beauty treatment [0.1:<30 mL/min) renal impairment (n = 6 each). Renal clearance of alvimopan was related to renal function; however, because renal clearance was only a small fraction (35%) of the total clearance, renal impairment had a small effect on the apparent oral clearance of alvimopan. The half-lives of alvimopan were comparable in the mild, moderate, and control renal impairment groups but longer in the severe renal impairment group. Exposure to the 'metabolite' tended to be 2- to 5-fold higher in patients with moderate or severe renal impairment compared with patients with mild renal impairment or control subjects. Thus, there may be accumulation of alvimopan and 'metabolite' in patients with severe renal impairment receiving multiple doses of Entereg. Patients with end-stage renal disease were not studied [see Warnings and Precautions (5.5) and Use in Specific Populations (8.7) ]. Crohn's Disease: There was no relationship between disease activity in patients with Crohn's disease (measured as Crohn's Disease Activity Index or bowel movement frequency) and alvimopan pharmacokinetics (AUC or C max ). Patients with active or quiescent Crohn's disease had increased variability in alvimopan pharmacokinetics, and exposure tended to be 2-fold higher in patients with quiescent disease than in those with active disease or in normal subjects. Concentrations of the 'metabolite' were lower in patients with Crohn's disease. Drug Interactions: Potential for Drugs to Affect Alvimopan Pharmacokinetics: Concomitant administration of Entereg with inducers or inhibitors of CYP enzymes is unlikely to alter the metabolism of alvimopan because Entereg is metabolized mainly by non-CYP enzyme pathway. No clinical studies have been performed to assess the effect of concomitant administration of inducers or inhibitors of cytochrome P450 enzymes on alvimopan pharmacokinetics. In vitro studies suggest that alvimopan and its 'metabolite' are substrates for p-glycoprotein. A population pharmacokinetic analysis did not reveal any evidence that alvimopan or 'metabolite' pharmacokinetics were influenced by concomitant medications that are mild-to-moderate p-glycoprotein inhibitors. No clinical studies of concomitant administration of alvimopan and strong inhibitors of p-glycoprotein (e.g., verapamil, cyclosporine, amiodarone, itraconazole, quinine, spironolactone, quinidine, diltiazem, bepridil) have been conducted. A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers or antibiotics. However, plasma concentrations of the 'metabolite' were lower in patients receiving acid blockers or preoperative oral antibiotics (49% and 81%, respectively). No dosage adjustments are necessary in these patients. Potential for Alvimopan to Affect the Pharmacokinetics of Other Drugs: Alvimopan and its 'metabolite' are not inhibitors of CYP 1A2, 2C9, 2C19, 3A4, 2D6, and 2E1 in vitro at concentrations far in excess of those observed clinically. Alvimopan and its 'metabolite' are not inducers of CYP 1A2, 2B6, 2C9, 2C19, and 3A4. In vitro studies also suggest that alvimopan and its 'metabolite' are not inhibitors of p-glycoprotein. These in vitro findings suggest that Entereg is unlikely to alter the pharmacokinetics of coadministered drugs through inhibition or induction of CYP enzymes or inhibition of p-glycoprotein. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Two-year carcinogenicity studies were conducted with alvimopan in CD-1 mice at oral doses up to 4000 mg/kg/day and in Sprague Dawley rats at oral doses up to 500 mg/kg/day. Oral administration of alvimopan for 104 weeks produced significant increases in the incidences of fibroma, fibrosarcoma, and sarcoma in the skin/subcutis, and of osteoma/osteosarcoma in bones of female mice at 4000 mg/kg/day (about 674 times the recommended human dose based on body surface area). In rats, oral administration of alvimopan for 104 weeks did not produce any tumor up to 500 mg/kg/day (about 166 times the recommended human dose based on body surface area). Mutagenesis: Alvimopan was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK +/ ) forward mutation test, the Chinese Hamster Ovary (CHO) cell chromosome aberration test, or the mouse micronucleus test. The pharmacologically active 'metabolite' ADL 08-0011 was negative in the Ames test, chromosome aberration test in CHO cells, and mouse micronucleus test. Impairment of Fertility: Alvimopan at intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male or female rats. Clinical Studies Postoperative Ileus The efficacy of Entereg in the management of postoperative ileus was evaluated in 6 multicenter, randomized, double-blind, parallel-group, placebo-controlled studies: 5 US studies (Studies 1-4 and 6) and 1 non US study (Study 5). Patients 18 years of age or older undergoing partial large or small bowel resection surgery with primary anastomosis for colorectal or small bowel disease, total abdominal hysterectomy, or radical cystectomy for bladder cancer (in this procedure, resected segments of bowel are used for reconstruction of the urinary tract) under general anesthesia were randomly assigned to receive oral doses of Entereg 12 mg or matching placebo. The initial dose was administered at least 30 minutes and up to 5 hours prior to the scheduled start of surgery for most patients, and subsequent doses were administered twice daily beginning on the first postoperative day and continued until hospital discharge or a maximum of 7 days. There were no limitations on the type of general anesthesia used, but intrathecal or epidural opioids or anesthetics were prohibited. All patients in the US studies were scheduled to receive intravenous patient-controlled opioid analgesia. In the non US study, patients were scheduled to receive opioids either by intravenous patient-controlled opioid analgesia or bolus parenteral administration (intravenous or intramuscular). In all studies, there was no restriction on the type of opioid used or the duration of intravenous patient-controlled opioid analgesia. A standardized accelerated postoperative care pathway was implemented: early nasogastric tube removal (before the first postoperative dose); early ambulation (day following surgery); early diet advancement (liquids offered the day following surgery for patients undergoing bowel resection and by the third day following surgery for patients undergoing radical cystectomy; solids by the second day following surgery for patients undergoing bowel resection and by the fourth day following surgery for patients undergoing radical cystectomy), as tolerated. Patients who received more than 3 doses of an opioid (regardless of route) during the 7 days prior to surgery and patients with complete bowel obstruction or who were scheduled for a total colectomy, colostomy, or ileostomy were excluded. The primary endpoint for all studies was time to achieve resolution of postoperative ileus, a clinically defined composite measure of both upper and lower gastrointestinal recovery. Although both 2-component (GI2: toleration of solid food and first bowel movement) and 3-component (GI3: toleration of solid food and either first flatus or bowel movement) endpoints were used in all studies, GI2 is presented as it represents the most objective and clinically relevant measure of treatment response in patients undergoing surgeries that include a bowel resection. The time from the end of surgery to when the discharge order was written represented the length of hospital stay. In the 6 studies, 1,058 patients who underwent a surgery that included a bowel resection received placebo (not including 157 for total abdominal hysterectomy) and 1,096 patients received Entereg 12 mg (not including 143 for total abdominal hysterectomy). The efficacy of Entereg following total abdominal hysterectomy has not been established. Therefore, the following data are presented only for surgeries that included a bowel resection (i.e., bowel resection or radical cystectomy). Bowel Resection or Radical Cystectomy: A total of 2,154 patients underwent a surgery that included a bowel resection. The average age was 62 years, 54% were males, and 89% were Caucasian. The most common indications for surgery were colon or rectal cancer/malignancy, bladder cancer, and diverticular disease. In the non US bowel resection study (Study 5), average daily postoperative opioid consumption was approximately 50% lower and the use of non-opioid analgesics substantially higher, as compared with the US bowel resection studies (Studies 1-4) for both treatment groups. During the first 48 hours postoperatively, the use of non-opioid analgesics was 69% compared with 4% for the non US and US bowel resection studies, respectively. In each of the 6 studies, Entereg accelerated the time to recovery of gastrointestinal function, as measured by the composite endpoint GI2, and time to discharge order written as compared with placebo. Hazard ratios greater than 1 indicate a higher probability of achieving the event during the study period with treatment with Entereg than with placebo. Table 1 provides the Hazard Ratios, Kaplan Meier means, medians, and mean and median treatment differences (hours) in gastrointestinal recovery between Entereg and placebo. Table 1: GI2 Recovery (Hours) in Bowel Resection Patients Study No. * Entereg 12 mg Placebo Treatment Difference Hazard Ratio (95% CI) Mean † Median Mean † Median Means † Medians * Study 1 = 14CL314; Study 2 = 14CL313; Study 3 = 14CL308; Study 4 = 14CL302; Study 5 = SB-767905/001; Study 6 = 14CL403 † The estimates of the means and differences of treatment means are biased because of the censoring of events not achieved prior to the end of the observation period (10 days). The estimates of the differences of treatment means are likely to be underestimates. 1 92.0 80.0 111.8 96.6 19.8 16.6 1.533 (1.293, 1.816) 2 105.9 98.0 132.0 115.2 26.1 17.2 1.625 (1.256, 2.102) 3 116.4 101.8 130.3 116.8 14.0 15.0 1.365 (1.057, 1.764) 4 106.7 101.4 119.9 113.3 13.2 11.9 1.400 (1.035, 1.894) 5 98.2 92.8 108.8 95.9 10.6 3.1 1.299 (1.070, 1.575) 6 132.7 117.0 164.2 145.6 31.5 28.5 1.773 (1.359, 2.311) The Kaplan Meier estimate probabilities of patients receiving Entereg who achieved GI2 were numerically higher at all times throughout the study observation period compared with those of patients receiving placebo (see Figures 1 and 2 ). Figure 1: Time to GI2 Based on Results from Studies 1 through 5 Figure 2: Time to GI2 Based on Results from Study 6 In Studies 1 4, the differences between Entereg and placebo patient groups in median time to 'discharge order written' ranged from 6 to 22 hours, in favor of Entereg patients. The group differences in mean time to 'discharge order written' ranged from 13 to 21 hours. In Study 6, the median time difference was 19 hours in favor of Entereg patients (mean time difference 22 hours). Entereg did not reverse opioid analgesia as measured by visual analog scale pain intensity scores and/or amount of postoperative opioids administered across all 6 studies. There were no gender-, age-, or race-related differences in treatment effect. The incidence of anastomotic leak was low and comparable in patients receiving either Entereg or placebo (0.7% and 1.0%, respectively). How Supplied/Storage and Handling Entereg capsules, 12 mg, are blue, hard-gelatin capsules printed with "ADL2698" on both the body and the cap of the capsule. Entereg capsules are available in unit-dose packs of 30 capsules (30 doses) (NDC 67919-020-10) for hospital use only. Store at 25 C (77 F); excursions permitted to 15 30 C (59 86 F) [see USP Controlled Room Temperature]. Patient Counseling Information Recent Use of Opioids Patients should be informed that they must disclose long-term or intermittent opioid pain therapy, including any use of opioids in the week prior to receiving Entereg. They should understand that recent use of opioids may make them more susceptible to adverse reactions to Entereg, primarily those limited to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). Hospital Use Only Entereg is available only through a program called the Entereg Access Support and Education (E.A.S.E.) Program under a REMS that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of Entereg. Patients should be informed that Entereg is for hospital use only for no more than 7 days after their bowel resection surgery. Most Common Side Effect Patients should be informed that the most common side effect with Entereg in patients undergoing surgeries that include bowel resection is dyspepsia. Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA Manufactured by: Pharmaceutical Manufacturing Research Services, Inc., Horsham, PA 19044, USA For patent information: www.merck.com/product/patent/home.html The trademarks depicted herein are owned by their respective companies. Copyright 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. uspi-mk3753-c-1508r000 PRINCIPAL DISPLAY PANEL - 12 mg Capsule Blister Pack Carton NDC 67919-020-10 Entereg (alvimopan) capsules 12 mg Rx only HOSPITAL USE ONLY 30 capsules 12 mg unit dose pack CUBIST Entereg alvimopan capsule Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:67919-020 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength alvimopan (alvimopan anhydrous) alvimopan 12 mg Inactive Ingredients Ingredient Name Strength polyethylene glycols gelatin Product Characteristics Color BLUE Score no score Shape CAPSULE Size 20mm Flavor Imprint Code ADL2698 Contains Packaging # Item Code Package Description 1 NDC:67919-020-10 6 BLISTER PACK in 1 CARTON 1 5 CAPSULE in 1 BLISTER PACK Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021775 04/16/2012 Labeler - Merck Sharp & Dohme Corp. (001317601) Registrant - Cubist Pharmaceuticals LLC (808394928) Revised: 08/2015 Merck Sharp & Dohme Corp. Next Interactions Print this page Add to My Med List More about Entereg (alvimopan) Side Effects During Pregnancy Dosage Information Drug Images Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: peripheral opioid receptor antagonists Consumer resources Entereg Entereg (Advanced Reading) Professional resources Entereg (AHFS Monograph) Related treatment guides Postoperative Ileus Gastrointestinal Surgery> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only B Pregnancy Category No proven risk in humans N/A CSA Schedule Not a controlled drug 9 years Approval History FDA approved 2008 Manufacturer Merck & Co., Inc. Drug Class Peripheral opioid receptor antagonists Related Drugs peripheral opioid receptor antagonists Movantik , Relistor , alvimopan , naloxegol , methylnaltrexone , Symproic Postoperative Ileus alvimopan , More... Gastrointestinal Surgery lidocaine topical , Xylocaine Jelly , alvimopan , LTA II Kit , More... Entereg Rating No Reviews - Be the first! No Reviews - Be the first! Not Rated - Be the first! Entereg Images Entereg 12 mg (ADL2698 ADL2698) View larger images} } new version
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