29% of those receiving placebo. In addition, bowel urgency occurred in this group no more than 2 days per week in any of the 12 weeks of the study in 12% of those receiving alosetron versus 1% of those receiving placebo. Response to alosetron also was evaluated in these studies by patient daily reports of stool frequency, stool consistency, and sense of incomplete evacuation. After 12 weeks of treatment, improvements were noted in average stool consistency (i.e., from loose to formed) and stool frequency in patients receiving alosetron compared with placebo; however, sense of incomplete evacuation was not consistently different between the treatment groups. In one of the studies, satisfactory control of urgency was reported on 73 or 57% of days by women receiving alosetron or placebo, respectively, over the 12 weeks of the study. In the same study, patients were also asked to evaluate their IBS symptoms over the preceding 4 weeks using a 7-point global improvement scale (ranging from substantially worse to substantially improved); at 4, 8, and 12 weeks, 67, 69, and 76% of women receiving alosetron or 41, 43, and 44% of those receiving placebo, respectively, reported moderate or substantial improvement in IBS symptoms and were considered responders.

In the remaining study in women with severe diarrhea-predominant IBS, patients with abdominal pain of at least moderate severity, bowel urgency on at least 50% of days, and/or restriction of daily activities on at least 25% of days were randomized to receive alosetron (0.5 mg once daily, 1 mg once daily, or 1 mg twice daily) or placebo for 12 weeks. Patients were asked to evaluate their IBS symptoms every 4 weeks using a 7-point global improvement scale (ranging from substantially worse to substantially improved), and were considered responders to therapy if they reported moderate or substantial improvement from baseline. At 12 weeks, the proportion of responders was substantially greater in all 3 alosetron groups compared with placebo (43-51 versus 31%, respectively). Patients in the alosetron groups also had greater relief of IBS pain and discomfort, decreased sense of urgency and stool frequency, and more formed stools compared with those who received placebo.

Long-term efficacy and safety of alosetron 1 mg twice daily was evaluated in a 48-week double-blind, placebo-controlled study in women with diarrhea-predominant (nonconstipated) IBS. In the subset of women with severe diarrhea-predominant IBS who had more frequent urgency (defined as those with urgency on at least 10 days during a 2-week baseline screening period), higher rates of adequate relief of IBS pain and discomfort (52 versus 41%, respectively) and satisfactory control of bowel urgency (60 versus 48%, respectively) were observed with alosetron compared with placebo. Such improvements were observed within 2 weeks and were maintained throughout the 48-week treatment period.

Dosage and Administration

General

Restricted Distribution Programs

Commercially available alosetron hydrochloride (Lotronex or generic alosetron hydrochloride) is prescribed and distributed under restricted distribution programs (Prescribing Program for Lotronex or Alosetron REMS Program) that were designed to help mitigate the risk of serious GI events associated with the drug. (See Warnings under Cautions: Warnings/Precautions, and also see REMS.) In accordance with the risk-management goals of these programs, alosetron should be prescribed only by clinicians who have enrolled in the Prescribing Program for Lotronex or Alosetron REMS Program by attesting to their understanding of the risks and benefits of the drug.

Additional information on the Prescribing Program for Lotronex may be obtained by calling 888-423-5227 or visiting the website (http://www.lotronexppl.com). Additional information on the Alosetron REMS Program may be obtained by calling 844-267-8675 or visiting the website (http://www.AlosetronREMS.com).

Administration

Alosetron is administered orally without regard to meals.

Dosage

Dosage of alosetron hydrochloride is expressed in terms of alosetron.

For the treatment of severe diarrhea-predominant irritable bowel syndrome (IBS) in women, the recommended initial dosage of alosetron is 0.5 mg twice daily. Data from a dose-ranging study indicate that risk of constipation is reduced with this dosage compared with a dosage of 1 mg twice daily; however, efficacy of the 0.5-mg twice-daily dosage in women with severe diarrhea-predominant IBS has not been adequately evaluated in clinical studies. If constipation occurs at a dosage of 0.5 mg twice daily, therapy should be withheld until constipation resolves; upon resolution, alosetron may be reinitiated at a reduced dosage of 0.5 mg once daily. If constipation recurs at a dosage of 0.5 mg once daily, treatment with alosetron should be immediately discontinued.

Patients may continue receiving an alosetron dosage of 0.5 mg once or twice daily as maintenance therapy if the dosage is well tolerated and symptoms of IBS are adequately controlled. If the patient tolerates but does not respond adequately to the dosage after 4 weeks, dosage may be increased up to 1 mg twice daily. If adequate control of symptoms is not achieved after 4 weeks of treatment on a dosage of 1 mg twice daily, alosetron therapy should be discontinued.

Alosetron should be discontinued immediately and permanently in patients who develop ischemic colitis.(See Ischemic Colitis under Warnings/Precautions: Warnings, in Cautions.)

Special Populations

Although the manufacturer does not make specific dosage recommendations for patients with hepatic impairment, alosetron should be used with caution in patients with mild or moderate hepatic impairment because of the possibility of increased exposure to the drug.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Alosetron also should be used with caution and appropriate follow-up in geriatric or debilitated patients because of the possibility of an increased risk for complications related to constipation in these populations.(See Serious Complications of Constipation under Warnings/Precautions: Warnings, in Cautions.)

Cautions

Contraindications

Current constipation, history of chronic or severe constipation, or history of complications related to constipation. History of intestinal obstruction, stricture, toxic megacolon, GI perforation, and/or adhesions. History of ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state. History of Crohn's disease, ulcerative colitis, or diverticulitis.

History of severe hepatic impairment.

Inability to understand or comply with the Patient Acknowledgment Form.

Concomitant use of fluvoxamine.(See Drug Interactions: Fluvoxamine.)

Warnings/Precautions

Warnings

Serious Complications of Constipation

Constipation is a common dose-related adverse effect of alosetron therapy. However, serious complications related to constipation including obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia have been reported infrequently in patients receiving alosetron, in some cases occurring without warning and resulting in hospitalization, surgery (e.g., colectomy), and/or death. Such complications were reported in about 0.1% of patients receiving alosetron or placebo in clinical studies. In addition, rare cases of perforation and death have been reported during postmarketing experience with the drug. A dose-response relationship for the development of serious complications of constipation has not been established; in reported cases, patients were receiving alosetron dosages of 1 mg twice daily or less. Geriatric or debilitated patients or those taking other drugs that decrease GI motility may be at increased risk for complications of constipation.

Because of the risk of serious GI complications, use of alosetron is restricted to women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have not responded adequately to conventional therapy. Alosetron may be prescribed only through a restricted distribution program.(See Restricted Distribution Programs under Dosage and Administration: General.) Alosetron should be discontinued immediately in patients who develop constipation during therapy, and if constipation resolves, the drug should be resumed only on the advice of a clinician.(See Dosage and Administration: Dosage.)

Ischemic Colitis

Ischemic colitis has been reported infrequently in patients receiving alosetron, in some cases occurring without warning and resulting in hospitalization, blood transfusion, and/or death. In clinical trials, the cumulative incidence of ischemic colitis in women receiving alosetron for the treatment of IBS was 0.2% through 3 months and 0.3% through 6 months; ischemic colitis was reported in one patient receiving placebo. There are insufficient data to estimate the incidence of ischemic colitis in patients receiving alosetron for longer than 6 months. A dose-response relationship for the development of ischemic colitis has not been established; in reported cases, patients were receiving alosetron dosages of 1 mg twice daily or less.

Because of the risk of serious GI complications, use of alosetron is restricted to women with severe diarrhea-predominant IBS. Alosetron may be prescribed only through a restricted distribution program.(See Restricted Distribution Programs under Dosage and Administration: General.) Alosetron should be discontinued immediately in patients who develop symptoms of ischemic colitis such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. Patients with such symptoms should be promptly evaluated and appropriate diagnostic tests should be performed. Alosetron treatment should not be resumed in patients who develop ischemic colitis.

Specific Populations

Pregnancy

Category B. There are no adequate and well-controlled studies of alosetron in pregnant women; animal reproduction studies using alosetron doses up to 160-240 times the recommended human dose have not demonstrated any evidence of fetal harm. Alosetron should be used during pregnancy only if clearly needed.

Lactation

Alosetron and/or its metabolites are distributed into milk in rats; it is not known whether alosetron is distributed into milk in humans. Caution is advised if the drug is administered in nursing women.

Pediatric Use

Safety and efficacy of alosetron have not been established in pediatric patients younger than 18 years of age. The drug is not recommended for use in the pediatric population because of the risk of serious GI complications.

Geriatric Use

In some studies in healthy individuals, plasma concentrations of alosetron were increased by approximately 40% in those 65 years of age or older compared with younger adults.

Because of evidence suggesting that geriatric patients may be at greater risk for complications of constipation, alosetron should be used with caution and appropriate follow-up in such patients.

Hepatic Impairment

Because alosetron is extensively metabolized in the liver, increased systemic exposure to the drug and/or its metabolites is likely in patients with hepatic impairment; increased exposure may increase the risk of serious adverse effects of the drug. Pharmacokinetic findings from a limited number of patients with hepatic impairment indicate that exposure to alosetron is substantially increased in patients with severe hepatic impairment, but increased to a smaller extent in patients with moderate hepatic impairment. Following administration of a single 1-mg dose of alosetron in a female patient with severe hepatic impairment (Child-Pugh score greater than 9), systemic exposure to the drug was increased by approximately 14-fold compared with historic controls with normal hepatic function. Following administration of the same dose of alosetron in a female patient with moderate hepatic impairment (Child-Pugh score 7-9), systemic exposure was increased by approximately 1.6-fold.

Alosetron should be used with caution in patients with mild or moderate hepatic impairment. Use of alosetron is contraindicated in patients with severe hepatic impairment.

Renal Impairment

Renal impairment (creatinine clearance of 4-56 mL/minute) has no effect on renal elimination of alosetron. However, the effects of renal impairment on pharmacokinetics of the metabolites are not known. Alosetron has not been evaluated in patients with end-stage renal disease.

Common Adverse Effects

Adverse effects occurring in 2% or more of patients with IBS receiving alosetron in clinical studies include constipation, abdominal discomfort or pain, nausea, GI discomfort or pain, abdominal distention, regurgitation and reflux, and hemorrhoids. In women with severe diarrhea-predominant IBS, diarrhea and flatulence also were reported in addition to the adverse effects observed in the general IBS population.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Alosetron is metabolized by the cytochrome P-450 (CYP) enzyme system, principally by CYP1A2, and to a lesser extent by CYP3A4 and 2C9; therefore, drugs that inhibit or induce these isoenzymes may alter the clearance of alosetron.

In vitro and in vivo studies indicate that alosetron is not likely to inhibit the clearance of drugs metabolized by CYP 2C9, 2C19, or 2E1. Alosetron also does not appear to inhibit CYP3A4 and has not been shown to substantially alter metabolism or plasma concentrations of CYP3A4 substrates. In an in vitro study, alosetron inhibited CYP1A2 and 2E1 at very high concentrations (27-fold higher than peak plasma concentrations observed with 1-mg dose); however, the drug inhibited CYP1A2 but had no effect on CYP2E1 in vivo. Although results of an in vivo probe study indicated that alosetron has the potential to inhibit CYP1A2 activity, the drug did not affect the metabolism of theophylline (a CYP1A2 substrate) in a clinical interaction study. Alosetron does not appear to induce CYP 3A, 2E1, or 2C19.

CYP1A2 Inhibitors

Concomitant use of alosetron and CYP1A2 inhibitors should be avoided because of the possibility of increased exposure and half-life of alosetron.

Concomitant administration of alosetron with a potent inhibitor of CYP1A2 (fluvoxamine) substantially increased systemic exposure and half-life of alosetron.(See Drug Interactions: Fluvoxamine.) Although specific drug interaction studies have not been conducted with moderate inhibitors of CYP1A2 (e.g., quinolone anti-infectives, cimetidine), similar interactions are possible; the manufacturer states that such concomitant use should be avoided unless clinically necessary.

CYP3A4 Inhibitors

Concomitant use of alosetron and CYP3A4 inhibitors may increase exposure to alosetron; caution is advised when these drugs are used concomitantly.

Concomitant administration of alosetron with a potent inhibitor of CYP3A4 (ketoconazole) increased systemic exposure of alosetron.(See Drug Interactions: Ketoconazole.) Although specific drug interaction studies have not been conducted with other CYP3A4 inhibitors (e.g., clarithromycin, telithromycin, protease inhibitors, voriconazole, itraconazole), similar interactions are possible.

Drugs Metabolized by N-Acetyltransferase

Alosetron was shown to inhibit N-acetyltransferase in an in vivo probe study. Although specific drug interaction studies have not been conducted, inhibition of N-acetyltransferase may have clinically important consequences for drugs metabolized by this enzyme (e.g., hydralazine, isoniazid, procainamide).

Cisapride

Concomitant administration of alosetron and cisapride had no substantial effect on cisapride metabolism or the QT interval.

Fluvoxamine

In a pharmacokinetic study in healthy women, concomitant administration of fluvoxamine (50-200 mg daily for 16 days) (a potent inhibitor of CYP1A2 that also inhibits CYP 3A4, 2C9, and 2C19) and alosetron (1 mg on day 16) increased area under the plasma concentration-time curve (AUC) and half-life of alosetron by approximately sixfold and threefold, respectively. Concomitant use of alosetron and fluvoxamine is contraindicated.

Hormonal Contraceptives

Concomitant administration of alosetron and an oral contraceptive containing ethinyl estradiol and levonorgestrel did not result in clinically important changes in plasma concentrations of the hormonal contraceptive components.

Ketoconazole

In a pharmacokinetic study in healthy women, concomitant administration of ketoconazole (200 mg twice daily for 7 days) (a potent inhibitor of CYP3A4) and alosetron (1 mg on day 7) increased systemic exposure of alosetron by 29%. Alosetron and ketoconazole should be used concomitantly with caution.

Theophylline

Alosetron did not affect the metabolism of theophylline when the drugs were administered concomitantly.

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