lotronex

Starting dose is 0.5 mg twice a day ( 2.1 ) May increase dose to 1 mg twice a day after 4 weeks if starting dosage is well tolerated but does not adequately control IBS symptoms ( 2.1 ) Discontinue LOTRONEX in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day. ( 2.1 ) 2.1 Adult Patients To lower the risk of constipation, LOTRONEX should be started at a dosage of 0.5 mg twice a day. Patients who become constipated at this dosage should stop taking LOTRONEX until the constipation resolves. They may be restarted at 0.5 mg once a day. If constipation recurs at the lower dose, LOTRONEX should be discontinued immediately. Patients well controlled on 0.5 mg once or twice a day may be maintained on this regimen. If after 4 weeks the dosage is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to up to 1 mg twice a day . LOTRONEX should be discontinued in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day. LOTRONEX can be taken with or without food [see Clinical Pharmacology ( 12.3 )] . LOTRONEX should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. LOTRONEX should not be restarted in patients who develop ischemic colitis. Clinical trial and postmarketing experience suggest that…

The following adverse reactions are described in more detail in other sections of the label: Complications of constipation [see Boxed Warning , Warnings and Precautions ( 5.1 )] Ischemic colitis [see Boxed Warning , Warnings and Precautions ( 5.2 )] Most common adverse reactions (incidence >2% and >placebo) in clinical studies were constipation, abdominal discomfort and pain, nausea, and gastrointestinal discomfort and pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sebela at 1-844-732-3521 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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…

Do not initiate in patients with constipation ( 4.1 ) History of chronic or severe constipation or sequelae from constipation; intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions; ischemic colitis; impaired intestinal circulation, thrombophlebitis, or hypercoagulable state; Crohn's disease or ulcerative colitis; diverticulitis; severe hepatic impairment ( 4.2 ) Concomitant use of fluvoxamine ( 4.3 ) 4.1 Constipation LOTRONEX should not be initiated in patients with constipation [see Warnings and Precautions ( 5.1 )] . 4.2 History of Severe Bowel or Hepatic Disorders LOTRONEX is contraindicated in patients with a history of the following: chronic or severe constipation or sequelae from constipation intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state Crohn's disease or ulcerative colitis diverticulitis severe hepatic impairment 4.3 Concomitant Use of Fluvoxamine Concomitant administration of LOTRONEX with fluvoxamine is contraindicated. Fluvoxamine, a known strong inhibitor of CYP1A2, has been shown to increase mean alosetron plasma concentrations (AUC) approximately 6-fold and prolong the half-life by approximately 3-fold [see Drug Interactions ( 7.1 )] .

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 )].

U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.

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. CYP1A2 inhibitors: Avoid concomitant uses because of increased exposure and half-life of alosetron. Use with fluvoxamine is contraindicated. ( 4.3 , 7.1 ) CYP3A4 inhibitors: Use with caution in combination due to increased exposure of alosetron. ( 7.2 ) 7.1 CYP1A2 Inhibitors 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 [see Contraindications ( 4.3 )] . 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. 7.2 CYP3A4 Inhibitors 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. 7.3 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.